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Item 1. Business

2025-03-27 compared with 2024-03-26 · 181 added, 176 removed, 451 unchanged (44% of the section changed)

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Alzheimer’s disease is a progressive neurodegenerative disease of the brain that leads to loss of memory and cognitive functions and ultimately results in death.

Alzheimer’s disease currently affects over 6 million people in the United States and approximately 32 million people worldwide and is the sixth-leading cause of death in the United States.

However, due to the aging population, patient populations in the United States impacted by AD are expected to grow to approximately 13 million people by 2050 without effective preventative measures or safe and effective disease-modifying treatments.

By 2050, healthcare costs for AD in the United States alone are estimated to exceed $1 trillion.

Alzheimer’s disease is currently estimated to affect approximately seven million people in the United States and approximately 55 million people worldwide and was the fifth-leading cause of death among individuals aged 65 and older in 2021 in the United States.

Due to the aging population, patient populations in the United States impacted by AD are expected to grow to approximately 13 million people by 2050 without effective preventative measures or safe and effective disease-modifying treatments.

By 2050, healthcare costs for AD in the United States alone are estimated to near $1 trillion.

Our scientific founders pioneered research on soluble amyloid-beta oligomers, or AßOs, which are globular assemblies of the amyloid-beta, or Aß, peptide that are distinct from Aß monomers and amyloid plaques.

Based on decades of research and supporting evidence, AßOs have gained increasing scientific acceptance as a primary toxin involved in the initiation and propagation of AD pathology.

We are currently focused on advancing a targeted immunotherapy drug candidate, sabirnetug* (ACU193), in clinical development following Phase 1 results in “early AD” patients (patients with mild cognitive impairment or mild dementia due to Alzheimer’s pathology) that were reported in July 2023.

We are currently focused on advancing a targeted immunotherapy drug candidate, sabirnetug (ACU193), in our Phase 2 ALTITUDE-AD clinical trial following Phase 1 results in “early AD” patients (patients with mild cognitive impairment, or MCI, or mild dementia due to AD) that were reported in July 2023.

Sabirnetug is a recombinant humanized immunoglobulin gamma 2, or IgG2, monoclonal antibody, or mAb, that was designed to selectively target AßOs, has demonstrated functional and protective effects in in vitro assays, and has demonstrated in vivo safety and pharmacologic activity in multiple animal species, including transgenic mouse models for AD.

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We believe the development and commercialization of a drug that reduces toxicity of AßOs is one of the most promising approaches for the potential treatment and prevention of the progression of AD.

The target population for sabirnetug and other monoclonal antibodies approved and in development is what is now being called “early AD.” This population includes people with a clinical diagnosis of mild cognitive impairment, or MCI, or mild dementia due to AD who are also amyloid positive based on either imaging studies or cerebrospinal fluid biochemical analyses.

The term “mild cognitive impairment or mild dementia due to AD” has also been used and is accepted by regulators as inclusion/exclusion criteria in clinical trials.

While epidemiologic studies of this population are evolving, approximately 4-5 million people in the United States are likely to have early AD who also exhibit amyloid pathology associated with AD.

In our nonclinical studies, we observed that sabirnetug has over 500-fold greater selectivity for targeting AßOs over Aß monomers and 87-fold selectivity for targeting AßOs over Aß fibrils.

The target population for sabirnetug and other mAbs approved and in development is what is now being called “early AD.” This population includes people with a clinical diagnosis of MCI or mild dementia due to AD who are also amyloid positive based on either imaging studies or cerebrospinal fluid, or CSF, biochemical analyses.

The term “mild cognitive impairment or mild dementia due to AD” has also been used and is accepted by regulators as an inclusion/exclusion criterion in clinical trials.

While epidemiologic studies of this population are evolving, approximately four to five million people in the United States are likely to have early AD who also exhibit amyloid pathology associated with AD.

In our nonclinical studies using an enzyme-linked immunosorbent assay, or ELISA assay, we observed that sabirnetug has over 500-fold greater selectivity for targeting AßOs over Aß monomers and 87-fold selectivity for targeting AßOs over Aß fibrils.

In 2024, we completed a nonclinical study using Surface Plasmon Resonance, or SPR, technology, which demonstrated that sabirnetug is 8750-fold more selective for AßOs than Aß monomers.

In immunohistochemical studies of human AD brain tissue, sabirnetug appears to have limited or no binding to amyloid plaques.

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An important safety measure was the use of magnetic resonance imaging, or MRI, to assess the presence or absence of amyloid-related imaging abnormalities, or ARIA.

Secondary endpoints included pharmacokinetics in plasma and cerebrospinal fluid, or CSF, and target engagement as evidenced by detection of sabirnetug bound to AßOs in CSF.

Clinical scales typically used in AD trials as well as computerized cognitive testing and arterial spin labelling with MRI scans (which can be used to assess cerebral blood flow) were included as exploratory measures.

In July 2023, we announced topline results from INTERCEPT-AD, which demonstrated that sabirnetug met the primary and secondary objectives of this study in 62 participants with early AD.

Secondary endpoints included pharmacokinetics in plasma and CSF and target engagement as evidenced by detection of sabirnetug bound to AßOs in CSF.

Clinical scales typically used in AD trials as well as computerized cognitive testing and arterial spin labeling, or ASL, with MRI scans (which can be used to assess cerebral blood flow) were included as exploratory measures.

In July 2023, we announced topline results from INTERCEPT-AD, which demonstrated that sabirnetug met the primary and secondary objectives of this clinical trial in 62 participants with early AD.

Sabirnetug was well-tolerated throughout the SAD and MAD dose cohorts, with an overall rate of ARIA-E of 10.4%.

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Statistically significant, dose-related central target engagement was observed as measured by sabirnetug-AßO complex, establishing the first target engagement assay developed that is specific to an AßO-targeting antibody.

This assay also demonstrated near maximal target engagement for patients receiving 25 mg/kg every two weeks or 60 mg/kg every four weeks, an important finding for dose selection in the upcoming Phase 2 study.

A number of downstream biomarkers in cerebrospinal fluid, or CSF, specific to amyloid and tau pathology and synaptic injury showed improvement in the MAD cohorts, further supporting a drug effect of sabirnetug on Alzheimer’s pathology.

These included effects of sabirnetug on p-tau181, which reflects damage to neurons and is known to be elevated in CSF of patients with AD, and effects of sabirnetug on neurogranin and VAMP2, which reflect damage to neuronal synapsis and are elevated in CSF of patients with AD.

We expect to initiate a Phase 2 clinical trial of sabirnetug, called ALTITUDE-AD, in the first half of 2024.

ALTITUDE-AD is a randomized, double-blind, placebo-controlled, three arm study designed to evaluate the clinical efficacy, safety and tolerability of sabirnetug, with up to 180 participants per arm for a total of up to 540 participants with MCI or mild dementia due to AD.

We intend to use the Integrated Alzheimer's Disease Rating Scale, or iADRS at 18 months as the primary outcome measure.

Our planned doses for ALTITUDE-AD are 35 mg/kg and 50 mg/kg both dosed every four weeks, or Q4W.

These dose levels and frequency were selected based on extensive pharmacokinetic, or PK, and pharmacodynamic, or PD, modeling of our Phase 1 data.

Based on regulatory feedback from the European Medicines Agency, or EMA, and to enhance the probability that the EMA will consider our Phase 2 study a registration-eligible study for sabirnetug, we anticipate amending the ALTITUDE-AD protocol later this year to change the current Phase 2/3 study to a Phase 2 standalone study.

If this happens, any interim analysis may then lead to an initiation of a confirmatory Phase 3 study.

In November 2023, we announced a global collaboration and license agreement with Halozyme to develop a subcutaneous formulation of sabirnetug.

We expect to initiate a Phase 1 trial investigating a subcutaneous dosing option of sabirnetug in mid-2024.

This assay also demonstrated near maximal target engagement for patients receiving 25 mg/kg every two weeks, or Q2W, or 60 mg/kg every four weeks, or Q4W.

A number of downstream biomarkers in CSF specific to amyloid and tau pathology and synaptic injury showed improvement in the MAD cohorts, further supporting a drug effect of sabirnetug on Alzheimer’s pathology.

These included effects of sabirnetug on p-tau181, which reflects damage to neurons and is known to be elevated in CSF of patients with AD, and effects of sabirnetug on neurogranin and vesicle-associated membrane protein 2, or VAMP2, which reflect damage to neuronal synapsis and are elevated in CSF of patients with AD.

We announced the initiation of our Phase 2 ALTITUDE-AD clinical trial of sabirnetug in May 2024 and completed enrollment in March 2025 .

ALTITUDE-AD is a randomized, double-blind, placebo-controlled, three-arm clinical trial designed to evaluate the clinical efficacy, safety and tolerability of sabirnetug, with up to 180 participants per arm for a total of up to 540 participants with MCI or mild dementia due to AD.

We plan to use the Integrated Alzheimer’s Disease Rating Scale, or iADRS, at 18 months as the primary outcome measure.

Our active doses for ALTITUDE-AD are 35 mg/kg and 50 mg/kg, both dosed IV Q4W.

These dose levels and frequency were selected based on extensive pharmacokinetic, or PK, and pharmacodynamic, or PD, modeling of our Phase 1 clinical trial data.

In November 2023, we announced a global collaboration and license agreement with Halozyme, Inc., or Halozyme, to develop a subcutaneous formulation of sabirnetug.

We announced the results of a Phase 1 clinical trial investigating a subcutaneous dosing option of sabirnetug in March 2025.

This study in healthy volunteers enrolled 16 subjects who received four weekly subcutaneous doses of 1,200 mg of sabirnetug and 12 subjects who received single IV doses of 2,800 mg of sabirnetug.

The most frequently reported adverse events included injection site reactions (62.5%), all of which were mild (Grade 1) in severity and resolved.

No other safety issues were identified.

Additionally, subcutaneous administration of sabirnetug was shown to produce sufficient systemic exposure to support further development of this formulation as a more convenient administration option for patients.

Understanding the Foundation of Our Therapeutic Approach

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The primary constituent of amyloid plaques is the Aß peptide, although other proteins are present to lesser degrees.

Historically, the primary hypothesis of decades of AD research, known as the amyloid hypothesis, held that AD dementia is the clinical consequence of Aß peptide monomers accumulating into extracellular amyloid plaques, or amyloid plaques, which in turn contribute to the formation of intracellular neurofibrillary tangles composed of the tau protein, which is directly linked to neuronal cell death.

Historically, the primary hypothesis of decades of AD research, known as the amyloid hypothesis, held that AD dementia is the clinical consequence of Aß peptide monomers accumulating into extracellular amyloid plaques, which in turn contribute to the formation of intracellular neurofibrillary tangles composed of the tau protein, which is directly linked to neuronal cell death.

Additionally, amyloid plaques cause inflammation.

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These mutations were found in genes coding for the Amyloid Precursor Protein, or APP, and the genes coding for one of the enzymes which cleaves APP, creating the Aß peptide.

Based on this hypothesis, a number of monoclonal antibodies currently or previously in clinical development for AD have primarily targeted either Aß monomers or amyloid plaques;

Based on this hypothesis, a number of mAbs currently or previously in clinical development for AD have primarily targeted either Aß monomers or amyloid plaques;

for our purposes, this broadly defined class is referred to as anti-Aß/plaque antibodies.

One of these antibodies, lecanemab, or LEQEMBI ® , which was developed to target soluble aggregated species of Aß known as protofibrils, received approval from the U.S.

Food and Drug Administration, or FDA, in 2023.

Another antibody, donanemab, which was developed to target amyloid plaques, is under review for FDA approval, which is expected in 2024.

Food and Drug Administration, or the FDA, in 2023.

Another antibody, donanemab, which was developed to target amyloid plaques, was approved by the FDA in 2024.

The clinical data available to date, even for these approved mAbs, indicate some of the potential limitations of these approaches with respect to clinically meaningful patient benefit and safety.

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Aß monomers (single Aß peptides), amyloid plaques (insoluble fibrillar Aß), and soluble AßOs (dimers and up to 200-mers).

Some experts in the field differentiate soluble AßO oligomers into globular structures or linear protofibrils.

Some experts in the field differentiate soluble AßO oligomers into globular structures

or linear protofibrils.

Linear soluble Aß protofibrils may elongate to form the insoluble fibrils that make up deposited amyloid plaques.

Sabirnetug was developed to bind to globular AßOs rather than to Aß monomers, fibrils or deposited

amyloid plaques.

Sabirnetug was developed to bind to globular AßOs rather than to Aß monomers, fibrils or deposited amyloid plaques.

The more recent recognition of the direct toxicity of soluble AßOs to neurons is the central tenet of our therapeutic approach.

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Our Product Candidate

Our product candidate, sabirnetug, is a recombinant humanized, affinity-matured, immunoglobulin G2, or IgG2, subclass monoclonal antibody, derived from the murine immunoglobulin G1, or IgG1, parent, ACU3B3.

We are currently developing sabirnetug for IV administration every four weeks (Q4W) for the treatment of early AD, and we intend to explore subcutaneous administration as well.

Our product candidate, sabirnetug, is a recombinant humanized, affinity-matured IgG2 subclass mAb, derived from the murine immunoglobulin G1, or IgG1, parent, ACU3B3.

We are currently developing sabirnetug for IV administration Q4W for the treatment of early AD, and we have begun developing sabirnetug for subcutaneous administration as well.

We believe that sabirnetug represents a differentiated approach from current and prior anti-Aß/plaque immunotherapies because it is highly selective for soluble toxic AßOs.

Sabirnetug has a nanomolar affinity for AßOs, over 500-fold greater selectivity for AßOs over Aß monomers, 87-fold greater selectivity for AßOs over Aß fibrils and, based on immunohistochemical experiments with human AD tissues, limited or no binding to dense core amyloid plaques.

Sabirnetug has a nanomolar affinity for AßOs, with up to 8750-fold greater selectivity for AßOs over Aß monomers, 87-fold greater selectivity for AßOs over Aß fibrils and, based on immunohistochemical experiments with human AD tissues, limited or no binding to dense core amyloid plaques.

We believe that sabirnetug is the most advanced immunotherapy candidate in development that was designed to selectively target toxic AßOs.

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We announced results from INTERCEPT-AD, a proof of mechanism Phase 1 clinical trial involving early AD patients, in July 2023.

We expect to initiate ALTITUDE-AD, our Phase 2 clinical trial, in the first half of 2024.

We also expect to initiate a Phase 1 clinical trial investigating a subcutaneous dosing option of sabirnetug in mid-2024.

We initiated ALTITUDE-AD, our Phase 2 clinical trial, in May 2024 and completed enrollment in March 2025.

We expect to announce top-line results for ALTITUDE-AD in late 2026.

We also announced the results of a Phase 1 clinical trial investigating a subcutaneous dosing option of sabirnetug in healthy volunteers in March 2025.

Clinical Development Plan

As noted above, we expect to initiate a Phase 2 clinical trial, ALTITUDE-AD, in the first half of 2024.

It is a randomized, double-blind, placebo-controlled, three arm study designed to evaluate the clinical efficacy, safety and tolerability of sabirnetug, with up to 180 participants per arm for a total of up to 540 participants with MCI or mild dementia due to AD.

As noted above, we initiated a Phase 2 clinical trial, ALTITUDE-AD, in May 2024 and completed enrollment in March 2025.

It is a randomized, double-blind, placebo-controlled, three-arm clinical trial designed to evaluate the clinical efficacy, safety and tolerability of sabirnetug, with up to 180 participants per arm for a total of up to 540 participants with MCI or mild dementia due to AD.

We intend to use iADRS, a measurement of cognitive and functional decline, at 18 months as the primary outcome measure.

Our planned doses for ALTITUDE-AD are 35 mg/kg and 50 mg/kg both dosed IV Q4W.

Participants randomized to the 50 mg/kg dose will be administered 35 mg/kg for the first two doses and then will be increased to 50 mg/kg.

The 35 and 50 mg/kg doses were selected based on extensive PK/PD modeling of our Phase 1 data.

The doses for ALTITUDE-AD are 35 mg/kg and 50 mg/kg, both dosed IV Q4W.

Participants randomized to the 50 mg/kg dose are being administered 35 mg/kg for the first two doses, which is then increased to 50 mg/kg.

The 35 and 50 mg/kg doses were selected based on extensive PK/PD modeling of our Phase 1 clinical trial data.

Design of ALTITUDE-AD

We reported topline results from INTERCEPT-AD, a U.S.-based, multi-center, randomized, placebo-controlled, single and multiple ascending dose Phase 1 clinical trial of sabirnetug in July 2023.

We reported topline results from INTERCEPT-AD, a U.S.-based, multi-center, randomized, placebo-controlled, SAD and MAD Phase 1 clinical trial of sabirnetug in July 2023.

This trial enrolled 65 participants with early AD, and 62 participants received at least one dose of study drug.

The early AD patient group was comprised of individuals who have mild dementia or MCI due to AD, and our trial excluded patients with moderate to severe AD dementia.

Patients were enrolled across seven cohorts, consisting of a single ascending dose in Part A and an overlapping multiple ascending dose in Part B.

Patients were enrolled across seven cohorts, consisting of a SAD in Part A and an overlapping MAD in Part B.

Part A contained Cohorts 1 through 4;

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each cohort received a total of three doses of sabirnetug or placebo as follows:

10 mg/kg every four weeks (Q4W), 60 mg/kg Q4W, or 25 mg/kg every two weeks (Q2W).

10 mg/kg Q4W, 60 mg/kg Q4W, or 25 mg/kg Q2W.

Design of INTERCEPT-AD

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One IV dose of sabirnetug (60 mg/kg) or placebo.

The double-blind treatment period for Cohorts 1-4 of Part A was approximately 20 weeks and included ten visits (four inpatient and six outpatient).

The double-blind treatment period for Cohorts 1-4 of Part A was approximately 20 weeks and included 10 visits (four inpatient and six outpatient).

A sequential dosing scheme was followed for each cohort in Part A.

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In Part B of our clinical trial, participants were randomized in an 8:2 ratio into one of three cohorts to receive a total of three doses of sabirnetug or placebo as follows:

One IV dose of sabirnetug (10 mg/kg) or placebo once every four weeks.

One IV dose of sabirnetug (60 mg/kg) or placebo once every four weeks.

One IV dose of sabirnetug (25 mg/kg) or placebo once every two weeks.

One IV dose of sabirnetug (10 mg/kg) or placebo once Q4W.

One IV dose of sabirnetug (60 mg/kg) or placebo once Q4W.

One IV dose of sabirnetug (25 mg/kg) or placebo once Q2W.

Participants in Cohorts 5 and 6 were evaluated over approximately 35 weeks, consisting of a seven-week screening period followed by a 28-week, double-blind treatment period.

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If a potential safety signal, an unexpected adverse reaction, or higher than expected exposure had occurred, our internal blinded safety team would have notified the independent, unblinded DMC to review the safety and PK data and advise on dose escalation.

Cohort 7 allowed for additional pharmacokinetic modeling to more accurately determine if every two-week dosing is necessary and if accumulation of sabirnetug occurs with this dosing frequency.

Cohort 7 allowed for additional PK modeling to more accurately determine if Q2W dosing is necessary and if accumulation of sabirnetug occurs with this dosing frequency.

Our Phase 1 clinical trial established clinical proof of mechanism of sabirnetug in patients with early AD.

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• evaluation of possible changes in amyloid plaque load as determined by PET imaging;

• exploratory evaluation of possible changes in cerebral blood flow as determined by MRI imaging, using Arterial Spin Labeling (ASL) pulse sequence;

• exploratory evaluation of possible changes in cerebral blood flow as determined by MRI, using ASL pulse sequence;

• exploratory evaluation of possible changes in cognitive, functional and behavioral measures using computerized testing and standard clinical measures for AD.

The main objective of INTERCEPT-AD was to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and target engagement of single and multiple ascending doses of sabirnetug administered by IV infusion.

The main objective of INTERCEPT-AD was to evaluate the safety, tolerability, PK, PD, and target engagement of single and multiple ascending doses of sabirnetug administered by IV infusion.

Exploratory outcomes included cognitive scales and computerized cognitive testing.

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We announced INTERCEPT-AD topline data in July of 2023, which demonstrated that sabirnetug met the primary

and secondary objectives of this study in 62 participants with early AD.

and secondary objectives of this clinical trial in 62 participants with early AD.

• An analysis of change in amyloid plaque load, as measured by PET Centiloids, demonstrated a rapid, dose-related mean decrease at the higher dose levels studied.

Sabirnetug (60 mg/kg every four weeks [Q4W] and 25 mg/kg every two weeks [Q2W]) showed a statistically significant reduction in amyloid plaque load as determined by amyloid PET after 6-12 weeks (from baseline to endpoint within cohorts (p = 0.01)).

Sabirnetug (60 mg/kg Q4W and 25 mg/kg Q2W) showed a statistically significant reduction in amyloid plaque load as determined by amyloid PET after 6-12 weeks (from baseline to endpoint within cohorts (p=0.01)).

This finding provides evidence that sabirnetug is active in the brain.

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Three treatment-emergent serious adverse events were observed after administration of sabirnetug;

all were deemed not related or unlikely related to sabirnetug.

The most common treatment-emergent adverse events from all dose groups combined were ARIA-E (10.4%), ARIA-H (hemorrhage) (8.3%), COVID-19 (6.3%), hypersensitivity (6.3%), bronchitis (4.2%), headache (4.2%), fall (4.2%) and post LP syndrome (4.2%).

all were deemed not related or unlikely to be related to sabirnetug.

The most common treatment-emergent adverse events from all dose groups combined were ARIA-E (10.4%), ARIA-H (hemorrhage) (8.3%), COVID-19 (6.3%), and hypersensitivity (6.3%).

The overall rate of ARIA-E was 10.4%, which included one case of symptomatic ARIA-E (2.1%).

Of note, no apolipoprotein E, or APOE4, homozygote patients exhibited ARIA-E (n=6 treated).

Of note, no apolipoprotein E homozygote patients exhibited ARIA-E (n=6 treated).

• Pharmacokinetic results in CSF demonstrated statistically significant dose proportionality.

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Near maximal target engagement of AßOs observed in INTERCEPT-AD

• Exploratory measures of potential acute drug effects including assessment of cognition, as determined by a computerized cognitive battery, and changes in cerebral blood flow, as determined by arterial spin labelling with magnetic resonance imaging (Siemens MRI), did not show discernible effects from the immediate administration of sabirnetug.

• Exploratory measures of potential acute drug effects including assessment of cognition, as determined by a computerized cognitive battery, and changes in cerebral blood flow, as determined by ASL with MRI (Siemens MRI), did not show discernible effects from the immediate administration of sabirnetug.

This was not unexpected due to the short duration and small sample size of INTERCEPT-AD.

• Biofluids for assessment of biomarkers of downstream neurodegeneration were collected during the study.

• Biofluids for assessment of biomarkers of downstream neurodegeneration were collected during the clinical trial.

◦ A dose-dependent trend was observed in the MAD cohorts toward sabirnetug effect on CSF biomarkers specific to amyloid and tau pathology and synaptic injury.

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CSF biomarker changes observed in INTERCEPT-AD

◦ At the 60 mg/kg MAD cohort of sabirnetug, consistent trends were observed in plasma biomarkers, including GFAP, p-tau181 and p-tau217.

◦ At the 60 mg/kg MAD cohort of sabirnetug, consistent trends were observed in plasma biomarkers, including glial fibrillary acidic protein, p-tau181 and p-tau217.

After dosing completed, biomarkers also rebounded toward placebo, further supportive of a drug effect of sabirnetug.

Plasma biomarker changes observed in INTERCEPT-AD

In October of 2023, we met with the FDA to discuss the ALTITUDE-AD study design, and the potential pathway for registration of sabirnetug.

In October of 2023, we met with the FDA to discuss the ALTITUDE-AD clinical trial design, and the potential pathway for registration of sabirnetug.

The FDA had previously granted Fast Track designation to ACU193 in October 2022.

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In nonclinical studies, sabirnetug has demonstrated promising characteristics that indicate its potential to inhibit AßOs as a possible therapeutic treatment of AD.

Sabirnetug has high selectivity, with over 500-fold binding selectivity for AßOs compared to Aß monomers, 87-fold selectivity for AßOs over Aß fibril, and limited or no binding to amyloid plaques.

Sabirnetug has high selectivity, with over 500-fold greater binding selectivity for AßOs compared to Aß monomers, 87-fold greater selectivity for AßOs over Aß fibril, and limited or no binding to amyloid plaques.

Recent SPR data demonstrated that sabirnetug has up to 8750-fold greater selectivity for AßOs over Aß monomers.

Sabirnetug binds to a broad spectrum of small to large soluble AßOs.

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Sabirnetug has also demonstrated suitable in vivo pharmacology, target engagement, blood-brain barrier penetration and reduction of behavioral deficits.

Lastly, Good Laboratory Practice, or GLP, toxicity studies conducted in two animal species supported

the Phase 1 clinical trial.

Lastly, Good Laboratory Practice, or GLP, toxicity studies conducted in two animal species supported the Phase 1 clinical trial.

We believe these data, combined with our Phase 1 clinical trial results, indicate that sabirnetug has the potential to offer patients a reduction in cognitive decline.

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(i) preferential selectivity for binding to AßOs versus other forms of Aß monomers and amyloid plaques in in vitro assays, human AD tissue samples and in vivo transgenic mouse models;

(ii) consistent data in support of sabirnetug protective effects against AßO toxicity in in vitro and ex vivo assays;

(ii) consistent data in support of sabirnetug’s protective effects against AßO toxicity in in vitro and ex vivo assays;

(iii) in vivo pharmacology in multiple species confirming blood-brain barrier penetration, target engagement, and behavioral effects;

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We demonstrated that sabirnetug shows significant preferential selectivity for AßOs compared to Aß monomers.

In a competition ELISA assay, sabirnetug’s binding to AßOs was 556-fold greater than binding to Aß monomers.

In a competition ELISA assay, sabirnetug’s binding to AßOs was 556-fold greater than sabirnetug’s binding to Aß monomers.

Figure 6[A] shows comparative syn-AßO versus Aß monomer affinity data for sabirnetug and illustrates the high selectivity of sabirnetug for AßOs.

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Sabirnetug binding to AßOs versus amyloid plaques

The upper left portion of the immunohistochemistry figure shows that in areas with no amyloid plaque binding (no green fluorescence staining, A) there is substantial binding by sabirnetug (red fluorescence staining, B) that is not related to

amyloid plaque.

The upper left portion of the immunohistochemistry figure shows that in areas with no amyloid plaque binding (no green fluorescence staining, Panel A) there is substantial binding by sabirnetug (red fluorescence staining, Panel B) that is not related to amyloid plaque.

The merge of these panels (Panel E) shows sabirnetug binding with no amyloid plaque present.

On the upper right portion of the figure, the area that is positive for amyloid plaque (green fluorescence staining, C) shows minimal sabirnetug binding (red fluorescence staining, Panel D).

The merge of these panels (F) shows the minimal binding of sabirnetug (red fluorescence staining) on the periphery of the amyloid plaque (green fluorescence staining), which may be related to AßO binding in the halo of the amyloid plaque.

On the upper right portion of the figure, the area that is positive for amyloid plaque (green fluorescence staining, Panel C) shows minimal sabirnetug binding (red fluorescence staining, Panel D).

The merge of these panels (Panel F) shows the minimal binding of sabirnetug (red fluorescence staining) on the periphery of the amyloid plaque (green fluorescence staining), which may be related to AßO binding in the halo of the amyloid plaque.

Binding to a broad spectrum of molecular weight AßOs

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These data show sabirnetug binds AßOs ranging from dimers to approximately 100-mers, with preferential binding to mid-molecular weight oligomers compared to hu266.

This range of sizes is very similar to the range of sizes of oligomers thought to be most toxic.

Binding of humanized antibodies to size exclusion chromatography fractions of synthetic Aß species

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Collectively the data show that sabirnetug binds AßOs with 556-fold selectivity versus Aß monomers and demonstrates limited to no binding to amyloid plaques, but does bind to a broad range of synthetic and endogenous low, mid, and higher molecular weight AßOs.

Based on these and other data, we believe that sabirnetug can target therapeutically relevant AßOs in the brain of early AD patients.

Based on these and our target engagement data demonstrated in our INTERCEPT-AD Phase 1 clinical trial data, we believe that sabirnetug can target therapeutically relevant AßOs in the brains of early AD patients.

In Vivo Pharmacology

In order to understand the effects of sabirnetug in intact animals, we performed behavioral studies in transgenic mice with genetic alterations that overproduce a mutant amyloid precursor protein that forms amyloid plaques.

In order to understand the effects of sabirnetug in intact animals, we performed behavioral studies in transgenic mice with genetic alterations that overproduce a mutant APP that forms amyloid plaques.

The transgenic mouse models are generally based on autosomal dominant mutations in the APP gene causing rare forms of human AD.

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The behavioral effects seen in these studies indicate that sufficient amounts of ACU3B3 cross the blood-brain barrier to engage the target, resulting in behavioral improvements in these transgenic mice.

A study conducted at QPS and using nine- to ten-month-old APP/SL transgenic mice treated weekly with 20 mg/kg ACU3B3 for four weeks demonstrated statistically significant behavioral improvements in swim path length and swim speed during the water maze learning test (Figure 10).

A study conducted at QPS and using nine- to 10-month-old APP/SL transgenic mice treated weekly with 20 mg/kg ACU3B3 for four weeks demonstrated statistically significant behavioral improvements in swim path length and swim speed during the water maze learning test (Figure 9).

Results of ACU3B3 treatment in mice study

ACU3B3 treatment in nine- to ten-month-old APPSL mice (n=10/group) improves performance on the first day of water maze training (A;

ACU3B3 treatment in nine- to 10-month-old APP/SL mice (n=10/group) improves performance on the first day of water maze training (A;

p=0.057), decreases swim path length (B;

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Prior to dosing, Thy1-hAPP/SL mice showed increased activity in the activity chamber compared to wild-type mice.

After treatment with ACU3B3, Thy1-hAPP/SL mice activity fell to a level comparable to wild-type mice, particularly activity in the center of the test arena (Figure 11[A]).

After treatment with ACU3B3, Thy1-hAPP/SL mice activity fell to a level

comparable to wild-type mice, particularly activity in the center of the test arena (Figure 10[A]).

Similar effects of ACU3B3 were found with changes in Y-maze behavior (Figure 10[B]) and passive avoidance (Figure 10[C]).

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Pharmacokinetics and Pharmacodynamics

A study of pharmacokinetics in CSF was conducted in rhesus monkeys.

A study of PK in CSF was conducted in rhesus monkeys.

An intrathecal catheter was implanted in the monkeys, and two doses at 20 mg/kg IV were administered.

As shown in Figure 14, the concentrations of sabirnetug in CSF should provide adequate target engagement with dosing every four weeks.

As shown in Figure 13, the concentrations of sabirnetug in CSF should provide adequate target engagement with dosing Q4W.

This was recapitulated in our INTERCEPT-AD Phase 1 results, which demonstrated near-maximal target engagement of AßOs at both 25 mg/kg Q2W and 60 mg/kg Q4W.

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Safety Profile

GLP studies using IV administration of sabirnetug established a no-observed-adverse-effect level, or NOAEL, of 250 mg/kg/dose, which was the maximum feasible dose, given every two weeks in a 28-day study in Sprague-Dawley rats.

The NOAEL in cynomolgus monkeys was 300 mg/kg/dose in a 14-week study in cynomolgus monkeys using IV dosing every two weeks.

GLP studies using IV administration of sabirnetug established a no-observed-adverse-effect level, or NOAEL, of 250 mg/kg/dose, which was the maximum feasible dose, given Q2W in a 28-day study in Sprague-Dawley rats.

The NOAEL in cynomolgus monkeys was 300 mg/kg/dose in a 14-week study in cynomolgus monkeys using IV dosing Q2W.

In Sprague Dawley rats, no adverse findings were noted.

In the 14-week study in cynomolgus monkeys, doses of 60, 300, or 600 mg/kg/dose sabirnetug once every two weeks were administered.

In the 14-week study in cynomolgus monkeys, doses of 60, 300 or 600 mg/kg/dose sabirnetug once Q2W were administered.

Three animals administered the highest 600 mg/kg/dose were sacrificed early for humane reasons on Days 43 or 60 due to sabirnetug-related, anaphylactoid-type reactions.

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We believe our current manufacturers have the scale, the systems and the experience to supply our currently planned clinical trials.

In June 2021, the FDA granted approval for Biogen’s Aduhelm® (aducanumab) under the FDA’s Accelerated Approval Pathway, or AAP.

In June 2021, the FDA granted approval for Biogen Inc.’s, or Biogen’s, Aduhelm ® (aducanumab) under the FDA’s Accelerated Approval Pathway, or AAP.

Aduhelm was the first new AD product approval since 2004 and the first approved disease-modifying product.

In April 2022, the Centers for Medicare and Medicaid Services, or CMS, released a final National Coverage Decision, or NCD, that restricts reimbursement for monoclonal antibodies directed against amyloid for the treatment of AD, including Aduhelm, under a Coverage with Evidence Development, or CED, designation.

The CED limits reimbursement of anti-amyloid antibodies, including Aduhelm, to placebo-controlled clinical trials.

In May 2022, Biogen announced its decision to eliminate substantially all commercial support for Aduhelm in the U.S.

and withdrew its marketing application for Aduhelm in Europe.

In April 2022, the Centers for Medicare and Medicaid Services, or CMS, released a final National Coverage Decision that restricts reimbursement for mAbs directed against amyloid for the treatment of AD, including Aduhelm, under a Coverage with Evidence Development, or CED, designation.

The CED designation limits reimbursement of anti-amyloid antibodies, including Aduhelm, to placebo-controlled clinical trials.

In May 2022, Biogen announced its decision to eliminate substantially all commercial support for Aduhelm in the United States and withdrew its marketing application for Aduhelm in Europe.

In January 2024, Biogen announced its decision to discontinue the development and commercialization of Aduhelm.

In September 2022, Eisai announced results from its Leqembi® (lecanemab) Phase 3 CLARITY-AD trial.

Leqembi is a recombinant humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble (protofibrils) and insoluble (plaque) forms of amyloid beta.

In September 2022, Eisai Co., Ltd., or Eisai, announced results from its Leqembi ® (lecanemab) Phase 3 CLARITY-AD trial.

Leqembi is a recombinant humanized IgG1 mAb directed against aggregated soluble (protofibrils) and insoluble (plaque) forms of Aß.

In CLARITY-AD, Leqembi demonstrated highly statistically significant effects on primary and secondary clinical measures (including a 27% slowing of cognitive decline as measured by CDR-SB) and a lower rate of ARIA-E (12.6%) than observed for aducanumab in the Phase 3 EMERGE and ENGAGE studies.

In January 2023, the FDA granted approval for Leqembi under the AAP based on results of its Phase 2 study.

In July 2023, the FDA approved the supplemental Biologics License Application, or sBLA, supporting the approval of Leqembi.

In January 2023, the FDA granted approval for Leqembi under the AAP based on results of its Phase 2 clinical trial.

In July 2023, the FDA approved the supplemental Biologics License Application, or BLA, supporting the approval of Leqembi.

Also in July 2023, CMS announced it would cover Leqembi when a physician and care team participates in a CMS-facilitated registry.

While this approval and coverage determination are encouraging developments, the need for additional options for AD treatment and prevention becomes more urgent with each passing year, and we believe that our novel approach can potentially help address this pressing need.

In January 2023, the FDA issued a complete response letter to Eli Lilly and Company for the accelerated approval submission of donanemab.

Eisai and Biogen have submitted a BLA to the FDA for a subcutaneous weekly dosing option of Leqembi, with a Prescription Drug User Fee Act date in August 2025.

In January 2023, the FDA issued a complete response letter, or CRL, to Eli Lilly and Company, or Eli Lilly, for the accelerated approval submission of donanemab.

In May 2023, Eli Lilly announced results from its donanemab Phase 3 TRAILBLAZER-ALZ 2 trial.

Donanemab is an immunoglobulin gamma 1 (IgG1) monoclonal antibody that specifically targets deposited amyloid plaque.

In the TRAILBLAZER-ALZ 2 trial, donanemab demonstrated highly statistically significant effects on primary and secondary clinical measures (including a 29% slowing of cognitive decline as measured by CDR-SB in its high and intermediate tau patient group) with a higher rate of ARIA-E (24%) than Leqembi.

Eli Lilly expects regulatory action from the FDA on donanemab in 2024.

Donanemab is an IgG1 mAb that specifically targets deposited amyloid plaque.

In the TRAILBLAZER-ALZ 2 trial, donanemab demonstrated highly statistically significant effects on primary and secondary clinical measures (including a 29% slowing of cognitive decline, as measured by CDR-SB in its high and intermediate tau patient group) with a higher rate of ARIA-E (24%) among all donanemab-treated patients when compared to Leqembi.

In July 2024, the FDA approved Kisunla ® (donanemab) for the treatment of early AD.

There have been no comprehensive head-to-head clinical trials between any of the product candidates discussed above.

Study designs and protocols for each product candidate were different, and results may not be comparable between product candidates.

Study designs and protocols for each product candidate were different, and results may not be comparable among product candidates.

We face competition from several different institutions, including pharmaceutical and biotechnology companies, research institutions, governmental organizations and universities developing novel therapies for AD.

We believe that the key factors affecting the clinical and commercial success of sabirnetug will include safety profile, efficacy, cost, method of administration, level of marketing activity, insurance reimbursement and intellectual property protection.

If approved, sabirnetug can be used in combination with therapies currently approved for the treatment of AD which treat the symptoms of AD rather than the underlying cause of the disease, such as memantine and cholinesterase inhibitors.

Other companies known to be developing therapies with Aß-, AßO-, and amyloid plaque-related targets include AbbVie Inc., Alnylam Pharmaceuticals, AltPep Corporation, Alzheon, Inc., Alzinova AB, BioArctic AB, Biogen Inc., Chugai Pharmaceutical Co.

Ltd., Cognition Therapeutics, Inc., Eisai Co., Ltd., Eli Lilly and Company, Grifols, S.A., KalGene Pharmaceuticals, Inc., Neurimmune AG, Novartis AG, Priavoid GmbH, ProMIS Neurosciences, Inc., Prothena Biosciences, Inc., Roche Holding AG (including Genentech, its wholly owned subsidiary),Vaxxinity, Inc., Vivoryon Therapeutics N.V.

We believe that the key factors affecting the clinical and commercial success of sabirnetug will include safety profile, efficacy, method of administration, level of marketing activity, insurance reimbursement and intellectual property protection.

If approved, sabirnetug can be used in combination with therapies currently approved for the treatment of AD that treat the symptoms of AD rather than the underlying cause of the disease, such as memantine and cholinesterase inhibitors.

Other companies known to be developing therapies with Aß-, AßO- and amyloid plaque-related targets include AbbVie Inc., or Abbvie, Alector, Inc., or Alector, Alnylam Pharmaceuticals, Inc., AltPep Corporation, Alzheon, Inc., Alzinova AB, BioArctic AB, Biogen, Bristol-Myers Squibb Company, Cognition Therapeutics, Inc., Denali Therapeutics, Inc., or Denali, Eisai, Eli Lilly, Grifols, S.A., KalGene Pharmaceuticals, Inc., Neurimmune AG, Priavoid GmbH, ProMIS Neurosciences, Inc., Prothena Biosciences, Inc., Roche Holding AG (including Genentech, Inc., its wholly-owned subsidiary), or Roche, Vivoryon Therapeutics N.V.

and Wavebreak Therapeutics, Inc.

Additionally, sabirnetug, if approved, may also compete with other potential therapies intended to address underlying causes of AD that are being developed by several companies, including AbbVie Inc., AC Immune SA, Alector, Inc., Anavex Life Sciences Corp., Annovis Bio, Inc., Athira Pharma, Inc., Biogen Inc., Biohaven Pharmaceuticals, Inc., Cassava Sciences, Inc., Denali Therapeutics, Inc., Eisai Co., Ltd., Johnson & Johnson (including Janssen, its wholly-owned subsidiary), H.

Lundbeck A/S, Lighthouse Pharma, Roche Holding AG, and Takeda Pharmaceutical Co.

Additionally, sabirnetug, if approved, may also compete with other potential therapies intended to address underlying causes of AD that are being developed by several companies, including AbbVie, AC Immune SA, Alector, Anavex Life Sciences Corp., Annovis Bio, Inc., Athira Pharma, Inc., Biogen, Biohaven Pharmaceuticals, Inc., Cassava Sciences, Inc., Denali, Eisai, Johnson & Johnson (including Janssen Inc., its wholly-owned subsidiary), H.

Lundbeck A/S, Lighthouse Pharmaceuticals, Inc., Roche and Takeda Pharmaceutical Co.

Additional Treatment Modalities

While Aß and amyloid are generally considered to be the proximal cause of AD pathology, and alternative hypotheses to the amyloid hypothesis propose that amyloid accumulation is a consequence of other processes such as infection and that other pathogens lead to amyloid accumulation, downstream targets such as tau, inflammation-related targets, and growth factors may eventually be useful approaches in the treatment of AD and are being explored.

While Aß and amyloid are generally considered to be the proximal causes of AD pathology, and alternative hypotheses to the amyloid hypothesis propose that amyloid accumulation is a consequence of other processes such as infection and that other pathogens lead to amyloid accumulation, downstream targets such as tau, inflammation-related targets and growth factors may eventually be useful approaches in the treatment of AD and are being explored.

Some of these treatment modalities have made nonclinical and early-stage clinical progress, although these efforts are still significantly less advanced than those approaches targeting Aß or amyloid plaques.

Collaboration Agreement with Merck

In December 2003, we entered into an exclusive license and research and development collaboration agreement with Merck to research, discover and develop certain technology related to amyloid beta-derived diffusible ligands, or ADDLs, which agreement was amended and restated in October 2006.

The agreement generally provided that, during the course of the collaboration, Merck would be responsible for the preclinical and clinical development and commercialization of any products covered by the agreement and, in return, we were eligible to receive potential nonclinical, clinical and regulatory milestone payments and royalties on future product sales.

In December 2003, we entered into an exclusive license and research and development collaboration agreement with Merck to research, discover and develop certain technology related to Aß-derived diffusible ligands, or ADDLs, which agreement was amended and restated in October 2006.

The agreement generally provided that, during the course of the

collaboration, Merck would be responsible for the preclinical and clinical development and commercialization of any products covered by the agreement and, in return, we were eligible to receive potential nonclinical, clinical and regulatory milestone payments and royalties on future product sales.

During the collaboration, Merck developed sabirnetug, an ADDL antibody, and intellectual property related to sabirnetug was filed by Merck.

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The Company is also required to pay certain royalties upon commercialization and annual payments on a country-by-country basis in respect of the manufacturing and sale of the Lonza Product, which include (i) a royalty of less than 1.0% on net sales where Lonza manufactures the Lonza Product, (ii) an annual royalty payment in Swiss Francs in the low six-digits and a royalty of less than 1.0% on net sales where the Company manufactures the Lonza Product and (iii) an annual payment in Swiss Francs in the mid six-digits per sublicense and a royalty on net sales in the low single digits where a third party manufactures the Lonza Product.

These payment obligations would expire ten years from the first commercial sales of the Lonza Product in such country of sale.

These payment obligations would expire 10 years from the first commercial sales of the Lonza Product in such country of sale.

The Lonza License Agreement continues until terminated, and the Company or Lonza may terminate the Lonza License Agreement for uncured material breaches or insolvency of the other party.

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Halozyme License Agreement

On November 5, 2023, the Company entered into a Non-exclusive Collaboration and License Agreement, or the Halozyme License Agreement, with Halozyme, Inc., or Halozyme.

On November 5, 2023, the Company entered into a non-exclusive collaboration and license agreement, or the Halozyme License Agreement, with Halozyme.

Under the terms of the Halozyme License Agreement, Halozyme granted the Company a non-exclusive license to Halozyme’s ENHANZE ® drug delivery technology for the development of a subcutaneous formulation of sabirnetug, or the Halozyme Product.

Halozyme will also be the Company’s exclusive supplier of clinical and commercial supplies of the API for Halozyme’s PH20 product.

Halozyme will also be the Company’s exclusive supplier of clinical and commercial supplies of the active pharmaceutical ingredient for Halozyme’s PH20 product.

Pursuant to the Halozyme License Agreement, the Company paid Halozyme a seven-figure upfront payment for the license to Halozyme’s technology.

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The Company will also make single-digit royalty payments based on worldwide net sales of the Halozyme Product.

The Halozyme Agreement includes customary termination rights, representations and warranties, covenants and indemnification obligations for a transaction of this nature.

The Halozyme License Agreement includes customary termination rights, representations and warranties, covenants and indemnification obligations for a transaction of this nature.

Intellectual Property

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The main form of commercial exclusivity for our product candidate, sabirnetug, is expected to come from biologic regulatory exclusivity.

We expect that once approved by regulatory agencies, sabirnetug will receive the benefit of 12 years of market exclusivity in the U.S.

and 10 to 11 years of data and market exclusivity in Europe, in each case, against competitors seeking approval for a biosimilar product.

We expect that once approved by regulatory agencies, sabirnetug will receive the benefit of 12 years

of market exclusivity in the United States and 10 to 11 years of data and market exclusivity in Europe, in each case, against competitors seeking approval for a biosimilar product.

We have an exclusive license grant from Merck to patents claiming the composition and method of use of our product candidate, sabirnetug.

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As of March 27, 2025, Acumen licenses from Merck one issued U.S.

patent, 18 issued foreign patents including issued patents in Brazil, China, Canada, Australia, Japan, South Korea, France, Germany and the UK drawn to our product candidate, sabirnetug.

These patents are projected to expire in July of 2031, without taking into account any possible extensions and assuming payment of all appropriate maintenance, renewal, annuity, or other governmental fees.

patent and 18 issued foreign patents, including issued patents in Brazil, China, Canada, Australia, Japan, South Korea, France, Germany and the UK drawn to our product candidate, sabirnetug.

These patents are projected to expire in July 2031, without taking into account any possible extensions and assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees.

Throughout the development of our product candidate, 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.

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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 candidate.

Where one patent covers multiple products or product candidate, it may only receive an extension for one of the covered products;

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.

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 the earliest effective filing date of a non-provisional patent application, such as a Patent Cooperation Treaty, or 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.

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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 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.

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Government Regulation

The FDA and other regulatory authorities at federal, state, and local levels, as well as in foreign countries, extensively regulate, among other things, the research, development, testing, manufacture, quality control, import, export, safety, effectiveness, labeling, packaging, storage, distribution, record keeping, approval, advertising, promotion, marketing, post-approval monitoring, and post-approval reporting of biologics such as those we are developing.

The process of obtaining regulatory approvals and the subsequent compliance with applicable federal, state, local and foreign statutes and regulations require the expenditure of substantial time and financial resources.

The FDA and other regulatory authorities at federal, state and local levels, as well as in foreign countries, extensively regulate, among other things, the research, development, testing, manufacture, quality control, import, export, safety, effectiveness, labeling, packaging, storage, distribution, record keeping, approval, advertising, promotion, marketing, pricing, reimbursement, post-approval monitoring and post-approval reporting of biologics such as those we are developing.

The process of obtaining regulatory approvals and the subsequent compliance with applicable federal, state, local and foreign statutes and regulations, both pre-approval and post-approval, require the expenditure of substantial time and financial resources.

The regulatory requirements applicable to drug and biological product development, approval and marketing are subject to change, and regulations and administrative guidance often are revised or reinterpreted by the agencies in ways that may have a significant impact on our business.

Biologics Regulation

In the United States, biological products are subject to regulation under the Federal Food, Drug, and Cosmetic Act, or FDCA, the Public Health Service Act, or PHSA, and other federal, state and local statutes and regulations.

In the United States, biological products are subject to regulation under the Federal Food, Drug, and Cosmetic Act, or FDCA, the Public Health Service Act and other federal, state and local statutes and regulations.

The process required by the FDA before biologics may be marketed in the United States generally involves the following:

• completion of preclinical laboratory tests and animal studies performed in accordance with the FDA’s Good Laboratory Practice requirements, or GLPs;

• completion of preclinical laboratory tests and animal studies performed in accordance with the FDA’s GLP requirements;

• submission to the FDA of an investigational new drug application, or IND, which must become effective before clinical trials may begin and must be updated annually and when certain changes are made;

• approval by an institutional review board, or IRB, or independent ethics committee at each clinical site before the trial is commenced;

• performance of adequate and well-controlled human clinical trials in accordance with Good Clinical Practices, or GCP, requirements and other clinical trial-related regulations to establish the safety, purity and potency of the proposed biologic product candidate for its intended purpose;

• preparation of and submission to the FDA of a biologics license application, or BLA, after completion of all pivotal clinical trials;

• performance of adequate and well-controlled human clinical trials in accordance with Good Clinical Practices, or GCPs, requirements and other clinical trial-related regulations to establish the safety, purity and potency of the proposed biologic product candidate for its intended purpose;

• preparation of and submission to the FDA of a BLA after completion of all pivotal clinical trials;

• payment of user fees for FDA review of the BLA;

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The conduct of preclinical studies is subject to federal and state regulations and requirements, including GLP requirements for safety and toxicology studies.

The results of the preclinical studies, together with manufacturing information and analytical data must be submitted to the FDA as part of an IND.

The results of the preclinical studies, together with manufacturing information and analytical data, must be

submitted to the FDA as part of an IND.

An IND is a request for authorization from the FDA to administer an investigational new drug to humans.

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In addition, the IRB 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, that the trial is unlikely to meet its stated objectives or that the trial is not being conducted in accordance with FDA requirements.

Some studies also include oversight by an independent group of qualified experts organized by the clinical study sponsor, known as a data safety monitoring board, or data monitoring committee, which provides authorization for whether or not a study 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 to subjects or on other grounds, such as lack of efficacy.

Some studies also include oversight by an independent group of qualified experts organized by the clinical study sponsor, known as a data safety monitoring board or DMC, which provides authorization for whether or not a study may move forward at designated checkpoints 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 to subjects or on other grounds, such as lack of efficacy.

Information about applicable clinical trials, including clinical trials results, must be submitted within specific timeframes for publication on the www.clinicaltrials.gov website.

IND sponsors must submit annual reports on the progress of investigations under the IND to FDA and submit IND safety reports when certain serious and unexpected adverse reactions and certain other safety issues occur.

In December 2022, with the passage of the Food and Drug Omnibus Reform Act, Congress added a requirement for sponsors to develop and submit a diversity action plan for each Phase 3 clinical trial or any other “pivotal study” of a new drug or biological product.

Action plans must include the sponsor’s goals for enrollment, the underlying rationale for those goals, and an explanation of how the sponsor intends to meet them.

IND sponsors must submit annual reports on the progress of investigations under the IND to the FDA and submit IND safety reports when certain serious and unexpected adverse reactions and certain other safety issues occur.

In December 2022, with the passage of the Food and Drug Omnibus Reform Act, or FDORA, Congress added a requirement for sponsors to develop and submit a diversity action plan for each Phase 3 clinical trial or any other “pivotal study” of a new drug or biological product.

Action plans must include the sponsor’s goals for enrollment, the underlying rationale for those goals, and an explanation of how the sponsor intends to meet its enrollment goals.

This requirement will apply with respect to clinical investigations for which enrollment commences 180 days after the publication of a final guidance by the FDA on diversity action plans.

The statute directs FDA to issue new or revised draft guidance on diversity action plans by the end of 2023, and final guidance within 9 months of closing the comment period on such draft guidance.

FDA has not yet published new or revised draft guidance.

The FDA published a draft guidance on diversity action plans in June 2024, and the statute directs the FDA to issue final guidance within nine months of closing the comment period on such draft guidance.

For purposes of BLA approval, human clinical trials are typically conducted in three sequential phases that may overlap or be combined:

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Within 60 days following submission of the application, the FDA reviews a BLA submitted to determine if it is substantially complete before the FDA accepts it for filing.

Once a BLA has been accepted for filing, the FDA’s goal is to review standard applications within ten months after the filing date, or, if the application qualifies for priority review, six months after the FDA accepts the application for filing.

Once a BLA has been accepted for filing, the FDA’s goal is to review standard applications within 10 months after the filing date, or, if the application qualifies for priority review, six months after the FDA accepts the application for filing.

In both standard and priority reviews, the review process may also be extended by FDA requests for additional information or clarification.

Before approving a BLA, the FDA will typically inspect the facility or facilities where the product is manufactured.

The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance

with cGMP and adequate to assure consistent production of the product within required specifications.

The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMPs and adequate to assure consistent production of the product within required specifications.

Additionally, before approving a BLA, the FDA will typically inspect one or more clinical sites to assure compliance with GCP and other requirements and the integrity of the clinical data submitted to the FDA.

After the FDA evaluates a BLA and conducts inspections of manufacturing facilities where the investigational product and/or its drug substance will be produced, the FDA may issue an approval letter or a Complete Response Letter, or CRL.

An approval letter authorizes commercial marketing of the product with specific prescribing information for specific indications.

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A product candidate is eligible for priority review if it is designed to treat a serious or life-threatening disease or condition, and if approved, would provide a significant improvement in safety or effectiveness compared to available alternatives for such disease or condition.

For original BLAs, priority review designation means the FDA’s goal is to take action on the marketing application within six months of the 60-day filing date (as compared to ten months under standard review).

For original BLAs, priority review designation means the FDA’s goal is to take action on the marketing application within six months of the 60-day filing date (as compared to 10 months under standard review).

Fast Track designation, Breakthrough Therapy designation and priority review do not change the standards for approval but may expedite the development or approval process.

Even if a product candidate qualifies for one or more of these

programs, the FDA may later decide that the product no longer meets the conditions for qualification or decide that the time period for FDA review or approval will not be shortened.

Even if a product candidate qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or decide that the time period for FDA review or approval will not be shortened.

Accelerated approval pathway

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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 Food and Drug Omnibus Reform Act of 2022, or FDORA, signed by President Biden on December 29, 2022 as part of the Consolidated Appropriations Act, 2023 (H.R.

2617) includes numerous reforms to the accelerated approval process for drugs and biologics and enables FDA to require, as appropriate, that a post-approval study be underway prior to granting accelerated approval.

FDORA also expands the expedited withdrawal procedures already available to FDA to allow the agency to use expedited procedures if a sponsor fails to conduct any required post-approval study of the product with due diligence including with respect to “conditions specified by the Secretary [of HHS].” FDORA also adds the failure of a sponsor of a product approved under accelerated approval to conduct with due diligence any required post-approval study with respect to such product or to submit timely reports with respect to such product to the list of prohibited acts in the FDCA.

FDORA, signed by President Biden on December 29, 2022 as part of the Consolidated Appropriations Act, 2023 (H.R.

2617), includes numerous reforms to the accelerated approval process for drugs and biologics and enables the FDA to require, as appropriate, that a post-approval study be underway prior to granting accelerated approval.

FDORA also expands the expedited withdrawal procedures already available to the FDA to allow the agency to use expedited procedures if a sponsor fails to conduct any required post-approval study of the product with due diligence, including with respect to “conditions specified by the Secretary [of HHS].” FDORA also adds the failure of a sponsor of a product approved under accelerated approval to conduct with due diligence any required post-approval study with respect to such product or to submit timely reports with respect to such product to the list of prohibited acts in the FDCA.

Orphan Drug Designation and Exclusivity

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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 a waiver of the BLA application user fee.

Among the other benefits of ODD are tax credits for certain research and a waiver of the BLA user fee.

Post-approval Requirements

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After approval, most changes to the approved product, such as adding new indications or other labeling claims, are subject to prior FDA review and approval.

There also are continuing, annual program fees for any marketed products.

manufacturers and their subcontractors are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with ongoing regulatory requirements, including cGMP.

There are also continuing annual program fees for any marketed products.

Biologic manufacturers and their subcontractors are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with ongoing regulatory requirements, including cGMPs.

Changes to the manufacturing process are strictly regulated, and, depending on the significance of the change, may require prior FDA approval before being implemented.

Accordingly, manufacturers must continue to expend time, money and effort in the area of production and quality control to maintain compliance with cGMP and other aspects of regulatory compliance.

Accordingly, manufacturers must continue to expend time, money and effort in the area of production and quality control to maintain compliance with cGMPs and other aspects of regulatory compliance.

The FDA may withdraw approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market.

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In addition, government proposals have sought to reduce the 12-year reference product exclusivity period.

Other aspects of the Patient Protection and Affordable Care Act, some of which may impact the BPCIA exclusivity provisions, have also been the subject of recent

Other aspects of the ACA, some of which may impact the BPCIA exclusivity provisions, have also been the subject of recent litigation.

As a result, the ultimate impact, implementation and regulatory interpretation of the BPCIA remain subject to significant uncertainty.

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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, which may constrain their business operations, including financial arrangements related to the research, marketing and distribution of drug products.

Such laws include, without limitation, federal and state laws intended to prevent fraud and abuse in the healthcare industry, protect data privacy and security and promote transparency.

Such laws include, without limitation, the following, some of which may apply to our operations only if and when we have a marketed product:

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In addition, the government may assert that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the FCA;

• the federal civil monetary penalties laws, which impose civil fines for, among other things, the offering or transfer or remuneration to a Medicare or state healthcare program beneficiary if the person knows or should know it is likely to influence the beneficiary’s selection of a particular provider, practitioner, or supplier of services reimbursable to Medicare or a state health program, unless an exception applies;

know it is likely to influence the beneficiary’s selection of a particular provider, practitioner or supplier of services reimbursable to Medicare or a state health program, unless an exception applies;

• the federal Health Insurance Portability and Accountability Act, or HIPAA, which created additional federal criminal statutes which prohibit, among other things, a person from knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program, including private third-party payors and knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services.

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• federal laws, such as the Medicaid Drug Rebate Program, that require pharmaceutical manufacturers to report certain calculated product prices to the government or provide certain discounts or rebates to government authorities or private entities, often as a condition of reimbursement under governmental healthcare programs;

• the so-called federal “sunshine law,” or Open Payments, which requires manufacturers of drugs, devices, biologics and medical supplies to report to the CMS information related to payments and other transfers of value to teaching hospitals, physicians and other healthcare practitioners, as well as ownership and investment interests held by physicians and their immediate family members;

• federal and state consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm consumers;

• the so-called federal “sunshine law” or Open Payments which requires manufacturers of drugs, devices, biologics, and medical supplies to report to the Centers for Medicare & Medicaid Services information related to payments and other transfers of value to teaching hospitals, physicians, and other healthcare practitioners, as well as ownership and investment interests held by physicians and their immediate family members;

• analogous state laws and regulations, such as state anti-kickback and false claims laws, which may apply to sales or marketing arrangements and claims involving healthcare items or services reimbursed by non- governmental third-party payors, including private insurers, and state laws which regulate interactions between pharmaceutical companies and healthcare providers, require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government, require pharmaceutical companies to report information on transfers of value to other healthcare providers, marketing expenditures or pricing information and/or require licensing or registration of sales representatives.

Given the breadth of the laws and regulations and narrowness of any exceptions, limited guidance for certain laws and regulations and evolving government interpretations of the laws and regulations, it is possible that some of our business activities could be subject to challenge under one or more of such laws.

It is possible that governmental authorities will conclude that our business practices may not comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws and regulations.

Ensuring compliance with healthcare laws is time-consuming and costly.

Given the breadth of the laws and regulations and narrowness of any exceptions, limited guidance for certain laws and regulations and evolving government interpretations of the laws and regulations, governmental authorities may possibly conclude that our business practices are non-compliant.

Efforts to ensure that our business arrangements with third parties will comply with applicable healthcare laws and regulations will involve substantial costs.

Any action against us for violation of these laws, even if we successfully defend against it, could cause us to incur significant legal expenses and divert our management’s attention from the operation of our business.

If our operations are found to be in violation of any of these laws or any other governmental regulations that may apply to us, we may be subject to significant penalties, including, without limitation, civil, criminal and administrative penalties, damages, fines, disgorgement, imprisonment, exclusion from participating in federal and state funded healthcare programs, such as Medicare and Medicaid, additional reporting requirements and oversight if we become subject to a corporate integrity agreement or similar agreement to resolve allegations of non-compliance with these laws, contractual damages, diminished profits and future earnings, reputational harm and the curtailment or restructuring of our operations, any of which could harm our business.

If our operations are found to be in violation of any of the laws described above or any other government regulations that apply to us, we may be subject to penalties, including, without limitation, civil and criminal penalties, damages, fines, imprisonment, exclusion from participating in federal and state funded healthcare programs, such as Medicare and Medicaid, additional reporting requirements and oversight if we become subject to a corporate integrity agreement or similar agreement to resolve allegations of non-compliance with these laws, contractual damages, diminished profits and future earnings, reputational harm and the curtailment or restructuring of our operations, any of which could adversely affect our business, financial condition, results of operations and prospects.

Coverage and Reimbursement

The ability of a pharmaceutical company to successfully commercialize and achieve market acceptance of a product depends in significant part on adequate coverage and reimbursement from third-party payors, including government healthcare programs, such as the Medicare and Medicaid programs, and private entities, such as managed care organizations and private health insurers.

In the United States, no uniform policy of coverage and reimbursement for drug products exists among third-party payors.

Therefore, coverage and reimbursement for drug products can differ significantly from payor to payor.

In the United States, no uniform policy of coverage and reimbursement for drug products exists among third-party payors and coverage and reimbursement for drug products can differ significantly from payor to payor.

The process for determining whether a third-party payor will provide coverage for a product may be separate from the process for setting the price or reimbursement rate that the payor will pay for the product once coverage is approved.

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and neither cosmetic, experimental nor investigational.

To obtain or maintain coverage and reimbursement for any approved drug product, a pharmaceutical manufacturer may need to conduct expensive pharmacoeconomic studies or otherwise provide evidence to demonstrate to demonstrate the medical necessity and cost-effectiveness of our product.

To obtain or maintain coverage and reimbursement for any approved drug product, a pharmaceutical manufacturer may need to conduct expensive pharmacoeconomic studies or otherwise provide evidence to demonstrate the medical necessity and cost-effectiveness of our product.

These studies will be in addition to the studies required to obtain or maintain regulatory approvals.

If third-party payors do not consider a product to be cost-effective compared to other available therapies, they may not cover the product or, if they do, the level of payment may not be sufficient to allow sale of a product at a profit.

Even if third party payors provide some coverage, the third-party payors may impose limits on the coverage or controls to manage utilization of products.

If third-party payors do not consider a product to be cost-effective compared to other available therapies, the payors may not cover the product or, if they do, the level of payment may not be sufficient to allow sale of a product at a profit.

Even if third-party payors provide some coverage, they may impose limits on the coverage or controls to manage utilization of products.

Third-party payors may limit coverage to specific products on an approved list, or formulary, which might not include all of the approved products for a particular indication and can exclude drugs from their formularies in favor of competitor drugs or alternative treatments.

prescription for each patient (to allow the payor to assess medical necessity) or impose a moratorium on coverage for products while the payor makes a coverage decision.

Payors may also impose step edits that require patients to try alternative, including generic, treatments before authorizing payment for our products, limit the types of diagnoses for which coverage will be provided, require pre-approval (known as “prior authorization”) for coverage of a prescription for each patient (to allow the payor to assess medical necessity) or impose a moratorium on coverage for products while the payor makes a coverage decision.

Moreover, a third-party payor’s decision to provide coverage for a product does not mean that an adequate reimbursement rate will be approved.

A pharmaceutical company may be required to provide discounts or rebates to certain purchasers to obtain coverage under federal healthcare programs, or to sell products to government purchasers.

A pharmaceutical company may be required to provide mandatory discounts or rebates to certain purchasers to obtain coverage under federal healthcare programs or to sell products to government purchasers.

A pharmaceutical company may also have to offer discounts or rebates to private third-party payors to obtain favorable coverage.

There has been significant consolidation in the health insurance industry, increasing the leverage of large insurers and pharmacy benefit managers in pricing and other negotiations and potentially impacting potential drug product sales, business and results of operations.

Adequate third-party reimbursement may not be available to enable a company to realize an appropriate return on an investment in product development.

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In the United States and some foreign jurisdictions, there have been, and likely will continue to be, a number of legislative and regulatory healthcare reform initiatives directed at broadening the availability of healthcare, improving the quality of healthcare, and containing or lowering the cost of healthcare.

These reform initiatives, if implemented, could impact our ability to sell a product candidate profitably if and when approved for marketing.

For example, in 2010, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, or collectively, the ACA, was enacted, which, among other things, subjected biologic products to potential competition by lower-cost biosimilars;

These reform initiatives, if and when implemented, could impact our ability to sell a product candidate profitably if and when approved for marketing.

For example, in 2010, the ACA was enacted, which, among other things, subjected biologic products to potential competition by lower-cost biosimilars;

addressed a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected;

increased the minimum Medicaid rebates owed by most manufacturers under the Medicaid Drug Rebate Program;

increased the minimum

Medicaid rebates owed by most manufacturers under the Medicaid Drug Rebate Program;

extended the Medicaid Drug Rebate Program to utilization of prescriptions of individuals enrolled in Medicaid managed care organizations;

subjected manufacturers to new annual fees and taxes for certain branded prescription drugs;

and created a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D.

More generally, the ACA expanded health care coverage through Medicaid expansion and the implementation of the “individual mandate” for health insurance coverage.

Beyond the ACA, there have been ongoing health care reform efforts.

Drug pricing and payment reform was a focus of the Trump Administration and has been a focus of the Biden Administration.

For example, federal legislation enacted in 2021 eliminated the statutory cap on Medicaid drug rebate program rebates (currently set at 100% of a drug’s “average manufacturer price”) effective January 1, 2024.

and established a Medicare Part D coverage gap discount program.

More generally, the ACA expanded healthcare coverage through Medicaid expansion and the implementation of the “individual mandate” for health insurance coverage.

Beyond the ACA, there have been ongoing healthcare reform efforts, including with respect to drug pricing and payment reform.

For example, effective January 1, 2024, federal legislation has eliminated the statutory cap on Medicaid Drug Rebate Program rebates (previously set at 100% of a drug’s “average manufacturer price”).

As another example, the Inflation Reduction Act of 2022, or IRA, includes a number of changes intended to address rising prescription drug prices in Medicare Parts B and D.

These changes, which have varying implementation dates, include caps on Medicare Part D out-of-pocket costs, Medicare Part B and Part D drug price inflation rebates, a new Medicare Part D manufacturer discount drug program (replacing the ACA Medicare Part D coverage gap discount program) and a drug price negotiation program for certain high spend Medicare Part B and D drugs.

The focus on health care reform, including reform of drug pricing and payment, has continued in the wake of the IRA.

For example, in 2022, subsequent to the enactment of the IRA, the Biden administration released an executive order directing the HHS to report on how the Center for Medicare and Medicaid Innovation, or CMMI, could be leveraged to test new models for lowering drug costs for Medicare and Medicaid beneficiaries, which report proposed various models that CMMI is currently developing.

The IRA is anticipated to have a significant impact on the pharmaceutical industry.

The focus on healthcare reform, including reform of drug pricing and payment, has continued in the wake of the IRA.

For example, in 2022, subsequent to the enactment of the IRA, the Biden administration announced its commitment to expanding certain IRA reforms.

There have been significant and wide-ranging reforms to federal policy and the federal government under the new Trump administration.

Drug pricing and payment reform was a focus of the prior Trump administration and that focus is likely to continue under the new Trump administration.

Other potential healthcare reform efforts under the Trump administration may affect access to healthcare coverage or the funding of healthcare benefits.

There is significant uncertainty regarding the nature or impact of any such reform implemented by the Trump administration through executive action or by Congress.

Healthcare reform efforts have been and may continue to be subject to scrutiny and legal challenge.

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As another example, revisions to regulations under the federal anti-kickback statute would remove protection for traditional Medicare Part D discounts offered by pharmaceutical manufacturers to pharmacy benefit managers and health plans.

Pursuant to court order, the removal was delayed and subsequent legislation imposed a moratorium on

implementation of the rule until January 2032.

Pursuant to court order, the removal was delayed and subsequent legislation imposed a moratorium on implementation of the rule until January 2032.

As another example, the IRA drug price negotiation program has been challenged in litigation filed by various pharmaceutical manufacturers and industry groups.

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We cannot, however, predict the ultimate content, timing or effect of any federal and state reform efforts.

There is no assurance that federal or state health care reform will not adversely affect our future business and financial results.

There is no assurance that federal or state healthcare reform will not adversely affect our future business and financial results.

Employees and Human Capital Resources

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The principal purposes of our equity incentive plans are to attract, retain and reward personnel through the granting of stock-based compensation awards.

As of March 20, 2024, we had 52 employees, 51 of which were full time.

Of the 52 employees, there were 36 in research and development and 16 in general and administrative functions.

As of March 24, 2025, we had 61 employees, all of whom were full time.

Of our 61 employees, 41 were engaged in research and development and 20 were engaged in general and administrative functions.

We also utilized consultants in various roles related to research and development and general and administrative functions.

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We were incorporated under the laws of the State of Delaware in 1996.

Our principal executive offices are located at 427 Park St., Charlottesville, Virginia 22902 and our telephone number is (434) 297-1000.

Our principal executive offices are located at 1210-1220 Washington Street, Suite 210, Newton, MA 02465 and our telephone number is (617) 344-4190.

Available Information

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Our website and information included in or linked to our website are not part of this Annual Report on Form 10-K.

Our annual reports on Form 10-K, quarterly reports on Form 10-Q, current reports on Form 8-K and amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended, are available free of charge through our website as soon as reasonably practicable after they are electronically filed with or furnished to the SEC.

Securities and Exchange Commission, or the SEC.

Additionally, the SEC maintains an internet site that contains reports, proxy and information statements and other information.

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business