annx-10k_20211231.htm

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 10-K

(Mark One)

For the fiscal year ended December 31, 2021

Commission File Number 001-39402

ANNEXON, INC.

(Exact name of Registrant as specified in its Charter)

1400 Sierra Point Parkway, Bldg C, Suite 200

Brisbane, California94005

(Address of principal executive offices including zip code)

Registrant’s telephone number, including area code: (650) 822-5500

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 ANNX The Nasdaq Stock 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, a 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. ☒

Indicate by check mark whether the Registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act). Yes ☐ No ☒

As of June 30, 2021, the aggregate market value of shares held by non-affiliates of the Registrant (based upon the closing sale prices of such shares on the Nasdaq Global Select Market on June 30, 2021) was approximately $750 million. For purposes of calculating the aggregate market value of shares held by non-affiliates, we have assumed that all outstanding shares are held by non-affiliates, except for shares held by each of our executive officers, directors and 10% or greater stockholders. This calculation does not reflect a determination that such parties are affiliates for any other purpose.

The number of shares of Registrant’s Common Stock outstanding as of February 25, 2022 was 38,563,565.

DOCUMENTS INCORPORATED BY REFERENCE

Portions of the Registrant’s definitive proxy statement relating to the 2022 Annual Meeting of Stockholders, which will be filed with the Securities and Exchange Commission within 120 days after the end of the Registrant’s fiscal year ended December 31, 2021, are incorporated by reference into Part III of this Annual Report on Form 10-K.

Table of Contents

Page

PART I

Item 1. Business 6

Item 1A. Risk Factors 46

Item 1B. Unresolved Staff Comments 95

Item 2. Properties 95

Item 3. Legal Proceedings 95

Item 4. Mine Safety Disclosures 95

PART II

Item 6. [Reserved] 96

Item 7A. Quantitative and Qualitative Disclosures About Market Risk 105

Item 8. Financial Statements and Supplementary Data 107

Item 9A. Controls and Procedures 132

Item 9B. Other Information 133

Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 133

PART III

Item 10. Directors, Executive Officers and Corporate Governance 134

Item 11. Executive Compensation 134

Item 14. Principal Accountant Fees and Services 134

PART IV

Item 15. Exhibits, Financial Statement Schedules 135

EXPLANATORY NOTE

Annexon, Inc., or the Company, was previously an “emerging growth company,” as defined in the Jumpstart Our Business Startups Act, and a “non-accelerated filer” and “smaller reporting company,” each as defined under Rule 12b-2 under the Securities Exchange Act of 1934, as amended, or the Exchange Act.

As of December 31, 2021, the Company ceased to qualify as an emerging growth company and was deemed to be a “large accelerated filer,” as defined under Rule 12b-2 under the Exchange Act.

Although the Company is no longer an emerging growth company or a smaller reporting company, and on the cover page of this Annual Report on Form 10-K, the Company has checked the box indicating its status as a large accelerated filer, the Company remains eligible to take advantage of smaller reporting company reporting requirements through this Annual Report on Form 10-K, including reduced disclosure obligations regarding executive compensation that will be incorporated in this Annual Report on Form 10-K by reference to the information set forth in its proxy statement for its 2022 Annual Meeting of Stockholders, which will be filed with the U.S. Securities and Exchange Commission no later than 120 days after December 31, 2021. The Company has elected to take advantage of certain of the reduced disclosure obligations available to smaller reporting companies in this Annual Report on Form 10-K.

SPECIAL NOTE REGARDING FORWARD-LOOKING STATEMENTS

This Annual Report on Form 10-K contains forward-looking statements about us and our industry that involve substantial risks and uncertainties. All statements other than statements of historical facts contained in this Annual Report on Form 10-K, including statements regarding our strategy, future financial condition, future operations, projected costs, prospects, plans, objectives of management and expected market growth, are forward-looking statements. In some cases, you can identify forward-looking statements by terminology such as “aim,” “anticipate,” “assume,” “believe,” “contemplate,” “continue,” “could,” “design,” “due,” “estimate,” “expect,” “goal,” “intend,” “may,” “objective,” “plan,” “positioned,” “potential,” “predict,” “seek,” “should,” “target,” “will,” “would” and other similar expressions that are predictions of or indicate future events and future trends, or the negative of these terms or other comparable terminology. These forward-looking statements include, but are not limited to, statements about:

• our clinical and regulatory development plans;

• the pricing and reimbursement of our product candidates, if approved;

• our future financial performance; and

We have based these forward-looking statements largely on our current expectations, estimates, forecasts and projections about future events and financial trends that we believe may affect our financial condition, results of operations, business strategy and financial needs. In light of the significant uncertainties in these forward-looking statements, you should not rely upon forward-looking statements as predictions of future events. Although we believe that we have a reasonable basis for each forward-looking statement contained in this Annual Report on Form 10-K, we cannot guarantee that the future results, levels of activity, performance or events and circumstances reflected in the forward-looking statements will be achieved or occur at all. You should refer to the sections titled “Risk Factor Summary” and “Risk Factors” for a discussion of important factors that may cause our actual results to differ materially from those expressed or implied by our forward-looking statements. Furthermore, if our forward-looking statements prove to be inaccurate, the inaccuracy may be material. Except as required by law, we undertake no obligation to publicly update any forward-looking statements, whether as a result of new information, future events or otherwise.

You should read this Annual Report on Form 10-K and the documents that we reference in this Annual Report on Form 10-K and have filed as exhibits completely and with the understanding that our actual future results may be materially different from what we expect. We qualify all of the forward-looking statements in this Annual Report on Form 10-K by these cautionary statements.

RISK FACTOR SUMMARY

The following summarizes the most material risks that make an investment in our securities risky or speculative. If any of the following risks occur or persist, our business, financial condition and results of operations could be materially and adversely affected and the price of our common stock could significantly decline. This summary should be read in conjunction with the section titled “Risk Factors” and should not be relied upon as an exhaustive summary of the material risks we face.

PART I

Item 1. Business.

In this Annual Report on Form 10-K, “we,” “our,” “us,” “Annexon” and the “Company” refer to Annexon, Inc. and its consolidated subsidiary. Annexon, Annexon, Inc., the Annexon logo and other trade names, trademarks or service marks of Annexon are the property of Annexon, Inc. This report contains references to our trademarks and to trademarks belonging to other entities. Trade names, trademarks and service marks of other companies appearing in this report are the property of their respective holders. We do not intend our use or display of other companies’ trade names or trademarks to imply a relationship with, or endorsement or sponsorship of us by, any other companies.

Overview

We are a clinical-stage biopharmaceutical company pioneering a new class of complement medicines designed to stop the classical complement pathway at its start, C1q, in order to bring therapies to patients suffering from serious complement-mediated autoimmune, neurodegenerative and ophthalmic disorders. C1q, the initiating molecule of the classical complement pathway, is a core component to the body’s immune system that activates a powerful inflammatory cascade. We believe that by stopping the classical complement pathway at its start, our approach may have the potential to provide more complete protection against complement-mediated disorders of the body, brain and eye.

Our proprietary platform leverages well-researched classical complement-mediated autoimmune and neurodegenerative disease processes, both of which are triggered by aberrant activation of C1q. Evidence suggests that potent and selective inhibition of C1q can prevent tissue damage triggered in antibody-mediated autoimmune disease and preserve loss of functioning synapses associated with cognitive and functional decline in complement-mediated neurodegeneration. By taking an upstream complement approach targeting C1q, our treatments are designed to act as an “on/off switch” to block all downstream components of the classical complement pathway that lead to excess inflammation, tissue damage and patient disability in a host of complement-mediated disorders, while preserving the normal immune function of the lectin and alternative complement pathways involved in the clearance of pathogens and damaged cells.

We are advancing a broad pipeline of product candidates designed to block the activity of C1q and the entire classical complement pathway for a range of complement-mediated diseases. Our development strategy is focused on areas where C1q and the classical complement pathway is the key driver of disease. Our pipeline includes three clinical-stage assets across three therapeutic franchises:

Beyond our clinical-stage assets, our preclinical portfolio of next generation product candidates includes ANX105, an investigational monoclonal antibody targeting neurodegenerative indications, and ANX1502, an investigational oral small molecule in development for the treatment of certain autoimmune indications. Based on learnings from our initial trials and our expertise in the role of C1q and the classical complement pathway, we are evaluating additional orphan and large market indications that are driven by aberrant or excess classical complement activation.

Our Company was co-founded by the late Dr. Ben Barres, former member of the National Academy of Sciences, Chair of Neurobiology at Stanford University and a pioneer in complement-mediated neurodegeneration, and Dr. Arnon Rosenthal, a world-renowned scientist and industry executive. We have assembled a seasoned and accomplished management team that has been involved in the discovery, development, approval and commercialization of numerous marketed drugs, and has been studying the complement pathway and autoimmune and neurodegenerative disorders for decades. Our team is further supported by an experienced scientific advisory board, board of directors, and leading healthcare investors that share our commitment to advancing transformative medicines for patients suffering from debilitating autoimmune and neurodegenerative diseases.

We hold worldwide development and commercialization rights, including through exclusive licenses, to all of our product candidates, which allows us to strategically maximize value from our product portfolio over time. Our patent portfolio includes patent protection for our upstream complement platform and each of our product candidates.

Our Pipeline

Our pipeline is focused on antibody-mediated autoimmune and complement-mediated neurodegenerative disorders for which there is significant unmet medical need. Our product candidates are summarized below:

Our first clinical-stage product candidate is ANX005, an investigational monoclonal antibody designed to block C1q and activation of the classical complement cascade. For GBS, ANX005 is designed to act early in the disease course to prevent nerve damage and irreversible neurological disability in GBS patients. In the Phase 1b dose-ranging trial in GBS patients, treatment with ANX005 was well-tolerated and resulted in full and prolonged C1q engagement and classical cascade inhibition in the blood and cerebrospinal fluid, or CSF. While our Phase 1b trial was not powered to show statistical significance, we did observe a significant reduction in neurofilament light chain, or NfL, a well-accepted marker of nerve damage in neurodegenerative disease that has been shown to correlate with disease severity and clinical outcomes. Patients treated with ANX005 also showed positive numerical trends across key GBS outcome measures. GBS is a rare, acute, antibody-mediated autoimmune disease impacting the peripheral nervous system. There are currently no approved therapies for GBS in the United States, but intravenous immunoglobulin, or IVIg, and plasma exchange are the current standards of care in the Western world and parts of Asia.

In March 2021, we completed the evaluation of our drug-drug interaction, or DDI, study of ANX005 co-administered with Intravenous Immunoglobulin (IVIg) in 14 patients with GBS. The DDI study was conducted to evaluate the safety and tolerability of ANX005 and IVIg co-administration in GBS patients, and measured pharmacokinetics (PK) and pharmacodynamics (PD) of ANX005 when administered in combination with IVIg. IVIg, though not approved by the U.S. Food and Drug Administration (FDA) in the United States for GBS, is currently the standard of care for GBS. Results from the DDI study demonstrated that co-administration of IVIg-ANX005 was well-tolerated and achieved full C1q target engagement, and C1q suppression was maintained within the targeted range. The open-label DDI study was not placebo-controlled or powered for statistical significance on efficacy measures. Several key GBS outcome measures were recorded from baseline, and early improvement was observed in GBS patients, including increased muscle strength, decreased neurofilament light chain (NfL) and improved GBS disability score. Results from the DDI study were presented at the Peripheral Nerve Society in 2021.

A randomized, placebo-controlled Phase 2/3 trial of ANX005 is ongoing in GBS patients in developing countries and we plan to release data from this trial in 2023. The Phase 2/3 trial is statistically powered to evaluate the efficacy of ANX005 in improving disability in GBS patients. ANX005 has received both Orphan Drug and Fast Track designations from the FDA for the treatment of GBS.

Beyond GBS, we are evaluating ANX005 in patients with warm autoimmune hemolytic anemia, or wAIHA, an antibody-mediated autoimmune disease characterized by the premature destruction of red blood cells. The classical complement pathway plays an important role in wAIHA through the removal of red blood cells labeled by activated complement components in the spleen or liver (extra-vascular hemolysis) and less common destruction of red blood cells in the blood vessels by the classical complement generated membrane attack complex (intravascular hemolysis). We initiated a Phase 2 trial in patients with the primary diagnosis of wAIHA in 2021. We are conducting a non-interventional screening study in wAIHA patients to utilize complement activation markers to identify and select patients who may be more likely to respond to our anti-C1q therapy in the Phase 2 trial. We plan to report data from this trial in the second half of 2022.

We are also studying ANX005 in patients with HD as well as patients with ALS – two neurodegenerative disorders in which aberrant classical complement activation has been shown to be associated with synapse loss, elevated levels of NfL and disease progression. Phase 2 trials evaluating ANX005 in patients with HD and ALS are ongoing, each designed to assess ANX005’s safety, tolerability, target engagement and impact on disease-related biomarkers and clinical outcomes. In January 2022, we announced interim data from the HD trial from patients who completed the 24-week treatment period. Interim data showed that as of a safety cutoff date of October 17, 2021, treatment with ANX005 has been generally well-tolerated, with full target engagement of C1q in both serum and CSF observed through the dosing period as of a cutoff date of December 14, 2021. Evaluable patients maintained clinical function, as measured by changes in mean Composite Unified Huntington's Disease Rating Scale (cUHDRS), relative to baseline after six months of treatment, and improvement in cUHDRS was observed in more than half of all evaluable patients and in 75% of evaluable patients who showed excess complement activity at baseline. NfL levels observed after six months of treatment remained generally consistent and were comparable to NfL levels described in published natural history data for HD patients. We currently anticipate reporting full data from all patients treated, including data from the three-month follow-up period, in the second quarter of 2022. The ALS trial is ongoing and we plan to report data in 2023.

Our second clinical-stage product candidate is ANX007, an investigational C1q Fab designed for intravitreal administration in patients with complement-mediated neurodegenerative ophthalmic disorders. Consistent with the results we observed in preclinical studies, in the Phase 1b trial with intravitreal administration in glaucoma patients, ANX007 was well-tolerated and showed full target engagement and inhibition of C1q in the eye for at least four weeks. We believe inhibition of C1q may provide neuroprotective benefit by preventing the aberrant loss of functioning synapses in the retina in a variety of ophthalmic disorders, including glaucoma and geographic atrophy, or GA. A Phase 2 trial of ANX007 in patients with GA is ongoing, with the goal of protecting against the loss of photoreceptor neurons in a well-defined patient population. We plan to report data from this trial in 2023.

Our third clinical-stage product candidate is ANX009, an investigational C1q Fab designed for subcutaneous delivery, which was evaluated in a first-in-human, or FIH, clinical trial. In this trial, ANX009 was well-tolerated at all dose levels tested and no drug-related safety signals were observed. The trial showed that ANX009 led to sustained C1q inhibition at multiple doses, supporting the potential for twice weekly subcutaneous administration with the

current formulation. We are developing ANX009 to potentially enable chronic dosing for patients with antibody-mediated autoimmune disorders where anti-C1q may have a disease-modifying effect and where we can utilize our targeted biomarker-driven approach. These disorders may include autoimmune hemolytic anemias and a subset of lupus nephritis patients who are selected for pathogenic anti-C1q antibodies, or PACA, and who have a high risk of renal flare.

We are developing additional next-generation product candidates, including ANX105, an investigational monoclonal antibody with enhanced dosing and PK properties designed for chronic neurodegenerative diseases, and ANX1502, an oral small molecule being developed for certain autoimmune indications. We intend to initiate a FIH trial of ANX105 in the first half of 2022, with data anticipated in 2023. We intend to initiate a FIH trial of ANX1502 in the second half of 2022, with data expected in 2023.

Our Strategy

Our goal is to develop disease-modifying medicines for patients suffering from classical complement-mediated diseases. Key elements of our strategy include:

Overview of the Complement System and C1q Biology

The Complement System—three main complement pathways

The complement system is an integral component of the immune system that consists of many circulating and locally-produced molecules. This system evolved to enhance, or complement, other components of the adaptive and innate immune systems. The complement system, also known as the complement cascade, rapidly responds to pathogens, damaged cells and unwanted tissue components to facilitate their removal by the immune system.

There are three main complement pathways (also called cascades)—the classical, lectin and alternative pathways. Each pathway is initiated by different molecules that respond to distinct triggers. When activated, the initiating molecules set in motion a cascade of enzymatic reactions that greatly amplify, or complement, an inflammatory response. The classical pathway is initiated by C1q, which recognizes antibody complexes, specific pathogens, damaged cells or unwanted cellular components. The lectin pathway is triggered by carbohydrates on the surface of pathogens or cells. The alternative pathway amplifies the action of the other two pathways and also self-activates to eliminate pathogens or cells that are not specifically shielded by the body’s built-in self-protective systems. While these three pathways are initiated by distinct molecules, they converge downstream on common pathway components known as C3 and C5.

Thethreemainpathwaysof thecomplement cascadeare activated byindependentmoleculesbut convergeatC3

Aberrant activation of the complement system can result in a range of diseases characterized by an attack on healthy tissue, such as red blood cells, nerve cells or kidney components. A broad range of diseases are known to be associated with pathological activation of the complement cascade, including antibody-mediated autoimmune disorders such as GBS, wAIHA, CAD and lupus nephritis, and complement-mediated neurodegeneration disorders in

the eye and brain such as glaucoma, GA, HD, ALS, frontotemporal dementia and Alzheimer’s disease. We believe intervening in the activation of the complement cascade offers a potent and selective mechanism for specifically slowing or reversing these disease processes.

Specific activated components of the complement cascade have important immune functions that contribute to three key outcomes:

Aberrantactivationof theinitiatingmolecule,C1q,can leadtothreemainoutcomes

InhibitingC1qupstreamblocksdownstreamcomponentsandfunctional activitiesoftheclassicalcomplementcascade

Broad potential for Classical Complement pathway targeted therapeutics in Autoimmune and Neurodegenerative Diseases

Theclassicalcomplementcascadehasawell-establishedroleinaugmentingantibodyfunctionwithinthe immunesystem.C1qrecognizesantibodiesboundtopathogensorcellsandactivatestheclassicalpathwayto triggertheirremovalandclearancebytheimmunesystem.C1qcanalsodirectlyrecognizepathogens,damaged cellsorunwantedcellularcomponentsleadingtosimilardownstreamclearance.Amorerecentfindingmadeby thelaboratoryofDr.Ben Barres,ourscientificfounder,isthatC1qalso directlyinteractswith neuronal connections,orsynapses,duringearlydevelopment.RecognitionofweakersynapsesbyC1qtriggers the classical complement cascade and directs immune cells to “prune” the synapses away from neurons, thereby reinforcing stronger synapses to establish appropriate neuronal connections.

Because of its central role in immune function, aberrant activation of C1q can lead to damage of healthy tissue and destruction of functioning synapses. We are focused on two distinct disease processes involving C1q as a key mediator of tissue damage: antibody-mediated autoimmune disease and complement-mediated neurodegeneration.

Inantibody-mediatedautoimmunedisease,self-reactiveantibodiesbindtocellsortissues,activatingC1q andleadingtodamaginginflammatoryresponses.WehaveobservedthatinhibitionofC1qwasprotectivein severalanimalmodelsofantibody-mediatedautoimmunedisease,includingneuromyelitisoptica,orNMO,and twovariantsofGBS.InNMO,auto-antibodiesrecognizecellswithinthecentralnervoussystem,orCNS,and canleadtorapidlocalizeddestructionoftheopticnerveandregionsofthespinalcord,whileinGBSpathogenic antibodiesreactwithcomponentsoftheperipheralnervesystem,orPNS,tocausewidespreadperipheralnerve damageandparalysis.Thisdiseaseprocessisalsoevidentinantibody-mediatedautoimmunediseaseinvolving bloodcomponents,suchaswAIHAandCAD,characterizedbyauto-reactiveantibodiesthattriggerdestruction ofredbloodcells,andsystemiclupuserythematosus,orSLE,whereendogenouspathogenicantibodiesagainst C1qitselfdriveaberrantC1qactivationand are highly associatedwith kidney damage, or lupus nephritis.

Incomplement-mediatedneurodegeneration,aberrantactivationofC1q atsynapsesinaginganddiseasecan leadtoexcessivesynapselossandneuronaldamage,drivingdiseaseprogressioninmultipleneurodegenerative disordersregardlessoftheinitiatingfactor.Inanimalmodels,C1qaccumulatedonsynapseswithage,building upto300-foldhigherlevelsthaninyoungeranimals.Itdidnotactivatewithnormalaging,butother inflammatorystimuli,includingmisfoldedproteins,metabolicdysfunctionorincreasesinintraocularpressure, appearedtoaberrantlyreactivateC1q’sdevelopmentalroleinsynapseelimination.Complementactivationand aberrantsynapsepruningindiseasemayleadtoneuroinflammation,lossofsynapticneuronalconnectionsand neurodegeneration.Insupportofthishypothesis,weandotherinvestigatorshaveobservedthatC1qinhibition was protective in numerous models of neurodegenerative disease, including diseases of the eye, such as glaucomaandage-relatedmaculardegeneration,chronicdiseasesoftheCNS,suchasfrontotemporaldementia, Alzheimer’s,HDandSpinalMuscularAtrophy,orSMA,andacuteinjury,suchastraumaticbraininjuryand stroke.

Synapticloss isa pathogenicdriver of disabilityinmany neurodegenerative diseases, protectedwith C1qinhibition

Our differentiated approach to treating complement-mediated autoimmune and neurodegenerative disease through inhibition of C1q

Webelievethatinordertoselectivelyinhibitaberrantactivationoftheclassicalcomplementpathway implicatedindrivingcertaincomplement-mediatedautoimmuneandneurodegenerativediseases,itisimportant totargettheearlycomponentsoftheclassicalcascade,particularlyC1q,C4andC3.ActivatedfragmentsofC4 andC3inducevascularleakinessandimmunecellrecruitmentintothetissue,whileotherfragmentsofC4and C3,aswellasC1q,worktogethertodirectimmunecellattacktothecellorsynapsesurface.Furthermore,C1q inhibitionblocksdownstreamclassicalpathwayactivationofC5anditsmembranedamagingeffects.Webelieve thatinhibitionofC1qdoesnotblocktheactivityofthesecomponentsinthelectinoralternativecomplement pathways, and both of thesepathways will continueto performtheirnormalimmunefunctions.

Our Platform

Ournovelupstreamcomplementplatformisdesignedtocompletelyinhibitclassicalcomplementactivity forthetreatmentofantibody-mediatedautoimmunediseaseandcomplement-mediatedneurodegeneration.We believe there arepotentialadvantages toourapproach ofupstreaminhibition oftheclassical complement cascade,which include:

Our Pipeline

Our First Product Candidate, ANX005

ANX005 is an investigational humanized recombinant monoclonal antibody that is designed to potently bind and inhibit C1q. We have completed a Phase 1b clinical trial for ANX005 in patients with GBS in which ANX005 was well-tolerated and achieved full target engagement and C1q suppression in the PNS and CNS. Based on the results from our Phase 1b trial, we are now evaluating ANX005 in a Phase 2/3 trial in patients with GBS and Phase 2 trials in HD, ALS and wAIHA. ANX005 has been granted Orphan Drug and Fast Track designations from the FDA for the treatment of GBS.

ANX005for the Treatmentof GBS

Overview of Guillain-BarréSyndrome

GBSisasevereacute inflammatory disease typically triggered by a preceding infection, in which aberrant auto-antibodies that recognize neurons or associated cells cause neuronal injury and acute paralytic neuropathy. In 2011, the estimated annual incidence of GBS was approximately 12,000 in North America and Europe. In 2004, the annual economic cost of GBS in the United States was $1.7 billion, largely due to the permanent disability and mortality it can cause.

There are currently no FDA-approved therapies for the treatment of GBS. Treatment guidelines published by the American Academy of Neurology recommend early initiation of IVIg or plasma exchange in patients diagnosed with GBS. IVIg and plasma exchange are the established standards of care in the Western world and parts of Asia. Although IVIg and plasma exchange have been shown to provide some benefit, significant unmet need still exists, and many patients, despite receiving the standard of care, are left with residual neurological disability, accompanied by chronic pain and fatigue.

The clinical course of GBS usually involves rapidly progressive weakness in the limbs culminating in neuromuscular paralysis within two to four weeks of onset. According to 2011 estimates, 20 to 30 percent of patients require mechanical ventilation, over 20 percent have permanent motor or sensory disability and 2 to 17 percent of cases result in death globally. Many patients with GBS require extensive monitoring and supportive care and will seek treatment in a hospital within a few days of onset of the disease. Because approximately a quarter of patients need artificial ventilation due to respiratory muscle weakness, and many develop autonomic disturbances, admission in an intensive care unit is frequentlynecessary.Symptomspeakwithinfourweeksastheauto-antibodyresponsedeclines,followedbyarecoveryperiodthatcanlastmonthsoryears,asthenervoussystemrepairsitself.

C1q is a key driver of pathogenesis in GBS

GBSisanacute,autoimmunediseasedrivenbyantibodiesthatleadtoactivationoftheclassical complementcascade.Pathologicalnerve-targetingauto-antibodies,whichmaybetriggeredbyaninfection,lead totheactivation ofC1qandtheclassical complement cascade.Studieshaveshownthatpathogenicauto-antibodiesarepresentintheserumandCSFandthatactivatedcomponentsofthecomplementcascadeare depositedonperipheralnervetissuefromGBSpatients.PeripheralnerverootsareimmersedinCSFasthey emergefromthespinalcordandareprominentsitesofdamageinGBS.Thefigurebelowillustrates the activationoftheclassicalcomplementpathwaywithinperipheralnervesinaGBSpatient.Theleftimageshows alowmagnificationviewofaperipheralnervefromaGBSpatientwithnumerousindividualnervefiberscoated withmembrane-damagingcomplementactivationproducts(C5b-9;darkstaining).ThemiddleimageshowsahighmagnificationviewofanindividualnervefiberwithdepositionofC3d(darkstaining),acomplement activationproductthatdirectsimmunecellattack.Therightimageshowsahighpowerimageofanindividualnerve fiberbeing probed by an infiltratingimmunecell(macrophage).

WebelievethatbyblockingtheactivityofC1qearlyintheonsetofthedisease,wecanminimizethe neuronaldamagecausedbythesepathogenicauto-antibodies,inturnreducingthepatients’symptomsand acceleratingtheirneurologicalrecovery.

Neurofilamentlightchain (NfL), a marker of neurodegeneration,is highlyelevatedin GBS

NfL,an intracellular neuron-specificprotein,hasemergedasawell-acceptedbiomarkerofnervedamageindisorderscharacterizedbydamagedordegeneratingnerves.NfLisasubunitofneurofilaments,whicharecylindricalproteinsexclusivelylocatedinthecytoplasmofnervecellsandarereleasedintotheCSFandbloodwhennervesaredamaged(illustrationbelow).Recentultrasensitivetechniques(e.g.,single-moleculearraytechnology)havemadeitpossibletoaccuratelyandquantitativelydetectlongitudinalchangesofNfLinbothbloodandCSF,withverylowanalyticalvariation.Theseassayproperties,inadditiontoneuron-specificity,positionNfLasanimportantdecision-enablingtoolinproof-of-conceptstudiesofneuroprotectiveagentsacrossawidevarietyofdiseases.

Neurofilament LightChain(NfL)isreleased from damaged nerve cells

ElevatedNfLlevelscorrelatewithcurrentpatientdisabilityandpredictpatientoutcomesinautoimmune neurologicaldiseasessuchasGBS,multiplesclerosis,orMS,chronicinflammatorydemyelinatingpolyneuropathyandmultifocalmotorneuropathyaswellasinchronicneurodegenerativediseasessuchas Huntington’sdisease,amyotrophiclateralsclerosis,spinalmuscularatrophy,orSMA,frontotemporaldementia,andAlzheimer’sdisease.Moreover,effectivetreatmentsforMS(e.g.,ocrelizumab,natalizumabandfingolimod) andSMA(e.g.,nusinersen)thatpreventneurologicaldisabilityinpatientshavebeenshowntosignificantly reduceNfLlevelsinthesesamepatients.InpatientswithGBS,NfLisveryhighlyelevated(insomeinstances, greaterthan100-foldabovenormal).RetrospectiveandprospectivestudiesinGBSpatientshaveshownthatNfL levelsin CSFand serummay correlatewith diseasecourse,severityand prognosisin GBS.

PreclinicalDevelopmentin GBS

Asillustratedbelow,inamousemodelofsevereGBS,ANX005treatmentblockedcomplementdeposition onnerveterminals(leftpanel)andprotectedrespiratoryandmotorfunction(rightpanel)whencomparedtoan irrelevantimmunoglobulinG,orIgG,isotypecontrolantibody.Ap-valueisameasureofthestatistical significanceoftheobservedresult.Byconvention,ap-valuelowerthan0.05isconsideredstatisticallysignificant.

Respiratoryandmotorfunction

Phase 1a Trial in Healthy Volunteers

ANX005wasinitiallyevaluatedinaPhase1adose-escalationsingle-dosetrialdesignedtoassesssafety, pharmacokineticsandpharmacodynamics.Thistrialwasconductedin27healthyvolunteersinAustralia.The dosinglevelsofANX005deliveredinthistrialrangedfrom1mg/kgto8.2mg/kg.Weterminatedthetrialin healthyvolunteersandtransitionedourclinicaldevelopmenttoevaluateANX005directlyinpatientswithGBS based on guidancefromthe FDAin orderto expedientlyadvance thisprogramin the United States.

Phase 1b Trial in GBS Patients

WehavecloselycoordinatedourclinicaleffortswithleadingresearchersoftheInternationalGBSOutcome Study,orIGOS,inpursuinganoveltherapyforGBS.Withthegoalofaidingthedevelopmentofeffective treatmentsforGBS,practitionersestablishedIGOSinMay2012,andhavecollectednaturalhistorydatafrom over1,750newly-diagnosedGBSpatientsworldwide.IGOSisaprospective,observational,multicentercohort studythataimstoidentifytheclinicalandbiologicaldeterminantsandpredictorsofdiseaseonsetaswellasthe subtype,courseandoutcomeofGBS.IGOSwasestablishedtohelpdevelopabetterunderstandingofthe mechanismofdiseaseprogressionandrecoveryandtoconductselectivetherapeutictrialstoimprovepatient outcomes.Thisnaturalhistorydatabaseisaninvaluableresourcetoclinicaldevelopment,facilitatingthedesign ofclinicaltrials,optimalselectionofendpoints,andpatientfollow-upforonetothreeyears.WeinitiatedourGBSclinicaldevelopmentinBangladesh,acountrywheretheincidenceofGBSisseveraltimeshigherthanin NorthAmericaandEuropeandwhere17%ofpatientsdiefromthediseaseand20%sufferpermanentdisability andareunabletowalk.Additionally,oursiteinBangladeshiswellsituatedtoconductclinicalresearchinGBS inamannercompliantwithgoodclinicalpractice,orGCP,requirements.AsofMarch2017,BangladeshhadenrolledmorepatientsinIGOSthananyothercountry,representingapproximately15%ofallenrolledpatients worldwide.

WeconductedaPhase1bplacebo-controlled,doseescalationtrial(n=31)ofANX005inGBSpatientsatatertiarycarehospitalinBangladesh,incompliancewithGCPasdescribedabove.Thetrialobjectivesincluded safetyandtolerability,dosinglevelsandtargetengagement, and included a follow up of eight weeks. The dosing levels of ANX005 delivered in this trial ranged from 3 mg/kg to 75 mg/kg. ANX005 was well tolerated, and no drug-related serious adverse events or drug-related discontinuations occurred. The most common adverse events were acute infusion-related reactions, or IRRs, which occurred in the majority of patients and presented as low grade, non-serious, transient skin rash. These acute IRRs were mitigated by standard anti-inflammatory pre-medications.

Results from the Phase 1b trial showed increasing serum levels of ANX005 and its duration in the circulation at increasing dose levels, and that the drug was present in the serum for up to three weeks at a dose of 75 mg/kg (left panel). When ANX005 was present in the circulation C1qfunctionwasfullyinhibited,andrapidlyreturnedtonormallevelsasANX005serumlevelsdeclined(rightpanelshowingdatafromapatientreceiving75mg/kg).

MuchoftheproximalweaknessinGBSpatientsisduetoinvolvementofperipheralnerverootsthatareimmersedinCSF astheyexitthespinalcord.Hence,webelieveproductcandidatelevelsandtargetinhibition in CSFmaybeanimportantcontributortoefficacy.WeobservedthatANX005enteredtheCSF of GBS patientstreatedwithdosesof18-75mg/kgofANX005,resultinginfullengagementofC1qinhibitionintheCSF(asshownbelow).

Inhibitionof C1qObserved inCSF at18-75mg/kg

InthePhase1btrialinGBSpatients,ANX005treatmentatdosesthatengagedC1qinbothserumandCSF(i.e.,18-75mg/kgdose)resultedinastatisticallysignificantearlydeclineinserumNfLlevelscomparedto placebo(2-4weekposttreatmentp-value<0.05,leftpanelbelow).InthisPhase1btrial,wealsoexploredthe administrationofANX005onmultiplevalidatedclinicaldisabilitymeasuresincludingGBS-DisabilityScore,or GBS-DS,MedicalResearchCouncilMuscleStrengthScale,orMRC,andInflammatoryRasch-builtOverall DisabilityScale,orI-RODS,overaneight-weekperiod.WeobservedthatearlydeclineinNfLcorrelatedwith improvementintheGBS-DSattheendofthestudy(2-8weekposttreatmentp-value<0.05;rightpanelbelow). WebelievetheseresultssuggestthatANX005hadarapidimpactonthediseaseprocessbyameliorating antibody-inducednerve damage, likelywithin the firsttwo weeks of dosing.

Delta NfL wk 2-4

Thoughthetrialwasnotpoweredforstatisticalsignificance,treatmentwithANX005resultedinconsistent, positivenumericaltrends,includinganimprovementinMRCscoreandthenumberofdaysofventilation.We observeda dose-dependenttrendfor improvementin MRCwithin the firstweek of treatment(as shownbelow).

Mean Change in MRC Score

Week 1 from Baseline

Dose ANX005 (mg/kg)

EarlyimprovementinMRCisknowntohavestrongprognosticimplications onlong-termfunctional recovery(modifiedErasmusGBSOutcomeScore).Inlinewiththispublisheddata,wefoundthatearly improvementinMRCcorrelatedwithpatients’disabilityscoresattheendofthePhase1btrial(GBS-DS atweekeight).ThisresultisimportantbecauseGBS-DSistypicallyusedastheprimaryendpointinGBSregistrational studies.Inaddition,usingaresponderanalysis,28%ofpatientstreatedwithhighdoseANX005(18-75mg/kg)improvedbyatleastthreepointsonGBS-DSbyweek8comparedto0%ofplacebo-treatedpatients(asshown below).PatientstreatedwithANX005showedatrendofimprovementonGBS-DSwhenusingameananalysis. Both resultsare promisingbut not statisticallysignificant.

BasedontheresultsofthePhase1btrial,we selectedthe75mg/kgdoseofANX005for ongoing developmentinGBS.FollowingthecompletionofthePhase1btreatmentcohorts(through75mg/kg),two unblindedexploratorycohortswereenrolledtoestablishhigherdoseandmultipledosesafetyandPK/PDto informsubsequentchronicdosingtrials.Thesetwoexploratorycohortswereasingledoseof 100 mg/kg, and two dosesof75mg/kgseparatedbyoneweek(150mg/kgtotal).Atthesehigherdoselevels,ANX005waswell-tolerated,andnodrug-relatedseriousadverseeventsordrug-relateddiscontinuationsoccurred;moreover,wedid notreachamaximumtolerateddose.Similarly,we observedfullinhibitionof C1qin serumand CSF,a reduction inNfLandtrendsofimprovementinclinicalmeasureswhencomparedtoplacebo;however,therewasno additionalimpacton theseclinicalmeasuresbeyond thatseen at 75 mg/kg.

TheresultsofthePhase1bdoserangingtrialinGBSshowedthatANX005waswell-tolerated,fully inhibitedC1qinthebloodandCSFattargetdoses, anddemonstratedanearlyreductioninNfLlevels.DrugtreatmentwasassociatedwithatrendforearlyimprovementinMRC,andearlychangesinMRCsignificantly correlatedwithimprovedclinicalmeasuresinGBSpatients.Anadditionalkeylearningfromthestudyisthe

importanceofusingbaselineMRCforpatientstratification atthetimeofhospitalizationandstudyentry. AccountingforbaselineMRCstrengthenedtheimpactofANX005treatmentinthebiomarkerandclinical measures,demonstratingthatMRCwill be an importantstratificationtool in futureGBStrials.

Ongoing Development of ANX005 for GBS

We completed a DDI trial which demonstrated that concomitant use of ANX005 and IVIg in GBS patients was well-tolerated and achieved full target engagement. A randomized, placebo-controlled Phase 2/3 trial designed to evaluate the efficacy of ANX005 in improving disability in GBS patients is ongoing, and we anticipate reporting data from this trial in 2023.

ANX005 for the Treatment of Autoimmune Hemolytic Anemias

Overview of Autoimmune Hemolytic Anemias

Autoimmune hemolytic anemias, or AIHA, are characterized by the presence of auto-antibodies that bind red blood cells and activate the classical complement pathway. The temperature at which these auto-antibodies bind to red blood cells determines whether the hemolytic anemia is labelled “cold” or “warm.” In both cases, the antibodies trigger classical complement activation, which tags red blood cells with complement components (e.g., C3d, C4d) for removal in the spleen or liver (via extra-vascular hemolysis) or, less commonly, leads to their direct lysis within blood vessels by the C5b-9 membrane attack complex (intravascular hemolysis). The “cold” forms of AIHA are known to be complement-mediated disorders, whereas complement is hypothesized to play a dominant role in a subset of patients with the “warm” form of AIHA. It is estimated that less than 5,000 people have the cold form while approximately 30,000 people have the warm form of AIHA in the United States. There are no approved treatments for AIHA in the United States; however, blood transfusions, steroids, rituximab, chemotherapies and splenectomies are currently used to treat patients with AIHA. It is estimated that up to 30% of patients require second-line treatment when treated with the standard of care treatment and approximately 11% of cases after symptom onset result in death.

Ongoing Developmentof ANX005in Autoimmune Hemolytic Anemias

We have found that ANX005 inhibited complement deposition on human red blood cells (left panel) and prevented direct red blood cell lysis (right panel) induced by sera from CAD patients as ex vivo models of extravascular and intravascular lysis, respectively.

WehaveobservedinbothpreclinicalstudiesandinourPhase1btrialinpatientswithGBSthattreatment withANX005resultedinnearcompleteinhibitionofC1q,asmeasuredinserumbythesameexvivohemolysis assayusedforhemolyticanemiaconditions.Thus,webelievethatANX005maybeabletoachievenearcompletesuppressionof complement-mediatedhemolysisin patientswith wAIHA.

We are conducting a non-interventional screening study in wAIHA patients to utilize complement activation markers in an effort to identify and select patients who may be more likely to respond to our anti-C1q therapy in our Phase 2 trial. The open label Phase 2 trial in wAIHA patients is designed to evaluate safety, tolerability, PK, pharmacodynamic impact and efficacy, as measured by biomarkers of hemolysis and changes in hemoglobin. We anticipate reporting data from this trial in the second half of 2022. We are also evaluating ANX005 in patients with CAD.

ANX005for the Treatmentof Huntington’sDisease

Overview of Huntington’sDisease

HDisanorphanhereditaryneurodegenerativediseasethatisfatalandforwhichtherearenoapproved treatmentsthatcanreverseorslowitscourseofprogression.HDsymptomstypicallybegintomanifestbetween the ages of 30 to 50 and progressas a devastatingneurodegenerativedisorder characterizedbyabnormal involuntarymovements,knownaschorea,spreadingtoallmuscles,progressivedementiaandpsychiatric manifestationssuchasdepressionandpsychosis.Ultimately,affectedindividualssuccumbtocardio-respiratory complications.Lifeexpectancyaftersymptomonsetisapproximately10to20years.Someofthesymptomsof HDsuch as choreaand depressioncan be managedwith medications.

Approximately25,000to35,000peopleintheUnitedStateshaveHD.Estimatesprojectthatapproximately 75,000peopleintheUnitedStatesandothermajormarketcountrieswillhaveHDby2025.BecauseHDisa geneticdiseaseinwhichanindividualwithasinglecopyofthedysfunctionalgenewilldevelopthedisease, everychildofaparentwithHDhasa50percentchanceofinheritingthefaultygeneanddevelopingthedisease. Thereareanestimated200,000individualsintheUnitedStateswhohavea50percentriskofdevelopingHD becauseoftheirfamilyrelationshiptoHDpatients.Itisestimatedthatonlyfivetosevenpercentoftheseat-risk individualshavevoluntarilyundergonegenetictestingduetothedevastatingnatureofthediseaseandthelackof anyeffectivetreatments.Thedevelopmentofadisease-modifyingtherapycouldencourageat-riskpatientsto seekouttestingandtherebybothprovidehopetogenecarriersandexpandthenumberofpatientswhomay benefitfromtreatment.

C1q is a key driver of pathogenesis in HD

HDiscausedbyageneticmutation,specifically,byexpansionofthenumberofcytosine-adenine-guanine,orCAG,nucleotidesequenceswithintheDNAofthehuntingtingene,whichleadstoproductionofamutant huntingtinproteinthatisthoughttobe neurotoxicand promotethe degenerationof neurons. Abovea thresholdof 35CAGrepeats,theageofdiseaseonsetisinverselycorrelatedwiththenumberofCAGrepeats.TheclassicalcomplementcascadeisactivatedinHDpatientsandisassociatedwithprogressivesynapseloss.Wehypothesize thatC1qplaysanimportantroleinthedegenerativeprocessbytaggingweakenedsynapsesandtriggeringa neuroinflammatoryresponsethatleadstoaberrantsynapselossandprogressiveneuronaldestruction.Asshown below,weobservedthatincreasedcomplementactivationinHDpatients(asmeasuredbythecomplement activationmarkerC4ain CSF)was associatedwith diseaseprogression.

NfL is elevated in HD patients

BothCSF(shownbelow)andplasmalevelswerefoundtobeelevatedinHDpatientscomparedtohealthy controls,consistentwithobservationsinotherneurodegenerativediseases.Furthermore,plasmaNfLisincreased withadvancingdiseaseseverityandincreasesatanearlieragewithagreaternumberoftheCAGrepeats.NfL levelsinbothplasmaandCSFcorrelatebetterthanlevelsofthemutanthuntingtin,ormHTT,proteinitself,with clinicalfunctional/cognitivemeasuressuchastotalUnifiedHuntington’sDiseaseRatingScaleandwithbrain volumemeasuresasdeterminedbyMRI.Inaddition,whileCSFmHTTlevelsaccuratelydifferentiatecontrols andHDmutationcarriers,onlyNfLinCSFandplasmaisabletodistinguishpresymptomaticfromsymptomatic (manifest)HDpatients,suggestingthatNfLmightbeoneoftheearliestdetectableabnormalitiesinthe progressiontomanifestHD.Ofnote,NfLlevelswereshowntoreflectfuturepatientoutcomesaswellascurrent disability.

Increased NflintheCSF withDiseaseProgression

Progressive synapse loss in HD patients

Asshownbelow,researchersobservedinpost-mortemtissuefromHDpatientsthatthenumberofsynapses onneuronsconnectingspecificregionsofthebrain(thecortexandstriatum)werereducedcomparedtohealthy controls,withpatientsmoreadvancedinthediseaseprocess(Huntington’sdiseasestage4)showinggreaterloss ofsynapsesthanearlierstagepatients(Huntington’sdiseasestage2).Theseresultsareconsistentwithour hypothesisthatcomplementactivationleadsto synapse eliminationand neuronaldamage.

ProgressiveSynapse LossinHuntington’sDisease Synapse number(%Control)

ANX005 protected against synapse loss and reduced NfL in a preclinical model of HD

IntransgenicmousemodelsofHD,weassessedthepotentialofperipherallyadministeredANX005to inhibitactivationoftheclassicalcomplementcascadeand protectagainstsynapse loss. Asshownbelow, ANX005treatmentreducedtheamountofactivatedcomplementfactorC3dthatwasdepositedonsynapsesin thestriatum

(thesameregionofthebrainasaffectedinHDpatients;leftpanel),reducedCSFlevelsofNfL (middlepanel),andreducedthelossofsynapses(rightpanel).Webelievethesethreelinesofevidencesupport thehypothesisthatANX005blockscomplement-mediatedneurodegenerationinHDandcanleadtopreservation of neuronalsynapses.

Developmentof ANX005in HD

We are currently conducting anopen-label Phase 2 trial in HD patients to evaluateANX005’sabilitytoinhibitC1qinthe CSFandtoreducelevelsofserumandCSFNfL. In January 2022, we reported interim results from patients who completed the 24-week treatment period. This interim analysis showed that treatment with ANX005 was generally well-tolerated as of the safety cutoff date of October 17, 2021, with full target engagement of C1q in both serum and cerebrospinal fluid (CSF) observed through the dosing period as of December 14, 2021. Evaluable patients maintained clinical function, as measured by changes in mean Composite Unified Huntington's Disease Rating Scale (cUHDRS), relative to baseline after six months of treatment, and improvement in cUHDRS was observed in more than half of all evaluable patients and in 75% of evaluable patients who showed excess complement activity at baseline. NfL levels observed after six months of treatment remained generally consistent and were comparable to NfL levels described in published natural history data for HD patients. Overall, these interim findings appeared to support the scientific hypothesis of our scientific founder, the late Ben Barres, who believed that blocking C1q protects synaptic loss and can lead to rapid functional impact on clinical outcomes in neurodegenerative diseases.

The Phase 2 trial remains ongoing, and we anticipate reporting full data from all patients treated, including data from the three-month follow-up period, in the second quarter of 2022. Pending results from the full dataset, we plan to evaluate the opportunity for a Phase 3 trial of ANX005 in HD patients.

ANX005for the Treatmentof ALS

Overview of ALS

ALSisadevastatingneurodegenerativediseasewithnocurativetreatmentthataffectsabout30,000patients worldwide.TherearerarefamilialformsofALS(e.g.,duetoDNAmutationsintheSOD1andC9ORF72 genes),butthemajorityofALScasesareconsideredsporadic.Thediseaseisamotorneurondiseaseimpacting boththecentralandperipheralnervoussystems.ALScausesprogressiveweaknessoflimb,respiratory, swallowingandspeakingmuscles,anddeathtypicallyoccurswithintwotofiveyearsaftersymptomonset. Thereisevidencethatneurodegenerationbeginsperipherally,attheneuromuscularjunction,orNMJ,andthen proceedsproximallytoinvolvetheperipheralmotornerves,ventralnerveroots,spinalcordandbrainmotor cortex(“dyingback”neurodegeneration).TheNMJisaspecializedsynapsebetweenperipheralmotornerveand musclefiber.As

illustratedbelow,“dyingback”oftheperipheralnerveinALSisassociatedwithC1q/classical complementdepositionon the NMJ.

C1qinvolvementin ALS

C1q and classical pathway activation is elevated in ALS patients. Specifically, C1q deposition has been noted in NMJs and C4d levels are increased in the CSF of ALS patients.

As shown below in a preclinical model of ALS, muscle levels of C1q (at NMJs) increased with age (left panel) and were observed to correlate with decline in muscle strength (right panel).

OurgoalwithourC1qinhibitoristopreventlossofNMJsandhenceprevent“dyingback” neurodegenerationofmotornervesinpatientswithALS.Ofnote,thereissignificantoverlapintheperipheral nervestructuresthatareinvolvedinbothGBSandALS;therefore,webelieveourANX005pharmacokinetics and pharmacodynamicsdata in GBSpatientscan be extrapolatedto ALSpatients.

Likewise,inanexperimentalmodelofSMA,anotherperipheralnervedegenerativediseasethatis pathologicallysimilartoALS,wefoundthattreatmentwithanti-C1qantibody(mouseprecursorofANX005) protectedagainstsynapselossandimprovedmotorfunction.Thesameperipheralnervepathwayisinvolvedin GBSand ALS,as illustratedbelow.

Thesameperipheralnerve pathwayisinvolved inGBSandALS

NfL is elevated in ALS patients

ALSpatientshavesubstantialelevationsofNfLinbothCSFandserumcomparedwithcontrolsandpre-symptomaticmutationcarriers.InALSpatients,serumlevelsofNfL increaseintheyearpriortoonsetofdisease symptoms(seebelow).Inaddition,ithasbeenobservedthatNfLlevelsinALSpatientscorrelatebothwith currentdisabilityand futurepatientoutcomes.

Serum NfL Elevated inALS Patientsa Year PriortoSymptom Onset

Developmentof ANX005in ALS

We are currently conducting an open-label Phase 2 trial in ALS patients to evaluate ANX005’s ability to inhibit C1q in the CSF and to reduce NfL levels in serum in ALS patients. We anticipate reporting data from this trial in 2023. Based on the results of this trial, we will evaluate whether to initiate a potential registrational program for ALS.

If either of the HD or ALS Phase 2 trials are successful, we will consider proof-of-concept studies in other CNS neurodegenerative indications,suchasAlzheimer’sdisease,frontotemporaldementiaandprogressivemultiplesclerosis.

Our Second Product Candidate, ANX007

ANX007isaninvestigationalmonoclonalantibodyantigen-bindingfragment,orFab,thatisdesignedtopotentlybindtoC1qandinhibitactivationoftheclassicalcomplementcascade.WeactivatedanINDforANX007in2018andaredevelopingANX007asanintravitrealinjectionforophthalmicindicationssuchasglaucomaandgeographicatrophy.WehaveconductedaPhase1btrialofANX007inpatientswithglaucoma,andbasedontheseandpreclinicalstudyresults,webelieveANX007mayhavepotentialtotreatpatientswithGA.

ANX007 for the Treatment of Ophthalmic Diseases, including Glaucoma and Geographic Atrophy

Overview of Glaucoma

Glaucoma is a major cause of blindness and results from progressive loss of neurons in the retina called Retinal Ganglion Cells, and optic nerve degeneration. A frequent risk factor for glaucoma is elevated intraocular pressure, or IOP, but there are patients with “normotensive” glaucoma who have normal IOP. Patients with glaucoma have progressive loss of peripheral vision, which can eventually result in functional blindness.

It is estimated that over three million people in the United States have glaucoma but only half of these people have been diagnosed. More than 120,000 people in the United States are blind due to glaucoma, accounting for 9 to 12% of all cases of blindness.Theworldwideprevalenceofglaucomahasbeenestimatedto beover60millionpeople.Glaucomaisadiseasethatismorefrequentlyfoundinolderadultswithrates increasingseveralfoldbetweenages50and70.Similartootherneurodegenerativediseases,theoverall prevalenceof glaucomais projectedto increaseas populationsage worldwide.

Glaucomaisoneofthelargestsegmentsoftheglobalophthalmicmarketandhasasignificantimpactonthe qualityoflife.Patients’abilitytoperformdailyactivitiesbecomesincreasinglylimitedasthediseaseprogresses. Individualswithglaucomaaremorelikelytoexperiencefalls,tobeinvolvedinmotorvehiclecollisions,to sufferdepressionand to requireadmissionto a nursinghome.

ThegoalofexistingtherapiesforglaucomaisreductionofIOP.IOP-loweringtreatmentsaretypically administeredintheformofeyedrops,andpatientsmayrequiresurgerytofacilitatedrainageoffluidintheeye. However,approximatelytenpercentofpeoplewho receiveappropriatetreatmentneverthelesscontinueto experienceprogressivevisionloss.Theopticnervedamageobservedinglaucomaisbelievedtobeirreversible, highlightingthe need for neuroprotectivetherapiesthatcan slow or stop the damageto opticnerves.

Role of C1q in Glaucoma

C1q,theinitiatingmoleculeoftheclassicalcomplementcascade,hasbeenimplicatedintheprogressionof neurodegenerativedisease,includingglaucoma.Thelabofourscientificfounder,Dr.BenBarres,reportedthat C1qaccumulatedonretinalneuronsandtheirsynapsesearlyinthediseaseprocessinachronicmousemodelof glaucoma,beforetheonsetofotherobservablechanges.C1qaccumulationcontinuedassynapseswerelost, followedbylossoftheopticnerve.SubsequentstudiesshowedthatgeneticdeletionofC1qprotectedagainst opticnerve damagein a chronicmouse modelof glaucomaat 12 monthsof age (leftpanel, figurebelow).

UsingpharmacologicalinhibitionofC1qwithANX007,weobservedthesefindingsinadifferentmouse modelofglaucomainvolvingacuteelevationofIOP.Inthismodel,animalsreceivedanintravitrealinjectionof theM1-FabmurineprecursorofANX007atthetimeofIOPelevation,followedbyaseconddoseoneweek later,andtheirretinaswereexaminedatweek2.Asshownintherightpanelofthefigurebelow,intravitreal administrationof ANX007protectedagainstopticnerve damage.

IndependentinvestigatorsobservedelevatedlevelsofC1qandothercomponentsoftheclassical complementcascadeintheinnerretinalsynapselayerof34outof34humandonoreyesfrompatientswith glaucoma,as illustratedbelow. C1qwas not found in donor eyes fromindividualswhodid not have glaucoma.

Overview of Geographic Atrophy

GAisan advanced, vision-threatening form of age-related macular degeneration, or AMD, and is a chronic, progressive disease of the macula that results in loss of central vision. The disease typically affects one eye first, with a high likelihood of it occurring in the second eye over time.

There are two forms of AMD, “dry” AMD and “wet” AMD. Dry AMD is the most common form, representing approximately 85% to 90% of all AMD cases. Geographic atrophy represents the advanced form of dry AMD and is characterized by progressive atrophy of retinal pigment epithelial cells, overlying photoreceptors and underlying choriocapillaries. An early feature of the disease is the presence of drusen, which is comprised of extracellular yellow deposits at the back of the retina.

GA accountsforabouttenpercentoflegalblindnessrelatedtoAMD.Approximatelyonemillion individualsintheUnitedStatesandfivemillionindividualsworldwidesufferfromgeographicatrophy.Aswith AMD, theprevalenceofgeographicatrophyincreaseswithage. There are no approved therapiesto preventeither the onset or progressionof geographicatrophy.

Role of C1qand Complement in Geographic Atrophy

Genome-wideassociationstudieshavestronglyimplicatedmultiplecomponentsofthecomplementcascadein AMDandgeographicatrophy.Forexample,specificallelesofthegeneforC3canincreasethelikelihoodof developingAMDby50percent.Histopathologicalinvestigationshavealsoobservedthepresenceofcomplement componentsingeographicatrophy.ThesestudieslargelypointtoaroleofexcessiveC3activityindisease,butdonot indicatehowC3isbeingactivated(classical,lectinoralternativepathways).Wehaveidentifiedapotentialdualroleof C1qandtheclassicalcascadeasanimportantcomplement-activatingsystemingeographicatrophy.First,wefound thatC1qstronglyaccumulated on photoreceptorcell synapses with normal ageor disease, as shown below (leftpanels), implicatingC1q’sroleinexcessivesynapsepruningandcomplement-mediatedneurodegeneration.Second,C1qand C1qligands,suchasC-reactiveprotein,alsoaccumulatedintheretinabelowphotoreceptorcellsinassociationwith drusen(extracellularmembraneandproteindebrisassociatedwithgeographicatrophy;rightpanel).Theseresults suggestthatthephotoreceptorneuronsandpigmentedretinalepithelialcells–celltypesthatarebothlostinGA–are sandwichedbetweendepositsofC1qandthattheclassicalcomplementcascademayhaveanongoingandpathogenic role in GA by activating C3.

In support of this hypothesis, we found that either deletion or pharmacologic inhibition of C1q was protective in an animal model of photoreceptor neuron loss induced by photo-oxidation, as shown below. Further, components of the classical complement cascade have been associated with photoreceptor cells in human GA tissue (C4 and C3) and implicated in photoreceptor cell targeting with an in vitro assay. Finally, C1q is locally produced within the retina during disease by infiltrating immune cells, indicating that its pathogenic role may be amenable to local inhibition of C1q. As described above, we believe inhibition of C1q would block all key components of the classical cascade, including C1q, C4, and C3 involved in immune cell attack and synapse pruning, as well as C5 involved in direct membrane damage.

As shown below, C1q inhibition was protective of photoreceptor cells and retinal function ina model of GA.

Developmentof ANX007for OphthalmicDiseases

WehavecompletedaPhase1btrialofANX007inpatientswithglaucoma.BasedonourPhase1bclinical resultsinglaucoma,ourpreclinicaldatashowingprotectioninthreeretinalneurodegenerationanimalmodels (glaucoma,opticneuritisandGA),andourknowledgeofC1qbiologyinthissetting,weinitiated a Phase 2 trial of ANX007in GA. Our rationaleto pursue ANX007for GAincludes:

• There is a well-established clinical and regulatory path for development.

Phase 1b Trial in Glaucoma

Wecompletedsingleascendingdose(n=9)andsham-controlledmultipledose(n=17)studiesofintravitreal ANX007inpatientswithglaucomatoevaluatesafety,tolerability,pharmacokineticsandtargetengagement. ThesepatientshadaqueoushumortapssothatocularfluidcouldbeanalyzedforlevelsofANX007 andfreeC1q immediatelypriortofirstdose(day1)andpriortoseconddose(day29).ThestudiesshowedthatANX007was well-toleratedatalldoses(1mg,2.5mg,5mg)andachievedcompletesuppressionofC1qat2.5mgand5mg, asillustratedbelow.WebelievetheseresultssuggestthatANX007canbedosedmonthlyorpotentiallyless

frequentlyinfuturePhase2efficacytrials.WeareexploringfurtherdevelopmentofANX007thatcouldenablepatientsto be dosed as infrequentlyas every six months.

Ongoing Phase 2 Trialin Geographic Atrophy

Arandomized, controlledPhase2trial inGApatients whoareatahighriskof progression is ongoing, and weanticipatereportingdatafromthistrialin2023.Priornaturalhistorydatasimilartothat foundinotherrecentlargePhase 3 trials may provide a wealth of natural history data from nearly 2,000 patients on how to successfully enrich fast progressors of GA to enable an efficacy read-out within a one-year time period. The Phase 2 trial is designed to evaluate clinical effect on slowing of GA lesion growth, leveraging the natural history data and patient selection criteria of prior GA trials.

Our Third Product Candidate, ANX009

ANX009is designed to potently bind to C1q and inhibit activation of the classical complement cascade. ANX009isaFabdesignedforsubcutaneousdelivery,andwaswelltoleratedinpreclinicaltoxicologystudies. APhase 1 FIH clinical trial was completed in 2021 and data showed that ANX009 was well tolerated and showed complete and sustained C1q inhibition, supporting potential twice weekly subcutaneous administration.

ANX009 for Future Autoimmune Indications

WearedevelopingANX009to potentiallyenablechronicdosing in antibody-mediated autoimmunediseases such ashemolyticanemias, wAIHAandCAD.Inaddition,weareevaluatingANX009asatreatmentoptionforasubsetoflupusnephritis patientswhoareatahighriskofrenalflareduetopathogenicanti-C1qantibodiesinthecirculation,andwho we believe mayrespondtotreatmentwithouranti-C1qapproach.Forthispurpose,we

haveidentifiedaplasma biomarkerthatidentifieslupus nephritispatientswith ongoing earlyclassicalcomplementcascadeactivation.

WehaveobservedthatdailysubcutaneousadministrationofANX009fullyinhibitedC1q functionalactivity intheserumofnon-humanprimates.Itsactivityoccurredrapidlyafterthefirstdoseandthisactivityrapidly reversedafterdosing was stopped.

Webelieve that ANX009’s inhibitory activity and its on/off function may benefit patients with hematological autoimmune disorders. Importantly,the use of plasma biomarkers that define an active complementsignaturewillallowustotakeaprecisionmedicineapproachtoidentifypatientsappropriatefor anti-C1qtherapy.

Our Next-Generation Product Candidates

Wearedevelopingnext-generationproductcandidates,includingANX105,aninvestigationalmonoclonalantibodydesigned to have enhanceddosingandPKpropertiesfacilitatinguseinchronicneurodegenerativediseases.We plan to initiate a FIH trial of ANX105 in the first half of 2022 with data expected in 2023. Oursmallmolecule program is targeting compounds suitable for oral dosing for the treatment of chronic autoimmune and neurodegenerative diseases. We are developing ANX1502, an investigational oral small molecule for the treatment of autoimmune indications, and plan to initiate a FIH clinical trial in the second half of 2022 with data anticipated in 2023.

Intellectual Property

Our intellectual property is critical to our business and we strive to protect it, including by obtaining and maintaining patent protection in the United States and internationally for our product candidates, new therapeutic approaches and potential indications, and other inventions that are important to our business. Our policy is to seek to protect our proprietary and intellectual property position by, among other methods, filing U.S. and foreign patent applications related to our proprietary technology, inventions and improvements that are important for the development and implementation of our business. We also rely on the skills, knowledge and experience of our scientific and technical personnel, as well as that of our advisors, consultants and other contractors. To help protect our proprietary know-how that is not patentable, we rely on confidentiality agreements to protect our interests. We generally require our employees, consultants, scientific advisors and contractors to enter into confidentiality agreements prohibiting the disclosure of confidential information and requiring disclosure and assignment to us of the ideas, developments, discoveries and inventions important to our business.

Our patent portfolio includes patents and patent applications that are licensed to us in whole or in part from a number of partners, including Stanford University and the University of California, and patents and patent applications that are owned by us. Our proprietary technology has been primarily developed by in-house research and development programs, and to a lesser extent through acquisitions, relationships with academic research centers and contract research organizations.

For our product candidates, we will, in general, initially pursue patent protection covering compositions of matter and methods of use. Throughout the development of our product candidates, we seek to identify additional means of obtaining patent protection that would potentially enhance commercial success, including by protecting inventions related to additional methods of use, processes of making, formulation and dosing regimens.

As of January 15, 2022, our patent portfolio, including patents licensed from our partners, comprised 15 different patent families filed in various jurisdictions worldwide. Our patent portfolio includes issued patents and patent applications in the United States and in other jurisdictions.

One patent family, which we exclusively license from Stanford University, includes nine granted U.S. patents covering various methods of treating neurodegeneration and related medical conditions by inhibiting the C1 complex or its components, such as by using an anti-C1q antibody. The U.S. patents in this family include claims covering uses of ANX005, ANX007, ANX009 and ANX105. These U.S. patents will expire between 2026 and 2030, absent any disclaimers, extensions or adjustments of patent term. There are no pending applications or foreign patents in this family.

Two other patent families, which we own, are directed to anti-C1q antibodies and methods of using them. These families include five granted U.S. patents, two pending U.S. patent applications, 15 granted foreign patents and 24 pending foreign patent applications. The U.S. patents in these families cover ANX005, ANX007, ANX009 and ANX105. These patents will expire between 2034 and 2037, absent any disclaimers, extensions or adjustments of patent term.

Another patent family that we own includes one granted U.S. patent, one pending U.S. patent application, one granted foreign patent, and 13 pending foreign patent applications. The granted U.S. patent in this family includes claims directed to antibody fragments of anti-C1q antibodies, including ANX007 and ANX009. This patent will expire in 2037, absent any disclaimers, extensions or adjustments of patent term.

Two other patent families that we own include two U.S. patent applications. The U.S. patent applications in these families include claims directed to anti-C1q antibodies, including ANX105. Patents that may be issued from this family would expire in 2042, absent any disclaimers, extensions or adjustments of patent term.

Another patent family that we own includes one pending U.S. patent application, one pending Patent Cooperation Treaty, or PCT, application, and three pending foreign patent applications. The pending U.S. patent application in this family includes claims covering certain small molecule modulators of the classical pathway, including ANX1502. Patents that may be issued from this family would expire in 2041, absent any disclaimers, extensions or adjustments of patent term.

Our patent portfolio also includes eight patent families, owned by us solely or jointly with the University of California or The J. David Gladstone Institutes or Fondazione Telthon and Universitia degla Studi di Trento, directed to the treatment of certain medical conditions using anti-C1q antibodies, including ANX005, ANX007, ANX009 and ANX105. These families include four pending U.S. patent applications, one granted foreign patent, five pending foreign patent applications, and four pending PCT applications. Patents that may be issued from these applications would expire between 2034 and 2042, absent any disclaimers, extensions or adjustments of patent term.

Exclusive (Equity) Agreement with The Board of Trustees of the Leland Stanford Junior University

In November 2011, we and The Board of Trustees of the Leland Stanford Junior University, or Stanford, entered into an exclusive licensing agreement, or the Stanford Agreement. Under the Stanford Agreement, Stanford granted to us an exclusive, worldwide, royalty-bearing, sublicensable license, under certain patent rights, or the Licensed Patents, to make, use, offer for sale, sell, import and otherwise commercialize products covered by the Licensed Patents for human or animal diseases, disorders or conditions. We are required to meet certain development and funding diligence milestones for the licensed products.

Under the Stanford Agreement, we are obligated to pay Stanford an upfront payment, license maintenance fees ranging from the single digit to tens of thousands of dollars per year, and milestone payments totaling up to $675,000. We also agreed to make royalty payments at a rate equal to a low single-digit percentage of worldwide net sales of licensed products and a portion of certain sublicensing income we receive from sublicensees at a rate in the low double digit percentages, subject to a specified maximum total payment.

Additionally, in accordance with the terms of the Stanford Agreement, upon closing our first financing event that raised at least $2.0 million, we granted Stanford $150,000 in shares of our redeemable convertible preferred stock. We may also have to pay a fee to Stanford if we assign our rights under the Stanford Agreement to a third party.

We may terminate the Stanford Agreement in its entirety, or as to a particular Licensed Patent or licensed product, for convenience on thirty days’ prior written notice. Stanford may terminate the Stanford Agreement for our breach that remains uncured for forty-five days or if we provide any false report, are delinquent on any report or payment, fail to achieve a milestone or fail to diligently develop and commercialize a licensed product.

Patent Term and Term Extensions

The terms of individual patents are determined based primarily on the filing date of the earliest non-provisional patent application to which a claim of priority is made or the date of patent issuance and the legal term of patents in the countries in which they are obtained. Generally, utility patents issued for applications filed in the United States are granted a term of 20 years from the filing date of the earliest non-provisional patent application to which a claim of priority is made. In addition, in certain instances, the term of a U.S. patent can be extended to recapture a portion of the United States Patent and Trademark Office, or USPTO, delay in issuing the patent as well as a portion of the term effectively lost as a result of the FDA regulatory review period. However, as to the FDA component, the restoration period cannot be longer than five years and the restoration period cannot extend the patent term beyond 14 years from FDA approval for the product covered by that patent. In addition, only one patent applicable to an approved drug may receive the extension, and the extension applies only to coverage for the approved drug, methods for using it and methods of manufacturing it, even if the claims cover other products or product candidates. Where one patent covers multiple products or product candidates, it may only receive an extension for one of the covered products; any extension related to a second product or product candidate must be applied to a different patent. The duration of foreign patents varies in accordance with provisions of applicable local law, but typically is also 20 years from filing date of the earliest non-provisional patent application to which a claim of priority is made, such as a PCT application. All taxes, annuities or maintenance fees for a patent, as required by the USPTO and various foreign jurisdictions, must be timely paid in order for the patent to remain in force during this period of time.

The actual protection afforded by a patent may vary on a product by product basis, from country to country, and can depend upon many factors, including the type of patent, the scope of its coverage, the availability of regulatory-related extensions and the availability of legal remedies in a particular country and the validity and enforceability of the patent.

Our patents and patent applications may be subject to procedural or legal challenges by others. We may be unable to obtain, maintain and protect the intellectual property rights necessary to conduct our business, and we may be subject to claims that we infringe or otherwise violate the intellectual property rights of others, which could materially harm our business. For more information, see the section titled “Risk Factors—Risks Related to Our Intellectual Property.”

Trademarks and Know-How

In connection with the ongoing development and advancement of our products and services in the United States and various international jurisdictions, we seek to create protection for our marks and enhance their value by pursuing trademarks and service marks where available and when appropriate. In addition to patent and trademark protection, we rely upon know-how and continuing technological innovation to develop and maintain our competitive position. We seek to protect our proprietary information, in part, by using confidentiality agreements with our commercial partners, collaborators, employees and consultants, and invention assignment agreements with our employees and consultants. These agreements are designed to protect our proprietary information and, in the case of the invention assignment agreements, to grant us ownership of technologies that are developed by our employees and through relationships with third parties. These agreements may be breached, and we may not have adequate remedies for any breach. In addition, our trade secrets may otherwise become known or be independently discovered by competitors. To the extent that our contractors, commercial partners, collaborators, employees and consultants use intellectual property owned by others in their work for us, disputes may arise as to the rights in related or resulting know-how and inventions. For more information, see the section titled “Risk Factors—Risks Related to Our Intellectual Property.”

Sales andMarketing

We hold worldwide commercialization rights, including through exclusive licenses, to our product candidates. Given our stage of development, we have not yet established a commercial organization or distribution capabilities. Should any of our product candidates be approved for commercialization, we intend to develop a plan to commercialize them in the United States and other key markets, through internal infrastructure and/or external partnerships in a manner that will enable us to realize the full commercial value of our programs.

Manufacturing

Oursuccessasacompanywilldependonourabilitytodeliverreliable,high-qualitypreclinicalandclinical drugsupply.Wedonotcurrentlyownoroperatefacilitiesforproductmanufacturing,storageanddistribution,or testing.Wecontractwiththirdpartiesforthemanufactureofour productcandidates.Because werelyon contract manufacturers,weemploypersonnelwithextensivetechnical,manufacturing,analyticalandqualityexperience. Ourstaffhasstrongprojectmanagementdisciplinetooverseecontractmanufacturingandtestingactivities,and to compilemanufacturingand qualityinformationfor our regulatorysubmissions.

Manufacturingissubjecttoextensiveregulationthatimposesvariousproceduralanddocumentation requirementsandthatgovernsrecordkeeping,manufacturingprocessesandcontrols,personnel,qualitycontrol andqualityassurance,andmore.Oursystemsandourcontractorsarerequiredtobeincompliancewiththese regulations,andcomplianceisassessedregularlythroughmonitoringofperformanceandaformalaudit program.

Ourcurrentsupplychainsforourleaddrugcandidatesinvolveseveralmanufacturersthatspecializein specificoperationsofthemanufacturingprocess,specifically,rawmaterialsmanufacturing,drugsubstance manufacturinganddrugproductmanufacturing.Wecurrentlyoperateunderworkorderprogramsforourdrug candidateswithmasterservicesagreementsinplacethatincludespecificsupplytimelines,volumeandquality specifications.Weintendtoestablishlong-termsupplyagreementsinthefuture.Webelieveourcurrent manufacturershave the scale,the system, and the experienceto supply our currentlyplanned clinicaltrials.

Wedonotcurrentlyrequirecommercialmanufacturingcapabilities.Shouldourneedschange,wewillneed toscaleupourmanufacturingprocessestoenablecommerciallaunch.Toensurecontinuityinoursupplychain, weplantoestablishsupplyarrangementswithalternativelargerscalesuppliersforcertainportionsofoursupply chain, as appropriate.

Competition

The pharmaceutical, biopharmaceutical and biotechnology industries are characterized by rapidly advancing technologies, intense competition and a strong emphasis on proprietary products. While we believe that our technology, the expertise of our executive and scientific team, research, clinical capabilities, development experience and scientific knowledge provide us with competitive advantages, we face potential competition from many different sources, including pharmaceutical, biopharmaceutical and biotechnology companies, academic institutions, governmental agencies and public and private research institutions. Product candidates that we successfully develop and commercialize may compete with existing therapies and new therapies that may become available in the future.

Our competitors may have significantly greater financial resources, established presence in the market, expertise in research and development, manufacturing, preclinical and clinical testing, and experience in obtaining regulatory approvals and reimbursement and marketing approved products than we do. These competitors also compete with us in recruiting and retaining qualified scientific, sales, marketing and management personnel, establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.

Guillain-BarréSyndrome

TherearecurrentlynoapprovedtherapiesforGBSintheUnitedStates.IVIgandplasmaexchangearethe currentstandardsofcareintheWesternworldandpartsofAsia and two products are in development.HansaBiopharmaAB is conductinganopenlabel Phase 2 trialof imlifidase in GBSpatients in Europe and AstraZeneca/Alexion is conducting a Phase 3 study of SOLIRIS in GBS in Japan.

Autoimmune HemolyticAnemias

There are currently no approved therapies for wAIHA in the United States and three products are in development in Phase 3 trials. Rigel is running a Phase 3 clinical trial of Tavalisse in wAIHA. Incyte initiated a Phase 3 wAIHA trial with parsaclisib, an oral PI3K delta inhibitor in January 2022. In addition, Janssen is conducting a Phase 2/3 trial of nipocalimab, an anti-neonatal Fc receptor antibody for wAIHA.

Sanofi’s sutimlimab is approved by the FDA for CAD. Other companies that have trials ongoing or planned in these rare anemias include Sanofi’s rilzabrutinib for wAIHA, Immunovant’s IMVT-1401 for wAIHA, Novartis’s iptacopan for CAD in Phase 2 and Sanofi’s BIVV020 for CAD in Phase 1.

Lupus Nephritis

There are currently two approved medicines specifically for LN: GSK’s Benlysta and Aurinia’s Lupkynis. There are three products in development targeting the complement pathway, all in Phase 2 development: AstraZeneca’s ravulizumab, a C5 inhibitor, and ALXN2050, an oral Factor D inhibitor, as well as Omeros’s narsoplimab, a MASP-2-targeting monoclonal antibody. Outside of the complement pathway, there are four products in Phase 3 development: Roche’s Obinutuzumab, Novartis’s secukinumab and ianalumab and AstraZeneca’s anifrolumab.

Huntington’sDisease

There are no approved disease-modifying therapies for HD. Multiple companies are developing potentially disease-modifying therapies, including Prilenia’s Pridopidine in Phase 3, PTC Therapeutics’s PTC518 in Phase 2, and uniQure’s AMT-130 in Phase 1. Additional early-stage products in development are Wave Life Sciences’s WVE-003 in Phase and Novartis’s branaplam in Phase 2.

AmyotrophicLateralSclerosis

The drugs riluzole and Radicava (edaravone) are currently approved for the treatment of ALS and have shown modest effects in slowing the progression of the disease. Amylyx has completed a Phase 3 trial and submitted AMX0035 for approval to the FDA. Zilucoplan, a C5a inhibitor from UCB, is in a Phase 2/3 study as a part of the HEALY ALS platform trial. Apellis has also initiated a Phase 2 study with APL-2, their C3-inhibitor. There are a significant number of companies conducting clinical trials in ALS patients, including Ionis, NurOwn, Biohaven, Prilenia, Cytokinetics and others.

Geographic Atrophy

No FDA-approved treatment is currently available for GA. We are aware of a number of companies developing products for the treatment of GA. Those products in clinical development targeting the complement cascade include: Apellis’s APL-2, a C3 inhibitor, which has completed a Phase 3 trial; Iveric Bio’s zimura, a C5 inhibitor in a Phase 3 trial; NGM Pharma’s NGM621, a C3 inhibitor in a Phase 2 trial; Ionis’s IONIS-FB-LR, an antisense molecule inhibitor of Complement Factor B in a Phase 2 trial; AstraZeneca’s danicopan, an oral, complement factor D inhibitor in a Phase 2 trial and Gemini Therapeutics’s GEM103, a recombinant complement factor H in a Phase 2 trial. Complement-directed therapies in clinical development for genetically selected patient populations include GT005, a Factor I gene therapy in Phase 2 development by Gyroscope, and GEM103, a Factor H replacement therapy in a Phase 2 trial being developed by Gemini Therapeutics. Other products that do not target the complement cascade currently in Phase 2 or 3 clinical trials are being developed by Roche, Stealth BioTherapeutics, Allegro, Alkeus Pharmaceuticals and Regenerative Patch Technologies.

GovernmentRegulation

TheFDAandotherregulatoryauthoritiesatfederal,stateandlocallevels,aswellasinforeigncountries, extensivelyregulate,amongotherthings,theresearch,development,testing,manufacture,qualitycontrol, import,export,safety,effectiveness,labeling,packaging,storage,distribution,recordkeeping,approval, advertising,promotion,marketing,post-approvalmonitoringandpost-approvalreportingofproduct candidatessuchasthosewearedeveloping.A new drug must be approved by the FDA through the new drug application, or NDA, process and a new biologic must be approved by the FDA through the biologics license application, or BLA, process before it may be legally marketed in the U.S. We, along with third-party contractors, will be required to navigate the various preclinical, clinical and commercial approval requirements of the governing regulatory agencies of the countries in which we wish to conduct studies or seek approval or licensure of our productcandidates.The processofobtainingregulatoryapprovalsandthesubsequentcompliancewithapplicablefederal,state,localand foreignstatutesand regulationsrequirethe expenditureof substantialtimeand financialresources.

U.S. Biologics Regulation

In the U.S., the FDA regulates drugs under the federal Food, Drug, and Cosmetic Act, or FDCA, and in the case of biologics, also under the Public Health Service Act, or PHSA, and their implementing regulations. The processrequiredbytheFDAbefore a drug orbiologicmaybemarketedintheUnitedStatesgenerally involvesthe following:

• satisfactory completion of an FDA Advisory Committee review, if applicable;

Preclinical studies include laboratory evaluation of product chemistry, toxicity and formulation, as well as animal studies to assess potential safety and efficacy. Prior to beginning the first clinical trial with a product candidate in the United States, a sponsor must submit an IND to the FDA, which isarequestforauthorizationfromtheFDAtoadministeraninvestigationalnewdrug producttohumans.ThecentralfocusofanINDsubmissionisonthegeneralinvestigationalplanandthe protocol(s)for the proposed clinicaltrial(s).TheINDalsoincludesresultsofanimalandinvitrostudiesassessingthetoxicology,pharmacokinetics,pharmacologyandpharmacodynamiccharacteristicsoftheproduct;chemistry, manufacturingandcontrolsinformation;andanyavailablehumandataorliteraturetosupporttheuseofthe investigationalproduct.An IND mustbecome effectivebeforehuman clinicaltrialsmay begin. The IND automatically goes into effect 30daysafterreceiptbytheFDA,unlesstheFDA,withinthe30-daytime period,raisessafetyconcernsorquestionsabouttheproposedclinicaltrial.Insuchacase,theINDmaybe placedonclinicalholdandtheINDsponsorandtheFDAmustresolveanyoutstandingconcernsorquestions beforetheclinicaltrialcanbegin.SubmissionofanIND thereforemayormaynotresultinFDA authorizationto begin a clinicaltrial.

Clinicaltrialsinvolvetheadministrationoftheinvestigationalproducttohumansubjectsunderthe supervisionofqualifiedinvestigatorsinaccordance with GCP, which include the requirement that all research subjects provide their informed consent for their participation in any clinical trial. Clinical trials are conducted under protocols detailing, among other things, the objectives of the study, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated. A separate submission to the existingINDmust bemadeforeachsuccessiveclinicaltrialconductedduringproductdevelopmentandforanysubsequentprotocol amendments.While the IND is active, progress reports summarizing the results of the clinical trials and nonclinical studies performed since the last progress report, among other information, must be submitted at least annually to the FDA, and written IND safety reports must be submitted to the FDA and investigators for serious and unexpected suspected adverse events, findings from other studies suggesting a significant risk to humans exposed to the same or similar drugs, findings from animal or in vitro testing suggesting a significant risk to humans, and any clinically important increased incidence of a serious suspected adverse reaction compared to that listed in the protocol or investigator brochure.

Furthermore,anindependentIRB or ECforeachsiteproposingtoconducttheclinicaltrialmustreview andapprovetheplanforanyclinicaltrialanditsinformedconsentformbeforetheclinicaltrialbeginsatthat site,andmust monitor the trial until completed. Some studies also include oversight by an independent group of qualified experts organized by the clinical trial sponsor, known as a Data Safety Monitoring Board, which provides authorization for whether or not a trial may move forward at designated check points based on access to certain data from the study and may halt the clinical trial if it determines that there is an unacceptable safety risk for subjects or other grounds, such as no demonstration of efficacy. Regulatory authorities, the IRB/ethics committee or the sponsor may suspend a clinical trial at any time on various grounds, including a finding that the subjects are being exposed to an unacceptable health risk or that the trial is unlikely to meet its stated objective(s). There are also requirements governing the reporting of ongoing clinical trials and clinical trial results to public registries.

ForpurposesofBLA or NDA approval,humanclinicaltrialsaretypicallyconductedinthreesequentialphasesthat may overlapor be combined:

In some cases, the FDA may require, or companies may voluntarily pursue, additional clinical trials after a product is approved to gain more information about the product. These so-called Phase 4 trials may also be made a condition to approval of the BLA or NDA.

Concurrent with clinical trials, companies may complete additional animal studies and develop additional information about the biological characteristics of the product candidate and must finalize a process for manufacturing the product in commercial quantities in accordance with cGMPs. The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other things, must develop methods for testing the identity, strength, quality and purity of the final product. Additionally, appropriate packaging must be selected and tested and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life.

FDA Review and Approval Process

Assumingsuccessfulcompletionofallrequiredtestinginaccordancewithallapplicableregulatory requirements,theresultsofproductdevelopment,nonclinicalstudiesandclinicaltrialsaresubmittedtotheFDA aspartofaBLA or NDArequestingapprovaltomarkettheproduct candidateforoneormoreindications.TheBLA or NDA mustinclude allrelevantdataavailablefrompreclinicalstudiesandclinicaltrials,includingnegativeorambiguousresultsaswellaspositivefindings,togetherwithdetailedinformationrelatingtotheproduct’schemistry,manufacturing, controlsandproposedlabeling,amongotherthings.Datacancomefromcompany-sponsoredclinicaltrials intendedtotestthesafetyandeffectivenessofauseoftheproduct candidateorfromanumberofalternativesources, includingstudiesandtrialsinitiatedbyinvestigators.ThesubmissionofaBLA or NDArequirespaymentofasubstantial userfeetotheFDA,andthesponsorofanapprovedBLA or NDAisalsosubjecttoanannualprogramfee.Awaiverof userfeesmaybeobtainedundercertainlimitedcircumstances.Additionally,nouserfeesareassessedonBLAs or NDAs for productsdesignatedas Orphan Drugs, unlessthe applicationalso seeksa non-orphan-designatedindication.

Within 60 days following submission of the application, the FDA reviews a BLA or NDA submitted to determine if it is substantially complete before the FDA accepts it for filing. The FDA may refuse to file any BLA or NDA that it deems incomplete or not properly reviewable at the time of submission and may request additional information. In this event, the BLA or NDA must be resubmitted with the additional information. OnceaBLA or NDAhasbeen accepted for filing,theFDA’sgoalistoreviewstandardapplicationswithintenmonthsafter itacceptstheapplicationforfiling,or,iftheapplicationqualifiesforpriorityreview,sixmonthsafterthefiling date.Priorityreviewdesignationwilldirectoverallattentionandresourcestothe evaluationofapplicationsforproductsthat,ifapproved,would representsignificantimprovementsinthesafetyor effectivenessofthetreatment,diagnosisorpreventionofseriousconditions.Inbothstandardandpriority reviews, thereviewprocess isoften significantlyextendedbyFDArequestsforadditional information or clarification.The FDA reviews an NDA to determine, among other things, whether a product is safe and effective for its intended use and whether its manufacturing is cGMP‐compliant to assure and preserve the product’s identity, strength, quality and purity. TheFDAreviewsaBLAtodetermine,amongotherthings,whetheraproductissafe,pureand potentandthefacilitiesinwhichitismanufactured,processed,packedorheldmeetstandardsdesignedtoassure theproduct’scontinuedsafety,purityandpotency.TheFDAmayalsoconvenea public AdvisoryCommitteeto provide additional expert

insightonapplicationreviewquestions.TheFDAisnotboundbyrecommendationsofan Advisory Committee, but it considerssuch recommendationswhenmakingdecisionsregardingapproval.

BeforeapprovingaBLA or NDA,theFDAwilltypicallyinspectthefacilityorfacilitieswheretheproduct candidateis manufactured.TheFDAwillnotapproveanapplicationunlessitdeterminesthatthemanufacturingprocesses andfacilitiesareincompliancewith cGMP requirementsandadequatetoassureconsistentproductionoftheproduct candidatewithinrequired specifications.Additionally,beforeapprovingaBLA or NDA,theFDAwilltypicallyinspectoneormoreclinicalsites and/orthesponsor’sofficestoassurecompliancewithGCP.

AftertheFDAevaluatesaBLA or NDAandconductsinspectionsofclinicaltrialsitesandmanufacturingfacilities wheretheinvestigationalproductand/oritsdrugsubstancewillbeproduced,theFDAmayissueanApproval LetteroraCompleteResponseLetter.An ApprovalLetterauthorizescommercialmarketingoftheproductwith specificprescribinginformationforspecificindications.ACompleteResponseLetterindicatesthattheBLA or NDAis notreadyforapprovalinitspresentformandendsthecurrentreviewcycle, andwilldescribeallofthe deficienciesthattheFDAhasidentifiedintheBLA or NDA. TheFDAmayissuetheCompleteResponseLetterwithout firstconductingrequiredinspections,testingsubmittedproductlots,and/orreviewingproposedlabeling.In issuingtheCompleteResponseLetter,theFDAmayrecommendactionsthattheapplicantmighttaketoplace theBLA or NDAinconditionforapproval,includingrequestsforadditionalinformationorclarification.TheFDAmay delayorrefuseapprovalofaBLA or NDAifapplicableregulatorycriteriaarenotsatisfied,requireadditionaltestingor informationand/orrequirepost-marketingtestingand surveillanceto monitorsafetyor efficacyof a product.

Ifregulatoryapprovalofaproductisgranted,suchapprovalwillbegrantedforparticularindicationsand mayentaillimitationsontheindicatedusesforwhichsuchproductmay be marketed.Additionally,the FDAmay approveaBLA or NDAwithaRiskEvaluationandMitigationStrategy,orREMS,toensurethebenefitsoftheproduct outweighitsrisks.AREMSisasafetystrategy to manage a known or potential serious risk associated with a medicine and to enable patients to have continued access to such medicines by managing their safe use, and could include medication guides, physician communication plans, or elements to assure safe use, such as restricted distribution methods, patient registries, and other risk minimization tools. The FDA also may condition approval on, among other things, changes to proposed labeling or the development of adequate controls and specifications. Once approved, the FDA may withdraw the product approval if compliance with pre- and post- marketing requirements is not maintained or if problems occur after the product reaches the marketplace. The FDA may also require one or more Phase 4 post-marketing studies and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization, and may limit further marketing of the product based on the results of these post-marketing studies.

Expedited DevelopmentandReview Programs

A sponsor may seek approval of its product candidate under programs designed to accelerate FDA’s review and approval of product candidates that meet certain criteria. Specifically, drugs and biologics s are eligible for Fast Track designation if they are intended to treat a serious or life-threatening disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition. For a Fast Track product candidate, the FDA may consider sections of the BLA or NDA for review on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the application, the FDA agrees to accept sections of the application and determines that the schedule is acceptable and the sponsor pays any required user fees upon submission of the first section of the application. A BLA or NDA for a Fast Track-designated product candidate may also qualify for priority review, under which the FDA sets the target date for FDA action on the BLA or NDA at six months after the FDA accepts the application for filing. Priority review is granted when there is evidence that the product candidate, if approved, would provide a significant improvement in the safety or effectiveness of the treatment, diagnosis, or prevention of a serious disease or condition. If criteria are not met for priority review, the application is subject to the standard FDA review period of 10 months after FDA accepts the application for filing.

A product candidate intended to treat a serious or life-threatening disease or condition may also be eligible for Breakthrough Therapy designation to expedite its development and review. A product candidate can receive Breakthrough Therapy designation if preliminary clinical evidence indicates that the product candidate, alone or in

combination with one or more other drugs or biologics, may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. The designation includes all of the Fast Track program features, as well as more intensive FDA interaction and guidance beginning as early as Phase 1 and an organizational commitment to expedite the development and review of the product candidate, including involvement of senior managers.

In addition, a product candidate may be eligible for accelerated approval. Drugs and biologics intended to treat serious or life threatening diseases or conditions may be eligible for accelerated approval upon a determination that the drug or biologic has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or 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. Post-marketing studies or completion of ongoing studies after marketing approval are generally required to verify the drug or biologic’s clinical benefit in relationship to the surrogate endpoint or ultimate outcome in relationship to the clinical benefit. In addition, the FDA currently requires as a condition for accelerated approval pre-approval of promotional materials, which could adversely impact the timing of the commercial launch of the product. The FDA may withdraw approval of a product or indication approved under accelerated approval if, for example, the sponsor fails to conduct any required post-marketing studies in a timely manner, or if such studies fail to verify the predicted clinical benefit of the product.

Fast Track designation, priority review, accelerated approval and Breakthrough Therapy designation do not change the standards for approval but may expedite the development or approval process. Even if a product qualifies for one or more of these programs,theFDAmaylaterdecidethattheproductnolongermeetsthe conditionsfor qualificationor decidethatthe timeperiodfor FDAreview or approvalwill not be shortened.

OrphanDrugDesignation andExclusivity

Under the Orphan Drug Act, the FDA may grant Orphan designation to a drug or biologic intended to treat a rare disease or condition, defined as a disease or condition with a patient population of fewer than 200,000 individuals in the United States, or a patient population greater than 200,000 individuals in the United States and when there is no reasonable expectation that the cost of developing and making available the biologic in the United States will be recovered from sales in the United States for that drug or biologic. Orphan Drug designation must be requested before submitting a BLA or NDA. After the FDA grants Orphan Drug designation, the generic identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA. Orphan designation does not convey any advantage in or shorten the duration of the regulatory review and approval process

If a product candidate that has Orphan Drug designation subsequently receives the first FDA approval for the disease or condition for which it has such designation, the product is entitled to orphan product exclusivity, which means that the FDA may not approve any other applications, including a full BLA or NDA, to market the same biologic for the same disease or condition for seven years, except in limited circumstances, such as a showing of clinical superiority to the product with Orphan Drug exclusivity or if the FDA finds that the holder of the Orphan Drug exclusivity has not shown that it can assure the availability of sufficient quantities of the Orphan Drug to meet the needs of patients with the disease or condition for which the drug was designated. Orphan Drug exclusivity does not prevent the FDA from approving a different drug or biologic for the same disease or condition, or the same drug or biologic for a different disease or condition. Among the other benefits of Orphan Drug designation are tax credits for certain research and development activities and a waiver of the BLA or NDA application user fee.

A designated Orphan DrugmaynotreceiveOrphanDrugexclusivityifitisapprovedforausethatis broader thantheindication forwhichitreceivedOrphandesignation.Inaddition,OrphanDrugexclusive marketingrightsintheUnitedStatesmaybelostiftheFDAlaterdeterminesthattherequestfordesignationwas materiallydefectiveor,asnotedabove,ifthesecondapplicantdemonstratesthatitsproductisclinicallysuperior totheapprovedproductwithOrphanexclusivityorthemanufactureroftheapprovedproductisunabletoassure sufficientquantitiesof the productto meetthe needs of patientswith the rarediseaseor condition.

Post-Approval Requirements

Anydrugs or biologicsmanufacturedor distributed pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to record-keeping, reporting of adverse experiences, periodic reporting, productsamplinganddistribution,andadvertisingand promotionoftheproduct.Afterapproval,mostchangestotheapprovedproduct,suchasaddingnewindications orotherlabelingclaims,aresubjecttopriorFDAreviewandapproval.Therealsoarecontinuing,annual programfeesforanymarketedproducts. Drug and biologicmanufacturersandtheirsubcontractorsarerequiredtoregister theirestablishmentswiththeFDAandcertainstateagencies,andaresubjecttoperiodicunannounced inspectionsbytheFDAandcertainstateagenciesforcompliancewithcGMPs,whichimposecertainprocedural anddocumentationrequirementsuponusandourthird-partymanufacturers.Changestothemanufacturing processarestrictlyregulated,and,dependingonthesignificanceofthechange,mayrequirepriorFDAapproval beforebeingimplemented.FDAregulationsalsorequireinvestigationandcorrectionofanydeviationsfrom cGMPsandimposereportingrequirementsuponusandanythird-partymanufacturersthatwemaydecidetouse. Accordingly,manufacturersmustcontinuetoexpend time,money and effortin the areaof productionand quality controlto maintaincompliancewith cGMPs and otheraspectsof regulatorycompliance.

TheFDAmaywithdrawapprovalifcompliancewithregulatoryrequirementsandstandardsisnot maintainedorifproblemsoccuraftertheproductreachesthemarket.Laterdiscoveryofpreviouslyunknown problemswithaproduct,includingadverseeventsofunanticipatedseverityorfrequency,orwithmanufacturing processes,orfailuretocomplywithregulatoryrequirements,mayresultinrevisionstotheapprovedlabelingto addnewsafetyinformation;impositionofpost-marketstudiesorclinicalstudiestoassessnewsafetyrisks;or impositionofdistributionrestrictionsorotherrestrictionsunderaREMSprogram.Otherpotentialconsequences include,among otherthings:

• fines, Warning Letters, or untitled enforcement letters;

• clinical holds on clinical studies;

• injunctions or the imposition of civil or criminal penalties.

The FDA closely regulates the marketing, labeling, advertising and promotion of drugs and biologics. A company can make only those claims relating to safety and efficacy, purity and potency that are approved by the FDA and in accordance with the provisions of the approved label. The FDA and other agencies actively enforce the laws and regulationsprohibitingthepromotionofso-called “off-label” uses. Failure to comply with these requirements can result in, among other things, adverse publicity, Warning Letters,correctiveadvertisingandpotentialcivilandcriminal penalties.Physiciansmayprescribelegallyavailableproductsforusesthatarenotdescribedintheproduct’s labelingandthatdifferfromthosetestedbyusandapprovedbytheFDA. Suchoff-labelusesarecommonacross medicalspecialties.Physiciansmaybelievethatsuch off-label usesarethebesttreatmentformanypatientsin variedcircumstances.TheFDAdoesnotregulatethebehaviorofphysiciansintheirchoiceoftreatments.The FDAdoes, however, restrictmanufacturer’scommunicationson the subjectof off-labeluse of theirproducts.

BiosimilarsandExclusivity

The Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act, or collectively the ACA, signed into law in 2010, includes a subtitle called the BPCIA, which created an abbreviated approval pathway for biological products that are biosimilar to, or interchangeable with, an FDA-licensed reference biological product. The FDA has issued several guidance documents outlining an approach to review and approval of biosimilars. Biosimilarity, which requires 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 study or studies. Interchangeability requires that a product is biosimilar to the reference product and the product must demonstrate that it can be expected to produce the same clinical results as the reference product in any given patient and, for products that are administered multiple times to an individual, the biologic and the reference biologic 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 biologic.

Under the BPCIA, an application for a biosimilar product may not be submitted to the FDA until four years following the date that the reference product was first licensed by the FDA. In addition, the approval of a biosimilar product may not be made effective by the FDA until 12 years from the date on which the reference product was first licensed. During this 12-year period of exclusivity, another company may still market a competing version of the reference product if the FDA approves a full BLA for the competing product containing that applicant’s own preclinical data and data from adequate and well-controlled clinical trials to demonstrate the safety, purity and potency of its product. The BPCIA also created certain exclusivity periods for biosimilars approved as interchangeable products. At this juncture, it is unclear whether products deemed “interchangeable” by the FDA will, in fact, be readily substituted by pharmacies, which are governed by state pharmacy law.

A biological product can also obtain pediatric market exclusivity in the United States. Pediatric exclusivity, if granted, adds six months to existing exclusivity periods and patent terms. This six-month exclusivity, which runs from the end of other exclusivity protection or patent term, may be granted based on the voluntary completion of a pediatric study in accordance with an FDA-issued “Written Request” for such a study.

Drug Product Marketing Exclusivity

Market exclusivity provisions authorized under the FDCA can delay the submission or the approval of certain marketing applications. For example, the FDCA provides a five-year period of non-patent data exclusivity within the U.S. to the first applicant to obtain approval of an NDA for a new chemical entity. A drug is a new chemical entity if the FDA has not previously approved any other new drug containing the same active moiety, which is the molecule or ion responsible for the action of the drug substance. During the exclusivity period, the FDA may not approve or even accept for review an abbreviated new drug application, or ANDA, or an NDA submitted under Section 505(b)(2), or 505(b)(2) NDA, submitted by another company for another drug based on the same active moiety, regardless of whether the drug is intended for the same indication as the original innovative drug or for another indication, where the applicant does not own or have a legal right of reference to all the data required for approval. However, an application may be submitted after four years if it contains a certification of patent invalidity or non-infringement to one of the patents listed with the FDA by the innovator NDA holder.

The FDCA alternatively provides three years of marketing exclusivity for an NDA, or supplement to an existing NDA if new clinical investigations, other than bioavailability studies, that were conducted or sponsored by the applicant are deemed by the FDA to be essential to the approval of the application, for example new indications, dosages or strengths of an existing drug. This three-year exclusivity covers only the modification for which the drug received approval on the basis of the new clinical investigations and does not prohibit the FDA from approving ANDAs or 505(b)(2) NDAs for drugs containing the active agent for the original indication or condition of use. Five-year and three-year exclusivity will not delay the submission or approval of a full NDA. However, an applicant submitting a full NDA would be required to conduct or obtain a right of reference to any preclinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.

Pediatric exclusivity is another type of marketing exclusivity available in the U.S. Pediatric exclusivity provides for an additional six months of marketing exclusivity attached to another period of exclusivity if a sponsor conducts clinical trials in children in response to a written request from the FDA. The issuance of a written request does not

require the sponsor to undertake the described clinical trials. In addition, orphan drug exclusivity, as described above, may offer a seven-year period of marketing exclusivity, except in certain circumstances.

Other Healthcare Laws and Compliance Requirements

Pharmaceutical companies are subject to additional healthcare regulation and enforcement by the federal government and by authorities in the states and foreign jurisdictions in which they conduct their business. Such laws include, without limitation, U.S. federal and state fraud and abuse laws, including false claims, civil monetarypenalties, consumerprotection and transparency laws regarding drug pricing and payments or other transfers of value made to physicians and other licensed healthcare professionals, as well as similar foreign laws in the jurisdictions outside the United States. Violation of any of such laws or any other governmental regulations that apply may result in penalties, including, without limitation, significant administrative, civil and criminal penalties, damages, fines, disgorgement, additional reporting obligations, contractual damages, the curtailment or restructuring of operations, exclusion from participation in governmental healthcare programs and imprisonment.

Data Privacy and Security Laws

Numerous state, federal and foreign laws, regulations, and standards govern the collection, use, access to, confidentiality and security of health-related and other personal information, including clinical trial data, and could apply now or in the future to our operations or the operations of our partners. In the United States, numerous federal and state laws and regulations, including data breach notification laws, health information privacy and security laws and consumer protection laws and regulations govern the collection, use, disclosure, and protection of health-related and other personal information. In addition, certain foreign laws govern the privacy and security of personal data, including health-related data. For example, the General Data Protection Regulation, or the GDPR, imposes strict requirements for processing the personal data of individuals within the European Economic Area, or the EEA. Companies that must comply with the GDPR face increased compliance obligations and risk, including more robust regulatory enforcement of data protection requirements and potential fines for noncompliance of up to €20 million or 4% of the annual global revenues of the noncompliant company, whichever is greater. Further, from January 1, 2021, companies have had to comply with the GDPR and also the UK GDPR, which, together with the amended UK Data Protection Act 2018, retains the GDPR in UK national law. The UK GDPR mirrors the fines under the GDPR, i.e., fines up to the greater of €20 million (£17.5 million) or 4% of global turnover. Privacy and security laws, regulations, and other obligations are constantly evolving, may conflict with each other to complicate compliance efforts, and can result in investigations, proceedings, or actions that lead to significant civil and/or criminal penalties and restrictions on data processing.

Coverage and Reimbursement

Salesofanypharmaceuticalproductdepend,inpart,ontheextenttowhichsuchproductwillbecoveredby third-partypayors,suchasfederal,stateandforeigngovernmenthealthcareprograms,commercialinsuranceand managedhealthcareorganizations,andthelevelofreimbursementforsuchproductbythird-partypayors.No uniformpolicyexistsforcoverageandreimbursementforproductsexistsamongU.S.third-partypayors. Therefore,decisionsregardingtheextentofcoverageand amountof reimbursementto be providedare made on a plan-by-planbasis.Theprocessfordeterminingwhetherathird-partypayorwillprovidecoverageforaproduct typicallyisseparatefromtheprocessforsettingthepriceofsuchproductorforestablishingthereimbursement ratethatthepayorwillpayfortheproductoncecoverageisapproved.Third-partypayorsmaylimitcoverageto specificproductsonanapprovedlist,alsoknownasaformulary,whichmightnotincludeallofthe FDA-approvedproductsforaparticularindication,orplaceproductsatcertainformularylevelsthatresultin lowerreimbursementlevelsandhighercost-sharingobligationimposedonpatients.Onethird-partypayor’s decisiontocoveraparticularmedicalproductorservicedoesnotensurethatotherpayorswillalsoprovide coverageforthemedicalproductorservice.Asaresult,thecoveragedeterminationprocesswilloftenrequireus toprovidescientificandclinicalsupportfortheuseofourproductcandidatestoeachpayorseparatelyandcan beatime-consumingprocess,withnoassurancethatcoverageandadequatereimbursementwillbeapplied consistently or obtained in the first instance. For products administered under the supervision of a physician, obtaining coverage and adequate reimbursement may be particularly difficult because of the higher prices often associated with such drugs. Additionally, separate reimbursement for the product itself or the treatment or procedure in which the product is used may not be available, which may impact physician utilization.

Ininternationalmarkets,reimbursementandhealthcarepaymentsystemsvarysignificantlybycountry,and manycountrieshaveinstitutedpriceceilingsonspecificproductsandtherapies.Forexample,theEuropean Unionprovidesoptionsforitsmemberstatestorestricttherangeofmedicinalproductsforwhichtheirnational healthinsurancesystemsprovidereimbursementandtocontrolthepricesofmedicinalproductsforhumanuse. Amemberstatemayapproveaspecificpriceforthemedicinalproductoritmayinsteadadoptasystemofdirect orindirectcontrolsontheprofitabilityofthecompanyplacingthemedicinalproductonthemarket. Pharmaceuticalproductsmayfacecompetitionfromlower-pricedproductsinforeigncountriesthathaveplaced pricecontrolsonpharmaceuticalproducts.Furthermore,therecanbenoassurancethataproductwillbeconsideredmedicallyreasonableandnecessaryforaspecificindication,thataproductwillbeconsideredcost-effectivebythird-partypayors,thatanadequatelevelofreimbursementwillbeestablishedevenifcoverageis availableorthatthethird-partypayor’sreimbursementpolicieswillnotadverselyaffecttheabilitytosella productprofitably.

Healthcare Reform

IntheUnitedStatesandcertainforeignjurisdictions,therehavebeen,andweexpecttherewillcontinueto be,anumberoflegislativeandregulatorychangestothehealthcaresystem.InMarch2010,theACAwassignedintolaw,whichsubstantiallychangedthewayhealthcareisfinancedbybothgovernmentaland privateinsurersintheUnitedStatesandsignificantlyaffectedthepharmaceuticalindustry.TheACA containsanumberofprovisions,includingthosegoverningenrollmentinfederalhealthcareprograms, reimbursementadjustmentsandfraudandabusechanges.Additionally,theACA increasedthe minimumlevelofMedicaidrebatespayablebymanufacturersofbrandnamedrugsfrom15.1%to23.1%; requiredcollectionofrebatesfordrugspaidbyMedicaidmanagedcareorganizations;requiredmanufacturersto participateinacoveragegapdiscountprogram,underwhichtheymustagreetooffer70percentpoint-of-sale discountsoffnegotiatedpricesofapplicablebranddrugstoeligiblebeneficiariesduringtheircoveragegap period,asaconditionforthemanufacturer’soutpatientdrugstobecoveredunderMedicarePartD;imposeda non-deductibleannualfeeonpharmaceuticalmanufacturersorimporterswhosellcertain“brandedprescription drugs”tospecifiedfederalgovernmentprograms;implementedanewmethodologybywhichrebatesowedbymanufacturersundertheMedicaidDrugRebateProgramarecalculatedfordrugsthatareinhaled,infused, instilled,implantedorinjected;expandedeligibilitycriteriaforMedicaidprograms;createdanewPatient-CenteredOutcomesResearchInstitutetooversee,identifyprioritiesin,andconductcomparativeclinical effectivenessresearch,alongwithfundingforsuchresearch;andestablishedaCenterforMedicareandMedicaid InnovationatCMStotestinnovativepaymentandservicedeliverymodelstolowerMedicareandMedicaid spending, potentiallyincludingprescriptiondrug spending.

Since its enactment, there have been judicial, Congressional and executive branch challenges to certain aspects of the Affordable Care Act. On June 17, 2021, the U.S. Supreme Court dismissed the most recent judicial challenge to the ACA without specifically ruling on the constitutionality of the ACA. Prior to the Supreme Court’s decision, President Biden issued an executive order to initiate a special enrollment period from February 15, 2021 through August 15, 2021 for purposes of obtaining health insurance coverage through the ACA marketplace. The executive order also instructed certain governmental agencies to review and reconsider their existing policies and rules that limit access to healthcare, including among others, reexamining Medicaid demonstration projects and waiver programs that include work requirements, and policies that create unnecessary barriers to obtaining access to health insurance coverage through Medicaid or the ACA. It is unclear how other healthcare reform measures of the Biden administration will impact our business.

OtherlegislativechangeshavebeenproposedandadoptedsincetheAffordableCareActwasenacted, includingaggregatereductionsofMedicarepaymentstoprovidersof2%perfiscalyearandreducedpaymentsto severaltypesofMedicareproviders,whichwillremainineffectthrough2031, with the exception of a temporary suspension from May 1, 2020 through March 31, 2022,absentadditionalCongressional action.

Moreover, there has recently been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in several Congressional inquiries and proposed and enacted legislation designed, among other things, to bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs and reform government program reimbursement methodologies for pharmaceutical products. Individual states in the United States have also become increasingly active in implementing regulations designed to control pharmaceutical product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and

transparencymeasuresand,insomecases,mechanismstoencourageimportationfromothercountriesandbulk purchasing.Furthermore,therehasbeenincreasedinterestbythird-partypayorsandgovernmentalauthoritiesinreferencepricingsystemsand publicationof discountsand listprices.

Human Capital Resources

Asof December 31,2021,wehad 61 full-timeemployees, 45 ofwhomwereprimarilyengagedinresearchand developmentactivities.Atotalof 22 employeeshaveanM.D.,Ph.D.orPharm.D.degree.Mostofour employeesarebasedin our Brisbane,California facility, subject to hybrid and remote work arrangements.

We believe that our future success will depend, in part, on our ability to continue to attract, hire, and retain qualified personnel. We continue to seek additions to our science and technical staff. Through our experience with technological innovation, we appreciate the importance of retention, growth and development of our employees. We believe we offer competitive compensation (including salary, incentive bonus, and equity) and benefits packages. Noneofouremployeesisrepresentedbyalabor union, and weconsiderour employeerelationsto be good.

Corporate Information

We were incorporated under the laws of the State of Delaware on March 3, 2011. Our principal executive offices are located at 1400 Sierra Point Parkway, Bldg C, Suite 200, Brisbane, California 94005, and our telephone number is (650) 822-5500. Our corporate website address is www.annexonbio.com. Information contained on, or accessible through, our website shall not be deemed incorporated into and is not a part of this Annual Report on Form 10-K.

Available Information

We file Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, proxy statements, and related amendments, exhibits and other information with the Securities and Exchange Commission, or the SEC. You may access and read our filings without charge through the SEC’s website at www.sec.gov or through our website at https://ir.annexonbio.com/financial-information/sec-filings, as soon as reasonably practicable after such materials are electronically filed with or furnished to the SEC pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended, or the Exchange Act. Information contained on, or accessible through, our website shall not be deemed incorporated into and is not a part of this Annual Report on Form 10-K.

Item 1A. Risk Factors.

Our business involves significant risks, some of which are described below. You should carefully consider the risks and uncertainties described below, together with all of the other information contained in this Annual Report on Form 10-K, including "Management's Discussion and Analysis of Financial Condition and Results of Operations" and the financial statements and the related notes. If any of the following risks actually occur, it could harm our business, prospects, operating results and financial condition and future prospects. In such event, the market price of our common stock could decline and you could lose all or part of your investment. Additional risks and uncertainties not presently known to us or that we currently deem immaterial may also impair our business operations. This Annual Report on Form 10-K also contains forward-looking statements that involve risks and uncertainties. Our actual results could differ materially from those anticipated in the forward-looking statements as a result of factors that are described below and elsewhere in this Annual Report on Form 10-K.

Risks Related to Our Limited Operating History, Financial Condition and Capital Requirements

We are a clinical-stage biopharmaceutical company with a limited operating history and no products approved for commercial sale. We have incurred significant losses since our inception, and we anticipate that we will continue to incur significant losses for the foreseeable future, which, together with our limited operating history, makes it difficult to assess our future viability.

We are a clinical-stage biopharmaceutical company, and we have only a limited operating history upon which you can evaluate our business and prospects. Biopharmaceutical product development is a highly speculative undertaking and involves a substantial degree of risk. We have no products approved for commercial sale and have not generated any revenue from sales of our product candidates and have incurred losses in each year since our inception in March 2011. We have only a limited operating history upon which you can evaluate our business and prospects. In addition, we have not yet demonstrated an ability to successfully overcome many of the risks and uncertainties frequently encountered by companies in new and rapidly evolving fields, particularly in the pharmaceutical, biopharmaceutical and biotechnology industry.

We have had significant operating losses since our inception. Our net loss for the years ended December 31, 2021 and 2020 was approximately $130.3 million and $63.4 million, respectively. As of December 31, 2021, we had an accumulated deficit of $296.3 million. Substantially all of our losses have resulted from expenses incurred in connection with our research and development programs and from general and administrative costs associated with our operations. We expect to continue to incur losses for the foreseeable future, and we anticipate these losses will increase as we continue to develop our product candidates, conduct clinical trials and pursue research and development activities. Even if we achieve profitability in the future, we may not be able to sustain profitability in subsequent periods. Our prior losses, combined with expected future losses, have had and will continue to have an adverse effect on our stockholders’ equity and working capital.

We will require substantial additional financing to achieve our goals, and a failure to obtain this necessary capital when needed on acceptable terms, or at all, could force us to delay, limit, reduce or terminate our product development programs, commercialization efforts or other operations.

Since our inception, we have invested a significant portion of our efforts and financial resources in research and development activities. Our product candidates will require additional clinical development, and we intend to conduct additional research and development activities to discover and develop new product candidates, including conducting preclinical studies and clinical trials, all of which will require substantial additional funds. We will continue to expend significant resources for the foreseeable future in connection with these activities. These expenditures will include costs associated with conducting preclinical studies and clinical trials, obtaining regulatory approvals and manufacturing and supply, as well as marketing and selling any products approved for sale. In addition, other unanticipated costs may arise. Because the outcome of any preclinical study or clinical trial is highly uncertain, we cannot reasonably estimate the actual amounts necessary to successfully complete the development and commercialization of our product candidates or any future product candidates.

As of December 31, 2021, we had capital resources consisting of cash and cash equivalents and short-term investments of approximately $242.7 million. We expect our existing capital resources will fund our planned operating expenses into the first quarter of 2024. However, our operating plans may change as a result of many factors currently

unknown to us, and we may need to seek additional funds sooner than planned through public or private equity offerings or debt financings or other sources, such as strategic collaborations. Such financing may result in dilution to our stockholders, imposition of burdensome debt covenants and repayment obligations, or other restrictions that may affect our business. In addition, we may seek additional capital due to favorable market conditions or strategic considerations even if we believe we have sufficient funds for our current or future operating plans.

Our future capital requirements depend on many factors, including:

• any product liability or other lawsuits related to our products;

• the expenses needed to attract, hire and retain skilled personnel;

• the costs associated with being a public company;

• the timing, receipt and amount of sales of any future approved products; and

Additional funds may not be available when we need them, on terms that are acceptable to us, or at all. Our ability to raise additional capital may be adversely impacted by potential worsening global economic conditions and the recent disruptions to and volatility in the credit and financial markets in the United States and worldwide resulting from the ongoing COVID-19 pandemic. If adequate funds are not available to us on a timely basis, we may be required to:

• delay, limit, reduce or terminate our research and development activities; or

We also could be required to seek funds through arrangements with collaborators or others that may require us to relinquish rights to some of our technologies or product candidates that we would otherwise pursue on our own.

We do not expect to realize revenue from sales of products or royalties from licensed products in the foreseeable future, if at all, and unless and until our product candidates are clinically tested, approved for commercialization and successfully marketed. To date, we have primarily financed our operations through the sale of equity securities. We will be required to seek additional funding in the future and currently intend to do so through public or private equity offerings or debt financings, credit or loan facilities, collaborations or a combination of one or more of these funding sources. Our ability to raise additional funds will depend on financial, economic and other factors, many of which are beyond our control. Additional funds may not be available to us on acceptable terms or at all. If we raise additional funds by issuing equity securities, our stockholders will suffer dilution and the terms of any financing may adversely affect the rights of our stockholders. In addition, as a condition to providing additional funds to us, future investors may demand, and may be granted, rights superior to those of existing stockholders. Debt financing, if available, is likely to involve restrictive covenants limiting our flexibility in conducting future business activities, and, in the event of insolvency, debt holders would be repaid before holders of our equity securities received any distribution of our corporate assets.

Due to the significant resources required for the development of our product candidates, we must prioritize development of certain product candidates and/or certain disease indications. We may expend our limited resources on candidates or indications that do not yield a successful product and fail to capitalize on product candidates or indications that may be more profitable or for which there is a greater likelihood of success.

We are currently focused on developing product candidates to address classical complement-mediated autoimmune and neurodegenerative diseases. We seek to maintain a process of prioritization and resource allocation among our programs to maintain a balance between aggressively advancing our product candidates in identified indications and exploring additional indications or mechanisms as well as developing future product candidates. However, due to the significant resources required for the development of our product candidates, we must focus on specific diseases and disease pathways and decide which product candidates to pursue and the amount of resources to allocate to each such product candidate.

Our decisions concerning the allocation of research, development, collaboration, management and financial resources toward particular product candidates or therapeutic areas may not lead to the development of any viable commercial product and may divert resources away from better opportunities. Similarly, any decision to delay, terminate or collaborate with third parties in respect of certain programs may subsequently also prove to be suboptimal and could cause us to miss valuable opportunities. If we make incorrect determinations regarding the viability or market potential of any of our programs or product candidates or misread trends in the autoimmune or neurodegenerative or pharmaceutical, biopharmaceutical or biotechnology industry, our business, financial condition and results of operations could be materially adversely affected. As a result, we may fail to capitalize on viable commercial products or profitable market opportunities, be required to forego or delay pursuit of opportunities with other product candidates or other diseases and disease pathways that may later prove to have greater commercial potential than those we choose to pursue, or relinquish valuable rights to such product candidates through collaboration, licensing or other royalty arrangements in cases in which it would have been advantageous for us to invest additional resources to retain development and commercialization rights.

Our operating results may fluctuate significantly, which makes our future operating results difficult to predict and could cause our operating results to fall below expectations.

Our quarterly and annual operating results may fluctuate significantly, which makes it difficult for us to predict our future operating results. These fluctuations may occur due to a variety of factors, many of which are outside of our control and may be difficult to predict, including:

• the timing and status of enrollment for our clinical trials;

• future accounting pronouncements or changes in our accounting policies;

The cumulative effects of these factors could result in large fluctuations and unpredictability in our quarterly and annual operating results. As a result, comparing our operating results on a period-to-period basis may not be meaningful. Investors should not rely on our past results as an indication of our future performance.

This variability and unpredictability could also result in our failing to meet the expectations of industry or financial analysts or investors for any period. If our revenue or operating results fall below the expectations of analysts or investors or below any forecasts we may provide to the market, or if any forecasts we provide to the market are below the expectations of analysts or investors, the price of our common stock could decline substantially. Such a stock price decline could occur even when we have met any previously publicly stated revenue or earnings guidance we may provide.

Risks Related to Our Business

Our business is heavily dependent on the successful development, regulatory approval and commercialization of our product candidates which are in early stages of clinical development.

We have no products approved for sale, and our product candidates are in early stages of clinical development. The success of our business, including our ability to finance our company and generate revenue in the future, will primarily depend on the successful development, regulatory approval and commercialization of our product candidates and, in particular, the advancement of our current clinical-stage product candidates. However, given our stage of development, it may be many years, if we succeed at all, before we have demonstrated the safety, purity, potency and/or efficacy of a product candidate sufficient to warrant approval for commercialization. We cannot be certain that our product candidates will receive regulatory approval or be successfully commercialized even if we receive regulatory approval.

While inhibition of the complement pathway has been validated as a therapeutic approach, C1q inhibition is a novel therapeutic approach, which exposes us to certain risks. For example, we may discover that our product candidates do not possess certain properties required for therapeutic effectiveness, or that even if found to be effective in one type of disease, a product candidate, or the therapeutic approach, is not effective in other diseases. In addition, given the novel nature of this therapeutic approach, designing preclinical studies and clinical trials to demonstrate the effect of the product candidates is complex and exposes us to risks, including that our biomarker-driven approach may not translate into therapeutic effectiveness.

In the future, we may also become dependent on other product candidates that we may develop or acquire. The clinical and commercial success of our product candidates and future product candidates will depend on a number of factors, including the following:

• the convenience of our treatment or dosing regimen;

These factors, many of which are beyond our control, could cause us to experience significant delays or an inability to obtain regulatory approvals or commercialize our product candidates. Even if regulatory approvals are obtained, we may never be able to successfully commercialize any of our product candidates. Accordingly, we cannot provide assurances that we will be able to generate sufficient revenue through the sale of our product candidates or any future product candidates to continue our business or achieve profitability.

Public health crises such as pandemics or similar outbreaks could materially and adversely affect our preclinical and clinical trials, business, financial condition and results of operations.

In March 2020, the World Health Organization declared COVID-19 a global pandemic and the United States declared a national emergency with respect to the COVID-19 pandemic. In response to the COVID-19 pandemic and more recently in connection with the spread of the Delta and omicron variants, “shelter in place” orders and other public health guidance measures have been implemented across much of the United States and Europe, including in the locations of our offices, clinical trial sites, key vendors and partners. We expect that our clinical development program timelines will continue to be negatively affected by the COVID-19 pandemic, which could materially and adversely affect our business, financial condition and results of operations. For instance, we have experienced interruption in clinical trial activities in Bangladesh due to quarantines, shortages in clinical site staff, longer timelines for clinical site initiation and temporary shortages in lab kits and supplies. Further, due to “shelter in place” orders and other public health guidance measures, we have implemented a work-from-home policy for all staff members excluding those necessary to maintain minimum basic operations. Our increased reliance on personnel working from home may negatively impact productivity, or disrupt, delay or otherwise adversely impact our business. For example, with our personnel working from home, some of our research activities that require our personnel to be in our laboratories have been delayed.

As a result of the COVID-19 pandemic, or similar pandemics, and related “shelter in place” orders and other public health guidance measures, we have experienced, and may in the future experience disruptions that could materially and adversely impact our clinical trials, business, financial condition and results of operations. These disruptions include but are not limited to:

• delays or difficulties in enrolling patients in our clinical trials;

These and other factors arising from the COVID-19 pandemic could worsen or could return in countries where the COVID-19 pandemic has been partially contained, each of which could further adversely impact our ability to conduct clinical trials and our business generally, and could materially and adversely affect our business, financial condition and results of operations.

In particular, the COVID-19 pandemic has adversely impacted hospitals and medical facilities where we are currently conducting our clinical trials and has resulted in increased competition among companies conducting clinical trials for more limited hospital space.

The COVID-19 pandemic continues to rapidly evolve. The extent to which the outbreak may continue to affect our clinical trials, business, financial condition, results of operations, and clinical development timelines and plans will depend on future developments, which are highly uncertain and cannot be predicted at this time, such as the duration of the outbreak, the emergence of new variants, rates of infection in the locations in which we and our CROs, third-party manufacturers, regulatory authorities and other third parties with whom we do business operate, travel restrictions and actions to contain the outbreak or treat its impact, such as social distancing and quarantines or lock-downs in the United States and other countries, business closures or business disruptions and the effectiveness of actions taken in the United States and other countries to contain and treat the disease. Future developments in these and other areas present material uncertainty and risk with respect to our clinical trials, business, financial condition and results of operations.

Research and development of biopharmaceutical products is inherently risky. We cannot give any assurance that any of our product candidates will receive regulatory approval, which is necessary before they can be commercialized.

We are at an early stage of clinical development of our product candidates. Our future success is dependent on our ability to successfully develop, obtain regulatory approval for and then successfully commercialize our product candidates, and we may fail to do so for many reasons, including the following:

If any of these events occur, we may be forced to abandon our development efforts for a product candidate or candidates, which would have a material adverse effect on our business and could potentially cause us to cease

operations. Failure of a product candidate may occur at any stage of preclinical or clinical development, and we may never succeed in developing marketable products or generating product revenue.

We may not be successful in our efforts to further develop our current and future product candidates. We are not permitted to market or promote any of our product candidates before we receive regulatory approval from the FDA or comparable foreign regulatory authorities, and we may never receive such regulatory approval for any of our product candidates. Each of our product candidates will require significant additional clinical development, management of preclinical, clinical and manufacturing activities, regulatory approval, adequate manufacturing supply, a commercial organization and significant marketing efforts before we generate any revenue from product sales, if at all. Any clinical studies that we may conduct may not demonstrate the efficacy and safety necessary to obtain regulatory approval to market our product candidates. If the results of our ongoing or future clinical studies are inconclusive with respect to the efficacy of our product candidates, if we do not meet the clinical endpoints with statistical significance or if there are safety concerns or adverse events associated with our product candidates, we may be prevented or delayed in obtaining marketing approval for our product candidates.

The FDA or other regulatory agencies may not agree with our clinical development plan and require that we conduct additional clinical trials to support our regulatory submissions. We have not yet conducted an end of Phase 2 meeting with the FDA to discuss the registration pathway for ANX005, and our current clinical development plans for ANX005 in GBS may change as a result of future interactions with the FDA. For example, the FDA may require that we conduct more than one pivotal trial in order to gain approval in GBS. Furthermore, any approval of ANX005 for GBS may be limited to ANX005 in combination with the existing standard of care. While not approved for use in GBS in the United States due to differing levels of efficacy in GBS patients, IVIg has developed as the standard of care in the Western world and parts of Asia for patients with GBS and has led to clinical responses in some GBS patients.

If any of our product candidates successfully completes clinical trials, we plan to seek regulatory approval to market our product candidates in the United States, the European Union, or the EU, and in additional foreign countries where we believe there is a viable commercial opportunity. We have never commenced, compiled or submitted an application seeking regulatory approval to market any product candidate. We may never receive regulatory approval to market any product candidates even if such product candidates successfully complete clinical trials, which would adversely affect our viability. To obtain regulatory approval in countries outside the United States, we must comply with numerous and varying regulatory requirements of such other countries regarding safety, efficacy, chemistry, manufacturing and controls, clinical trials, commercial sales, pricing and distribution of our product candidates. We may also rely on collaborators or partners to conduct the required activities to support an application for regulatory approval and to seek approval for one or more of our product candidates. We cannot be sure that any such collaborators or partners will conduct these activities successfully or do so within the timeframe we desire. Even if we or any future collaborators or partners are successful in obtaining approval in one jurisdiction, we cannot ensure that we will obtain approval in any other jurisdictions. If we are unable to obtain approval for our product candidates in multiple jurisdictions, our revenue and results of operations could be negatively affected.

Even if we receive regulatory approval to market any of our product candidates, we cannot assure you that any such product candidate will be successfully commercialized, widely accepted in the marketplace or more effective than other commercially available alternatives. Any approval we may obtain could be for indications or patient populations that are not as broad as intended or desired or may require labeling that includes significant use or distribution restrictions or safety warnings. We may also be required to perform additional or unanticipated clinical trials to obtain approval or be subject to additional post-marketing testing requirements to maintain approval. In addition, regulatory authorities may withdraw their approval of a product or impose restrictions on its distribution, such as in the form of a Risk Evaluation and Mitigation Strategy, or REMS. The failure to obtain timely regulatory approval of product candidates, any product marketing limitations or a product withdrawal would negatively impact our business, results of operations and financial condition.

We may encounter substantial delays in our clinical trials or may not be able to conduct or complete our clinical trials on the timelines we expect, if at all.

Clinical testing is expensive and can take many years to complete, and its outcome is inherently uncertain. We cannot guarantee that any clinical trials will be conducted as planned or completed on schedule, if at all. We cannot

ANNX US Equity

ANNX · 10-K · period ended 2021-12-31

Item 1. Business.

Item 1A. Risk Factors.

ANNX US Equity☆

ANNX · 10-K · period ended 2021-12-31

Item 1. Business.

Item 1A. Risk Factors.

ANNX US Equity