10-K
.
UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 10-K
(Mark One)
For the fiscal year ended December 31, 2025
OR
Commission file number 001-40407
Vera Therapeutics, Inc.
(Exact name of registrant as specified in its charter)
(Address of principal executive offices) (Zip Code)
Registrant’s telephone number, including area code: (650) 770-0077
Securities registered pursuant to Section 12(b) of the Act:
Title of each class TradingSymbol(s) Name of each exchange on which registered
Securities registered pursuant to Section 12(g) of the Act: None
Indicate by check mark if the Registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☒ No ☐
Indicate by check mark if the Registrant is not required to file reports pursuant to Section 13 or 15(d) of the Act. Yes ☐ No☒
Indicate by check mark whether the Registrant: (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the Registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. Yes ☒ No ☐
Indicate by check mark whether the Registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the Registrant was required to submit such files). Yes ☒ No ☐
Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, smaller reporting company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act.
Large accelerated filer ☒ Accelerated filer ☐
Non-accelerated filer ☐ Smaller reporting company ☐
Emerging growth company ☐
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐
Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report. ☒
If securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant included in the filing reflect the correction of an error to previously issued financial statements. ☐
Indicate by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation received by any of the registrant’s executive officers during the relevant recovery period pursuant to §240.10D-1(b). ☐
Indicate by check mark whether the Registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act). Yes ☐ No☒
The aggregate market value of the Registrant’s Class A common stock held by non-affiliates of the Registrant as of June 30, 2025, the last business day of the Registrant’s most recently completed second fiscal quarter, was approximately $1.3 billion based on the closing price of the Registrant’s Class A common stock on the Nasdaq Global Select Market of $23.56 per share.
As of February 23, 2026, the registrant had 71,355,667 shares of Class A common stock, $0.001 par value per share, andno shares of Class B common stock, $0.001 par value per share, outstanding.
DOCUMENTS INCORPORATED BY REFERENCE
Portions of the Registrant’s definitive proxy statement for its 2026 Annual Meeting of Stockholders, which the Registrant intends to file pursuant to Regulation 14A with the Securities and Exchange Commission not later than 120 days after the Registrant’s fiscal year ended December 31, 2025, are incorporated by reference into Part III of this Annual Report on Form 10-K.
Table of Contents
Page
SPECIAL NOTE REGARDING FORWARD-LOOKING STATEMENTS ii
SUMMARY OF RISKS ASSOCIATED WITH OUR BUSINESS iv
PART I
Item 1. Business 1
Item 1A. Risk Factors 41
Item 1B. Unresolved Staff Comments 91
Item 1C. Cybersecurity 91
Item 2. Properties 93
Item 3. Legal Proceedings 93
Item 4. Mine Safety Disclosures 93
PART II
Item 6. Reserved 95
Item 7A. Quantitative and Qualitative Disclosures About Market Risk 103
Item 8. Financial Statements and Supplementary Data 104
Item 9A. Controls and Procedures 129
Item 9B. Other Information 129
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 130
PART III
Item 10. Directors, Executive Officers and Corporate Governance 131
Item 11. Executive Compensation 131
Item 14. Principal Accountant Fees and Services 131
PART IV
Item 15. Exhibit and Financial Statement Schedules 132
i
SPECIAL NOTE REGARDING FORWARD-LOOKING STATEMENTS
This Annual Report on Form 10-K (the Annual Report) may contain “forward-looking statements” within the meaning of the federal securities laws made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Our actual results could differ materially from those anticipated in these forward-looking statements as a result of various factors, including those set forth under Part I, Item 1A, “Risk Factors” in this Annual Report. Except as required by law, we assume no obligation to update these forward-looking statements, whether as a result of new information, future events or otherwise. These statements, which represent our current expectations or beliefs concerning various future events, may contain words such as “may,” “will,” “expect,” “anticipate,” “intend,” “plan,” “believe,” “estimate” or other words indicating future results, though not all forward-looking statements necessarily contain these identifying words. Such statements may include, but are not limited to, statements concerning the following:
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our financial performance;
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the sufficiency of our existing cash to fund our future operating expenses and capital expenditure requirements;
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the accuracy of our estimates regarding expenses, future revenue, capital requirements, and needs for additional financing;
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the scope, progress, results and costs of developing our product candidates and conducting nonclinical studies and clinical trials;
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the timing and costs involved in obtaining and maintaining regulatory approval of our product candidates and the timing or likelihood of regulatory filings and approvals, including our expectation to seek special designations for our product candidates for various diseases;
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our plans relating to commercializing our product candidates, if approved, including the geographic areas of focus and our ability to grow a sales team;
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the ability to license additional intellectual property relating to any future product candidates and to comply with our existing license agreements;
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the impact of unfavorable geopolitical and macroeconomic conditions on our business and operations;
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the implementation of our strategic plans for our business and current product candidates or any other product candidates we may develop;
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the size of the market opportunity for our product candidates in each of the diseases we target;
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our reliance on third parties to conduct nonclinical research activities, and for the manufacture of our product candidates;
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the beneficial characteristics, safety, efficacy and therapeutic effects of our product candidates;
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our estimates of the number of patients in potential commercial markets who suffer from the diseases we target and the number of subjects that will enroll in our clinical trials;
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the progress and focus of our current and future clinical trials, and the reporting of data from those trials;
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our ability to advance product candidates into and successfully complete clinical trials;
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the ability of our clinical trials to demonstrate the safety and efficacy of our product candidates, and other positive results;
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the success of competing therapies that are or may become available;
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developments relating to our competitors and our industry, including competing product candidates and therapies;
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our plans relating to the further development and manufacturing of our product candidates, including additional indications that we may pursue;
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existing regulations and regulatory developments in the United States and other jurisdictions;
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our potential and ability to successfully manufacture and supply our product candidates for clinical trials and for commercial use, if approved;
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the rate and degree of market acceptance of our product candidates, as well as the pricing and reimbursement of our product candidates, if approved;
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our continued reliance on third parties to conduct additional clinical trials of our product candidates, and for the manufacture of our product candidates;
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our plans and ability to obtain and protect intellectual property rights;
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the scope of protection we are able to establish and maintain for intellectual property rights, including our product candidates and any other product candidates we may develop; and
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our ability to retain the continued service of our key personnel and to identify, hire, and then retain additional qualified personnel.
Moreover, we operate in a very competitive and rapidly changing environment. New risks emerge from time to time. It is not possible for our management to predict all risks, nor can we assess the impact of all factors on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in any forward-looking statements we may make. You should be aware that the occurrence of any of the events discussed under Part I, Item 1A, “Risk Factors” and elsewhere in this Annual Report could substantially harm our business, results of operations and financial condition and that if any of these events occurs, the trading price of our Class A common stock (common stock) could decline and you could lose all or a part of the value of your shares of our common stock.
The cautionary statements made in this Annual Report are intended to be applicable to all related forward-looking statements wherever they may appear in this Annual Report. We urge you not to place undue reliance on these forward-looking statements, which speak only as of the date of this Annual Report. Except as required by law, we assume no obligation to update our forward-looking statements publicly, or to update the reasons actual results could differ materially from those anticipated in any forward-looking statements, whether as a result of new information, future events or otherwise.
iii
SUMMARY OF RISKS ASSOCIATED WITH OUR BUSINESS
An investment in shares of our common stock involves a high degree of risk. Below is a list of some of the material risks associated with our business. This summary does not address all of the risks that we face. Additional discussion of the risks listed in this summary, as well as other risks that we face, is set forth under Part I, Item 1A, “Risk Factors” in this Annual Report on Form 10-K:
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We have completed a limited number of clinical trials for our lead product candidate, atacicept, and have no products approved for commercial sale, which may make it difficult to evaluate our current business and predict our future success and viability.
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We will require substantial additional capital to finance our operations. If we are unable to raise such capital when needed, or on acceptable terms, we may be forced to delay, reduce and/or eliminate one or more of our research and drug development programs of our product candidates or future commercialization efforts.
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We have incurred net losses since inception, and have never generated revenue from product sales. We expect to continue to incur net losses at least until we have one or more approved products that achieve commercial success.
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The terms of our loan agreement place restrictions on our operating and financial flexibility. If we raise additional capital through debt financing, the terms of any new debt could further restrict our ability to operate our business.
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We are substantially dependent on the success of our product candidates. If we are unable to complete development of, obtain regulatory approval for and commercialize our product candidates in one or more indications and in a timely manner, our business, financial condition, results of operations and prospects will be significantly harmed.
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Enrollment and retention of participants in clinical trials is an expensive and time-consuming process and could be made more difficult or rendered impossible by multiple factors outside our control, including difficulties in identifying patients with immunoglobulin A nephropathy, the availability of competitive products, and significant competition for recruiting participants in clinical trials.
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The incidence and prevalence for target patient populations of our product candidates in specific indications are based on estimates and third-party sources. If the market opportunities for our product candidates, if and when approved, are smaller than we estimate or if any approval that we obtain is based on a narrower definition of the patient population, our revenue and ability to achieve profitability might be materially and adversely affected.
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Interim, initial, “top-line” and preliminary data from our clinical trials that we announce or publish from time to time may change as more participant data become available and are subject to audit and verification procedures that could result in material changes in the final data.
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We face significant competition, which may result in others discovering, developing or commercializing products before or more successfully than us.
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Changes in methods of manufacturing or formulation of our product candidates may result in additional costs or delays.
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Our product candidates may cause significant adverse events, toxicities or other undesirable side effects when used alone or in combination with other approved products or investigational new drugs that may result in a safety profile that could inhibit regulatory approval, prevent market acceptance, limit their commercial potential or result in significant negative consequences.
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Even if any product candidate we develop receives regulatory approval, it could be subject to significant post-marketing regulatory requirements and will be subject to continued regulatory oversight.
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Disruptions at the FDA and other government agencies caused by funding shortages, staffing limitations, or global health concerns could hinder their ability to hire, retain or deploy key leadership and other personnel, and prevent new or modified products from being developed, reviewed, approved or commercialized in a timely manner or at all, which could negatively impact our business.
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Biosimilars to our product candidates may provide competition sooner than anticipated.
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Unfavorable geopolitical and global economic conditions, including tariffs and trade tensions, could adversely affect our business, financial condition and results of operations.
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Our success is highly dependent on our ability to attract and retain highly skilled executive officers, employees and key consultants.
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We have never commercialized a product candidate before and may lack the necessary expertise, personnel and resources to successfully commercialize any products on our own or together with suitable collaborators.
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Our success depends on our ability to protect our intellectual property and our proprietary technologies.
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If we breach our license agreement with Ares Trading S.A., an affiliate of Merck KGaA, Darmstadt, Germany, related to atacicept, the license agreement with Novartis International Pharmaceutical AG related to MAU868, or the license agreement with the Board of Trustees of Leland Stanford Junior University related to VT-109, we could lose the ability to continue the development and commercialization of atacicept, MAU868, or VT-109, respectively.
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We may be required to make significant payments under our license agreements related to our product candidates.
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If the scope of any patent protection we obtain is not sufficiently broad, or if we lose any of our patent protection, our ability to prevent our competitors from commercializing similar or identical product candidates would be adversely affected.
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Patent terms may be inadequate to protect our competitive position on our product candidates for an adequate amount of time.
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We rely, and expect to continue to rely, on third parties, including independent clinical investigators and contract research organizations, to conduct certain aspects of our nonclinical studies and clinical trials. If these third parties do not successfully carry out their contractual duties, comply with applicable regulatory requirements or meet expected deadlines, we may not be able to obtain regulatory approval for or commercialize our product candidates and our business, financial condition, results of operations and prospects could be significantly harmed.
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The manufacture of drugs is complex and our third-party manufacturers may encounter difficulties in production. If any of our third-party manufacturers encounter such difficulties, our ability to provide adequate supply of our product candidates for clinical trials or our product for patients, if approved, could be delayed or prevented.
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If we engage in future acquisitions or strategic partnerships, this may increase our capital requirements, dilute our stockholders, cause us to incur debt or assume contingent liabilities, and subject us to other risks.
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The price of our common stock may be volatile, and you could lose all or part of your investment.
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If we experience material weaknesses in internal control over financial reporting in the future or otherwise fail to maintain an effective system of internal controls in the future, we may not be able to accurately or timely report our financial condition or results of operations, which may adversely affect investor confidence in us and, as a result, the value of our common stock.
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Provisions in our amended and restated certificate of incorporation and amended and restated bylaws and Delaware law could make an acquisition of us, which may be beneficial to our stockholders, more difficult and may prevent attempts by our stockholders to replace or remove our current management.
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We may be subject to securities litigation, which is expensive and could divert management attention.
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PART I
Item 1. Business.
Overview
We are a late clinical-stage biotechnology company focused on developing and commercializing transformative treatments for patients with serious immunological diseases. Our lead product candidate, atacicept, is currently being evaluated for the treatment of immunoglobulin A nephropathy (IgAN) and other autoimmune kidney diseases. Atacicept is a native human TACI-Fc fusion protein that binds both the B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL) cytokines and is self-administered subcutaneously at home. We are conducting ORIGIN 3, the pivotal Phase 3 trial of atacicept 150 mg in IgAN. The trial met the primary efficacy endpoint of reduction in proteinuria as measured by 24-hour urine protein-to-creatinine ratio (UPCR) at week 36, where participants treated with atacicept achieved a 46% reduction from baseline in UPCR with a statistically significant and clinically meaningful 42% reduction in UPCR compared to placebo (p<0.0001). The incidence of adverse events was generally balanced between the atacicept and placebo groups, with fewer serious adverse events reported with atacicept (n=1 [0.5%]) than placebo (n=11 [5%]), no safety signals indicating immunosuppression, and no deaths in either treatment group. In November 2025, we submitted a Biologics License Application (BLA) for atacicept for the treatment of adults with IgAN to the U.S. Food and Drug Administration (FDA) through the Accelerated Approval Program. On January 7, 2026, the FDA granted priority review to the application and assigned a Prescription Drug User Fee Act (PDUFA) target action date of July 7, 2026. If approved, atacicept would be the first B-cell modulator inhibiting both BAFF and APRIL for IgAN, offering patients an autoinjector for at-home self-administration. The ORIGIN 3 key secondary endpoint to support full approval is estimated glomerular filtration rate (eGFR) at 104 weeks, with results expected in 2027.
The ORIGIN Phase 2b clinical trial evaluated the safety and efficacy of atacicept in 116 participants with IgAN and reported positive results at 24 weeks in January 2023, 36 weeks in June 2023, and 96 weeks in October 2024. The trial remained blinded through 36 weeks, after which all participants were eligible for the open label extension portion of the study and received atacicept 150 mg through 96 weeks. Atacicept met its primary endpoint at 24 weeks with a statistically significant reduction in UPCR. Through 36 weeks, participants treated with atacicept demonstrated reductions in galactose-deficient IgA1 (Gd-IgA1, the autoantigen produced by B cells in patients with IgAN), hematuria, and UPCR, with stable eGFR. The improvements in Gd-IgA1, hematuria, UPCR and eGFR represent the quartet of findings consistent with IgAN disease modification. The 96-week open label extension results showed consistent and sustained reductions in Gd-IgA1, hematuria, and UPCR, with continued eGFR stabilization at a rate similar to the general population without kidney disease. Atacicept’s safety profile appeared favorable, and comparable to placebo, across the ORIGIN program in IgAN.
We believe that atacicept has pipeline-in-a-molecule potential, with expected application in multiple diseases. Based on data from the ORIGIN Phase 2b trial, the FDA granted Breakthrough Therapy Designation to atacicept for the treatment of IgAN. We have also committed to providing long-term access to atacicept for ORIGIN participants through ORIGIN EXTEND, a long-term Phase 2 extension study that offers atacicept to participants who completed ORIGIN Phase 2b or 3 until, if approved, commercial availability in their country or region. We are evaluating atacicept in other autoimmune kidney diseases, including primary membranous nephropathy (pMN), focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD), in patients with anti-phospholipase A2 receptor (PLA2R) or anti-nephrin autoantibodies in the Phase 2 PIONEER clinical trial. Potential future indications include anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), lupus nephritis (LN), Sjogren’s disease, systemic lupus erythematosus (SLE), systemic sclerosis, generalized myasthenia gravis, and idiopathic thrombocytopenic purpura.
We also hold worldwide, exclusive development and commercial rights to MAU868, a potentially first-in-class monoclonal antibody to treat reactivated BK virus (BKV) infections, for which we completed a Phase 2 clinical trial in 2022. In January 2025, we acquired worldwide, exclusive development and commercial rights to VT-109, a novel, next-generation dual BAFF/APRIL inhibitor that is in preclinical development. We believe that our current pipeline programs leverage the deep expertise of our team and have strong potential commercial synergies.
Pipeline
Beyond our lead indication in IgAN, we have several late-stage opportunities for potential patient benefit – including indication expansion opportunities for atacicept, the development of VT-109 in B-cell–mediated diseases, and MAU868 for BK viremia among kidney transplant recipients. We are currently evaluating these opportunities for future development.
As part of our life cycle management strategy for atacicept, we are actively enrolling participants in a monthly dose range finding study to evaluate extended dosing intervals. As discussed above, there are also multiple indications in which blocking BAFF and APRIL may offer therapeutic benefit and which offer an attractive commercial opportunity, some of which we are evaluating in the PIONEER phase 2 clinical trial.
In January 2025, we announced a license agreement (Stanford Agreement) with the Board of Trustees of Leland Stanford Junior University (Stanford) to acquire global rights to VT-109, a novel, next generation fusion protein targeting BAFF and APRIL that is in preclinical development with wide therapeutic potential across the spectrum of B-cell-mediated diseases. These rights are for all therapeutic, prophylactic, diagnostic, and treatment uses in humans.
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Finally, we have exclusive worldwide rights, pursuant to the license agreement (Novartis License) with Novartis International Pharmaceutical AG (Novartis), to the investigational drug MAU868 for BK viremia among kidney transplant recipients. BKV is a common polyoma virus in adults (90%) that remains latent except in severely immunocompromised populations such as kidney transplant recipients. BKV infection or reactivation can cause BKV nephropathy (BKVN), a condition in which BK infection (first identified as BK viremia) triggers inflammation, then progresses to fibrosis and tubular injury; BKVN is a leading cause of allograft loss. Approximately 15% of kidney transplant recipients develop BK viremia; 3–4% of kidney transplant recipients develop BKVN. Currently, there are no approved treatment options for BK viremia or BKVN. Final results from the Phase 2 clinical trial of MAU868 versus placebo were presented at ASN Kidney Week 2022 and showed that MAU868 was well tolerated and it demonstrated clinically meaningful reductions in BK antiviral activity through 36 weeks in kidney transplant patients with BK viremia. Following feedback from the FDA on the Phase 2 clinical trial, we are evaluating strategies for continued development, including a potential next clinical trial. We believe that MAU868 has the potential to become standard of care for the treatment of reactivated BK infection in order to prevent devastating consequences following kidney transplantation such as BKVN and graft loss.
Our business principles and strategy
Our goal is to develop and commercialize transformative treatments for patients suffering from severe immunological diseases. We believe the successful translation of biomedical science into innovative therapeutic products for patients with immunological diseases will enable outsized growth over the next decade and beyond. Specifically, our strategy is based on the following business principles:
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Develop disease-modifying medicines to improve patients’ lives. Our team seeks to bring transformative medical products to patients with severe immunological diseases, who often receive steroids as the current standard of care. The non-specific immunosuppressive effect of steroids, with known acute and chronic side effects, presents an important opportunity for innovation. We aim to develop and commercialize disease-modifying drugs that target the source of disease, minimize side effects, and have high potential to meaningfully change standard medical care and improve patients’ lives.
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Establish clear line-of-sight to successful products. We apply our deep drug development experience, scientific rigor, and disciplined decision making to establish clear line-of-sight along the full spectrum of drug development. We pursue biologic targets, product candidates, and disease indications with a strong scientific rationale, de-risked profile, and capital-efficient development pathway, and optimize for high probability of clinical, regulatory, and commercial success.
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Build a leading biotech company that delivers innovative medicines to patients. We believe our team’s expertise and our business culture are fundamental to our success. Our Research and Development and Commercial teams are led by experienced drug development executives with proven track records in clinical and commercial development who have led or been involved in the approvals of more than 15 medicines from leading companies, including Gilead Sciences and Amgen. We leverage our team’s know-how with additional outsourced resources and enable focused clinical development of our product candidates with the goal of improving patients’ lives.
These principles have guided us to the successful in-licensing of atacicept from Ares Trading S.A. (Ares), VT-109 from Stanford, and obtaining the rights to MAU868 via the Novartis License from Amplyx Pharmaceuticals, Inc. (Amplyx), a wholly-owned subsidiary of Pfizer, in each case with worldwide rights for development and commercialization. We take a gated-capital raise approach and scale product candidate investment and exposure in close step with key development milestones to ensure high return on development costs.
Our near- and long-term objectives in pursuit of our goal include:
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Complete global development of atacicept in IgAN. Our BLA for atacicept in IgAN was granted Priority Review by the FDA, with a PDUFA target action date of July 7, 2026. We have also committed to providing access to atacicept through the ORIGIN EXTEND study for ORIGIN participants until atacicept is available in their region. The PIONEER study is evaluating atacicept in an expanded IgAN population beyond the ORIGIN program. We anticipate clinical results from the ORIGIN EXTEND and PIONEER studies in 2026.
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Build and scale organizational capabilities to support commercialization of atacicept. Under the leadership of our experienced management team, we are building a specialized commercial organization with deep launch experience in nephrology, B cell, and autoimmune therapeutics, to successfully launch atacicept in the United States and other key markets, if approved.
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Explore additional disease areas where atacicept holds significant therapeutic promise. By targeting BAFF and APRIL, atacicept’s ability to reduce disease-causing autoantibodies may provide clinical benefit. We are exploring additional immunologic diseases where BAFF and APRIL are involved in the pathophysiology of disease, or where autoantibodies play an important role.
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Advance the development of VT-109 and explore its potential in multiple B-cell–mediated diseases. We acquired rights to this novel, next-generation dual BAFF/APRIL inhibitor in January 2025 and plan to leverage our research, translational medicine, clinical development and commercial expertise in developing this program.
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Identify next clinical trial for MAU868 in BK viremia in kidney transplant recipients and align with regulatory authorities. We reported positive final results from our Phase 2 clinical trial in kidney transplant recipients in 2022 and are evaluating strategies for continued development, including a potential next clinical trial.
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Expand our pipeline by acquiring or in-licensing product candidates for immunologic diseases with unmet needs. We believe our expertise and track record will enable us to identify and acquire or in-license additional product candidates that represent opportunities to expand the potential value of our pipeline. We will leverage our lean clinical development operation to bring to market additional product candidates to address kidney and immunologic diseases.
Atacicept in IgAN
We are developing atacicept as a potential treatment for patients with IgAN, a serious and progressive autoimmune disease of the kidney with a high unmet medical need and limited treatment options available. IgAN is driven by the B-cell production of Gd-IgA1 and its corresponding autoantigen. We reported positive topline 24-week results in January 2023, 36-week results in June 2023, and 96-week results in October 2024 from the ORIGIN 2b trial. Our pivotal Phase 3 clinical trial, ORIGIN 3, met the primary endpoint in June 2025, leading to a BLA filing with a PDUFA date of July 7, 2026. We believe that atacicept has the potential to be the best-in-class, leading B-cell modulator therapy for IgAN.
Disease burden, diagnosis, and predictors of disease progression
IgAN is considered a rare disease in the United States and Europe, but it is the predominant cause of primary glomerulonephritis. Patients with IgAN are most often diagnosed in the second and third decades of life. Diagnosis often occurs when patients present with visible signs of chronic kidney disease (CKD), such as hematuria, proteinuria, and hypertension; in the US, most IgAN patients are in stage 3 CKD or greater at diagnosis. Once IgAN is suspected based on clinical history and laboratory data, kidney biopsy is performed for a definitive diagnosis. IgAN is associated with a high risk of kidney-related morbidity and mortality. Patients with IgAN consistently report lower quality of life, even with optimized supportive care. At least 50% of patients diagnosed with IgAN develop end-stage kidney disease (ESKD) within 10 to 20 years from diagnosis, requiring dialysis or kidney transplant. In addition to considerable morbidity and impact on patients’ lives, ESKD represents a significant health economic burden estimated to be greater than or equal to ~$3.8 billion over ten years in the U.S. based on a retrospective 2023 study of U.S. patients with IgAN.
IgAN market opportunity
We estimate there will be approximately 160,000 biopsy-confirmed IgAN patients in the United States, 136,000 in Europe, and 130,000 in Japan, at estimated peak year of sales, and that growth in the diagnosed prevalent population is due to overall population growth. Underlying genetic differences may contribute to the significantly higher rate in Japan. As therapies become commercially available, however, an increase in diagnosis rate or longer time to progression, due to better treatments, may increase the diagnosed population over time. We estimate the global market opportunity for novel, disease-modifying therapeutics in IgAN is approximately $6.0 billion to $10.0 billion annually, based on the disease prevalence and the segment of IgAN patients at high risk of progressing to ESKD.
Figure 1: Estimated IgAN epidemiology at estimated peak year of sales
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Pathophysiology of IgAN
As shown in Figure 2 below, B cell activation by BAFF and APRIL drives a process that leads to the ultimate development of progressive kidney injury.
Figure 2: IgAN pathophysiology
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BAFF and APRIL activate B cells by binding to TACI, a receptor on the surface of B cells. This leads to B cell maturation and survival, and antibody class switching, a mechanism that changes cells’ production from one immunoglobulin to another, causing an increase in the production of immunogenic Gd-IgA1.
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The Gd-IgA1 antibodies are immunogenic when found in the systemic circulation, and are recognized as an autoantigen by autoantibodies, or antibodies created by B cells in response to a constituent of the body’s own tissue.
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Gd-IgA1 and anti-Gd-IgA1 autoantibodies combine to form pathogenic immune complexes, or clusters of antibodies.
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Pathogenic immune complexes are deposited and become trapped in the mesangium of the kidney’s glomeruli. This initiates an inflammatory response that damages the membranes.
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As the glomeruli are destroyed, the kidney’s ability to remove waste products from the blood is reduced, and protein and blood leak into the urine. Over time, the decline in kidney function as measured by eGFR can result in potentially life-threatening complications that lead to the need for dialysis or kidney transplant in many patients.
Findings consistent with disease modification in IgAN
We believe that a therapy that may comprehensively address treatment goals outlined in current clinical guidelines, and offer potential for disease modification, would be designed to address the underlying autoimmune drivers of disease progression. Such a treatment would ideally achieve 1) a reduction in the burden of the immune complexes, which can be indirectly measured via reductions in the autoantigen, Gd-IgA1; 2) resolution of inflammation, which can be simply measured using a point of care device, urine dipstick, for hematuria; 3) reductions in proteinuria, and most importantly, 4) achievement of a stabilized kidney function profile, as measured by eGFR, consistent with that of the general population.
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Gd-IgA1 antibodies have been shown to be the target autoantigen for autoantibodies. A histopathological hallmark of IgAN is deposition of Gd-IgA1 in the glomerular mesangium, either alone or in combination with immunoglobulin G (IgG) and/or immunoglobulin M (IgM). Clinical trials of patients with IgAN have correlated higher serum levels of Gd-IgA1 with greater disease severity, suggesting that reduction in serum Gd-IgA1 may slow disease progression. In a prospective study of 275 patients with IgAN published in Kidney International, higher serum Gd-IgA1 levels were correlated with a higher likelihood of developing progressive kidney failure. A separate clinical trial of patients with IgAN of varying severity found that higher titers of autoantibodies specific for Gd-IgA1 corresponded to both absolute renal risk score and risk of ESKD or death.
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Hematuria, a clinical manifestation of glomerular inflammation seen in over 70% of patients with IgAN, correlates with worse clinical outcomes, such as greater rates of kidney failure, highlighting its potential as a marker of disease. Evidence from recent studies suggests that persistent heavy microscopic hematuria in IgAN likely reflects glomerular capillary wall damage caused by the deposition of immune complexes and is a contributing factor for proteinuria and disease progression.
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Patients with persistent hematuria in addition to persistent proteinuria are at higher risk than those with proteinuria alone, suggesting that hematuria should be considered when assessing the risk of disease progression. Patients with persistent microscopic hematuria are more likely to have a greater decline in kidney function during follow up compared to those with minimal or no hematuria. Resolution of microscopic hematuria has been associated with improved kidney outcomes in patients with IgAN
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Proteinuria is considered an appropriate surrogate endpoint to assess treatment response and monitor disease progression in IgAN. Current clinical guidelines define patients at risk for progressive disease as those with proteinuria >0.5 g/day. Although baseline proteinuria is predictive of eGFR decline, recent data have shown that even lower levels of proteinuria (0.44 to <0.88 g/g) are associated with an increased risk of kidney failure.
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eGFR stabilization is the ultimate treatment goal in order to minimize risk of disease progression and kidney function loss. Even with an eGFR decline of 1 mL/min/1.73m2/year, ~40% of patients diagnosed before age 50 will reach kidney failure. Reducing the rate of eGFR decline to ≤1 mL/min/1.73m2/year to be consistent with the general population without kidney disease is recommended by current clinical guidelines in order to minimize risk of disease progression and kidney function loss.
For these reasons, we believe a fusion protein that blocks both BAFF and APRIL, which has the potential to reduce serum Gd-IgA1, would address the upstream source of IgAN, and represent the first disease-modifying approach for IgAN.
Current standard of care for IgAN patients
Despite the high unmet medical need in IgAN, there are limited treatment options available. Current clinical guidelines recommend simultaneous use of the following two approaches for patients with IgAN:
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Non-specific measures to manage the consequences of existing kidney damage (i.e., CKD), including the use of renin-angiotensin system (RAS) inhibitors (e.g., angiotensin-converting enzyme [ACE inhibitors] or angiotensin II receptor blockers [ARBs]) and sodium-glucose cotransporter-2 (SGLT2) inhibitors.
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Treatments that have been proven to reduce immune complex formation and immune-complex-mediated glomerular injury, such as steroids with or without other immunosuppressive agents to non-specifically reduce inflammation resulting from immune complex deposition in the glomeruli.
Simultaneous use of both approaches is recommended to meet the key treatment goal of reducing the rate of loss of kidney function to that of the general population (i.e., 1 mL/min/year or less) in order to minimize the lifetime risk of ESKD. Treatment is selected based on perceived risk of progressive kidney disease, and clinical measures such as hematuria, proteinuria, and eGFR are used to monitor patients while on treatment. Even the combination of these treatments is currently seen as insufficient by physicians and patients; these treatment approaches have limited clinical efficacy and are not well tolerated. The use of steroids may cause significant side effects, including serious infections, high blood pressure, weight gain, diabetes, and osteoporosis. As such, there is a high unmet medical need for targeted therapies that address the underlying disease pathophysiology and have a more tolerable safety profile than systemic steroids.
Treatment landscape of approved and emerging therapies
The hypothesis of IgAN pathophysiology offers potential target points and approaches for therapeutic intervention. As of January 2026, there are five agents approved for the treatment of IgAN and several additional treatments are in clinical development. Most therapeutic candidates in clinical development have employed various approaches to target inflammation and the downstream effects.
These agents can be grouped mechanistically into the following categories: glucocorticoid receptor agonists, endothelin receptor antagonists (ERAs), complement inhibitors, B-cell modulators, and a variety of other approaches that are in the early stages of clinical development.
Glucocorticoid receptor agonists. Glucocorticoid receptor agonists are a well-known class of molecules that have broad anti-inflammatory effects, and well-established acute and chronic side effects. Though reduction in the risk of eGFR decline was shown in clinical trials, there is no consensus on whether glucocorticoids may improve kidney survival. The glucocorticoid budesonide has been reformulated to concentrate steroid effects locally on the gut mucosa, theoretically suppressing the abnormal B cell activity and reducing systemic steroid toxicity. Reformulated budesonide, a delayed-release corticosteroid developed by Asahi Kasei Corp., is currently approved by the FDA as TARPEYO® and European Commission as KINPEYGO® for reducing the loss of kidney function in adults with IgAN who are at risk for disease progression, though systemic steroid side effects have been observed in clinical trials.
ERAs. Aberrant endothelin signaling is implicated in structural podocyte changes and increased mesangial proliferation in chronic kidney diseases, including IgAN. ERAs block endothelin-induced cell proliferation and hence may reduce renal perfusion pressure and proteinuria. Since this mechanism of action works downstream of disease-related immune activities, it is not expected to reduce Gd-IgA1 or the resulting immune complexes that cause the disease. ERAs have previously been approved for the treatment of pulmonary arterial hypertension and erectile dysfunction and make use of a vasodilatory effect. ERAs have been associated with edema, significant
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liver toxicity and increased risk of heart failure. Sparsentan, a dual endothelin angiotensin receptor antagonist developed by Travere Therapeutics, is currently approved by the FDA and European Commission as FILSPARI®, with a boxed warning for hepatotoxicity and embryo-fetal toxicity and a Risk Evaluation and Mitigation Strategies (REMS) assigned for liver toxicity. Atrasentan is an endothelin A receptor antagonist developed by Novartis and approved by the FDA as VANRAFIA®.
Complement inhibitors. Increased complement activation is commonly observed in patients with IgAN. It is hypothesized that immune-complex deposition in glomeruli may contribute to complement activation, though the exact mechanism is not well understood. Iptacopan is a complement inhibitor developed by Novartis and approved by the FDA as FABHALTA®. Several other agents that inhibit complement activation are in early stages of clinical development for IgAN. As complement inhibition works downstream of immune complex formation, these agents are not expected to impact the upstream cause of disease and reduce Gd-IgA1 or the resulting immune complexes that cause inflammation and complement activation in the kidney.
B-cell modulators. B-cell modulators, including atacicept, are an important category of emerging therapies for IgAN. The disease-causing Gd-IgA1 is predominantly produced by B cells. Therefore, control of B cell activation may reduce production of Gd-IgA1 and the downstream formation of autoantibodies and immune complexes. Preclinical models have shown that dual inhibition of BAFF and APRIL offers improved suppression of B cell activities over blocking BAFF or APRIL alone. Sibeprenlimab is an APRIL-specific monoclonal antibody developed by Otsuka Pharmaceuticals and approved by the FDA as VOYXACT®.
Our solution: Atacicept
Atacicept is a fusion protein that blocks both BAFF and APRIL, which play key roles in the upstream pathways that cause IgAN and other autoimmune diseases, and is dosed once weekly via a 1-mL subcutaneous injection, self-administered at home. We believe that atacicept’s mechanism has the potential for clinically meaningful improvements in measures designed to assess efficacy in IgAN and other immunologic diseases. BAFF inhibition has been clinically and commercially validated through the approval of BENLYSTA (belimumab) in both SLE and LN. Preclinical and clinical evidence support that atacicept’s mechanism of dual inhibition of BAFF and APRIL may provide improved clinical outcomes, compared to inhibiting either signal alone, as measured by endpoints designed to assess efficacy.
Importantly, atacicept is the first agent in development to demonstrate Gd-IgA1 reductions, hematuria improvements, and UPCR reductions with eGFR stabilization at a rate of decline similar to the general population without kidney disease through 96 weeks, suggesting atacicept may offer a potential long-term, disease-modifying treatment for IgAN with a favorable safety profile. As a result, we believe atacicept has the potential to be the first disease-modifying therapy which inhibits both BAFF and APRIL for IgAN. Atacicept has a well-characterized clinical safety profile with >1,900 participants across all completed and ongoing clinical trials to date. We completed enrollment of participants in the ORIGIN 2b trial in 2022, and we reported positive results at 24 weeks in January 2023, 36 weeks in June 2023, 72 weeks in January 2024, and 96 weeks in October 2024. We are conducting a multinational, randomized, double-blind, placebo-controlled Phase 3 clinical trial in IgAN (ORIGIN 3). We completed enrollment for the primary endpoint cohort in September 2024 and completed full enrollment of the study in April 2025. In June 2025, we announced that atacicept met the primary endpoint of UPCR reduction at week 36, with a 46% reduction from baseline and a statistically significant and clinically meaningful 42% reduction compared to placebo (p<0.0001; atacicept n=106, placebo n=97). In November 2025, we presented additional results from the 36-week interim analysis in a featured oral presentation during the ASN Kidney Week opening plenary session, with simultaneous publication in The New England Journal of Medicine. We submitted a BLA for atacicept in IgAN to the FDA in November 2025. The FDA granted priority review to the application and assigned a PDUFA target action date of July 7, 2026. If approved, atacicept would be the first B cell modulator targeting both BAFF and APRIL for IgAN, offering patients an autoinjector for at-home self-administration.
Our approach to IgAN: B-cell modulation to reduce Gd-IgA1 and autoantibodies
Atacicept is a native human TACI-Fc fusion protein that is designed to modulate the B cell pathway, which has well characterized implications in immunologic diseases. Specifically, as shown in Figure 3 below, atacicept contains the soluble extracellular domain of the native TACI receptor fused with the inactivated Fc domain of IgG1. TACI is a native receptor for BAFF and APRIL, members of the tumor necrosis factor family that promote B cell survival and autoantibody production associated with IgAN and other immunologic diseases. Dual blockade of BAFF and APRIL by TACI has been shown to be more potent than blocking BAFF alone or APRIL alone and has the benefit of targeting long-lived plasma cells, in addition to B cells, thus reducing production of Gd-IgA1 and its autoantibodies. Therefore, atacicept is designed to precisely modulate B cell activity by binding both BAFF and APRIL, and follows a long history of impactful agents that are logically designed Fc fusion proteins. This mechanism acts directly on the source of IgAN, which we believe will significantly mitigate the downstream effects of the disease.
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Figure 3: Atacicept is the result of rational drug design to target the upstream source of disease
(1)
Atacicept inhibits BAFF and APRIL, leading to decreased Gd-IgA1 production by B cells.
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This leads to a reduction in the autoantibodies that bind to Gd-IgA1.
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Therefore, formation of pathogenic immune complexes is greatly reduced.
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This, in turn, reduces immune complex deposition in glomeruli and glomerular inflammation is reduced.
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Ultimately, progressive renal injury is attenuated, with reductions in hematuria and proteinuria, and stabilization of eGFR, which we believe will significantly lower the morbidity and mortality associated with IgAN.
Atacicept’s potential disease-modifying mechanism addresses the upstream processes that cause IgAN, while other therapies act on downstream processes. Therefore, we believe that the clinical outcomes of atacicept, measured by endpoints designed to assess efficacy and durability, will be favorable over competitors, with a tolerability profile assessed in a rigorous clinical development program of >1900 patient exposures to date. At home dosing with a once weekly, 1-mL subcutaneous injection via autoinjector also provides an attractive target product profile for patients.
Atacicept in IgAN: clinical development
Atacicept was the subject of a collaboration agreement between Ares and ZymoGenetics, Inc. in 2001, and was licensed on an exclusive basis to Ares in 2008. It was advanced by Merck KGaA (Merck), Darmstadt, Germany, in clinical trials for several autoimmune diseases, including rheumatoid arthritis (RA), multiple sclerosis, SLE, and IgAN. We have worldwide, exclusive rights to atacicept from Ares, an affiliate of Merck, pursuant to a license agreement (Ares Agreement), which advanced atacicept in randomized, double-blind, placebo-controlled clinical trials for several autoimmune diseases in over 1,500 patients, in which it was well tolerated. Previously, Merck conducted a randomized, double-blind, placebo-controlled Phase 2a trial in IgAN known as JANUS. Results from the JANUS trial showed a dose-dependent effect of atacicept 25 mg and 75 mg weekly on serum Gd-IgA1, proteinuria, and key biomarkers, including serum Ig levels. As reported at the American Society of Nephrology (ASN) Kidney Week conference in 2022, atacicept is also the first therapeutic candidate in IgAN to show reduction in all first three hits of pathophysiology—serum Gd-IgA1, anti-Gd-IgA1 autoantibody, and immune complex levels.
Atacicept was studied in the ORIGIN 2b clinical trial, a multinational, randomized, placebo-controlled, double-blind trial for the treatment of IgAN (Figure 4). The ORIGIN 2b trial was designed to evaluate the efficacy and safety of atacicept in participants with biopsy-proven IgAN and persistent proteinuria despite stable and maximum-tolerated renin-angiotensin-aldosterone (RAAS) inhibitor regimen for at least 12 weeks. The clinical trial consisted of a 36-week double-blind treatment period, followed by a 60-week open-label treatment period and a 26-week safety follow-up period. The trial assessed three doses (25 mg, 75 mg and 150 mg) of once-weekly 1-mL subcutaneous injections, administered at home, of atacicept versus placebo, for impact on kidney function as measured by proteinuria and eGFR. The primary endpoint was change from baseline in UPCR at 24 weeks based on 24-hour urine collection, with a secondary endpoint of UPCR at 36 weeks. Other secondary endpoints included UPCR and eGFR at multiple timepoints, and safety and tolerability. Exploratory endpoints included Gd-IgA1 change from baseline and hematuria resolution. We completed enrollment in mid-2022, enrolling a total of 116 participants at multiple global sites.
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Figure 4: ORIGIN 2b trial design
Results from the 36-week double-blind period were presented in a late-breaking oral presentation at the European Renal Association 2023 conference and published in Kidney International in 2024. The primary endpoint was met at 24 weeks as the mean UPCR was reduced from baseline by 31% in the combined atacicept group (defined as atacicept 75 mg and 150 mg groups) vs 8% with placebo, resulting in a statistically significant 25% reduction with atacicept vs placebo.
The results of the 36-week randomized period were consistent with a profile of disease modification in IgAN:
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Gd-IgA1 reduction of 64% from baseline with atacicept 150 mg.
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Hematuria resolution in 80% of participants on atacicept 150 mg vs 5% on placebo.
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Atacicept 150 mg achieved a 35% reduction vs placebo.
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Stable eGFR observed for participants on atacicept, with clinically meaningful difference of 5.8 mL/min/1.73m2 vs placebo.
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Atacicept was well tolerated, with a similar safety profile to placebo.
In October 2024, long-term results from the ORIGIN Phase 2b trial were simultaneously presented in a late-breaking oral presentation at ASN Kidney Week and published in the Journal of the American Society of Nephrology (JASN). Over 96 weeks, participants treated with atacicept demonstrated a 66% reduction in Gd-IgA1, resolution of hematuria in 75% of participants, a 52% reduction in proteinuria, and a mean annualized eGFR slope of -0.6 mL/min/1.73m2/year. This eGFR slope profile is consistent with the aging-related decline observed in the general population without biopsy-proven kidney disease.
Figure 5: ORIGIN Phase 2b long-term 96-week results with atacicept was consistent with disease-modifying IgAN profile
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In the randomized phase of the ORIGIN Phase 2b clinical trial, the clinical safety profile was similar between atacicept and placebo. The cumulative generally favorable safety profile of atacicept remained consistent with that observed during the randomized period (Figure 6), with a 90% completion rate of atacicept treatment in the open-label extension period. We believe these data support the potential for atacicept to offer long-term, comprehensive IgAN disease modification and provide further confidence in the ongoing pivotal ORIGIN 3 trial of atacicept in IgAN.
Figure 6: Phase 2b ORIGIN clinical trial adverse events profile
Ongoing Phase 3 ORIGIN clinical trial
We advanced atacicept 150 mg into a pivotal Phase 3 trial in IgAN in the second quarter of 2023, using the same formulation from the Phase 2b trial and learnings from the Phase 2b subgroup analyses to reduce risk in the design of a Phase 3 trial that aims to accurately assess treatment efficacy while minimizing potential confounders for proteinuria measure.
Figure 7: Phase 3 ORIGIN 3 trial design
ORIGIN 3 is a Phase 3 global, multicenter, randomized, placebo-controlled, double-blind trial (Figure 7) in participants with IgAN who have persistent proteinuria and remain at high risk of disease progression despite being on a stable prescribed regimen of renin-angiotensin system inhibitors (ACE inhibitors or ARBs) for at least 12 weeks that is the maximum labeled or tolerated dose, with the use of SGLT2 inhibitors (SGLT2i) also allowed. The clinical trial consists of a 104-week double-blind treatment period which is currently ongoing, followed by a 52-week open-label extension and a 26-week safety follow-up period. The trial assesses at-home self-administered once weekly 1-mL subcutaneous injections of atacicept 150 mg versus placebo for impact on kidney function as measured by proteinuria and eGFR. The primary endpoint is change from baseline in UPCR at 36 weeks based on 24-hour urine collection and the key secondary endpoint is change from baseline in eGFR at 104 weeks. Additional secondary endpoints are change in Gd-IgA1, hematuria resolution, change in eGFR at 52 weeks, and time from randomization to first occurrence of composite kidney failure endpoint event. In accordance with guidance from regulatory authorities to sponsors of registrational trials in IgAN, eGFR results are not reported while the trial is ongoing.
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We completed enrollment for the Phase 3 primary endpoint cohort in September 2024 and full enrollment of the study in April 2025. In June 2025, we announced that atacicept met the primary endpoint. In November 2025, we presented additional results from the 36-week interim analysis in a featured oral presentation during the ASN Kidney Week opening plenary session, with simultaneous publication in The New England Journal of Medicine.
A total of 428 participants were randomized and treated, with 214 in the atacicept group and 214 in the placebo group. Of the 203 patients included in the 36-week interim efficacy analysis, 99/106 (93%) in the atacicept group and 84/97 (87%) in the placebo group remained on treatment after 36 weeks. The baseline demographics and characteristics for the ORIGIN 3 participants were similar to the previous ORIGIN 2b trial, with the exception of a higher percentage of patients on SGLT2i in the Phase 3 trial, reflecting evolving clinical practices.
Figure 8: Demographics and baseline characteristics of ORIGIN 3 and ORIGIN 2b
The primary endpoint for the interim analysis was the change in UPCR at 36 weeks. Participants receiving atacicept had a 46% reduction in UPCR and the placebo-treated participants had a 7% reduction. Using a mixed effects model, the difference between the groups was statistically significant at 42% (p<0.0001).
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Figure 9: Primary endpoint of UPCR reduction through 36 weeks
The effect of atacicept on UPCR reduction was consistent across prespecified subgroups of age, sex, region, race, baseline proteinuria, baseline eGFR, and baseline SGLT2i use (Figure 10).
Figure 10: UPCR reduction across prespecified subgroups at 36 weeks
Secondary endpoint results with atacicept were consistent with the Phase 2b study, with a 67% reduction in Gd-IgA1, and an 81% reduction in hematuria in participants with baseline hematuria (Figure 11).
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Figure 11: Gd-IgA1 reduction and hematuria resolution through 36 weeks
Across the ORIGIN program in IgAN, the safety profile of atacicept appears favorable, and comparable to placebo. In the ORIGIN 3 safety analysis set (atacicept n=214, placebo n=214), the incidence of adverse events was generally balanced between the atacicept and placebo groups, with numerically fewer serious adverse events reported with atacicept (n=1 [0.5%]) than placebo (n=11 [5%]). There were more discontinuations due to adverse events in placebo treated participants, and the rates of infections were balanced. The one adverse event that was higher in atacicept treated individuals was the rate of injection site reactions; these were mild to moderate, and did not lead to discontinuation. There was a higher number of hypersensitivity reactions in placebo treated individuals.
Atacicept treatment led to reductions in serum immunoglobulin (Ig) levels consistent with its mechanism of B-cell modulation, but without evidence of B-cell depletion or immunosuppression: there were no reported cases of hypogammaglobulinemia (IgG <3 g/dL) and no serious, severe, or opportunistic infections. There were no deaths in either treatment group. (Figure 12)
Figure 12: Adverse event profile
The FDA granted priority review to the BLA for atacicept in IgAN and assigned a PDUFA target action date of July 7, 2026. If approved, atacicept would be the first B cell modulator targeting both BAFF and APRIL for IgAN, offering patients an autoinjector for at-home self-administration.
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ORIGIN EXTEND Phase 2 clinical trial
We initiated the ORIGIN EXTEND trial, a Phase 2 extension study in participants who complete ORIGIN Phase 2b or Phase 3. The objectives of the trial are to 1) capture longer-term safety and efficacy data of atacicept treatment, 2) evaluate the effect of reinitiation of atacicept treatment following an off-treatment period and 3) provide eligible participants with extended access to atacicept prior to commercial availability in their country or region. We anticipate clinical results from the trial in 2026.
PIONEER Phase 2 clinical trial to assess Atacicept in pMN, FSGS, and MCD
Due to the positive results of the ORIGIN program, in August 2025 we initiated the PIONEER trial, a global, open label, Phase 2 basket trial evaluating the safety and initial signals of efficacy of atacicept in an expanded cohort of IgAN patients and other autoimmune-mediated glomerular diseases. The expanded IgAN cohort includes participants aged 10 years or older, IgA vasculitis nephritis, and lower baseline thresholds for proteinuria and eGFR than were studied in ORIGIN 3. The trial also includes cohorts with additional autoimmune glomerular diseases characterized by the presence of antibodies to glomerular antigens, including pMN, FSGS, and MCD. We anticipate clinical results from the trial in 2026.
Atacicept in pMN
pMN Pathophysiology and Disease Overview
pMN is an autoimmune disease characterized by glomerular membrane thickening and long-term proteinuria. pMN patients are initially treated with ACEi / ARBs, and upon progression typically are treated with either immunosuppressive or CD20 therapies. Despite proper management, patients still progress to ESKD, highlighting the need for a more effective standard of care.
pMN Market Opportunity, Current Standard of Care, and Our Proposed Solution
There are approximately 50,000 patients in the United States with pMN. In 70-80% of cases, inflammation of the renal glomeruli is caused by autoantibodies targeting PLA2R and thrombospondin type 1 domain-containing 7A (THSD7A). The remaining 20-30% of cases develop as a secondary condition due to underlying issues such as infections, other autoimmune diseases, tumors, or drug poisoning. Most patients with biopsy-confirmed pMN have circulating anti-PLA2R autoantibodies, with approximately 70% of pMN cases associated with anti-PLA2R+ antibodies, and 65% of these cases considered moderate-to-severe. According to current KDIGO guidelines, PLA2R is recognized as a crucial diagnostic marker, eliminating the need for a kidney biopsy if the patient is seropositive for PLA2R and exhibits clinical symptoms. Additionally, the concentration of anti-PLA2R antibodies provides insights into disease activity and progression, serving as a clinical criterion for assessing the risk of progressive renal failure in pMN patients: 1) higher antibody concentrations indicate more active pMN and a greater risk of kidney failure, and 2) monitoring antibody levels can predict phases of clinical remission and relapses, as changes in anti-PLA2R antibody levels typically precede improvements or worsening of the disease.
Current treatments tackle the autoimmune aspect of pMN through B-cell depletion (e.g., agents such as rituximab) or immunosuppression via cyclophosphamide / high dose steroids; these therapies have been associated with significant toxicity. With no FDA-approved pMN therapies, significant unmet need remains for efficacious and safe agents, including those that can reduce adverse events associated with immunosuppressant therapy, offer benefit for the ~40% of patients that are refractory to rituximab, and further reduce disease progression to CKD and ESKD.
A more targeted approach that focuses on modulating autoimmune B-cell production, rather than broad immunosuppression, may offer a potential solution. Autoreactive B-cells are implicated in the immunopathogenesis of pMN, with PLA2R identified as the target antigen for the typical IgG deposition observed in renal biopsies. While immunosuppressive treatments have shown reductions in PLA2R autoantibody (PLA2R-Ab) levels, patients with higher serum levels of both BAFF and APRIL are less likely to achieve clinical remission on standard immunosuppressive therapy. Additionally, the BAFF-targeting immunomodulator belimumab has been shown to improve proteinuria and PLA2R titers in an open-label trial. This supports the rationale for using other treatments involving B-cell modulation, such as atacicept. Atacicept's ability to block pathogenic B-cell activation via BAFF and APRIL cytokine binding suggests it may be effective in treating pMN, particularly in patients who have been treated with immunosuppressive therapies but still maintain high BAFF and APRIL serum levels.
Atacicept in FSGS and MCD
FSGS and MCD Pathophysiology and Disease Overview
FSGS is characterized by histological lesions (scarring) on kidney glomeruli, manifestations of proteinuria & hypoalbuminemia, and chronic kidney disease, which can present at any age. FSGS often presents with nephrotic syndrome manifestations, including high-grade proteinuria (>3.5 g/day), hypoalbuminemia, and edema, with 30 – 40% progressing to ESKD by 10 years. Nephrin is a transmembrane protein found in kidney podocytes, plays a significant role in maintaining the integrity and function of the glomerular filtration barrier, and it can be used as a biomarker for early glomerular injury, since elevated levels of nephrin in the urine (nephrinuria)
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can indicate damage to the podocytes and the filtration barrier. Recently, anti-nephrin antibodies were identified in ~10% of primary FSGS patients, indicating potential autoimmune involvement in the disease pathology and demonstrating a strong correlation to urine albumin-to-creatinine ratio (uACR).
MCD is a kidney disorder that leads to glomeruli damage and is characterized by sudden onset of nephrotic syndrome, including increased proteinuria, edema, and hypoalbuminemia. Immune dysregulation, including the presence of autoantibodies against nephrin and other podocyte components, contributes to podocyte injury and disease progression. MCD accounts for 70 – 90% of pediatric and 15% of adult idiopathic nephrotic syndrome patients. MCD is distinguished from other nephrotic diseases based on sudden onset of clinical features such as proteinuria (i.e., days/weeks vs. months) and distinct morphological features (e.g., podocyte effacement, normal glomerulus) based on kidney biopsy. Approximately two-thirds of adult patients with MCD and active nephrotic syndrome have anti-nephrin autoantibodies, while this figure rises to about 90% in children with idiopathic nephrotic syndrome.
FSGS and MCD Market Opportunity, Current Standard of Care, and Our Proposed Solution
There are approximately 44,000 diagnosed primary FSGS patients in the United States, of which approximately 7,000 may be identified as auto-immune assuming improved diagnostic methods. Primary FSGS patients are typically treated with background ACEi / ARBs, followed by sequencing steroids, calcineurin inhibitors (CNIs), immunosuppressive therapies (ISTs), and / or rituximab, with the aim to preserve kidney function and reduce risk to ESKD. Despite the current standard of care (which includes steroids, CNIs), there is persistent unmet need as up to 40% of patients reach ESKD and there are no FDA-approved disease-modifying drugs. Given the severity of clinical symptoms (e.g., ESKD risk), autoimmune FSGS patients would benefit from novel, efficacious therapies.
There are approximately 15,000 adult MCD patients and almost 10,000 pediatric MCD patients in the United States. Recently, anti-nephrin antibodies were identified in approximately 50% of pediatric MCD and adult MCD patients, indicating potential autoimmune involvement in disease pathology, which correlated to higher uACR and serum albumin levels. Patients are typically managed via steroids or other immunosuppressive therapies including cyclophosphamide, mycophenalate mofetil (MMF) and Levamisole. Additional treatments include diuretics for edema, ACE inhibitors or ARBs to reduce proteinuria, and dietary changes like a low-sodium diet. No FDA-approved therapies are currently available for MCD.
Given the autoimmune involvement in the disease pathology for at least some sub-populations of FSGS and MCD patients, potentially via B-cell mediated immune/inflammatory pathways, as demonstrated by response to rituximab in some patients, there is reason to believe that therapies that inhibit the proliferation and maturation of auto-reactive B-cells, such as atacicept, may be efficacious.
MAU868 in reactivated BK infection among kidney transplant recipients
We have exclusive worldwide rights, pursuant to the Novartis License, toMAU868, which is a potential treatment for reactivated BK infection in kidney transplant recipients. While up to 90% of healthy adults have been infected with BKV at some point in their lives, it remains latent in everyone except severely immunocompromised populations such as kidney transplant recipients. There are approximately 80,000 kidney transplants annually worldwide, with approximately 20,000 in the United States. Approximately 225,000 kidney allograft recipients are living in the United States. Waitlists to receive kidneys are long: approximately 3–5 years and 75,000 people long in the United States. Up to 12% of transplants per year are re-transplants, which further limits organ availability for new patients. BKV is a polyoma virus that is tropic to the kidney and bladder tissue and can reactivate with the immunosuppression required for kidney transplant. This reactivation can cause BKVN, a condition in which BK infection, typically first identified as BK viremia, triggers inflammation, which then progresses to renal fibrosis and tubular injury; as shown in Figure 13, BKVN is a leading cause of allograft loss, a devastating outcome for kidney transplant recipients.
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Figure 13: Graft survival (%) in kidney transplant patients is worse with BKVN
Currently, there are no approved treatment options for BK viremia or BKVN. We shared full Cohort 1 and Cohort 2 results in 2022 from the Phase 2 trial conducted by Amplyx. Following feedback from the FDA on the Phase 2 clinical trial, we are evaluating strategies for continued development, including a potential next clinical trial. We believe that MAU868has the potential to become standard of care for the treatment of BK viremia in order to prevent devastating consequences such as BKVN.
Pathophysiology of BKV in kidney transplant
BKV has a worldwide seroprevalence of up to 90%. Primary BK infection is typically acquired during childhood, after which the virus establishes lifelong infection in the kidney and bladder tissue. Most people do not experience any known adverse effects from either primary or persistent infection. Control of infection is dependent on CD4+ and CD8+ T cell immunity, which can be displaced by immunosuppressants. In the setting of kidney transplant and related immunosuppression, latent virus can be reactivated or new virus can be transmitted via the donor kidney. BKV reactivation is marked first by viruria—or detection of virus in the urine, and then viremia—detection of viral DNA in the blood, and most commonly occurs within the first year of transplant.
Viremia typically occurs in 15% of kidney transplant recipients, after which BKVN may occur. Approximately 3-4% of kidney transplant recipients develop BKVN.
BKVN disease burden and diagnosis
BKVN may lead to allograft injury and in some cases, allograft loss. 24–60% of all graft losses are due to BKV-associated disease. The average cost of a kidney transplant in the United States is over $440,000. Pre-transplant, recipients are typically on dialysis, for which the cost is approximately $90,000 per year; there is an approximate 450% increase in annual medical cost to treat transplant recipients who experience graft loss.
Most institutions monitor for BK in both the urine, through polymerase chain reaction (PCR) and urinalysis, and plasma, via PCR. It is common practice to screen kidney transplant recipients for BK viremia via PCR test monthly in the first six months post-transplant and then every three months until two years post-transplant, after which patients are typically screened annually. Also, at any sign of allograft dysfunction, physicians will test for BK viremia. Viral load levels >1000 copies/mL are considered positive for BK viremia, and levels >10,000 copies/mL are considered presumptive BKVN. Kidney allograft biopsy is considered the gold standard for diagnosing BKVN. Late diagnosis of BKV can lead to irreversible renal function decline and poor treatment outcomes.
Kidney transplant market opportunity
An estimated 80,000 kidney transplants are conducted globally each year, with approximately 20,000 in the United States, 20,000 in Europe, 1,500 in Japan, and 10,000 in China. Approximately 225,000 kidney allograft recipients are living in the United States. Waitlists to receive kidneys are long: 3–5 years and 75,000 people deep in the United States. Up to 12% of transplants per year are re-transplants, which further limits organ availability for new patients. Approximately 15% of kidney transplant recipients develop BK viremia. Patients can be risk stratified for BK viremia based on the degree of immunosuppression employed, which is related to the degree of human leukocyte antigen (HLA) match between the graft and recipient; the greater the mismatch, the more intense immunosuppression required, which increases the risk of BKV reactivation.
We estimate the market for a novel agent to treat reactivated BK infection in kidney transplant recipients to be a large commercial opportunity. We believe that MAU868 has the potential to become standard of care for the treatment of reactivated BK infection in order to prevent devastating consequences following kidney transplantation such as BKVN and graft loss.
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Current standard of care for kidney transplant patients with BK viremia
Currently, there is no approved treatment specific to BKV. Upon detection of BK viremia, physicians’ first line of defense is to reduce immunosuppression with the goal of restoring CD4+ and CD8+ T cell immunity without causing acute rejection. Initial modification will typically consist of lowering MMF by 50% followed by a reduction in tacrolimus by 50%. If no improvement is observed, use of MMF and tacrolimus will be stopped and dose of prednisone will be increased. Other agents such as intravenous immunoglobulin (IVIG), leflunomide, and cidofovir, are occasionally used—but all have limited data and both leflunomide and cidofovir have serious safety concerns. After development of BKVN, patients have limited options and may continue to receive antivirals or IVIG. Physicians are not satisfied with current treatment options for BKV and highlight that there is a significant unmet need for a viable therapy.
Emerging therapies in development
Despite the high level of unmet need in treating BK viremia and preventing devastating consequences, there is limited development in the space. Memo Therapeutics is also developing a BKV-neutralizing monoclonal antibody and is in Phase 2 clinical development.
Our solution: MAU868
MAU868 is a human monoclonal antibody (IgG1/l isotype subclass) directed against the major viral capsid protein of BKV, VP1, which is essential for binding to and infection of new cells, as shown in Figure 14. MAU868 neutralizes all four serotypes of BKV at sub-nanomolar concentrations and has a high barrier to resistance in vitro (resistant isolates of BKV were not selected in vitro at any of the concentrations of MAU868 investigated). MAU868 is being developed for the treatment of BKV disease in kidney transplant recipients (BKV nephropathy) and being considered for hematopoietic stem cell transplant (HSCT) recipients (BKV-associated hemorrhagic cystitis). MAU868 also has neutralizing activity in vitro against the closely related JC virus, the cause of progressive multifocal leukoencephalopathy.
Figure 14: MAU868 blocks BK virion binding
Clinical development of MAU868
Phase 1
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A first-in-human, randomized, blinded, placebo-controlled, single ascending dose study to assess the safety, tolerability, and pharmacokinetics of MAU868 following IV or SC administration to healthy adult subjects was performed. Administration of up to 100 mg/kg MAU868 IV and 3 mg/kg MAU868 SC were well tolerated. No deaths or serious adverse events were reported, and there were no adverse events that led to the discontinuation of the drug or the study.
Phase 2
We completed a Phase 2 randomized, double-blind, placebo-controlled clinical trial designed to assess the safety, tolerability, and efficacy of MAU868 for the treatment of allograft-threatening BKV infection in kidney (or kidney-pancreas) transplant recipients in 2022. Two sequential cohorts enrolled a total of 28 participants with BK viremia. As shown in Figure 15, each cohort was designed to randomize approximately 12 participants (8 to MAU868 and 4 to placebo), for which Cohort 1 (1350 mg IV approximately every 28 days for a total of 4 doses) and Cohort 2 (6750 mg IV on Day 1, 1350 mg IV every 28 days for 3 additional doses) have completed dosing.
The primary objective of the clinical trial was to assess the safety and tolerability of MAU868, with secondary objectives to assess the impact of MAU868 on BKV related outcomes. MAU868 has been shown in an interim analysis of week 12 data from Cohorts 1 and 2 to be well-tolerated and showed a greater proportion of participants with decrease in BK plasma viral load versus placebo.
At the ASN 2022 conference, final results from the Phase 2 clinical trial of MAU868 versus placebo showed that MAU868 was well tolerated and demonstrated clinically meaningful reductions in BK antiviral activity through 36 weeks in kidney transplant patients with BK viremia.
Figure 15: MAU868 phase 2 clinical trial design
Future clinical trials
Following feedback from the FDA on the Phase 2 clinical trial, we are evaluating strategies for continued development, including a potential next clinical trial.
Exclusive license agreement with Ares Trading S.A.
On October 29, 2020, we entered into the Ares Agreement with Ares, an affiliate of Merck, pursuant to which Ares granted us an exclusive worldwide license to certain patents and related know-how to research, develop, manufacture, use and commercialize therapeutic products containing atacicept or any other compound that is covered by a claim of such licensed patents. Pursuant to the Ares Agreement, Ares also transferred inventory of licensed product to us for use in our clinical development of atacicept.
Per the Ares Agreement, we have obligations to use commercially reasonable efforts to develop at least one licensed product, to launch at least one licensed product in a major market country within a specified time frame after receiving marketing approval for such product and to maintain sufficient resources to manufacture and supply licensed products to meet the market demand in each country for which a licensed product has received marketing approval.
As consideration under the Ares Agreement, we paid Ares $25.0 million upon delivery and initiation of the transfer of specified information and supply of drug product and drug substance and $15.0 million upon achievement of the FDA’s filing of the BLA for atacicept for IgAN which was paid in January 2026. We are required to pay Ares additional aggregate milestone payments, including $20.0 million upon regulatory approval for IgAN in the U.S., and other potential milestone payments of up to $141.5 million upon the achievement of regulatory filing and approval milestones for other geographic regions and indications, and aggregate milestone payments of up to $515.0 million upon the achievement of specified worldwide aggregate annual net sales milestones, beginning with $15.0 million if net sales reach $250.0 million and $50.0 million if net sales reach $500.0 million. Commencing on the first commercial sale of licensed products, we are obligated to pay tiered royalties of low double-digit to mid-teen percentages on annual net sales of the products covered by the license. Our obligation to pay royalties on a licensed product-by-licensed product and country-by-country basis will expire at the latest of (i) 15 years after the first commercial sale of such licensed product in such country; (ii) the expiration of the last valid claim of a licensed patent that covers such licensed product in, or its use, importation or manufacture with respect to, such country; and (iii) expiration of all applicable regulatory exclusivity periods in such country with respect to such licensed product. In the
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event we sublicense our rights under the Ares Agreement, we are obligated to pay Ares a percentage ranging from the mid single-digit to the low double-digits of specified sublicensing income received.
The term of the Ares Agreement will expire on a licensed product-by-licensed product and country-by-country basis upon the expiration of our obligation to pay royalties to Ares with respect to such licensed product in such country. We have the right to terminate the Ares Agreement at will upon a specified notice period, provided that such termination is not within two years of the effective date of the Ares Agreement. Ares has the right to terminate the Ares Agreement in the event we challenge the validity of the licensed patents. Additionally, either party can terminate the Ares Agreement for the other party’s uncured material breach or bankruptcy.
Asset purchase agreement with Amplyx and exclusive license with Novartis
On December 16, 2021, we entered into an asset purchase agreement (Amplyx Agreement) with Amplyx.
Pursuant to the terms of the Amplyx Agreement, we acquired all of Amplyx’s right, title and interest in and to certain assets of Amplyx related to MAU868, a monoclonal antibody that was under development by Amplyx for the treatment of BKV infections (Purchased Assets). The Purchased Assets include an investigational new drug application filed with the U.S. Food and Drug Administration, patents, contracts, including the Novartis License, chemical and biological materials, and development and regulatory files, documentation, data, results and other electronic records related to MAU868. We also assumed certain liabilities of Amplyx arising out of the Purchased Assets. We and Amplyx have made customary representations and warranties and agreed to customary covenants in the Amplyx Agreement. Subject to certain limitations, each of we and Amplyx has also agreed to indemnify the other for breaches of representations and warranties and other specified matters.
As part of the consideration under the Amplyx Agreement, we are obligated to make certain milestone payments to Amplyx in an aggregate amount of up to $7.0 million based on certain regulatory milestones. Further, we are required to pay Amplyx low single digit percentage royalties based on net sales on a country-by-country and product-by-product basis.
MAU868 is subject to the Novartis License, which was assigned to us by Amplyx. Pursuant to the terms of the Novartis License, we obtained a worldwide, exclusive license from Novartis to develop, manufacture and commercialize MAU868, subject to certain retained rights for research and development by Novartis, provided that Novartis may not develop or sell products incorporating monoclonal antibody targeting BKV and treating BKV disease within a certain period. We will be solely responsible for all research, development, regulatory, manufacturing and commercialization activities of MAU868. Pursuant to the Novartis License, we are obligated to make certain milestone payments to Novartis in an aggregate amount of up to $62.0 million based on certain clinical development, regulatory and sales milestones. Further, we are required to pay Novartis mid- to high-single digit percentage royalties based on net sales on a country-by-country and product-by-product basis. Unless terminated earlier, the Novartis License will remain in effect with respect to each MAU868 product until the expiration of the royalty term for such product. We may terminate the Novartis License for convenience with 60 days’ prior written notice. We or Novartis may terminate the Novartis License for the other party’s uncured material breach. Novartis may terminate the Novartis License for our insolvency. Upon termination, any license granted by Novartis to us will terminate.
Exclusive License Agreement with Stanford
On January 13, 2025, we entered into an exclusive license agreement with Stanford to acquire global rights to VT-109, a novel, next-generation dual BAFF/APRIL inhibitor. This agreement enables us to develop and market VT-109 in return for an upfront license issue fee, annual license maintenance fees, development, regulatory, and commercial milestones, and earned royalties on net sales. In the event we sublicense our rights under the Stanford Agreement, we are obligated to pay Stanford a percentage of specified sublicensing income received.
Intellectual property
Our success depends in part upon our ability to protect our core technology and intellectual property. To protect our intellectual property rights, we rely on patents, trademarks, copyrights and trade secret laws, confidentiality procedures, and employee disclosure and invention assignment agreements. Our intellectual property is critical to our business and we strive to protect it through a variety of approaches, including by obtaining and maintaining patent protection in the United States and internationally for our product candidate, and other inventions that are important to our business. For our product candidates, we generally intend to pursue patent protection covering compositions of matter, including new formulations, methods of making and methods of use. As we continue the development of our product candidates, we intend to identify additional means of obtaining patent protection that would potentially enhance commercial success, including through claims covering additional methods of use.
As of December 31, 2025, we have licensed, including pursuant to sublicenses, from Ares, an affiliate of Merck, a patent portfolio related to atacicept that contains four issued U.S. patents (8,513,393, 8,637,021, 8,852,591, and 8,956,611), as well as certain foreign counterparts of a subset of these patents in foreign countries, including Australia, Brazil, Canada, China, Hong Kong, Israel, India, Japan, Mexico, Singapore, South Korea, South Africa, and countries within the European Patent Convention and the Eurasian Patent Organization. The issued patents include claims covering methods of purifying atacicept, formulations and various methods of
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treatment, and are expected to expire between 2027 and 2029, without considering any patent term extension. We have also licensed pending applications directed to treatment of IgAN with atacicept. These applications are pending in Australia, Brazil, Canada, China, the Eurasian Patent Organization, European Patent Office, Hong Kong, Indonesia, Israel, Japan, South Korea, Mexico, Malaysia, New Zealand, Philippines, Singapore, Thailand, Taiwan, the United States, and South Africa. Any issued patents would be expected to expire in 2041, without considering any patent term extension.
As of December 31, 2025, we have filed a patent cooperation treaty (PCT) application which gives us the opportunity to gain patent rights in multiple countries directed to treatment of autoimmune glomerulopathies other than IgAN with atacicept, including pMN, FSGS, and MCD. In addition, we have filed additional applications in Taiwan and Argentina directed to treatment of autoimmune glomerulopathies other than IgAN with atacicept, including pMN, FSGS, and MCD. Any issued patents would be expected to expire in 2045, without considering any patent term extension. We also own pending U.S. provisional applications directed to treating severe IgAN patient populations with atacicept, as well as treating IgAN with monthly dosing of atacicept. Any issued patents would be expected to expire in 2046, without considering any patent term extension.
Because atacicept is a biologic, marketing approval would also provide 12 years of market exclusivity from the approval date of a BLA in the United States. We are currently seeking orphan drug designation for atacicept in IgAN from the FDA, which, if secured, would provide seven and ten years, in the United States, respectively, of regulatory exclusivity protection from the approval date. We have received orphan drug designation for atacicept in the EU and Japan.
As of December 31, 2025, our patent portfolio licensed from Novartis and covering MAU868 includes three issued U.S. patents with claims covering the composition of matter of MAU868, and methods of neutralizing BKV or JC virus as well as methods of treating or reducing the likelihood of BKV or JC virus associated disorders. Corresponding foreign counterparts are granted in countries within the European Patent Convention, Australia, China, Japan, India, Israel, Mexico, Macau and Taiwan, and pending in Canada. Any issued patents in this family are expected to expire in 2036, without considering patent term extension. The 20-year expiration date for patents in this family is in 2036. In addition, we have applications co-owned with, and licensed from, Novartis directed to dosing regimens for MAU868, and includes applications pending in the U.S. as well as in Australia, Brazil, Canada, China, Eurasian Patent Organization, European Patent Office, Hong Kong, Indonesia, Israel, Japan, Korea, Mexico, Malaysia, New Zealand, Singapore, Thailand, Taiwan, and South Africa. Any issued patents would be expected to expire in 2041, without considering patent term extension.
As of December 31, 2025, we have licensed from Stanford a patent portfolio related to a soluble B-cell maturation antigen (sBCMA) variant FC-fusion proteins useful for treating diseases including IgAN, pending in the U.S., Australia, Canada, China, European Patent Convention, Hong Kong, India, Japan, South Korea, Singapore, Taiwan, and United Arab Emirates. Any issued patents in this patent portfolio would be expected to expire in 2041, without considering any patent term extension.
As of December 31, 2025, we own a pending United States provisional application directed to sBCMA variant FC-fusion proteins useful for treating diseases including IgAN. Any issued patents claiming priority to this provisional application would be expected to expire in 2046, without considering any patent term extension.
In addition to patents, we may rely upon unpatented trade secrets and know-how and continuing technological innovation to develop and maintain our competitive position. However, trade secrets and know-how can be difficult to protect. We seek to protect our proprietary information, in part, by executing confidentiality agreements with our collaborators and scientific advisors, and non-solicitation, confidentiality, and invention assignment agreements with our employees and consultants. We have also executed agreements requiring assignment of inventions with selected scientific advisors and collaborators. The confidentiality agreements we enter into are designed to protect our proprietary information and the agreements or clauses requiring assignment of inventions to us are designed to grant us ownership of technologies that are developed through our relationship with the respective counterparty. We cannot guarantee, however, that we have executed such agreements with all applicable counterparties, such agreements will not be breached, or that these agreements will afford us adequate protection of our intellectual property and proprietary rights. For more information, see “Risk factors—Risks related to our intellectual property.”
Furthermore, we seek trademark protection in the United States and internationally where available and when we deem appropriate.
Use of generative artificial intelligence in the workplace
In July 2025, we adopted a generative artificial intelligence (GenAI) policy to provide all employees and contractors with guidelines for the responsible use of GenAI tools and mitigate the risk of misuse, unethical outcomes, potential biases, inaccuracy, data leaks and information security breaches.
Under this policy, GenAI tools may only be used on pre-authorized equipment, and requests for the use of new GenAI tools will be evaluated on a case-by-case basis considering factors such as confidentiality, data sensitivity, ethical and legal implications, and potential business impact. We will review and update this policy periodically to respond to any changes in applicable laws, emerging risks, and strategic business requirements.
Manufacturing and supply
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We manage a number of external contract manufacturing organizations (CMOs) to develop and manufacture our product candidates.
Atacicept is a native human TACI-Fc fusion protein that impacts the B cell pathway, which has well characterized implications in immunologic diseases. The human IgG1-Fc was modified to reduce the Fc binding to the C1q component of complement and the interaction with Fc receptors.
Atacicept is designed to be manufactured in accordance with current Good Manufacturing Practices (cGMPs) using a process similar to that used routinely for production of monoclonal antibodies.
The atacicept drug product is available as a ready-to-use injection solution in a pre-filled syringe (PFS) at strengths of 25 mg/mL, 75 mg/mL, or 150 mg/mL of trial drug. Each atacicept PFS is designed to deliver a 1 mL solution of drug product. All formulation components are pharmacopeia grade.
The Ares Agreement includes the transfer of all existing inventory of atacicept drug substance and drug product, for our use in planned and future clinical trials.
We acquired approximately 35,000 PFS of atacicept and approximately 25,000 PFS of placebo, as part of the Ares Agreement. This drug product will be utilized for our ongoing clinical trials, as needed.
The atacicept manufacturing supply chain is fully established using CMOs and is operational to supply products for clinical and, if approved, commercial use. An atacicept PFS/autoinjector combination product is in development for clinical use and commercial use, if approved.
Raw materials and supplies required to produce our products candidates are available in some instances from one supplier and in other instances from multiple suppliers. In those cases where raw materials are only available through one supplier, such supplier may be either a sole source (the only recognized supply source available to us) or a single source (the only approved supply source for us among other sources). Although to date we have not experienced any significant delays in obtaining any raw materials from our suppliers, we cannot provide assurance that we will not face shortages from one or more of them in the future. Please see the risk factor, “We contract with third parties for the manufacture of our product candidates for our ongoing clinical trials, and expect to continue to do so for additional clinical trials of our product candidates and ultimately for commercialization. This reliance on third parties increases the risk that we will not have sufficient quantities of our product candidates necessary for their development or commercialization, or such quantities at an acceptable cost, which could delay, prevent or impair our development or commercialization efforts.” described in “Risk Factors” in Part I, Item 1A of this Annual Report.
MAU868 is an IgG1 monoclonal antibody that binds to BKV protein VP1. It is designed to be manufactured according to cGMP using a high expression Chinese hamster ovary (CHO) cell and a standard antibody manufacturing process that is completely free from animal or human derived raw materials. The MAU868 manufacturing supply chain is fully established using contract manufacturing organizations with contracts that are assignable to Vera Therapeutics.
The fully formulated MAU868 drug product is provided as a 3 mL fill in a 6 mL vial which can be combined with multiple vials to prepare infusions at different dosage strengths for use in clinical trials. The drug product formulation is composed of MAU868 as the active substance, a buffering agent, and both a sugar and a surfactant as stabilizing agents.
VT-109 is an engineered Fc-fusion protein containing BCMA variant. This molecule is in early-stage process development.
Commercialization plans
Our commercialization planning efforts are currently focused primarily on launch readiness for atacicept.
We estimate the market opportunity for novel therapeutics in IgAN to be approximately 160,000 patients in the United States, 136,000 patients in Europe and 130,000 in Japan, at estimated peak year of sales, based on our assumptions, secondary research, and primary market research with physicians and payors. In order to capitalize on this opportunity, we are developing a specialty commercial infrastructure focused on IgAN, engaging treating physicians, including nephrologists, educating and engaging patients, and ensuring market access for patients.
Through the Ares Agreement, we were granted worldwide rights to the development and commercialization of atacicept in all indications. We intend to commercialize atacicept ourselves in the United States and other key markets, if approved. Within certain ex-U.S. markets, we may consider strategic collaborations to facilitate commercialization.
Competition
The biotechnology and pharmaceutical industries are characterized by rapidly changing technologies, significant competition and a strong emphasis on intellectual property. This is also true for the development and commercialization of treatments for immunologic diseases. Though we believe that our focus, experienced team, scientific knowledge, and intellectual property provide us with
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competitive advantages, we face competition from a number of sources, including large and small biopharmaceutical companies, universities, and other research institutions.
Many of our competitors have significantly greater financial, technical, human and other resources than we do and may be better equipped to develop, manufacture and market technologically superior products. In addition, many of these competitors have significantly greater experience than we have in undertaking nonclinical studies and human clinical trials of new pharmaceutical products and in obtaining regulatory approvals of human therapeutic products. Accordingly, our competitors may succeed in obtaining FDA approval for superior products. Many of our competitors have established distribution channels for the commercialization of their products, whereas we have no such channel or capabilities. In addition, many competitors have greater name recognition and more extensive collaborative relationships. Mergers and acquisitions in the pharmaceutical and biotechnology industries may result in even more resources being concentrated among a smaller number of our competitors. Smaller or early stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.
Our competitors may obtain regulatory approval of their products more rapidly than we do or may obtain patent protection or other intellectual property rights that limit our ability to develop or commercialize our product candidates or any future product candidates. Our competitors may also develop drugs that are more effective, more convenient, more widely used and less costly or have a better safety profile than our products and these competitors may also be more successful than we are in manufacturing and marketing their products. If we are unable to compete effectively against these companies, then we may not be able to commercialize our product candidates or any future product candidates or achieve a competitive position in the market. This would adversely affect our ability to generate revenue. Our competitors also compete with us in recruiting and retaining qualified scientific, management and commercial personnel, establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.
Atacicept in IgAN
Despite the high morbidity associated with IgAN, current standard-of-care treatment relies largely on supportive care therapies, including renin-angiotensin system inhibitors (RASi) and SGLT2i, as well as immunosuppressive treatments such as corticosteroids. Supportive treatments fail to target the origin of pathophysiology in IgAN, putting patients at risk of progressive kidney damage and leading to high rates of kidney failure that result in dialysis or transplant and increased risk of early death.
Growing evidence suggests stringent treatment goals for IgAN including the fundamental treatment goal of minimizing eGFR loss to <1 mL/min/year, and highlights prevention or reduction of IgA immune complex formation via reduction in Gd-IgA1 as a first-line treatment goal. Most patients are not achieving recommended proteinuria and eGFR goals, leaving them at a substantial lifetime risk of ESKD.
As treatment guidelines have evolved, there is increasing emphasis on the use of disease-modifying therapies that address the immunologic drivers of disease simultaneously with supportive care.
Atacicept is expected to be indicated to reduce proteinuria in patients living with IgAN who are at risk of disease progression. In ORIGIN 3, all patients were previously treated with a RAAS inhibitor and 56% of patients were also treated with SGLT2i. At approval, atacicept will compete with corticosteroids, targeted budesonide, complement inhibitors in addition to other b-cell modulators like sibeprenlimab.
Among emerging therapies, we consider our most direct competitors with respect to atacicept in IgAN to be approved products: the reformulated steroid from Asahi Kasei Corp., the anti-APRIL monoclonal antibody from Otsuka Pharmaceuticals, both the complement inhibitor and selective ETA receptor antagonist from Novartis, and the endothelin and angiotensin II receptor antagonist from Travere Therapeutics, Inc.; programs in Phase 3 clinical development: Roche/Ionis, Vertex, AstraZeneca, Biogen, Takeda, and Novartis; and the following companies with programs in Phase 2 of clinical development: Arrowhead Pharmaceuticals, NovelMed, and Eladon Pharmaceuticals.
Atacicept in pMN, FSGS, and MCD
There are no FDA-approved therapies for pMN. Companies with pMN trials in Phases 2 or 3 include Vertex, Roche, BeOne Medicines, Biogen, Climb Bio, and Walden Biosciences. There are currently no FDA-approved therapies for FSGS. Travere’s FILSPARI received an extended FDA review of the sNDA in FSGS, with a PDUFA target action date of April 13, 2026. Companies with FSGS trials in Phases 2 or 3 include the following: Sanofi, Eli Lilly, Astellas, Walden Biosciences, Boehringer Ingelheim, Novartis, and Vertex. There are no FDA-approved therapies for MCD. Companies with MCD trials in Ph2/Ph3 include Sanofi, Travere Therapeutics, and Walden Biosciences.
MAU868
There are currently no anti-BKV therapies approved, either in the kidney transplant or HSCT setting. The standard of care in both settings is to reduce immunosuppression as a first line, and potentially to offer IVIG in kidney transplant recipients or antivirals with limited clinical evidence, including leflunomide and cidofovir, in either setting. There are few industry-sponsored programs in
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development for these indications; we consider our most direct competitor to be Memo Therapeutics AG’s AntiBKV, a neutralizing monoclonal antibody in a Phase 2/3 clinical trial.
VT-109
The current landscape of B cell modulators primarily includes monoclonal antibodies, or Fc-fusion proteins containing TACI or TACI variants, including atacicept. VT-109 is a novel BAFF/APRIL dual-inhibitor B cell maturation antigen (BCMA) molecule which, if successfully developed, approved, and commercialized, may compete with the existing approaches to treat B cell mediated autoimmune diseases, many of which are described in the preceding paragraphs on IgAN. We consider the most advanced direct competitor to VT-109 to be the BCMA Fc-fusion protein from Aurinia Pharmaceuticals Inc., which is currently in Phase 1 clinical development.
Government regulation
Government authorities in the United States at the federal, state and local level and in other countries and jurisdictions, including the EU, extensively regulate, among other things, the research, development, testing, manufacture, quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, post-approval monitoring and reporting, marketing and export and import of drug and biological products, such as our investigational medicines and any future investigational medicines. Generally, before a new drug or biologic can be marketed, considerable data demonstrating its quality, safety and efficacy must be obtained, organized into a format specific for each regulatory authority, submitted for review and approved by the regulatory authority.
Regulatory approval in the United States
In the United States, pharmaceutical products are subject to extensive regulation by the FDA. The Federal Food, Drug and Cosmetic Act (FDCA), and other federal and state statutes and regulations, govern, among other things, the research, development, testing, manufacture, storage, recordkeeping, approval, labeling, promotion and marketing, distribution, post- approval monitoring and reporting, sampling, and import and export of pharmaceutical products. Biological products used for the prevention, treatment or cure of a disease or condition of a human being are subject to regulation under the FDCA, except the section of the FDCA that governs the approval of a New Drug Application (NDA). Biological products are approved, or licensed, for marketing under provisions of the Public Health Service Act (PHSA) via a BLA. The application process and requirements for approval of BLAs for originator biological products are similar to those for NDAs for new chemical entities, and biologics are associated with similar approval risks and costs as drugs. Failure to comply with applicable U.S. requirements may subject a company to a variety of administrative or judicial sanctions, such as clinical hold, FDA refusal to approve pending NDAs or BLAs, warning or untitled letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, civil penalties, and criminal prosecution.
Biological products must be approved by the FDA pursuant to a BLA before they may be legally marketed in the United States. The process generally involves the following:
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completion of extensive preclinical laboratory and animal studies in accordance with applicable regulations, including studies conducted in accordance with good laboratory practice (GLP) requirements;
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submission to the FDA of an Investigational New Drug Application (IND), which must become effective before human clinical trials may begin;
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approval of the protocol and related documents by an institutional review board (IRB) or independent ethics committee representing each clinical trial site before each clinical trial may be commenced;
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performance of adequate and well controlled human clinical trials in accordance with applicable IND regulations, Good Clinical Practices (GCP) requirements and other clinical trial-related regulations to establish the safety and efficacy of the investigational product for each proposed indication;
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preparation of and submission to the FDA of a BLA for marketing approval that includes sufficient evidence of establishing the safety, purity, and potency of the proposed biological product for its intended indication, including from results of nonclinical testing and clinical trials;
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payment of any user fees for FDA review of the BLA;
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a determination by the FDA within 60 days of its receipt of a BLA to file the application for review;
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satisfactory completion of one or more FDA pre-approval inspections of the manufacturing facility or facilities where the biologic, or components thereof, will be produced to assess compliance with cGMP requirements to assure that the facilities, methods and controls are adequate to preserve the biologic’s identity, strength, quality and purity;
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satisfactory completion of any potential FDA audits of the clinical trial sites that generated the data in support of the BLA to assure compliance with GCPs and integrity of the clinical data;
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potential FDA audit of the nonclinical study and clinical trial sites that generated the data in support of the BLA;
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satisfactory completion of an FDA advisory committee review, if applicable; and
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FDA review and approval of the BLA to permit commercial marketing of the product for particular indications of use in the United States.
Preclinical studies
Before testing any biological product candidates in humans, the product candidate must undergo rigorous preclinical testing. Preclinical studies include laboratory evaluation of product chemistry and formulation, as well as in vitro and animal studies to assess the potential for adverse events and in some cases to establish a rationale for therapeutic use. The conduct of preclinical studies is subject to federal regulations and requirements, including GLP regulations for safety/toxicology studies.
Prior to beginning the first clinical trial with a product candidate in the United States, an IND must be submitted to the FDA and the FDA must allow the IND to proceed. An IND is an exemption from the FDCA that allows an unapproved product candidate to be shipped in interstate commerce for use in an investigational clinical trial and a request for FDA allowance that such investigational product may be administered to humans in connection with such trial. Such authorization must be secured prior to interstate shipment and administration. In support of a request for an IND, applicants must submit a protocol for each clinical trial and any subsequent protocol amendments must be submitted to the FDA as part of the IND. An IND sponsor must also submit the results of the preclinical tests, together with manufacturing information, analytical data, any available clinical data or literature and plans for clinical trials, among other things, to the FDA as part of an IND. Some long-term preclinical testing may continue after the IND is submitted. An IND automatically becomes effective 30 days after receipt by the FDA, unless before that time the FDA raises concerns or questions related to one or more proposed clinical trials and places the trial on clinical hold. In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin. As a result, submission of an IND may not result in the FDA allowing clinical trials to commence.
Clinical trials
The clinical stage of development involves the administration of the investigational product to healthy volunteers or patients under the supervision of qualified investigators, generally physicians not employed by or under the trial sponsor’s control. Clinical trials must be conducted: (i) in compliance with federal regulations; (ii) in compliance with GCPs, an international standard, codified in FDA regulations, meant to protect the rights and health of patients and to define the roles of clinical trial sponsors, administrators and monitors; as well as (iii) under protocols detailing, among other things, the objectives of the trial, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated in the trial. Each protocol involving testing on U.S. patients and subsequent protocol amendments must be submitted to the FDA as part of the IND.
Furthermore, each clinical trial must be reviewed and approved by an IRB for each institution at which the clinical trial will be conducted to ensure that the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits. The IRB also approves the informed consent form that must be provided to each clinical trial subject or his or her legal representative and must monitor the clinical trial until completed. An IRB must operate in compliance with FDA regulations. An IRB can suspend or terminate approval of a clinical trial at its institution, or an institution it represents, if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the product candidate has been associated with unexpected serious harm to patients.
Some trials are overseen by an independent group of qualified experts organized by the trial sponsor, known as a data safety monitoring board or committee (DSMB). This group provides authorization as to whether or not a trial may move forward at designated check points based on access that only the group maintains to available data from the study.
There also are requirements governing the reporting of ongoing clinical trials and completed clinical trial results to public registries. Information about certain clinical trials, including clinical trial results, must be submitted within specific timeframes for publication on the www.clinicaltrials.gov website. Information related to the product, patient population, phase of investigation, clinical trial sites and investigators and other aspects of the clinical trial is then made public as part of the registration. Disclosure of the results of these clinical trials can be delayed in certain circumstances for up to two years after the date of completion of the trial.
A sponsor who wishes to conduct a clinical trial outside of the United States may, but need not, obtain FDA authorization to conduct the clinical trial under an IND. If a foreign clinical trial is not conducted under an IND, the sponsor may submit data from the clinical trial to the FDA in support of a BLA. The FDA will accept a well-designed and well-conducted foreign clinical trial not conducted under an IND if the clinical trial was conducted in accordance with GCP requirements, and the FDA is able to validate the data through an onsite inspection if deemed necessary.
Clinical trials are generally conducted in three sequential phases, known as Phase 1, Phase 2 and Phase 3:
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Phase 1 clinical trials generally involve a small number of healthy volunteers, or in some cases, patients with a specified disease or condition. The primary purpose of these clinical trials is to assess the metabolism, pharmacokinetics, pharmacologic action, side effect tolerability, safety of the product candidate, and, if possible, obtain early evidence of effectiveness.
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Phase 2 clinical trials generally involve administration of a product candidate to a limited patient population with a specified disease or condition to identify possible short-term side effects and safety risks, to preliminarily evaluate the efficacy of the product candidate for the targeted disease or condition and to determine dosage tolerance and appropriate dosage.
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Phase 3 clinical trials generally involve a large number of patients at multiple sites and are designed to provide the data necessary to provide substantial evidence of efficacy for the product in its intended use, its safety in use and to establish the overall benefit/risk relationship of the product and provide an adequate basis for product labeling.
These Phases may overlap or be combined. In some cases, FDA may require, or firms may voluntarily pursue, post-approval clinical trials, sometimes referred to as Phase 4 clinical trials, after initial marketing approval. These clinical trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication, particularly for long-term safety follow-up.
During all phases of clinical development, regulatory agencies require extensive monitoring and auditing of all clinical activities, clinical data, and clinical trial investigators. Annual progress reports detailing the results of the clinical trials must be submitted to the FDA. Written IND safety reports must be promptly submitted to the FDA and the investigators for serious and unexpected adverse events, any findings from other studies, tests in laboratory animals or in vitro testing that suggest a significant risk for human subjects, or any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure. The sponsor must submit an IND safety report within 15 calendar days after the sponsor determines that the information qualifies for reporting. The sponsor also must notify the FDA of any unexpected fatal or life-threatening suspected adverse reaction within seven calendar days after the sponsor’s initial receipt of the information.
The FDA, the IRB, or the sponsor may suspend or terminate a clinical trial at any time on various grounds, including non-compliance with regulatory requirements or a finding that the patients are being exposed to an unacceptable health risk. Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the drug or biologic has been associated with unexpected serious harm to patients.
Concurrent with clinical trials, companies usually complete additional animal studies and also must develop additional information about the chemistry and physical characteristics of the drug or biologic as well as finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements. The manufacturing process must be capable of consistently producing quality batches of the product and, among other things, companies must develop methods for testing the identity, strength, quality, potency and purity of the final product. Additionally, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the investigational medicines do not undergo unacceptable deterioration over their shelf life.
FDA review processes
Following completion of the clinical trials, the results of preclinical studies and clinical trials are submitted to the FDA as part of a BLA, along with proposed labeling, chemistry and manufacturing information to ensure product quality and other relevant data. To support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety, purity and potency of the investigational product to the satisfaction of the FDA. FDA approval of a BLA must be obtained before a biologic or drug may be marketed in the United States.
The cost of preparing and submitting a BLA is substantial. Under the PDUFA, each BLA must be accompanied by a substantial user fee. The FDA adjusts the PDUFA user fees on an annual basis. Fee waivers or reductions are available in certain circumstances, including a waiver of the application fee for the first application filed by a small business. Additionally, no user fees are assessed on BLAs for products designated as orphan drugs, unless the product also includes a non-orphan indication. The applicant under an approved BLA is also subject to an annual program fee.
Within 60 days following submission of the application, the FDA reviews a BLA submitted to determine if it is substantially complete before the FDA accepts it for filing. The FDA may refuse to file any BLA that it deems incomplete or not properly reviewable at the time of submission and may request additional information. In this event, the BLA must be resubmitted with the additional information. The resubmitted application also is subject to review to determine if it is substantially complete before the FDA accepts it for filing. Once the submission is accepted for filing, the FDA begins an in-depth review of the BLA. The FDA reviews the BLA to determine, among other things, whether the proposed product is safe, pure and potent, for its intended use, and whether the product is being manufactured in accordance with cGMP to ensure its continued safety, purity and potency.
Under the goals and policies agreed to by the FDA under PDUFA, the FDA has 10 months, from the filing date, in which to complete its initial review of an original BLA and respond to the applicant, and six months from the filing date of an original BLA designated for priority review. The review process for both standard and priority review may be extended by the FDA for three additional months to consider certain late-submitted information, or information intended to clarify information already provided in the
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submission. The FDA does not always meet its PDUFA goal dates for standard and priority BLAs, and the review process can be extended by FDA requests for additional information or clarification.
Before approving a BLA, the FDA will conduct a pre-approval inspection of the manufacturing facilities for the new product to determine whether such facilities comply with cGMP requirements and to ensure readiness for commercial manufacturing . The FDA will not approve the product unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.
The FDA also may audit data from clinical trials to ensure compliance with GCP requirements and the integrity of the data supporting safety and efficacy. Additionally, the FDA may refer applications for novel products or products that present difficult questions of safety or efficacy to an advisory committee, typically a panel that includes clinicians and other experts, for review, evaluation and a recommendation as to whether the application should be approved and under what conditions, if any. The FDA is not bound by recommendations of an advisory committee, but it generally follows such recommendations when making decisions on approval.
After the FDA evaluates a BLA, it will issue either an approval letter or a Complete Response Letter. An approval letter authorizes commercial marketing of the biologic with specific prescribing information for specific indications. A Complete Response Letter indicates that the review cycle of the application is complete and the application will not be approved in its present form. A Complete Response Letter generally outlines the deficiencies in the BLA and may require additional clinical data, additional pivotal clinical trial(s) and/or other significant and time-consuming requirements related to clinical trials, preclinical studies or manufacturing in order for FDA to reconsider the application. If a Complete Response Letter is issued, the applicant may either resubmit the BLA, addressing all of the deficiencies identified in the letter, or withdraw the application or request an opportunity for a hearing. The FDA has committed to reviewing such resubmissions in two or six months, depending on the type of information included. Even if such data and information are submitted, the FDA may decide that the resubmitted BLA does not satisfy the criteria for approval.
If a product receives regulatory approval, the approval may be significantly limited to specific diseases and dosages or the indications for use may otherwise be limited, including to subpopulations of patients, which could restrict the commercial value of the product. Furthermore, as a condition of BLA approval, the FDA may require a REMS to help ensure that the benefits of the biologic outweigh the potential risks to patients. A REMS can include medication guides, communication plans for healthcare professionals and elements to assure a product’s safe use (ETASU). An ETASU can include, but is not limited to, special training or certification for prescribing or dispensing the product, dispensing the product only under certain circumstances, special monitoring and the use of patient-specific registries. The requirement for a REMS can materially affect the potential market and profitability of the product. Moreover, the FDA may require substantial post-approval testing and surveillance to monitor the product’s safety or efficacy.
Orphan drug designation
Under the Orphan Drug Act, the FDA may grant orphan designation to a drug or biological product intended to treat a rare disease or condition, which is generally a disease or condition that affects fewer than 200,000 individuals in the United States, or more than 200,000 individuals in the United States but for which there is no reasonable expectation that the cost of developing and making the product for this type of disease or condition will be recovered from sales of the product in the United States.
Orphan drug designation must be requested before submitting a BLA. After the FDA grants orphan drug designation, the identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA. Orphan drug designation on its own does not convey any advantage in or shorten the duration of the regulatory review and approval process.
If a product that has orphan designation subsequently receives the first FDA approval for the disease or condition for which it has such designation, the product is entitled to orphan drug exclusivity, which means that the FDA may not approve any other applications to market the same product for the same indication for seven years from the date of such approval, except in limited circumstances, such as a showing of clinical superiority to the product with orphan exclusivity by means of greater effectiveness, greater safety, or providing a major contribution to patient care, or in instances of drug supply issues. A designated orphan drug may not receive orphan drug exclusivity if it is approved for a use that is broader than the indication for which it received orphan designation. Orphan drug exclusivity may be lost if the FDA later determines that the request for designation was materially defective. Further, competitors may receive approval of either a different product for the same indication or the same product for a different indication. In the latter case, because healthcare professionals are free to prescribe products for off-label uses, the competitor’s product could be used for the orphan indication despite another product’s orphan exclusivity.
Expedited development and review programs
The FDA has a number of programs intended to expedite the development or review of a marketing application for an investigational biologic. For example, fast track designation may be granted for product candidates that are intended to treat a serious or life-threatening disease or condition, where preclinical or clinical data demonstrate the potential to address unmet medical needs for the disease or condition. Fast track designation applies to both the product candidate and the specific indication for which it is being studied. The sponsor of a new biologic candidate can request the FDA to designate the candidate for a specific indication for fast track status
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concurrent with, or after, the submission of the IND for the candidate. The FDA must determine if the biologic candidate qualifies for fast track designation within 60 days of receipt of the sponsor’s request. For fast track products, sponsors may have greater interactions with the FDA and the FDA may initiate review of sections of a fast track product’s BLA before the application is complete. This “rolling review” is available if the FDA determines, after preliminary evaluation of clinical data submitted by the sponsor, that a fast track product may be effective. The sponsor must also provide, and the FDA must approve, a schedule for the submission of the remaining information and the sponsor must pay applicable user fees. Any product submitted to the FDA for marketing, including under a fast track program, may be eligible for other types of FDA programs intended to expedite development and review, such as priority review and accelerated approval.
Breakthrough therapy designation may be granted for product candidates that are intended, alone or in combination with one or more other drugs or biologics, to treat a serious or life-threatening condition if preliminary clinical evidence indicates that the product may demonstrate substantial improvement over currently approved therapies on one or more clinically significant endpoints. Under the breakthrough therapy program, the sponsor of a new biologic candidate may request that the FDA designate the candidate for a specific indication as a breakthrough therapy concurrent with, or after, the submission of the IND for the biologic candidate. The FDA must determine if the biological product qualifies for breakthrough therapy designation within 60 days of receipt of the sponsor’s request. The FDA may take certain actions with respect to product candidates designated as breakthrough therapies, including holding meetings with the sponsor throughout the development process, providing timely advice to the product sponsor regarding development and approval, involving more senior staff in the review process, assigning a cross-disciplinary project lead for the review team and taking other steps to design the clinical trials in an efficient manner. The designation also includes all of the fast track program features, including the potential for rolling review of an application, if the relevant criteria are met.
Priority review may be granted to applications for products candidates that are intended to treat a serious or life-threatening condition and, if approved, would provide a significant improvement in safety and effectiveness compared to available therapies. The FDA will attempt to direct additional resources to the evaluation of an application designated for priority review in an effort to facilitate the review. Under priority review, the FDA’s goal is to review an application for an original biologic within six months after the filing date, compared to ten months for a standard review. Priority review designation does not change the standard for approval or the quality of evidence necessary to support approval.
In addition, depending on the design of the applicable clinical trials, a product candidate may be eligible for accelerated approval. Specifically, product candidates that are intended to treat a serious or life-threatening condition and that generally provide a meaningful therapeutic advantage to patients over existing treatments may be approved on the basis of either a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity or prevalence of the condition and the availability or lack of alternative treatments. In clinical trials, a surrogate endpoint is a measurement of laboratory or clinical signs of a disease or condition that substitutes for a direct measurement of how a patient feels, functions or survives. The accelerated approval pathway is most often used in settings in which the course of a disease is long, and an extended period of time is required to measure the intended clinical benefit of a product, even if the effect on the surrogate or intermediate clinical endpoint occurs rapidly. Use of the accelerated approval pathway entails submission of a BLA with the surrogate or intermediate clinical endpoint data while continuing to conduct the trial(s) to completion and is usually contingent on a sponsor’s agreement to complete and/or conduct additional post-approval confirmatory studies to verify and describe the product’s clinical benefit. These confirmatory trials must be completed with due diligence and, in some cases, the FDA may require that the trial be designed, initiated and/or fully enrolled prior to approval. Failure to conduct required post-approval studies, or to confirm a clinical benefit during post-marketing studies, would allow the FDA to withdraw the product from the market on an expedited basis. All promotional materials for product candidates approved under accelerated regulations are subject to prior review by the FDA.
Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or the time period for FDA review or approval may not be shortened. Furthermore, fast track designation, breakthrough therapy designation, priority review and accelerated approval do not change the standards for approval, but may expedite the development or approval process.
Additional controls for biologics
To help reduce the increased risk of the introduction of adventitious agents, the PHSA emphasizes the importance of manufacturing controls for products whose attributes cannot be precisely defined. The PHSA also provides authority to the FDA to immediately suspend licenses in situations where there exists a danger to public health, to prepare or procure products in the event of shortages and critical public health needs, and to authorize the creation and enforcement of regulations to prevent the introduction or spread of communicable diseases in the United States and between states.
After a BLA is approved, the product may also be subject to official lot release as a condition of approval. As part of the manufacturing process, the manufacturer is required to perform certain tests on each lot of the product before it is released for distribution. If the product is subject to official release by the FDA, the manufacturer submits samples of each lot of product to the FDA together with a release protocol showing a summary of the history of manufacture of the lot and the results of all of the manufacturer’s
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tests performed on the lot. The FDA may also perform certain confirmatory tests on lots of some products, such as viral vaccines, before releasing the lots for distribution by the manufacturer. In addition, the FDA conducts laboratory research related to the regulatory standards on the safety, purity, potency and effectiveness of biological products. As with drugs, after approval of biologics, manufacturers must address any safety issues that arise, are subject to recalls or a halt in manufacturing, and are subject to periodic inspection after approval.
Combination products
A combination product is a product comprised of two or more regulated components, e.g., drug and medical device, that are physically combined and produced as a single entity, packaged together in a single package, or packaged separately but intended to be labeled for use together. Atacicept in a prefilled autoinjector would be such a combination of therapeutic and delivery device.
FDA is divided into various branches, or Centers, by product type. Different Centers typically review drug, biologic, or device applications. In order to review an application for a combination product, FDA must decide which Center should be responsible for the review. FDA regulations require that FDA determine the combination product’s primary mode of action (PMOA), which is the single mode of a combination product that provides the most important therapeutic action of the combination product. The Center that regulates that portion of the product that generates the PMOA becomes the lead evaluator. If there are two independent modes of action, neither of which is subordinate to the other, FDA makes a determination as to which Center to assign the product based on consistency with other combination products raising similar types of safety and effectiveness questions or to the Center with the most expertise in evaluating the most significant safety and effectiveness questions raised by the combination product. When evaluating an application, a lead Center may consult other Centers but still retain complete reviewing authority, or it may collaborate with another Center, by which the Center assigns review of a specific section of the application to another Center, delegating its review authority for that section. Typically, FDA requires a single marketing application submitted to the Center selected to be the lead evaluator, although the agency has the discretion to require separate applications to more than one Center. We believe that our prefilled autoinjector would have a biologic PMOA.
Pediatric information
Under the Pediatric Research Equity Act (PREA), BLAs or supplements to BLAs must contain data to assess the safety and effectiveness of the biological product for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the biological product is safe and effective. The FDA may grant full or partial waivers, or deferrals, for submission of data. Unless otherwise required by regulation, PREA generally does not apply to any biological product for an indication for which orphan designation has been granted.
The Best Pharmaceuticals for Children Act (BPCA) provides a six-month extension of any exclusivity—patent or non-patent—for a biologic if certain conditions are met. Conditions for exclusivity include the FDA’s determination that information relating to the use of the biologic in the pediatric population may produce health benefits in that population, FDA making a written request for pediatric studies, and the applicant agreeing to perform, and reporting on, the requested studies within the statutory timeframe. Applications under the BPCA are treated as priority applications, with all of the benefits that designation confers.
Post-approval requirements
Once a BLA is approved, a product may be subject to certain post-approval requirements. For instance, the FDA closely regulates the post-approval marketing and promotion of biologics, including standards and regulations for direct-to-consumer advertising, off-label promotion, industry-sponsored scientific and educational activities and promotional activities involving the Internet. Biologics may be marketed only for the approved indications and in a manner consistent with the provisions of the approved labeling. Although physicians may prescribe products for off-label uses as the FDA and other regulatory authorities do not regulate a physician’s choice of drug treatment made in the physician’s independent medical judgment, they do restrict promotional communications from companies or their sales force with respect to off-label uses of products for which marketing clearance has not been issued. Companies may only share truthful and not misleading information that is otherwise consistent with a product’s FDA approved labeling.
Adverse event reporting and submission of periodic safety summary reports is required following FDA approval of a BLA. The FDA also may require post-marketing testing and surveillance to monitor the effects of an approved product, including requirements for REMS, or the FDA may place conditions on an approval that could restrict the distribution or use of the product. In addition, quality control, biological product manufacture, packaging and labeling procedures must continue to conform to cGMPs after approval. Biologic manufacturers and certain of their subcontractors are required to register their establishments with the FDA and certain state agencies. Registration with the FDA subjects entities to periodic unannounced inspections by the FDA, during which the agency inspects a biologic product’s manufacturing facilities to assess compliance with cGMPs. Accordingly, manufacturers must continue to expend time, money and effort in the areas of production and quality-control to maintain compliance with cGMPs. Regulatory authorities may withdraw product approvals or request product recalls if a company fails to comply with required regulatory standards, if it encounters problems following initial marketing, or if previously unrecognized problems are subsequently discovered.
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Once an approval is granted, the FDA may withdraw the approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market. Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information, imposition of post-market studies or clinical trials to assess new safety risks or imposition of distribution or other restrictions under a REMS program. Other potential consequences include, among other things:
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restrictions on the marketing or manufacturing of the product, suspension of the approval, complete withdrawal of the product from the market or product recalls;
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fines, warning or other enforcement-related letters or holds on ongoing or planned clinical trials;
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refusal of the FDA to approve pending BLAs or supplements to approved BLAs, or suspension or revocation of product approvals or licenses;
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consent decrees, corporate integrity agreements, debarment or exclusion from federal healthcare programs;
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the issuance of safety alerts, Dear Healthcare Provider letters, press releases and other communications containing warnings or other safety information about the product;
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product seizure or detention, or refusal to permit the import or export of products; or
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injunctions or the imposition of civil or criminal penalties.
U.S. marketing exclusivity
The Biologics Price Competition and Innovation Act of 2009 (BPCIA) created an abbreviated approval pathway for biological products shown to be biosimilar to, or interchangeable with, an FDA-licensed reference biological product. Biosimilarity, which requires that the biological product be highly similar to the reference product notwithstanding minor differences in clinically inactive components and that there be no clinically meaningful differences between the biological product and the reference product in terms of safety, purity and potency, can be shown through analytical studies, animal studies and a clinical trial or trials. Interchangeability requires that a biological product be biosimilar to the reference product and that the product can be expected to produce the same clinical results as the reference product in any given patient and, for products administered multiple times to an individual, that the product and the reference product may be alternated or switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biological product without such alternation or switch.
A reference biological product is granted 12 years of data exclusivity from the time of first licensure of the product and the FDA will not accept an application for a biosimilar or interchangeable product based on the reference biological product until four years after the date of first licensure of the reference product. “First licensure” typically means the initial date the particular product at issue was licensed in the United States. Date of first licensure does not include the date of licensure of (and a new period of exclusivity is not available for) a biological product if the licensure is for a supplement for the biological product or for a subsequent application by the same sponsor or manufacturer of the biological product (or licensor, predecessor in interest or other related entity) for a change (not including a modification to the structure of the biological product) that results in a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device or strength, or for a modification to the structure of the biological product that does not result in a change in safety, purity or potency.
Regulatory approval in the European Union
To market any product in the EU, we would need to comply with numerous and varying regulatory requirements regarding safety and efficacy and governing, among other things, clinical trials, marketing authorization, commercial sales and distribution of our products.
The process regarding approval of medicinal products in the EU follows roughly the same lines as in the United States and likewise generally involves satisfactorily completing each of the following:
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preclinical laboratory tests, animal studies and formulation studies all performed in accordance with the applicable EU GLP requirements;
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submission of a single clinical trial application (CTA) through the Clinical Trials Information System (CTIS) to the relevant national authorities of the member states of the EU (EU Member States) in which a clinical trial is planned to be conducted, which must be approved by such national authorities and the subject of a positive opinion from at least one independent ethics committee before the trial may begin in each country where the clinical trial is planned;
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performance of adequate and well-controlled clinical trials to establish the safety and efficacy of the product for each proposed indication;
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submission to the relevant competent authorities of a marketing authorization application which includes the data supporting safety and efficacy as well as detailed information on the manufacture and composition of the product in clinical development and proposed labeling;
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satisfactory completion of an inspection by the relevant competent national authorities of EU Member States of the manufacturing facility or facilities, including those of third parties, at which the product is produced to assess compliance with strictly enforced EU Good Manufacturing Practice (GMP);
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potential audits of the non-clinical and clinical trial sites that generated the data in support of the marketing authorization application; and
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review and approval by the relevant competent authority of the marketing authorization application before any commercial marketing, sale or shipment of the product.
Whether or not we obtain FDA approval for a product, we must obtain approval of the product by the EU regulatory authorities before we can commence clinical trials or marketing of the product in the EU. Approval by one regulatory authority does not ensure approval by regulatory authorities in other jurisdictions. The approval process varies from country to country, can involve additional testing beyond that required by FDA, and may be longer or shorter than that required for FDA approval. The requirements governing the conduct of clinical trials, product licensing, pricing, promotion, and reimbursement vary greatly from country to country.
Non-clinical studies
Similarly to the United States, the various phases of non-clinical and clinical research in the EU are subject to significant regulatory controls. Non-clinical studies are performed to demonstrate the health or environmental safety of new chemical or biological substances. Non-clinical (pharmaco-toxicological) studies must be conducted in compliance with the principles of GLP, as set forth in EU Directive 2004/10/EC (unless otherwise justified for certain particular medicinal products, e.g., radio-pharmaceutical precursors for radio-labeling purposes). In particular, non-clinical studies, both in vitro and in vivo, must be planned, performed, monitored, recorded, reported and archived in accordance with the GLP principles, which define a set of rules and criteria for a quality system for the organizational process and the conditions for non-clinical studies. These GLP standards reflect the Organization for Economic Co-operation and Development requirements. The results of the non-clinical studies, together with relevant manufacturing information and analytical data, are submitted as part of the CTA.
Clinical trials
Clinical trials of medicinal products in the EU must be conducted in accordance with EU and national regulations and the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use, guidelines on GCP, as well as the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki. If the sponsor of the clinical trial is not established within the EU, it must appoint an EU entity to act as its legal representative. The sponsor must take out a clinical trial insurance policy, and in most EU Member States, the sponsor is liable to provide ‘no fault’ compensation to any study subject injured in the clinical trial.
The regulatory landscape related to clinical trials in the EU has been subject to recent changes. The EU Clinical Trials Regulation No. 536/2014 (CTR), which was adopted in April 2014, entered into application on January 31, 2022, repealing and replacing the former Clinical Trials Directive 2001/20 (CTD).