UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 10-K
(Mark One)
☒ANNUAL REPORT PURSUANT TO SECTION 13
OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
For the fiscal year ended December 31, 2025
OR
☐TRANSITION REPORT PURSUANT TO SECTION
13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
FOR THE TRANSITION PERIOD FROM TO
Commission File Number 000-22873
Oruka Therapeutics, Inc.
(Exact name of Registrant as specified in its
Charter)
855 Oak Grove Avenue Suite 100 Menlo Park, California 94025
(Address of principal executive offices) (Zip Code)
Registrant’s telephone number, including
area code: (650)606-7910
Securities registered pursuant to Section 12(b)
of the Act:
Title of Each Class Trading Symbol(s) Name of Each Exchange on Which Registered
Common Stock, par value $0.001 per share ORKA The Nasdaq Global Market
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 voting and non-voting
common equity held by non-affiliates of the Registrant as of June 30, 2025, was approximately $371.5 million based on the closing price
of the Registrant’s shares of common stock on The Nasdaq Capital Market on such date.
The number of shares of the Registrant’s
common stock outstanding as of February 28, 2026 was 49,542,691.
Table of Contents
Page
PART I
Item 1. Business 1
Item 1A. Risk Factors 37
Item 1B. Unresolved Staff Comments 65
Item 1C. Cybersecurity 65
Item 2. Properties 65
Item 3. Legal Proceedings 65
Item 4. Mine Safety Disclosures 65
PART II
Item 6. [Reserved] 66
Item 7A. Quantitative and Qualitative Disclosures About Market Risk 78
Item 8. Financial Statements and Supplementary Data 79
Item 9A. Controls and Procedures 110
Item 9B. Other Information 111
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 111
PART III
Item 10. Directors, Executive Officers and Corporate Governance 112
Item 11. Executive Compensation 112
Item 14. Principal Accounting Fees and Services 112
PART IV
Item 15. Exhibits, Financial Statement Schedules 113
i
SPECIAL NOTE REGARDING FORWARD-LOOKING STATEMENTS
This Annual Report on Form
10-K, or Annual Report, contains “forward-looking statements” within the meaning of Section 27A of the Securities Act of 1933,
as amended, and Section 21E of the Securities Exchange Act of 1934, as amended (the “Exchange Act”). These forward-looking
statements reflect the current views of Oruka Therapeutics, Inc. (“Oruka”, the “Company”, “we”, or
“us”) with respect to future events and are based on assumptions and subject to known and unknown risks and uncertainties
and other factors that may cause our actual results, performance, time frames or achievements to be materially different from any future
results, performance, time frames or achievements expressed or implied by the forward-looking statements. Factors that might cause such
a difference are disclosed in the section titled “Risk Factors” in this Annual Report. We caution readers that any forward-looking
statement is not a guarantee of future performance and that actual results could differ materially from those contained in the forward-looking
statement. These statements are based on current expectations of future events. You should evaluate all forward-looking statements made
in this Annual Report in the context of these risks and uncertainties. We caution you that the risks, uncertainties and other factors
referred to in this Annual Report may not contain all of the risks, uncertainties and other factors that may affect our future results
and operations. Moreover, we operate in a very competitive and rapidly changing environment, and new risks and uncertainties emerge from
time to time.
All statements, other than
statements of historical facts contained in this Annual Report, including, without limitation, statements regarding: our future results
of operations and financial position, business strategy, the length of time that we believe our existing cash resources will fund our
operations, our market size, our competition, our potential growth opportunities, our clinical development activities and timeline, the
efficacy and safety profile of our product candidates, the potential therapeutic benefits and economic value of our product candidates,
the timing and results of preclinical studies and clinical trials, the expected impact of macroeconomic conditions, including inflation,
increasing interest rates and volatile market conditions, current or potential bank failures, as well as global events, including military
conflicts and geopolitical tensions on our operations, and the receipt and timing of potential regulatory designations, approvals and
commercialization of product candidates, are forward-looking statements. The words “believe,” “may,” “will,”
“potentially,” “estimate,” “continue,” “anticipate,” “predict,” “target,”
“intend,” “could,” “would,” “should,” “project,” “plan,” “expect,”
and similar expressions that convey uncertainty of future events or outcomes are intended to identify forward-looking statements, although
not all forward-looking statements contain these identifying words. These forward-looking statements are based on information available
to us as of the date of this Annual Report and are subject to a number of risks, uncertainties and assumptions, including those described
in Item 1A, “Risk Factors” and elsewhere in this Annual Report. Moreover, we operate in a very competitive and rapidly changing
environment, and 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. In light of these risks, uncertainties, and assumptions,
the forward-looking events and circumstances discussed in this Annual Report may not occur and actual results could differ materially
and adversely from those anticipated or implied in the forward-looking statements. While we believe that such information provides a reasonable
basis for these statements, such information may be limited or incomplete. Our statements should not be read to indicate that we have
conducted an exhaustive inquiry into, or review of, all relevant information. These statements are inherently uncertain, and investors
are cautioned not to unduly rely on these statements.
All subsequent written or
oral forward-looking statements attributable to us or any person acting on our behalf are expressly qualified in their entirety by the
cautionary statements contained or referred to in this section. We do not undertake any obligation to release publicly any revisions to
these forward-looking statements to reflect events or circumstances after the date of this Annual Report or to reflect the occurrence
of unanticipated events, except as may be required under applicable U.S. securities laws. You should read this Annual Report with the
understanding that our actual future results, levels of activity, performance and events and circumstances may be materially different
from what we expect. If we do update one or more forward-looking statements, no inference should be drawn that we will make additional
updates with respect to those or other forward-looking statements.
Unless the context indicates
otherwise, as used in this Annual Report, the terms “Oruka,” “ARCA biopharma, Inc.,” “the Company,”
“we,” “us,” and “our” refer to Oruka Therapeutics, Inc., a Delaware corporation, and its consolidated
subsidiary taken as a whole. “Oruka” and all product candidate names are our common law trademarks. This Annual Report contains
additional trade names, trademarks and service marks of other companies, which are the property of their respective owners. We do not
intend our use or display of other companies’ trade names, trademarks or service marks to imply a relationship with, or endorsement
or sponsorship of us by, these other companies.
ii
PART I
Item 1. Business.
Acquisition of Pre-Merger Oruka
On August 29, 2024 (the “Merger
Closing”), we completed our acquisition (the “Merger”) of Oruka Therapeutics, Inc. (“Pre-Merger Oruka”)
pursuant to an Agreement and Plan of Merger and Reorganization, dated as of April 3, 2024 (the “Merger Agreement”). Following
the transactions contemplated by the Merger Agreement, Pre-Merger Oruka merged with and into Atlas Merger Sub Corp., a wholly owned subsidiary
of ARCA biopharma, Inc. (“ARCA”) and following that, Pre-Merger Oruka then merged with and into Atlas Merger Sub II, LLC (“Second
Merger Sub”), with Second Merger Sub being the surviving entity. Second Merger Sub changed its corporate name to “Oruka Therapeutics
Operating Company, LLC”. Pre-Merger Oruka was a pre-clinical stage biotechnology company that was incorporated on February 6, 2024
under the direction of Peter Harwin, a Founding Partner at Fairmount Funds Management LLC (“Fairmount”), for the purposes
of holding rights to certain intellectual property being developed by Paragon Therapeutics, Inc. (“Paragon”). On August 29,
2024, we changed our name from “ARCA biopharma, Inc.” (“ARCA”) to “Oruka Therapeutics, Inc.” and our
Nasdaq ticker symbol from “ABIO” to “ORKA”.
Company Overview
We are a clinical-stage biopharmaceutical
company focused on developing novel monoclonal antibody therapeutics for psoriasis (“PsO”) and other inflammatory and immunology
(“I&I”) indications. Our name is derived from or, for “skin,” and arukah, for “restoration,”
and reflects our mission to deliver therapies for chronic skin diseases that provide patients the most possible freedom from their condition.
Our strategy is to apply antibody engineering and format innovations to validated modes of action, which we believe will enable us to
improve meaningfully upon the efficacy and dosing regimens of standard-of-care medicines while significantly reducing technical and biological
risk. Our programs aim to treat and potentially modify disease by targeting mechanisms with proven efficacy and safety involved in disease
pathology and the activity of pathogenic tissue-resident memory T cells (“TRMs”).
Our
lead program, ORKA-001, is designed to target the p19 subunit of interleukin-23 (“IL-23p19”) for the treatment of PsO. Our
co-lead program, ORKA-002, is designed to target interleukin-17A and interleukin-17F (“IL-17A/F”) for the treatment of PsO,
hidradenitis suppurativa (“HS”), psoriatic arthritis (“PsA”), and other conditions. The product candidates in
these programs each bind their respective targets at high affinity and incorporate half-life extension technology with the aim to increase
exposure and decrease dosing frequency. We believe that our focused strategy, differentiated portfolio, and deep expertise position us
to set a new treatment standard in large I&I markets with continued unmet need.
Our Portfolio and Development Plans
1
ORKA-001
ORKA-001 is a high affinity,
extended half-life monoclonal antibody (“mAb”) designed to target IL-23p19. IL-23 is a pro-inflammatory cytokine that plays
a critical role in the proliferation and development of T helper 17 (“Th17”) cells, which are the primary drivers of several
autoimmune and inflammatory disorders, including PsO. IL-23 is composed of two subunits: a p40 subunit that is shared with IL-12 and a
p19 subunit that is specific to IL-23. First-generation IL-23 antibodies bound p40 and inhibited both IL-12 and IL-23 signaling, while
more recent IL-23 antibodies targeting the p19 subunit have shown improved efficacy and safety. Based on clinical evidence, we believe
that ORKA-001 could achieve higher response rates than established therapies in PsO while requiring less frequent dosing and maintaining
the favorable safety profile of therapies targeting IL-23p19.
ORKA-001 is engineered with
YTE half-life extension technology, a specific three amino acid change in the fragment crystallizable (“Fc”) domain to modify
the pH-dependent binding to the neonatal Fc receptor (“FcRn”). As a result, it has a pharmacokinetic profile designed to support
a subcutaneous (“SQ”) injection as infrequently as once or twice per year. In addition, emerging evidence suggests that IL-23
blockade can modify the disease biology of PsO, possibly leading to durable remissions and preventing the development of PsA. We
believe that the anticipated characteristics of ORKA-001 enhance its potential to deliver these disease-modifying benefits.
We initiated a Phase 1
trial of ORKA-001 in the fourth quarter of 2024 and in September 2025, we announced the interim results at the European Academy of
Dermatology and Venereology (EADV) Congress. The data showed that ORKA-001 has a human half-life of approximately 100 days. Single
doses of ORKA-001 demonstrated complete and sustained inhibition of STAT3 signaling, a downstream marker of IL-23 activity, in an ex
vivo assay through 24 weeks. In addition, ORKA-001 was well tolerated at all dose levels, with a favorable safety profile consistent
with the anti-IL-23 class.
In the third quarter of 2025, we commenced dosing in a Phase 2a clinical trial of ORKA-001 in patients with moderate-to-severe PsO (also
known as “EVERLAST-A”). We expect to share Week 16 data for all patients in the second quarter of 2026. In addition, we plan
to share longer-term data, including Week 28 for all patients and 52-week follow-up for a portion of the cohort in the second half of
2026. EVERLAST-A enrolled 84 patients randomized 3:1 to receive 600 mg of ORKA-001 at Weeks 0 and 4 or matching placebo. The primary endpoint
is PASI 100, a 100% reduction from baseline in Psoriasis Area and Severity Index (“PASI”), at Week 16. At Week 28, patients
who have achieved PASI 100 will be randomized 2:1 to an arm where either (1) they do not receive another dose until disease recurrence
(to evaluate the possibility of both yearly dosing and extended off-treatment remissions) or (2) they receive 300 mg ORKA-001 every six
months. Patients who have not achieved PASI 100 will receive a 300 mg dose every six months.
Additionally, the first patients were dosed in EVERLAST-B in December
2025. EVERLAST-B is designed to enroll approximately 160 patients into a dose-ranging Phase 2b trial of ORKA-001 in patients with moderate-to-severe
PsO and will evaluate three dose levels of ORKA-001: 37.5 mg at Week 0, 300 mg at Weeks 0 and 4, and 600 mg at Weeks 0 and 4, versus placebo.
The primary endpoint is PASI 100 at Week 16. At Week 28, patients who have achieved PASI 100 will be re-randomized 1:1 to either a 600
mg dose once-yearly or matching placebo. Patients who have not achieved PASI 100 at Week 28 will receive a 300 mg dose every six months.
Building on EVERLAST-A, this design will further test the potential for ORKA-001 to achieve yearly dosing, higher efficacy and extended
off-treatment remissions. Data from EVERLAST-B is anticipated in 2027.
Based on recent precedent
in PsO, we anticipate that the overall development program, from first-in-human studies through biologics license application (“BLA”)
submission could take as little as six to seven years, based on averages observed for recently approved medicines. However, we have
no control over the duration of the United States Food and Drug Administration (“FDA”) review process, and the actual timeline
may vary.
ORKA-002
ORKA-002 is a high affinity, extended half-life mAb designed to target
IL-17A and IL-17F (“IL-17A/F”). IL-17 inhibition has become central to the treatment of psoriatic diseases, including PsO
and PsA, and has also shown efficacy in other I&I indications, such as HS and axial spondyloarthritis (“axSpA”). More
recently, the importance of inhibiting the IL-17F isoform along with IL-17A has become appreciated, and dual blockade with the recently
approved therapy Bimzelx (bimekizumab) has led to higher response rates in patients than blockade of IL-17A alone. ORKA-002 is designed
to bind IL-17A/F at similar epitopes, or binding sites, and affinity ranges as bimekizumab, but incorporates half-life extension technology
that could enable more convenient dosing intervals.
In January 2026, we announced
interim findings from the Phase 1 trial of ORKA-002 in healthy volunteers. The results showed that ORKA-002 has a half-life of approximately
75-80 days, which supports the potential for twice-yearly maintenance dosing in PsO and quarterly maintenance dosing in HS. Single doses
of ORKA-002 demonstrated potent and sustained inhibition of IL-17 signaling in an ex vivo assay through 24 weeks. ORKA-002 was well tolerated
at all dose levels, with a favorable safety profile consistent with the anti-IL-17 class. The trial remains blinded, and as of January 6, 2026, which was the data cutoff date, all subjects remained on trial.
Based on these Phase 1
results, we initiated ORCA-SURGE, a Phase 2 trial of ORKA-002 in patients with moderate-to-severe PsO, in February 2026. ORCA-SURGE
is designed to enroll approximately 160 patients randomized 1:1:1:1 to receive 40 mg, 160 mg or 320 mg of ORKA-002 at Weeks 0 and 4,
or matching placebo. The primary endpoint is PASI 100 at Week 16. Maintenance dosing will evaluate the potential for twice-yearly
dosing with ORKA-002. Data from ORCA-SURGE is anticipated in 2027. Moreover, we also expect to initiate a Phase 2 trial of ORKA-002
in patients with HS in the second half of 2026.
2
We view ORKA-002 and ORKA-001
as highly complementary. Patients with moderate-to-severe PsO that have purely skin manifestations are most often treated with IL-23 inhibitors
due to the high efficacy and tolerability of this mechanism. However, for patients who also have joint involvement or signs and symptoms
of PsA, an IL-17 inhibitor is typically used due to its efficacy in addressing both skin and joint symptoms. In addition, IL-17 inhibitors
are often used in patients with highly resistant skin symptoms that do not adequately resolve through treatment with an IL-23 inhibitor.
Furthermore, we plan to pursue a sequential combination regimen of ORKA-002 followed by ORKA-001, called ORKA-021. ORKA-021 has the potential
to combine the rapid response of an IL-17 inhibitor with the superior maintenance profile of an IL-23 inhibitor in a single regimen. We
believe that ORKA-001 and ORKA-002 provide the potential to offer a highly compelling product profile for most patients with PsO and/or
PsA, as well as the opportunity to address additional I&I indications.
Additional Pipeline Program
We have a third program,
ORKA-003, designed to target an undisclosed pathway. Our strategy as a company is to remain highly focused on I&I diseases, and
specifically on inflammatory dermatology conditions. Our third program provides the potential for indication expansion beyond PsO and
may create combination opportunities with our more advanced programs.
Our Team, Investors, and Paragon Collaboration
We are led by a management
team with significant experience in developing novel treatments for patients at biopharmaceutical companies such as CRISPR Therapeutics,
Celgene, Novartis, CymaBay Therapeutics and Protagonist Therapeutics. Together, our team has a proven track record of building successful
biotech organizations in high-growth environments.
Pre-Merger Oruka was founded
in February 2024 by leading healthcare investor Fairmount. Fairmount founded Paragon in 2021 to conduct biologics discovery and
optimization, including acting as the firm’s discovery engine for biologics that potentially overcome limitations of existing therapies.
We have entered into license agreements with Paragon pursuant to which Paragon granted us a royalty-bearing, world-wide, exclusive license
to develop, manufacture, commercialize or otherwise exploit certain antibodies and products targeting IL-23 outside of the field of inflammatory
bowel disease for ORKA-001 and for ORKA-002, certain antibodies and products targeting IL-17A/F in all fields.
Our Strategy
To achieve our goal of developing
leading therapeutic antibodies for patients with inflammatory skin diseases, we are applying antibody engineering to validated modes of
action. We believe this approach will enable us to improve meaningfully upon the efficacy and convenience of standard-of-care medicines
while significantly reducing technical and biological risk. The key elements of our strategy include:
3
We believe that pursuing
the focused strategy outlined above will help us to succeed in our mission of offering patients living with PsO, PsA, and other dermatologic
and inflammatory diseases the greatest possible freedom from their condition.
Targeting IL-23 and IL-17 to Treat Multiple I&I
Indications
Our programs benefit
from significant advances in the understanding of the biology of I&I diseases over the past four decades. ORKA-001 and
ORKA-002 are designed to target two key cytokines that play a related role in multiple indications. IL-23 is an upstream regulator
of Th17 cells, a pro-inflammatory subset of T helper cells characterized by their production of IL-17. IL-23 has a critical role in
maintaining Th17 cells in the tissue as well as activating these cells to secrete IL-17, which acts downstream to trigger
inflammation and other disease symptoms. Th17 cells are involved in PsO, HS, PsA, axSpA, and many other diseases. They play a
particularly central role in PsO and PsA. The diagram below depicting the immunopathogenesis of PsO provides an example of how Th17
cells can mediate disease and how blocking IL-23 or IL-17 can break the inflammatory cycle that drives disease.
4
Immunopathogenesis of PsO and the role of IL-23
and IL-17
PsO develops when environmental
triggers and a genetic predisposition combine to cause activation of an inflammatory cycle in the skin that leads to the formation of
plaques and other disease manifestations. This process begins with the aberrant activation of the dendritic cells (“DCs”),
specifically those producing IL-23 and other cytokines like IL-1β, IL-21, TNF-α, and IL-12. These cytokines induce the differentiation
of Th17 cells, as well as other cell types, such as T helper type 1 (“Th1”) cells that produce IFNγ and TNF-α
and T helper type 22 (“Th22”) cells that produce IL-22. IL-23 plays a key role in the differentiation and activation of Th17
cells to secrete IL-17, as well as Th22 cells to produce IL-22. IL-17 and these other cytokines induce keratinocyte hyperproliferation
leading to plaque formation and a feedforward inflammatory response, with changes in gene expression in keratinocytes, the production
of antimicrobial peptides, and neutrophil recruitment driving further inflammation. While many cytokines and cell types contribute to
the pathogenesis of PsO, the IL-23/IL-17 axis plays an important role, as supported by the success of therapies targeting this axis.
While the successful treatment
of PsO — for instance, with mAbs targeting IL-23 or IL-17 — can result in lesional skin returning to an apparently
normal state, disease tends to recur at previously affected sites following cessation of therapy, suggesting a mechanism of “immunological
memory” that predisposes individuals to recurrence in the same locations. Evidence suggests that pathogenic TRMs play a critical
role in this memory. TRMs may arise from the Th17 cells and other cells that drove disease in the first place and remain in their resident
tissue, in this case the epidermis and dermis, for long periods of time. Upon a disease trigger, these TRMs can actively produce proinflammatory
cytokines, causing disease recurrence. IL-23 appears to play an important role in maintaining and potentiating TRMs, as indicated by the
depletion of TRMs following treatment with an IL-23 inhibitor but not an IL-17 inhibitor, which may explain the longer remissions observed
with IL-23 inhibitors following withdrawal of therapy. This type of data has raised the prospect that efficient IL-23 blockade could modify
the disease biology of PsO, possibly leading to durable remissions.
5
The scientific discoveries
that refined our understanding of the immunopathogenesis of PsO have led to waves of therapeutic advances, ultimately leading to today’s
standard of care. Before the 1980s, PsO was not even thought of as an immunologic disease, but rather a disease of keratinocyte dysfunction,
leading to treatments such as phototherapy, methotrexate, and retinoids. The discovery in the 1980s that PsO results from immune dysfunction
led to the use of broad immunosuppressants like cyclosporine. From 1990 to 2008, it was believed that Th1 cells were the predominant mediators
of the disease, which led to the use of biologics targeting TNF-α such as Enbrel (etanercept) and Humira (adalimumab). Finally,
the revelation that PsO is driven principally by Th17 cells resulted in the development of the primary therapies used today, which target
IL-23 and IL-17. This increasingly refined understanding of the disease has narrowed the standard of care from broad immunosuppressive
agents (such as cyclosporine) to more specific immunomodulators (TNF-α inhibitors) to precise biologic therapies targeting the key
cytokines involved in disease pathology (IL-23 and IL-17 inhibitors), with each new therapeutic class raising the bar on both safety and
efficacy.
Biologic therapies, especially
mAbs, are now mainstays in the treatment of a wide variety of I&I diseases, including PsO and PsA. Therapies that have improved
upon efficacy and/or reduced dosing frequency have achieved the most commercial success, even when launched many years after other
biologics. Enbrel was first approved for PsO in 2004 with a weekly maintenance dosing schedule. Four years later, Humira was approved
for PsO with an every-other-week (Q2W) dosing schedule. Stelara (ustekinumab) was approved a year later with similar Phase 3 data
to Humira, but with a significantly improved dosing schedule of every twelve weeks (Q12W). Several drugs for PsO have been approved
since 2009 that demonstrated higher efficacy in their pivotal studies compared to Stelara, but with more burdensome dosing schedules,
including Tremfya (guselkumab), which has a dosing schedule of every eight weeks (Q8W), and Cosentyx (secukinumab) and Taltz (ixekizumab),
which have dosing schedules of every four weeks (Q4W). While these therapies have all become generally successful products, the most
commercially successful drug in the PsO market today is Skyrizi (risankizumab), which combines Stelara’s Q12W dosing schedule with
improvements in efficacy, as evidenced by a higher PASI score of PASI 90 and PASI 100 rates (i.e., a 90%
improvement in PASI score and a 100% improvement in PASI score (complete clearance), respectively) in clinical trials. In addition, Bimzelx
(bimekizumab), approved by the FDA in 2023, has shown evidence of efficacy that exceeds even Skyrizi, though with a less convenient Q8W
dosing schedule. Although many biologics have entered the PsO market over the past two decades, new entrants have had significant commercial
success when they have improved upon efficacy and/or dosing frequency, and room remains to improve in both areas to set a new standard
for the treatment of PsO.
Biologics have raised the bar on the standard
of care in PsO, but leave room for improvement
The biology driving PsO and
PsA is well understood today, and the standard of care has progressed dramatically. We believe that it is unlikely that a novel mechanism
will emerge that is as safe and efficacious as targeting the IL-23/IL-17 axis. Therefore, we believe that innovation now should be focused
on optimizing the product profile that can be offered to patients. While much effort is being directed toward daily oral formats to inhibit
this axis, oral medicines have yet to match the efficacy of biologics. We believe that a better biologic with a longer dosing interval
and the potential for improved efficacy will present a more attractive product profile for most patients.
6
Overview of Psoriasis (PsO)
PsO is a chronic autoimmune skin disorder that affects an estimated
125 million people worldwide with steadily increasing prevalence, estimated to be around 2 – 3% of the population
currently, according to the International Federation of Psoriasis Associations (“IFPA”). It is the largest pharmaceutical
market within dermatology, with annual global sales of approximately $28 billion in 2024, which is estimated to grow to approximately
$40 billion by 2032. The most common form of PsO is plaque psoriasis. Patients with chronic plaque psoriasis have well-demarcated,
erythematous plaques with overlying, coarse, silvery-scaled patches. These plaques can occur anywhere on the body, though are typically
found on the scalp, extensor areas of the knees and elbows, and gluteal cleft. Involvement of the palms, soles, or nails, and intertriginous
areas, including the genitals, can also occur and can be particularly difficult to treat. Between one-quarter and one-half of PsO patients
have moderate disease, defined as having 3% to 10% of the body surface area (“BSA”) involved, or severe disease, defined as
having more than 10% BSA involvement. The chronic inflammation in PsO is associated with multiple comorbidities, including PsA, obesity,
metabolic syndrome, hypertension, diabetes, and atherosclerotic cardiovascular disease.
As discussed earlier, PsO
is a complex immune-mediated disease driven primarily by Th17 cells and the cytokines IL-23 and IL-17. The interplay of environmental
and behavioral risk factors and genetics is believed to trigger PsO. Multiple lines of evidence support a genetic component to the
disease, including the observation that approximately 40% of patients with PsO and PsA have a family history of the disease and the identification
of multiple susceptibility loci, many containing genes related to the regulation of the immune system, in genome-wide association studies.
Current PsO Treatments and Limitations
While patients with mild
PsO typically rely on topical corticosteroids or oral therapies like Otezla (apremilast), these agents often do not provide an adequate
response for patients with moderate-to-severe PsO. As a result, the American Academy of Dermatology-National Psoriasis Foundation
recommends biologics as first-line therapy for moderate-to-severe PsO.
Several classes of biologic
therapies have been approved for PsO over the past 20 years, resulting in progressively more complete symptom relief. Efficacy in
PsO is typically measured via the PASI scoring system. The first biologics approved for PsO were tumor necrosis alpha (“TNF-α”)
inhibitors such as Enbrel (etanercept), Humira (adalimumab), and Remicade (infliximab), which achieved a PASI score of PASI 90 at 16 weeks
in around 25 – 50% of patients and a PASI score of PASI 100 in around 5 – 20% of patients. Stelara
(ustekinumab), which targets the p40 subunit of IL-23 that is shared with IL-12, was approved next and achieved efficacy on par with Humira.
IL-17 inhibitors Cosentyx (secukinumab), Taltz (ixekizumab), and Siliq (brodalumab) followed and achieved responses of PASI 90 in around 70%
of patients and PASI 100 in around 40% of patients with some risk of certain side effects such as oral candidiasis. Most recently,
IL-23p19 inhibitors such as Ilumya (tildrakizumab), Tremfya (guselkumab), and Skyrizi (risankizumab) have achieved responses of PASI 90
in around 70 – 80% of patients and PASI 100 in around 30 – 50% of patients with highly tolerable
profiles. Finally, IL-17A/F inhibitors such as Bimzelx (bimekizumab) have recently shown even higher response rates than IL-23 inhibitors,
but with slightly less tolerable profiles.
Treatment expectations in
PsO have evolved progressively with this continued innovation. A 75% improvement in PASI score was previously thought to be an adequate
depth of response, and weekly SQ dosing was viewed as acceptable. With each subsequent generation of innovation, patient and caregiver
expectations have advanced. Today, Skyrizi (risankizumab) is widely viewed as the leader in PsO biologic therapy. In Phase 3 clinical
trials, 43% and 58% of patients achieved PASI 100 at 16 and 52 weeks, respectively, with SQ maintenance dosing every three months.
Most recently, Bimzelx (bimekizumab) has shown evidence of efficacy that exceeds even Skyrizi, achieving a 64% PASI 100 rate at 16 weeks
in Phase 3 trials. However, the increased efficacy comes with a less convenient Q8W dosing schedule and an increased risk of certain
side effects, most notably oral candidiasis. While agents like Skyrizi and Bimzelx reflect the remarkable advancement in PsO treatment,
there remains significant unmet need. Approximately half of moderate-to-severe PsO patients do not achieve full skin clarity, and while
early signs are present, the promise of disease modifying therapy remains unrealized. In addition, a continued desire for more convenient
dosing options has driven significant interest in orally delivered medicines targeting these same pathways. However, oral therapies have
yet to match the efficacy and safety profile of biologics. We believe that ORKA-001 and ORKA-002 could represent the next step in biologic
innovation in PsO, with the potential for higher rates of complete skin clearance, more durable remissions, and markedly more convenient
dosing regimens.
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Overview of Hidradenitis Suppurativa (“HS”)
HS is a chronic inflammatory
skin disease characterized by deep-seated nodules and abscesses, draining sinus tracts, and fibrotic scarring that most commonly occur
in intertriginous areas, such as the axillae and groin. Due to the associated pain, sensitive anatomical locations, drainage, odor, scarring,
and recurrent disease flares, HS can have a substantial negative psychosocial impact across many areas of life, including interpersonal
relationships, education, and employment.
HS is believed to be underdiagnosed
and may have a prevalence exceeding 1% worldwide. Significant delays between symptom onset and diagnosis are common; an average delay
of 7–10 years has been reported, with some patients waiting more than 20 years for diagnosis. This compares to an average time to
diagnosis of approximately 1.6 years for psoriasis. Delayed diagnosis has been associated with worsening disease severity, progression,
and an increased burden of comorbidities, potentially due to delays in receiving appropriate anti-inflammatory treatment.
Current HS Treatments and Limitations
The overall treatment goals
for HS include alleviating lesion-related symptoms (e.g., pain), reducing the frequency and severity of disease flares, limiting the formation
of new inflammatory lesions, and preventing disease progression and associated comorbidities. Treatment varies depending on disease severity
and may include topical and systemic antibiotics, hormone therapy, immunomodulators, and surgical interventions. Humira (adalimumab) was
the only FDA-approved medication for the treatment of moderate-to-severe HS from its approval in 2015 until the approval of Cosentyx (secukinumab)
in October 2023 and Bimzelx (bimekizumab) in November 2024.
The hidradenitis suppurativa
clinical response (HiSCR) outcome measure is currently considered the standard primary endpoint for the assessment of new pharmacologic
interventions in HS clinical trials. HiSCR50, HiSCR75, and HiSCR90 are defined as at least a 50%, 75%, or 90% reduction from baseline
in the total abscess and inflammatory nodule count, with no increase from baseline in abscess or draining tunnel count. A recent network
meta-analysis comparing approved biologics for moderate-to-severe HS found that Bimzelx (bimekizumab) ranked highest across HiSCR efficacy
endpoints. In Phase 3 studies, Bimzelx (bimekizumab) demonstrated placebo-adjusted HiSCR50/75 rates of 18–20%, and 15–20%,
respectively, at Week 16 with Q2W dosing.
In addition to currently
approved therapies, multiple biologic and oral agents targeting a range of inflammatory pathways are advancing through clinical development
for HS. These investigational therapies span diverse mechanisms of action and several have demonstrated encouraging efficacy signals in
Phase 2 clinical trials. However, currently approved therapies and late-stage investigational agents are typically administered on weekly,
bi-weekly, or monthly dosing schedules, and a substantial proportion of patients continue to experience inadequate or incomplete disease
control. These factors underscore the ongoing unmet need for more effective, durable, and more conveniently administered treatment options.
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Overview of Psoriatic Arthritis (PsA)
PsA is a chronic inflammatory
condition that affects both the skin and joints, and often coexists with PsO. Around a quarter to a third of patients with moderate-to-severe
PsO also have PsA. Most individuals develop PsO before being diagnosed with PsA, with a median gap of seven to eight years between
the diagnosis of skin and joint disease, though in up to 30% of patients with PsA, joint symptoms appear before or simultaneously with
skin manifestations. Patients with PsA present with joint pain, stiffness, and swelling affecting the peripheral joints, axial skeleton,
or both. Enthesitis, dactylitis, nail lesions, fatigue, and ocular inflammation all occur commonly. PsA can lead to irreversible joint
damage, including bony fusion across a joint (ankylosis). The pathogenesis of PsA is likely to be closely related to the mechanisms that
underlie PsO. Like PsO, the exact cause of PsA remains unknown, but environmental triggers, including infection and trauma, and genetic
factors play a role.
Current PsA Treatments and Limitations
Effective treatment of PsA
requires a coordinated approach to address the unique combination of disease manifestations each patient has, which can include peripheral
and axial arthritis, enthesitis, dactylitis, and skin and nail involvement. Many patients with milder disease symptoms will start with
nonsteroidal anti-inflammatory drugs (“NSAIDs”) and/or local treatments to address specific disease manifestations. However,
those with more moderate or severe disease and/or multidomain involvement will typically receive a biologic therapy targeting TNF-α
or IL-17, or less commonly an oral Janus kinase (“JAK”) inhibitor. Comorbid conditions can also influence treatment selection.
For example, an IL-17 inhibitor would be preferred for a patient with significant skin involvement, but not for patients with IBD or ocular
symptoms, where a TNF-α inhibitor would be preferred. The most common endpoint used to measure the efficacy of TNF-α or IL-17
inhibitors in PsA is ACR response, or the proportion of patients achieving a specified percent improvement in American College of Rheumatology
(“ACR”) score, which measures peripheral joint disease. Approved TNF-α inhibitors, including Humira (adalimumab) and
Cimzia (certolizumab), achieved a placebo-adjusted ACR50 response of around 30 – 35% at 24 weeks with Q2W dosing.
Approved IL-17 inhibitors, including Cosentyx (secukinumab) and Taltz (ixekizumab), achieved a slightly lower placebo-adjusted ACR50 response
of around 25 – 30% at 24 weeks, but with more convenient Q4W dosing. Bimzelx (bimekizumab), which was recently
approved in the United States for PsA, achieved a placebo-adjusted ACR50 response of approximately 35% at 16 weeks with Q4W
dosing. A significant fraction of patients with PsA still do not achieve a satisfactory response with available therapies, and even the
most convenient regimens require monthly SQ dosing.
Overview of additional opportunities
In addition to PsO, HS, and PsA, inhibition of IL-23 or IL-17 has demonstrated
efficacy in a number of additional I&I indications, such as axSpA.
axSpA is a chronic inflammatory
disease that primarily affects the spine and sacroiliac joints that comprise the axial skeleton. The disease causes severe pain, stiffness,
and fatigue, and can have additional clinical manifestations like uveitis, enthesitis, peripheral arthritis, and PsO. Patients with
axSpA may develop further structural damage in their spine, which can lead to the fusion of vertebra (spinal ankylosis), which has a massive
negative impact on mobility, physical function, and quality of life. The overall prevalence of axSpA is estimated to be around 1% in the
United States. Treatment of axSpA starts with physical therapy and NSAIDs. If patients do not have an adequate response to NSAIDs,
a TNF-α inhibitor is typically used, followed by an IL-17 inhibitor, such as Cosentyx (secukinumab), Taltz (ixekizumab), or Bimzelx
(bimekizumab), or less frequently a JAK inhibitor. Patients often need to cycle through therapies over time due to inadequate responses
or loss of response.
Our Solution: Half-Life Extension and Antibody
Engineering Technologies
Our antibody engineering
campaigns are designed to optimize multiple attributes in parallel: binding affinity, potency in a variety of assays, developability,
and consistently extended serum half-life in non-human primates (“NHPs”). Half-life extension is possible by modifying the
pH-dependent binding affinity of the antibody Fc domain for FcRn. A primary mechanism of elimination of antibodies from the serum is through
pinocytosis and degradation in the lysosomes of cells. Throughout this process, antibodies can be recycled back into the serum by binding
to FcRn while they are in endosomes. The interior of the endosome is acidic, and therefore the efficiency of this recycling process depends
on the ability of the antibody Fc domain to bind to FcRn at low pH. If this low pH binding is efficient enough, antibody recycling
can be favored over degradation, potentially resulting in a much longer serum half-life.
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Antibody engineers have discovered methods of modifying the Fc domain
to optimize the efficiency of recycling via FcRn binding. Several engineering strategies have been identified over the past two decades,
with the so-called “YTE” mutations (M252Y/S254T/T256E) and “LS” mutations (M428L/N434S) being the most frequently
used. Importantly, while these strategies have been known for some time, it was only relatively recently that enough clinical precedent
was established to provide confidence in how these mutations perform in humans. Three products incorporating YTE or LS modifications are
currently approved by the FDA, Beyfortus (nirsevimab), Exdensur (depemokimab), and Ultomiris (ravulizumab), and several more candidates
are in clinical trials. Based on clinical data in humans, antibodies with YTE mutations typically have a half-life that is two to four
times longer than wildtype antibodies.
ORKA-001
Summary
ORKA-001 is a high affinity,
extended half-life mAb designed to target the p19 subunit of IL-23. Based on both preclinical and clinical data generated to date, we
believe ORKA-001 has the potential to become the leading IL-23 inhibitor and achieve an optimal product profile in PsO consisting of the
following:
We believe that this target
profile for ORKA-001 could offer improved freedom from disease to many patients affected by PsO and represent a step forward in the standard
of care.
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Clinical Development
We dosed the first
participants in a Phase 1 clinical trial of ORKA-001 in healthy volunteers in the fourth quarter of 2024. This trial is a
double-blind, placebo-controlled, single ascending dose study evaluating the safety, tolerability, and pharmacokinetics of ORKA-001
in healthy volunteers. The trial enrolled 24 healthy adult participants into three single ascending subcutaneous dose cohorts of 300
mg, 600 mg, and 1200 mg. In September 2025, we announced the interim results at the European Academy of Dermatology and Venereology
(EADV) Congress. The data showed that ORKA-001 has a human half-life of approximately 100 days. Single doses of ORKA-001
demonstrated complete and sustained inhibition of STAT3 signaling, a downstream marker of IL-23 activity, in an ex vivo assay
through 24 weeks. In addition, ORKA-001 was well tolerated at all dose levels, with a favorable safety profile consistent with the
anti-IL-23 class. We believe this data supports the key ways in which ORKA-001 could re-define the treatment paradigm in psoriasis:
annual dosing, higher efficacy, and off-treatment remission.
ORKA-001 showed a human half-life of
approximately 100 days
In the third quarter of 2025, we commenced dosing in a Phase 2a proof-of-concept study of ORKA-001 in moderate-to-severe PsO (also known
as “EVERLAST-A”). We expect to share Week 16 data for all patients in the second quarter of 2026. In addition, we plan to
share longer-term data, including Week 28 for all patients and 52-week follow-up for a portion of the cohort in the second half of 2026.
EVERLAST-A enrolled 84 patients randomized 3:1 to receive 600 mg of ORKA-001 at Weeks 0 and 4 or matching placebo. The primary endpoint
is PASI 100 at Week 16. At Week 28, patients who have achieved PASI 100 will be randomized 2:1 to an arm where either (1) they do not
receive another dose until disease recurrence (to evaluate the possibility of both yearly dosing and extended off-treatment remissions)
or (2) they receive 300 mg ORKA-001 every six months. Patients who have not achieved PASI 100 will receive a 300 mg dose every six months.
After completing the trial, subjects may have the option to roll over to an open-label extension study.
Additionally, the first
patients were dosed in the EVERLAST-B trial in December 2025. EVERLAST-B is designed to enroll approximately 160 patients, is a
dose-ranging Phase 2b trial of ORKA-001 in moderate-to-severe PsO patients and will evaluate three dose levels of ORKA-001: 37.5 mg
at Week 0, 300 mg at Weeks 0 and 4, and 600 mg at Weeks 0 and 4, versus placebo. The primary endpoint is PASI 100 at Week 16. At
Week 28, patients who have achieved PASI 100 will be re-randomized 1:1 to either a 600 mg dose once-yearly or matching placebo.
Patients who have not achieved PASI 100 at Week 28 will receive a 300 mg dose every six months. Building on EVERLAST-A, this design
will further test the potential for ORKA-001 to achieve yearly dosing, higher efficacy and extended off-treatment remissions. Data
from EVERLAST-B is anticipated in 2027.
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ORKA-002
Summary
ORKA-002 is a high affinity,
extended half-life mAb designed to target IL-17A/F. Dual inhibition of both IL-17A and IL-17F has shown superior efficacy compared to
IL-17A inhibition alone in PsO and other indications, as shown by the performance of Bimzelx (bimekizumab) compared to Cosentyx (secukinumab)
and Taltz (ixekizumab) in Phase 3 trials. These therapies all utilize Q4W maintenance dosing in PsO and PsA, except Bimzelx, where Q8W
maintenance dosing in PsO patients <120 kg is recommended. By binding IL-17A/F at similar epitopes and affinity ranges as Bimzelx while
incorporating half-life extension technology to potentially enable twice-yearly maintenance dosing in PsO and quarterly maintenance dosing
in HS, we believe that ORKA-002 could become the leading therapy in the IL-17 class.
Clinical Development
In January 2026, we announced
interim findings from the Phase 1 trial of ORKA-002 in healthy volunteers. The study enrolled 24 healthy adult participants into three
single-ascending subcutaneous dose cohorts of 160 mg, 320 mg and 640 mg. ORKA-002 showed a half-life of approximately 75-80 days, greater
than three times that of bimekizumab, and a comparable Cmax to bimekizumab at equivalent doses based on previously reported bimekizumab
data. Pharmacokinetic modeling based on these results supports achieving twice-yearly maintenance dosing in PsO and quarterly maintenance
dosing in HS. Additionally, single doses of ORKA-002 demonstrated potent and sustained inhibition of IL-17 signaling in an ex vivo
assay through 24 weeks. ORKA-002 was well tolerated at all dose levels, with a favorable safety profile consistent with the anti-IL-17
class. The trial remains blinded, and as of January 6, 2026, which was the data cutoff date, all subjects remained on trial.
ORKA-002 showed a half-life of approximately
75-80 days
We initiated ORCA-SURGE,
a Phase 2 trial of ORKA-002 in patients with moderate-to-severe PsO, in February 2026. ORCA-SURGE is designed to enroll approximately
160 patients randomized 1:1:1:1 to receive 40 mg, 160 mg or 320 mg of ORKA-002 at Weeks 0 and 4, or matching placebo. The primary endpoint
is PASI 100 at Week 16. Maintenance dosing will evaluate the potential for twice-yearly dosing with ORKA-002. Data from ORCA-SURGE is
anticipated in 2027.
We see ORKA-002 as highly
complementary to ORKA-001, with the potential to provide an improved therapy for the approximately one-quarter to one-third of moderate-to-severe
PsO patients who have PsA, as well as for PsO patients with highly resistant skin symptoms that do not respond adequately to an IL-23
inhibitor. Furthermore, ORKA-002 could address indications beyond PsO, including PsA with limited skin involvement, HS, axSpA, and additional I&I
diseases. We plan to initiate a Phase 2 trial of ORKA-002 in patients with HS in the second half of 2026.
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ORKA-021
The IL-17 and IL-23 inhibitor
classes each have distinct advantages. IL-17 inhibitors are generally associated with rapid onset of action and high peak response, while
IL-23 inhibitors are typically characterized by less frequent dosing and favorable durability and safety profiles. Sequential use of these
two mechanisms has the potential to combine attractive attributes of each class, including the rapid response associated with IL-17 inhibition
and the maintenance profile associated with IL-23 inhibition. Accordingly, following ORKA-002 and ORKA-001, we plan to evaluate a sequential
combination regimen of ORKA-002 and ORKA-001, which we refer to as “ORKA-021”.
Additional Pipeline Program
We have a third program, ORKA-003, that targets an undisclosed pathway.
A core tenet of our strategy is to remain highly focused on I&I diseases, and specifically on inflammatory dermatology conditions.
ORKA-003 provides the potential for indication expansion beyond PsO as well as combination opportunities with our more advanced programs.
In the future, we may add additional programs to our portfolio beyond ORKA-001, ORKA-002, ORKA-021 and ORKA-003 that fit our strategic
focus.
Intellectual Property
We seek to protect the proprietary programs and technologies that we
believe are important to our business through a combination of patent protection and other intellectual property strategies. Our intellectual
property portfolio is designed to protect our product candidates and related technologies, including patents directed to composition of
matter, methods of use and manufacture, and other inventions.
We and Paragon have filed,
and may continue to file, patent applications relating to antibodies that target IL-23, including applications covering composition of
matter, pharmaceutical formulations, and methods of use, including for ORKA-001. We and Paragon have also filed, and may continue to file,
patent applications relating to antibodies that target IL-17, including applications covering composition of matter, pharmaceutical formulations,
and methods of use, including for ORKA-002.
We hold exclusive rights to ORKA-001 and ORKA-002, as well as the associated
IL-23 and IL-17 patent rights, pursuant to license agreements with Paragon. Certain patent rights covering ORKA-001 are expected to expire
in 2045, absent any applicable patent term adjustments or extensions. Patent rights relating to ORKA-002, if issued, are also expected
to expire in 2045, absent any applicable patent term adjustments or extensions.
Commercial
If any of our product candidates
are approved for commercialization, we intend to commercialize them in the United States and other key markets either independently or
through strategic collaborations, with the objective of maximizing the commercial value of our programs. Given our current stage of development,
we have not yet established a commercial organization or distribution capabilities. Pursuant to license agreements with Paragon, we hold
exclusive worldwide rights to develop and commercialize ORKA-001 and ORKA-002.
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Manufacturing
We do not currently own or
operate facilities for product manufacturing, testing, storage, and distribution. We have contracted and expect to continue to contract
with third parties for the manufacture and distribution of our product candidates. Because we rely on contract manufacturers, we employ
personnel with extensive technical, manufacturing, analytical, and quality experience. Our team has deep knowledge and understanding of
the regulations that govern manufacturing, documentation, quality assurance, and quality control of drug supply that are required to support
our regulatory filings.
Competition
The biotechnology and biopharmaceutical
industries are characterized by continuing technological advancement and significant competition. While we believe that our programs,
technology, development experience and scientific knowledge provide us with competitive advantages, we face competition from major pharmaceutical
and biotechnology companies, academic institutions, governmental agencies, and public and private research institutions, among others.
Any product candidates that we successfully develop and commercialize will compete with existing therapies and therapies that may become
available in the future. Many of the companies with which we are currently competing or will compete against in the future have significantly