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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.
+Added: 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.
+Added: 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.
+Added: By 2050, healthcare costs for AD in the United States alone are estimated to exceed $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.
−Removed: We are currently focused on advancing a targeted immunotherapy drug candidate, ACU193, through clinical proof of mechanism trials in early AD patients.
−Removed: ACU193 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 models for AD.
−Removed: ACU193 is the result of over a decade of research and development undertaken by the company, which included a drug discovery partnership with Merck & Co., Inc., or Merck, from 2003 to 2011.
−Removed: ACU193’s mechanism of action is intended to slow disease progression and potentially preserve or improve memory function in early AD patients by binding to AßOs and neutralizing their toxicity.
+Added: 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.
+Added: 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.
+Added: Sabirnetug is the result of over a decade of research and development undertaken by the company, which included a drug discovery partnership with Merck & Co., Inc., or Merck, from 2003 to 2011.
+Added: Sabirnetug’s mechanism of action is intended to slow disease progression and potentially preserve or improve memory function in early AD patients by binding to AßOs and neutralizing their toxicity.
AßOs have been shown to bind to neurons, contributing to synaptic malfunction, memory deficits, cognitive impairment and, ultimately, neurodegeneration and cell death.
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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.
−Removed: In our nonclinical studies, we observed that ACU193 has over 500-fold greater selectivity for targeting AßOs over Aß monomers and, based on immunohistochemical studies of human AD brain tissue, appears to have limited or no binding to amyloid plaques.
−Removed: Also, ACU193 potently prevents binding of AßOs to hippocampal neurons and preserves long-term potentiation for those cell, an electrophysiological surrogate for brain circuit function such as memory.
−Removed: Recent laboratory studies conducted by Acumen and others suggest that inhibiting AßOs may enable damaged brain circuits to regain some function and prevent further degeneration from occurring.
−Removed: ACU193 has demonstrated in vivo biochemical and behavioral activity in several AD mouse models, including crossing the blood-brain barrier and forming complexes with AßOs in a dose-dependent manner.
−Removed: ACU193 has shown consistent pharmacokinetics and brain penetration properties in four animal species.
−Removed: Safety toxicology studies in rats and monkeys provide acceptable margins for acute and chronic dosing in the clinic.
−Removed: Additionally, studies in transgenic mice indicate low potential for microhemorrhage.
−Removed: Based in part on its binding selectivity for AßOs rather than amyloid plaques, ACU193 has the potential to have a lower rate of amyloid-related imaging abnormalities, or ARIA, than the plaque-directed anti-amyloid antibody therapies currently in development or approved.
−Removed: ARIA is a common adverse event for antibodies targeting amyloid plaque and can be a dose-limiting safety liability for those antibodies.
−Removed: We initiated a Phase 1 clinical trial of ACU193 in the second quarter of 2021, which we named “INTERCEPT-AD.” This trial enrolled 65 patients with mild dementia or mild cognitive impairment, or MCI, due to AD, conditions referred to as “early AD.” INTERCEPT-AD is a U.S.-based, multi-center, randomized, double-blind, placebo-controlled clinical trial with overlapping single ascending dose, or SAD, and multiple ascending dose, or MAD, cohorts involving patients with early AD.
−Removed: The overall objective of the trial is to evaluate the safety and tolerability of ACU193 and to establish clinical proof of mechanism of ACU193 administered intravenously.
−Removed: The primary trial endpoints are focused on safety and immunogenicity.
−Removed: An important safety measure will be the use of magnetic resonance imaging, or MRI, to assess the presence or absence of ARIA.
−Removed: Secondary endpoints include pharmacokinetics in plasma and cerebrospinal fluid, or CSF, and target engagement as evidenced by detection of ACU193 bound to AßOs in CSF.
−Removed: Clinical scales typically used in AD trials as well as computerized cognitive testing and arterial spin labelling with MRI scans are included as exploratory measures.
−Removed: In October 2021, we announced the initial dosing of the first patient in the INTERCEPT-AD trial and the subsequent successful sentinel safety review of the first two patients.
−Removed: In January 2023, we submitted a protocol amendment to the U.S.
−Removed: Food and Drug Administration, or FDA, to modify the planned dose level of Cohort 7 of INTERCEPT-AD to 25 mg/kg every two weeks from 60 mg/kg every two weeks.
−Removed: The proposed change was based in part on a blinded review of preliminary pharmacokinetic data, inclusive of plasma and cerebrospinal fluid levels, which indicated a dose of 60 mg/kg every two weeks should not be needed to attain central
−Removed: target engagement, and preliminary safety data, inclusive of two asymptomatic cases of ARIA-E (one in Cohort 4 after a single 60 mg/kg dose and one in Cohort 5 after a third 10 mg/kg dose).
−Removed: We announced the completion of enrollment in INTERCEPT-AD in February 2023 and we anticipate reporting topline data from this trial in the third quarter of 2023.
−Removed: Alzheimer’s disease is a progressive neurodegenerative disease that destroys memory and other important cognitive functions and ultimately leads to patient death.
−Removed: AD 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.
−Removed: 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.
−Removed: By 2050, healthcare costs for AD in the United States alone are estimated to exceed $1 trillion.
−Removed: The target population for ACU193 and other monoclonal antibodies 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.
+Added: 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.
−Removed: While epidemiologic studies of this population are evolving, approximately 4-5 million people in the United States are likely to have early AD.
−Removed: In June 2021, the FDA granted approval for Biogen’s Aduhelm (aducanumab) under the FDA’s Accelerated Approval Pathway, or AAP.
−Removed: Aduhelm was the first new AD product approval since 2004 and the first approved disease-modifying product.
−Removed: 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.
−Removed: The CED limits reimbursement of anti-amyloid antibodies, including Aduhelm, to placebo-controlled clinical trials.
−Removed: In May 2022, Biogen announced its decision to eliminate substantially all commercial support for Aduhelm in the U.S.
−Removed: and withdrew its marketing application for Aduhelm in Europe.
−Removed: In January 2023, the FDA granted approval for Eisai’s Leqembi™ (lecanemab) under the AAP based on results of its Phase 2 study.
−Removed: Lecanemab is a recombinant humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble (protofibrils) and insoluble (plaque) forms of amyloid beta.
−Removed: In September 2022, Eisai announced positive results of its lecanemab Phase 3 CLARITY-AD trial.
−Removed: In CLARITY-AD, lecanemab demonstrated highly statistically significant effects on primary and secondary clinical measures and a lower rate of ARIA than observed for aducanumab in the Phase 3 EMERGE and ENGAGE studies.
−Removed: Though a full FDA approval for Leqembi is anticipated for the third quarter of 2023 based on the Phase 3 CLARITY-AD results, 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.
+Added: 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.
+Added: 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.
+Added: In immunohistochemical studies of human AD brain tissue, sabirnetug appears to have limited or no binding to amyloid plaques.
+Added: Sabirnetug has also demonstrated in vivo biochemical and behavioral activity in several AD mouse models, and safety toxicology studies in rats and monkeys provide acceptable margins for acute and chronic dosing in the clinic.
+Added: We completed a Phase 1 clinical trial of sabirnetug in the second quarter of 2023, which we named “INTERCEPT-AD.” This trial enrolled 65 participants with early AD, and 62 participants received at least one dose of study drug.
+Added: INTERCEPT-AD was a U.S.-based, multi-center, randomized, double-blind, placebo-controlled clinical trial with overlapping single ascending dose, or SAD, and multiple ascending dose, or MAD, cohorts evaluating patients with early AD.
+Added: The overall objective of the trial was to evaluate the safety and tolerability of sabirnetug administered intravenously, or IV, and to establish clinical proof of mechanism of sabirnetug.
+Added: The primary trial endpoints were focused on safety and immunogenicity.
+Added: 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.
+Added: 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.
+Added: 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.
+Added: 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.
+Added: Sabirnetug was well-tolerated throughout the SAD and MAD dose cohorts, with an overall rate of ARIA-E of 10.4%.
+Added: The incidence of ARIA-E was dose dependent, with a rate of 7% for patients given 10 mg/kg or 25 mg/kg and 21% for patients given 60 mg/kg.
+Added: An analysis of change in amyloid plaque load, as measured by positron emission tomography,or PET, Centiloids, demonstrated a rapid, dose-related mean decrease at the higher dose levels studied.
+Added: 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.
+Added: 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.
+Added: 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.
+Added: 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.
+Added: We expect to initiate a Phase 2 clinical trial of sabirnetug, called ALTITUDE-AD, in the first half of 2024.
+Added: 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.
+Added: We intend to use the Integrated Alzheimer's Disease Rating Scale, or iADRS at 18 months as the primary outcome measure.
+Added: Our planned doses for ALTITUDE-AD are 35 mg/kg and 50 mg/kg both dosed every four weeks, or Q4W.
+Added: These dose levels and frequency were selected based on extensive pharmacokinetic, or PK, and pharmacodynamic, or PD, modeling of our Phase 1 data.
+Added: 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.
+Added: If this happens, any interim analysis may then lead to an initiation of a confirmatory Phase 3 study.
+Added: In November 2023, we announced a global collaboration and license agreement with Halozyme to develop a subcutaneous formulation of sabirnetug.
+Added: We expect to initiate a Phase 1 trial investigating a subcutaneous dosing option of sabirnetug in mid-2024.
Understanding the Foundation of Our Therapeutic Approach
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Alois Alzheimer in 1906, the amyloid hypothesis was not developed until the Aß peptide was first identified as a major constituent of amyloid plaques in the 1980s.
−Removed: 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 and cause inflammation, ultimately leading to neuronal cell loss and progressive dementia.
The primary constituent of amyloid plaques is the Aß peptide, although other proteins are present to lesser degrees.
+Added: 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.
+Added: Additionally, amyloid plaques cause inflammation.
+Added: The disruption of synaptic function, inflammation and brain cell loss ultimately lead to progressive Alzheimer’s related dementia.
The amyloid hypothesis was more firmly established when a series of genetic mutations causing AD were discovered in the early to mid-1990s.
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for our purposes, this broadly defined class is referred to as anti-Aß/plaque antibodies.
−Removed: Several of these antibodies are currently in late-stage development, two having received accelerated regulatory approval, and collectively they have provided a biological foothold for treating AD.
−Removed: While aducanumab targets deposited amyloid plaques, lecanemab was intended to target soluble aggregated species of Aß known as protofibrils (although it also lowers plaque).
−Removed: However, the clinical data available to date indicate some of the potential limitations of these approaches with respect to clinically meaningful patient benefit and safety.
−Removed: Though alternative hypotheses to the amyloid hypothesis propose that amyloid accumulation is a consequence of another process such as infection, the field has now developed an understanding that three predominant pools of Aß species exist in vivo:
+Added: 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.
+Added: Food and Drug Administration, or FDA, in 2023.
+Added: Another antibody, donanemab, which was developed to target amyloid plaques, is under review for FDA approval, which is expected in 2024.
+Added: 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.
+Added: Though alternative hypotheses to the amyloid hypothesis have been proposed, e.g., that neurodegeneration is a consequence of another process such as infection, the field has now developed an understanding that three predominant pools of Aß species exist in vivo:
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.
−Removed: Linear soluble protofibrils may elongate to form the insoluble fibrils that make up deposited amyloid plaques.
−Removed: ACU193 was developed to bind to globular AßOs rather than to Aß monomers or deposited amyloid plaques.
−Removed: The more recent appreciation of the crucial role of soluble AßOs in the pathologic process is the central tenet of our therapeutic approach.
−Removed: Our therapeutic approach focuses on targeting AßOs, which we believe are the most toxic and pathogenic form of Aß relative to Aß monomers and insoluble amyloid plaques.
−Removed: Growing evidence, spurred by advances in AD research and analytic techniques, supports our view that AßOs are one of the primary instigators of AD neurodegeneration.
+Added: Linear soluble Aß protofibrils may elongate to form the insoluble fibrils that make up deposited amyloid plaques.
+Added: Sabirnetug was developed to bind to globular AßOs rather than to Aß monomers, fibrils or deposited
+Added: amyloid plaques.
+Added: The more recent recognition of the direct toxicity of soluble AßOs to neurons is the central tenet of our therapeutic approach.
AßOs have been observed to be potent neurotoxins that cause both acute synaptic toxicity and induce neurodegeneration.
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Research has also shown that the accumulation of AßOs is associated with AD-related behavioral deficits, such as learning and memory impairment.
−Removed: In light of this evidence, we believe that blocking the toxicity of AßOs is a promising approach for maximizing the therapeutic index (efficacy compared to safety) for the treatment of AD, which led us to discover and develop ACU193.
+Added: In light of this evidence, we believe that blocking the toxicity of AßOs is a differentiated and promising approach for maximizing the therapeutic index (efficacy compared to safety) for the treatment of AD.
Our Product Candidate
−Removed: Our product candidate, ACU193, is a recombinant humanized, affinity-matured, immunoglobulin G2, or IgG2, subclass monoclonal antibody, derived from the murine immunoglobulin G1, or IgG1, parent, ACU3B3.
−Removed: We are developing ACU193 for intravenous, or IV, administration every four weeks for the treatment of early AD.
−Removed: We believe that ACU193 represents a differentiated approach from current and prior anti-Aß/plaque immunotherapies because it is highly selective for soluble AßOs.
−Removed: ACU193 has a nanomolar affinity for AßOs, over 500-fold greater selectivity for AßOs over Aß monomers, and limited or no binding to dense core amyloid plaques.
−Removed: We believe that ACU193 is the most advanced immunotherapy candidate in development that was designed to selectively target AßOs.
−Removed: We believe that ACU193 has characteristics that make it a promising potential treatment for AD relative to other antibodies that do not selectively target AßOs.
−Removed: ACU193 is designed to have reduce immune effector function signaling and to avoid binding to vascular amyloid plaques, which we expect will reduce the incidence of ARIA observed with amyloid plaque-targeting immunotherapies approved and in development for AD.
−Removed: We are currently assessing ACU193 in INTERCEPT-AD, a proof of mechanism Phase 1 clinical trial involving early AD patients.
−Removed: We anticipate our next clinical study, pending success in Phase 1, starting as a Phase 2 clinical trial with the potential to expand to a Phase 3 registration trial based in part on an interim expansion analysis.
−Removed: However, completion of a Phase 2 trial, with or without an expansion to Phase 3, will likely require us to raise capital in an amount sufficient to extend our cash runway into the second half of 2026.
−Removed: Our Differentiated Approach to the Treatment of AD
−Removed: We believe that, based on its differentiated mechanism of action, potential for symptomatic improvement and disease modification, and potential for higher dosing, ACU193 has several potential advantages in comparison to other AD drugs that are currently approved or in development:
−Removed: Differentiated mechanism of action:
−Removed: • Potentially addresses an underlying cause of AD .
−Removed: A growing body of evidence indicates that AßOs, rather than Aß monomers or amyloid plaques, are the primary toxic species of Aß that impair neuronal synaptic function and contribute to impairment in memory and cognition and neurodegeneration.
−Removed: We believe that AßOs are an optimal therapeutic target relative to other Aß species and that ACU193 has the potential to be the first AßO mAb treatment to slow the progression of AD.
−Removed: • Selectively binds to AßOs.
−Removed: ACU193 is the first monoclonal antibody discovered and designed to selectively target AßOs.
−Removed: In our nonclinical studies, ACU193 demonstrated a greater than 500-fold affinity to bind to AßOs over monomers and did not bind vascular amyloid or dense core amyloid plaques.
−Removed: In immunohistochemical studies using human AD brain tissue, little or no binding to thioflavin-S positive amyloid plaques appeared to be present.
−Removed: In comparison, most other non-selective anti-Aß/amyloid antibodies in development bind primarily to Aß monomers or amyloid plaques.
−Removed: • Binds to a broad spectrum of toxic AßOs.
−Removed: AßOs are present in the brain in a wide range of sizes.
−Removed: ACU193 has the ability to bind to a broad spectrum of toxic AßOs across various molecular weights.
−Removed: Nonclinical data shows that ACU193 binds to oligomeric species from dimers to approximately 100-mers of Aß.
−Removed: Potential for symptomatic improvement and disease modification:
−Removed: • May provide symptomatic improvement in addition to disease modification.
−Removed: While recent anti-Aß monoclonal antibody results have established a biological foothold for disease-modifying treatments for AD, they fail to demonstrate clinically meaningful symptomatic improvement as measured by AD clinical assessments.
−Removed: Recent nonclinical studies show that AßOs are acutely toxic to neuronal function.
−Removed: By selectively targeting and neutralizing AßO toxicity, we believe that ACU193 has the potential to build upon this biological foothold and provide improvements in cognitive function in addition to disease-modifying effects.
−Removed: Potential for higher dosing:
−Removed: • Selectivity for AßOs could result in reduced rates of ARIA, allowing a broader therapeutic window.
−Removed: Amyloid plaque binding antibodies have been associated with ARIA, with IgG1 monoclonal antibodies in particular showing elevated rates of ARIA, which presents a safety concern.
−Removed: In contrast, ACU193 was developed as an IgG2 subclass monoclonal antibody, which has reduced inflammatory effector functions compared to IgG1 antibodies.
−Removed: Because ACU193 exhibits limited or no binding to amyloid plaques and has reduced inflammatory effector functions, we believe that treatment with ACU193 could result in lower rates of ARIA-E relative to IgG1 monoclonal antibodies that bind to amyloid plaque.
−Removed: ACU193 has demonstrated a favorable pharmacokinetic profile in nonclinical studies.
−Removed: Based on the results of Good Laboratory Practice, or GLP, safety studies in rats and monkeys, dose-ranging for the INTERCEPT-AD study included doses up to 60 mg/kg, and based on ongoing blinded safety reviews, the ARIA rate to date has been low.
−Removed: While certain anti-plaque antibodies have dose limitations due to ARIA, we believe that ACU193 may be well-tolerated at higher doses compared to other antibodies.
−Removed: Summary comparison of ACU193 to anti-Aß/plaque antibodies in clinical development
−Removed: Despite recognition that AßOs are key structures contributing to AD memory dysfunction, cognitive deficits, and neurodegeneration, drug discovery efforts targeting these species have been hampered by technical difficulties of generating physiologically relevant preparations of synthetic AßOs, or syn-AßOs.
−Removed: Our founders and early-stage researchers were instrumental in the development of well-characterized preparations of syn-AßOs, initially termed Aß Derived Diffusible Ligands, or ADDLs, which are globular structures.
−Removed: ADDL preparations were used as the immunogen to generate and discover ACU3B3, the murine IgG1 parent of ACU193.
−Removed: In December 2003, we entered into an exclusive license and research and development collaboration agreement with Merck for the research, discovery, development, and commercialization of immunotherapies for AD.
−Removed: From 2003 to 2011, Merck carried out extensive research leading to the humanization of ACU3B3 and creation of ACU193.
−Removed: ACU193 emerged as the lead product candidate based on its preferential AßO binding, favorable immunogenicity profile, and an absence of off-target binding.
−Removed: In 2011, Merck chose to terminate the program largely based on internal strategic priorities.
−Removed: Consequently, we regained an exclusive, perpetual, irrevocable, royalty-free, worldwide license for the research, development, manufacturing or commercialization of ADDL antibodies, ADDL antigens, or products, including ACU193.
+Added: 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.
+Added: 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.
+Added: 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.
+Added: 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.
+Added: We believe that sabirnetug is the most advanced immunotherapy candidate in development that was designed to selectively target toxic AßOs.
+Added: We believe that sabirnetug has characteristics that make it a promising potential treatment for AD relative to other antibodies that lack selectivity for AßOs.
+Added: Sabirnetug is designed to have reduced immune effector function signaling and to avoid binding to vascular amyloid plaques, which we expect will reduce the incidence of ARIA as compared to amyloid plaque-targeting immunotherapies approved and in development for AD.
+Added: Sabirnetug’s selectivity for AßOs may increase the potential for greater efficacy as compared to these other immunotherapies.
+Added: We announced results from INTERCEPT-AD, a proof of mechanism Phase 1 clinical trial involving early AD patients, in July 2023.
+Added: We expect to initiate ALTITUDE-AD, our Phase 2 clinical trial, in the first half of 2024.
+Added: We also expect to initiate a Phase 1 clinical trial investigating a subcutaneous dosing option of sabirnetug in mid-2024.
Clinical Development Plan
−Removed: We are currently conducting INTERCEPT-AD, a U.S.-based, multi-center, randomized, placebo-controlled, single and multiple ascending dose Phase 1 clinical trial of ACU193 in 65 patients with early AD.
−Removed: The early AD patient group is comprised of individuals who have mild dementia or MCI due to AD, and our trial excludes patients with moderate to severe AD dementia.
−Removed: Patients have been enrolled across seven cohorts, consisting of a single ascending dose in Part A and an overlapping multiple ascending dose in Part B.
−Removed: Part A contains Cohorts 1 through 4;
+Added: As noted above, we expect to initiate a Phase 2 clinical trial, ALTITUDE-AD, in the first half of 2024.
+Added: 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.
+Added: We intend to use iADRS, a measurement of cognitive and functional decline, at 18 months as the primary outcome measure.
+Added: Our planned doses for ALTITUDE-AD are 35 mg/kg and 50 mg/kg both dosed IV Q4W.
+Added: 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.
+Added: The 35 and 50 mg/kg doses were selected based on extensive PK/PD modeling of our Phase 1 data.
+Added: Design of ALTITUDE-AD
+Added: 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.
+Added: This trial enrolled 65 participants with early AD, and 62 participants received at least one dose of study drug.
+Added: 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.
+Added: Patients were enrolled across seven cohorts, consisting of a single ascending dose in Part A and an overlapping multiple ascending dose in Part B.
+Added: Part A contained Cohorts 1 through 4;
each cohort received a single IV dose between 2mg/kg and 60 mg/kg, or placebo.
−Removed: Part B contains Cohorts 5 through 7;
−Removed: each cohort receives a total of three doses of ACU193 or placebo as follows:
+Added: Part B contained Cohorts 5 through 7;
+Added: 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).
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Trial Design Part A - Single Ascending Dose
−Removed: In Part A of our clinical trial, participants were randomized in a 6:2 ratio into one of four cohorts to receive a single dose of ACU193 or placebo as follows:
−Removed: One IV dose of ACU193 (2 mg/kg) or placebo.
−Removed: One IV dose of ACU193 (10 mg/kg) or placebo.
−Removed: One IV dose of ACU193 (25 mg/kg) or placebo.
−Removed: One IV dose of ACU193 (60 mg/kg) or placebo.
+Added: In Part A of our clinical trial, participants were randomized in a 6:2 ratio into one of four cohorts to receive a single dose of sabirnetug or placebo as follows:
+Added: One IV dose of sabirnetug (2 mg/kg) or placebo.
+Added: One IV dose of sabirnetug (10 mg/kg) or placebo.
+Added: One IV dose of sabirnetug (25 mg/kg) or placebo.
+Added: 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).
1 unchanged sentence
Dosing of Cohorts 1-3 began at least one week after all participants in the immediately preceding lower-dose cohort had received one administration of study drug and safety data had been reviewed by our internal blinded safety team.
−Removed: Dosing of Cohort 4 began at least one week after all participants in Cohort 3 received one administration of study drug and these safety data, along with Cohort 2 aggregate pharmacokinetic data, had been reviewed by our internal blinded safety team.
−Removed: An unblinded,
−Removed: independent Data Monitoring Committee, or DMC, also monitored the trial and was able to review safety data on an ad hoc basis if requested by the blinded study team.
+Added: Dosing of Cohort 4 began at least one week after all participants in Cohort 3 received one administration of study drug and these safety data, along with Cohort 2 aggregate PK data, had been reviewed by our internal blinded safety team.
+Added: An unblinded, independent Data Monitoring Committee, or DMC, also monitored safety data in the trial and was able to review data on an ad hoc basis if requested by the blinded study team.
Trial Design Part B - Multiple Ascending Dose
−Removed: 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 ACU193 or placebo as follows:
−Removed: One IV dose of ACU193 (10 mg/kg) or placebo once every four weeks.
−Removed: One IV dose of ACU193 (60 mg/kg) or placebo once every four weeks.
−Removed: One IV dose of ACU193 (25 mg/kg) or placebo once every two weeks.
−Removed: Participants in Cohorts 5 and 6 will be evaluated over approximately 35 weeks, consisting of a seven-week screening period followed by a 28-week, double-blind treatment period.
−Removed: A follow-up safety check will be performed approximately eight weeks after the final visit of the double-blind treatment period.
−Removed: Participants in Cohort 7 will be evaluated over approximately 31 weeks, consisting of a seven-week screening period, followed by a 24-week, double-blind treatment period.
−Removed: A follow-up safety check will be performed approximately eight weeks after the final visit of the double-blind treatment period.
−Removed: In order to maintain participant safety for Part B of the clinical trial, dosing of Cohort 5 began at least one week after all participants in Cohort 2 of Part A had received one administration of ACU193 or placebo and the Cohort 2 safety data had been reviewed by our internal blinded safety team.
−Removed: For Cohort 6, dosing began at least one week after all participants in Cohort 4 of Part A had received one administration of ACU193 or placebo and the Cohort 4 safety data had been reviewed by our internal blinded safety team.
+Added: 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:
+Added: One IV dose of sabirnetug (10 mg/kg) or placebo once every four weeks.
+Added: One IV dose of sabirnetug (60 mg/kg) or placebo once every four weeks.
+Added: One IV dose of sabirnetug (25 mg/kg) or placebo once every two weeks.
+Added: 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.
+Added: Participants in Cohort 7 were evaluated over approximately 31 weeks, consisting of a seven-week screening period, followed by a 24-week, double-blind treatment period.
+Added: In order to maintain participant safety for Part B of the clinical trial, dosing of Cohort 5 began at least one week after all participants in Cohort 2 of Part A had received one administration of sabirnetug or placebo and the Cohort 2 safety data had been reviewed by our internal blinded safety team.
+Added: For Cohort 6, dosing began at least one week after all participants in Cohort 4 of Part A had received one administration of sabirnetug or placebo and the Cohort 4 safety data had been reviewed by our internal blinded safety team.
Dosing of Cohort 7 began after review of Cohort 3 and Cohort 4 safety data at least one week after the last person in the cohort was dosed.
−Removed: 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 pharmacokinetic data and advise on dose escalation.
−Removed: Cohort 7 will allow for additional pharmacokinetic modeling to more accurately determine if every two-week dosing is necessary and if accumulation of ACU193 occurs with this dosing frequency.
−Removed: Our goal for the Phase 1 trial is to establish clinical proof of mechanism of ACU193 in patients with early AD.
−Removed: The endpoints we will measure as part of this trial include:
+Added: 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.
+Added: 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.
+Added: Our Phase 1 clinical trial established clinical proof of mechanism of sabirnetug in patients with early AD.
+Added: The endpoints we measured as part of this trial included:
Primary Endpoint
2 unchanged sentences
• pharmacokinetics in plasma;
−Removed: • determination of CSF concentrations of ACU193;
−Removed: • evaluation of central target engagement as measured by levels of ACU193 AßO complex in CSF;
+Added: • determination of CSF concentrations of sabirnetug;
+Added: • evaluation of central target engagement as measured by levels of sabirnetug AßO complex in CSF;
• evaluation of possible changes in concentration of biomarkers for AD in CSF or blood;
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• exploratory evaluation of possible changes in cognitive, functional, and behavioral measures using computerized testing and standard clinical measures for AD.
−Removed: The main objective of INTERCEPT-AD is to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and target engagement of single and multiple ascending doses of ACU193 administered by intravenous infusions.
−Removed: Exploratory outcomes will include cognitive scales and computerized cognitive testing.
−Removed: Our goal is to establish clinical proof of mechanism of ACU193 in early AD patients in order to enable progression into an adaptive Phase 2/3 clinical trial.
−Removed: In October 2021, we announced the initial dosing of the first patient in the INTERCEPT-AD trial and the subsequent successful sentinel safety review of the first two patients.
−Removed: Due to delays in clinical trial site activation and patient enrollment that we believe are principally related to effects of the COVID-19 pandemic, we expanded the anticipated number of trial sites to support our enrollment objectives and anticipated timelines.
−Removed: We announced enrollment completion in February 2023 and anticipate reporting our topline data from this trial in the third quarter of 2023.
−Removed: Following, and subject to the results of, INTERCEPT-AD, we plan to request an end-of-Phase 2/pre-Phase 3 meeting with the FDA, which we anticipate will occur in the fourth quarter of 2023, to discuss the clinical trial design for our next clinical study and potential pathway for registration.
−Removed: The FDA granted Fast Track designation to ACU193 in October 2022.
+Added: 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.
+Added: Exploratory outcomes included cognitive scales and computerized cognitive testing.
+Added: Our goal was to establish clinical proof of mechanism of sabirnetug in early AD patients in order to enable progression into further clinical development.
+Added: We announced INTERCEPT-AD topline data in July of 2023, which demonstrated that sabirnetug met the primary
+Added: and secondary objectives of this study in 62 participants with early AD.
+Added: • 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.
+Added: 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)).
+Added: This finding provides evidence that sabirnetug is active in the brain.
+Added: INTERCEPT-AD plaque reduction observed in highest dose MAD cohorts
+Added: • Sabirnetug was well-tolerated throughout the SAD and MAD dose cohorts.
+Added: Three treatment-emergent serious adverse events were observed after administration of sabirnetug;
+Added: all were deemed not related or unlikely related to sabirnetug.
+Added: 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%).
+Added: The overall rate of ARIA-E was 10.4%, which included one case of symptomatic ARIA-E (2.1%).
+Added: Of note, no apolipoprotein E, or APOE4, homozygote patients exhibited ARIA-E (n=6 treated).
+Added: • Pharmacokinetic results in CSF demonstrated statistically significant dose proportionality.
+Added: Serum PK was dose-related without drug accumulation, and CSF PK was dose- and dose-regimen proportional.
+Added: Levels of sabirnetug detected in CSF in all cohorts were in excess of endogenous levels of AßOs reported in CSF.
+Added: Evidence of treatment emergent immunogenicity was observed;
+Added: anti-drug antibodies were consistently low titer and there was no apparent effect on serum PK.
+Added: These data support monthly dosing of sabirnetug.
+Added: • Statistically significant, dose-related central target engagement was observed as measured by sabirnetug-AßO
+Added: complex, establishing the first target engagement assay developed that is specific to an AßO-targeting antibody.
+Added: An exposure response relationship (Emax) model revealed near maximal target engagement with repeated dosing at 25 mg/kg and 60 mg/kg.
+Added: Near maximal target engagement of AßOs observed in INTERCEPT-AD
+Added: • 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.
+Added: This was not unexpected due to the short duration and small sample size of INTERCEPT-AD.
+Added: • Biofluids for assessment of biomarkers of downstream neurodegeneration were collected during the study.
+Added: ◦ 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.
+Added: These included p-tau181, total tau, neurogranin, VAMP2 and the Aß-42/40 ratio.
+Added: At the 60 mg/kg Q4W dose of sabirnetug, nominally statistically significant improvements in p-tau181 and neurogranin were observed as compared to the placebo group (p=0.049 and p=0.037, respectively).
+Added: At all doses, statistically significant improvement in VAMP2 was observed compared to placebo (p=0.033 for the 10 mg/kg dose, p=0.041 mg/kg for 25 mg/kg dose and p=0.033 for the 60 mg/kg dose).
+Added: Nominally significant correlation was also observed between target engagement of AßOs and change in CSF neurogranin across all doses, and a trend was seen for target engagement versus CSF p-tau181.
+Added: CSF biomarker changes observed in INTERCEPT-AD
+Added: ◦ At the 60 mg/kg MAD cohort of sabirnetug, consistent trends were observed in plasma biomarkers, including GFAP, p-tau181 and p-tau217.
+Added: After dosing completed, biomarkers also rebounded toward placebo, further supportive of a drug effect of sabirnetug.
+Added: Plasma biomarker changes observed in INTERCEPT-AD
+Added: In October of 2023, we met with the FDA to discuss the ALTITUDE-AD study design, and the potential pathway for registration of sabirnetug.
+Added: The FDA had previously granted Fast Track designation to ACU193 in October 2022.
Nonclinical and Laboratory Data
−Removed: In nonclinical studies, ACU193 has demonstrated promising characteristics that indicate its potential to inhibit AßOs as a possible therapeutic treatment of AD.
−Removed: ACU193 has high selectivity, with over 500-fold binding selectivity for AßOs compared to Aß monomers and has limited or no binding to amyloid plaques.
−Removed: ACU193 binds to a broad spectrum of small to large soluble AßOs.
−Removed: Additionally, ACU193 has been shown to offer protection from synaptic toxicity by inhibiting binding of AßOs to primary hippocampal neurons.
−Removed: ACU193 has also demonstrated suitable in vivo pharmacology, target engagement, blood-brain barrier penetration and reduction of behavioral deficits.
−Removed: Based on nonclinical studies, AßO target engagement has the potential to be achieved at doses of ACU193 that will be tested in our Phase 1 clinical trial.
−Removed: Lastly, Good Laboratory Practice, or GLP, toxicity studies conducted in two animal species supported the Phase 1 study.
−Removed: We believe these data indicate that ACU193 has the potential to offer patients a reduction in cognitive decline.
+Added: In nonclinical studies, sabirnetug has demonstrated promising characteristics that indicate its potential to inhibit AßOs as a possible therapeutic treatment of AD.
+Added: 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.
+Added: Sabirnetug binds to a broad spectrum of small to large soluble AßOs.
+Added: Additionally, sabirnetug has been shown to offer protection from synaptic toxicity by inhibiting binding of AßOs to primary hippocampal neurons.
+Added: Sabirnetug has also demonstrated suitable in vivo pharmacology, target engagement, blood-brain barrier penetration and reduction of behavioral deficits.
+Added: Lastly, Good Laboratory Practice, or GLP, toxicity studies conducted in two animal species supported
+Added: the Phase 1 clinical trial.
+Added: 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.
Summary of Nonclinical Studies
−Removed: In our nonclinical studies, ACU193 has demonstrated:
+Added: In our nonclinical studies, sabirnetug has demonstrated:
(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;
−Removed: (ii) consistent data in support of ACU193 protective effects against AßO synaptic toxicity in in vitro and ex vivo assays;
+Added: (ii) consistent data in support of sabirnetug 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;
−Removed: and (iv) safety data in multiple species including GLP toxicology studies in Sprague-Dawley rats and cynomolgus monkeys confirming an adequate safety margin for the first in human clinical trial.
−Removed: Based on the strength of the data we observed in our nonclinical studies, we initiated INTERCEPT-AD, a Phase 1 clinical trial, in the second quarter of 2021.
−Removed: Key Characteristics and Data
−Removed: Selectivity • ACU193 binds a broad range of synthetic and human-derived AßOs (~dimers to ~100-mers).
−Removed: In vivo pharmacology • ACU193 crosses the blood-brain barrier and demonstrates dose-dependent target engagement in the brain following peripheral administration of antibody.
−Removed: Safety • GLP studies via IV route established no observed adverse effect level, or NOAEL, of 300 mg/kg/dose in a 14-week cynomolgus monkey study and 250 mg/kg/dose in a 28-day rat study.
+Added: and (iv) safety data in multiple species including GLP toxicology studies in Sprague-Dawley rats and cynomolgus monkeys supporting the clinical trials.
Selectivity for AßOs
−Removed: In order to understand ACU193 selectivity for AßOs, we performed biochemical assays and immunohistochemistry experiments.
+Added: In order to understand sabirnetug selectivity for AßOs, we performed biochemical assays and immunohistochemistry experiments.
Selectivity for AßOs versus Aß monomers
−Removed: We demonstrated that ACU193 shows significant preferential selectivity for AßOs compared to Aß monomers.
−Removed: In a competition ELISA assay, ACU193’s binding to AßOs was 556-fold greater than binding to Aß monomers.
−Removed: Figure 3A shows comparative syn-AßO versus Aß monomer affinity data for ACU193, and illustrates the high selectivity of ACU193 for AßOs.
−Removed: Further evidence of ACU193 selectivity for syn-AßOs was obtained using a very high concentration of monomeric Aß, 5 µm, which did not decrease binding to syn-AßOs (Figure 3B).
−Removed: We believe ACU193’s selectivity for AßOs in the presence of abundant Aß monomers is representative of the in vivo levels of these Aß species in AD patients.
−Removed: Thus, ACU193 does not experience “target distraction” from non-toxic Aß monomers in an environment simulating brain interstitial fluid.
−Removed: [A] Competitive ELISA for ACU193 binding to syn-AßO or monomeric Aß40 [B] 5µM monomeric Aß did not substantially change binding to syn-AßO
−Removed: These results support the conclusion that selectivity of ACU193 for AßOs is maintained in a biochemical environment simulating the brain.
+Added: We demonstrated that sabirnetug shows significant preferential selectivity for AßOs compared to Aß monomers.
+Added: In a competition ELISA assay, sabirnetug’s binding to AßOs was 556-fold greater than binding to Aß monomers.
+Added: Figure 7[A] shows comparative syn-AßO versus Aß monomer affinity data for sabirnetug and illustrates the high selectivity of sabirnetug for AßOs.
+Added: Further evidence of sabirnetug selectivity for synthetic-AßOs, or syn-AßOs, was obtained using a very high concentration of monomeric Aß, 5 µM, which did not decrease binding to syn-AßOs (Figure 7[B]).
+Added: We believe sabirnetug’s selectivity for AßOs in the presence of abundant Aß monomers is representative of the in vivo levels of these Aß species in AD patients.
+Added: Thus, sabirnetug does not experience “target distraction” from non-toxic Aß monomers in an environment simulating brain interstitial fluid.
+Added: [A] Competitive ELISA for sabirnetug binding to syn-AßO or monomeric Aß40 [B] 5µM monomeric Aß did not substantially change binding to syn-AßO
+Added: These results support the conclusion that selectivity of sabirnetug for AßOs is maintained in a biochemical environment simulating the brain.
Selectivity for AßOs versus amyloid plaques
−Removed: We have shown in our nonclinical data that ACU193 binds AßOs from AD patients with limited or no binding to amyloid plaques.
−Removed: In Figure 4 below, thioflavin S-positive ß-amyloid plaques are shown in green fluorescence while ACU193 binding is shown in red fluorescence.
−Removed: ACU193 binds significantly in regions that are thioflavin-S-negative, i.e., without
−Removed: amyloid plaques (Figure 4, Panels B and E), but only infrequently and minimally binds to thioflavin-S-positive fibrillar Aß structures (Figure 4, Panel D);
−Removed: close examination shows possible co-localization of ACU193 with thioflavin-S-positive Aß deposits in their periphery (Figure 4, Panel F).
−Removed: We believe a likely explanation of ACU193 infrequent binding near the periphery of some amyloid plaques is due to binding to AßOs that surround the periphery of amyloid plaques.
−Removed: Taken together, these results are consistent with the concept that ACU193 binds endogenous AßOs, does not block binding by thioflavin-S, and, importantly, preferentially binds AßOs versus fibrillar Aß.
−Removed: ACU193 binding to AßOs versus amyloid plaques
−Removed: 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 ACU193 (red fluorescence staining, B) that is not related to amyloid plaque.
−Removed: The merge of these panels (Panel E) shows ACU193 binding with no amyloid plaque present.
−Removed: On the upper right portion of the figure, the area that is positive for amyloid plaque (green fluorescence staining, C) shows minimal ACU193 binding (red fluorescence staining, Panel D).
−Removed: The merge of these panels (F) shows the minimal binding of ACU193 (red fluorescence staining) on the periphery of the amyloid plaque (green fluorescence staining), likely related to AßO binding in the halo of the amyloid plaque.
−Removed: AD stages based on AD neuropathic change, or ADNC, scoring
−Removed: ADNC scoring is a combination of amyloid plaque levels, neuritic plaque levels, and neurofibrillary tangle pathology, or NFT, levels (Braak stage).
−Removed: In human tissue samples, ACU193 shows a disease state-relevant signal based on
−Removed: immunohistochemistry shown on the left from aged controls, intermediate AD pathology, and advanced AD pathology.
−Removed: On the far-right panel, ACU193 detects AßOs in soluble hippocampal extracts from an autosomal dominant AD patient, but not from a cognitively normal patient.
−Removed: Furthermore, we have demonstrated that ACU193 does not bind to amyloid plaque surrounding blood vessels (cerebral amyloid angiopathy).
−Removed: In a study of transgenic mice, we did not observe binding to vascular amyloid, in contrast to hu3D6 (bapineuzumab), which displayed significant binding at all dose levels.
−Removed: ACU193 versus hu3D6 binding to vascular amyloids
−Removed: ACU193 (A and C) shows no binding to the vascular amyloid that is visible in the vessels stained by thioflavin-S (green fluorescence, B and D) in the brain 24 hours following IV dosing of 10 or 50 mg/kg in seven- to eight-month-old Tg2576 mice.
−Removed: In contrast, hu3D6 (bapineuzumab) binds vascular amyloid (E) at all dose levels assessed.
−Removed: The data above related to vascular plaque binding support our belief that ACU193 is likely to have limited ARIA liability.
−Removed: Given that the amyloid plaque-binding properties of multiple antibodies have been associated with ARIA (e.g., aducanumab, lecanemab, gantenerumab, and donenamab), we believe that ACU193’s negligible binding of amyloid plaques, including amyloid plaques associated with cerebral amyloid angiopathy, provides evidence that ACU193 may have a lower rate of ARIA in comparison.
+Added: We have shown in our human immunohistochemistry studies that sabirnetug binds AßOs from AD patients with limited or no binding to amyloid plaques.
+Added: In Figure 8 below, thioflavin S-positive ß-amyloid plaques are shown in green fluorescence while sabirnetug binding is shown in red fluorescence.
+Added: Sabirnetug binds significantly in regions that are thioflavin-S-negative, i.e., without amyloid plaques (Figure 8 , Panels B and E), but only infrequently and minimally may bind to thioflavin-S-positive fibrillar Aß structures in their periphery (Figure 8, Panels D and F).
+Added: Taken together, these results are consistent with the concept that sabirnetug binds endogenous AßOs, and preferentially binds AßOs versus fibrillar Aß.
+Added: Sabirnetug binding to AßOs versus amyloid plaques
+Added: 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
+Added: amyloid plaque.
+Added: The merge of these panels (Panel E) shows sabirnetug binding with no amyloid plaque present.
+Added: 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).
+Added: 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.
Binding to a broad spectrum of molecular weight AßOs
−Removed: In addition, we demonstrated that ACU193 binds a broad spectrum of AßOs across various molecular weights.
−Removed: In another series of experiments, syn-AßOs were fractionated by size exclusion chromatography and characterized by ELISA using ACU193, hu3D6 (bapineuzumab) or hu266 (solanezumab) as the capture antibody and biotinylated anti-human Aß antibody 82E1 for detection.
−Removed: These data show ACU193 binds AßOs ranging from dimers to approximately 100-mers, with preferential binding to mid-molecular weight oligomers compared to hu266.
+Added: In addition, we demonstrated that sabirnetug binds a broad spectrum of AßOs across various molecular weights.
+Added: In another series of experiments, syn-AßOs were fractionated by size exclusion chromatography and characterized by ELISA using sabirnetug, hu3D6 (bapineuzumab) or hu266 (solanezumab) as the capture antibody and biotinylated anti-human Aß antibody 82E1 for detection.
+Added: 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.
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hu266 is also known as solanezumab.
−Removed: These data demonstrate the specificity of ACU193 for oligomers versus monomers, and also demonstrate a range of oligomers that are bound by ACU193.
−Removed: Collectively the data show that ACU193 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.
−Removed: Based on these and other data, we believe that ACU193 can target therapeutically relevant AßOs in the brain of early AD patients.
−Removed: Protection from AßO-induced synaptic toxicity
−Removed: In order to understand ACU193’s ability to either neutralize or limit AßO-induced physiological changes, we performed ex vivo studies using brain slices or cell cultures.
−Removed: Prevention of AßO toxic effects on neuronal electrophysiology
−Removed: In ex vivo studies using the murine hippocampal slice long term potentiation, or LTP, model, pre-incubation with ACU193 or ACU3B3 has been shown to prevent the LTP deficit caused by AßOs (formed by administration of 50nM Aß 1-42 ).
−Removed: LTP is an electrophysiological phenomenon demonstrated in neurons that may be associated with memory formation and other important neurological functions.
−Removed: Disruption of LTP has been associated with animal models in a variety of central nervous system disease states.
−Removed: Effects of ACU3B3 and ACU193 on AßO-induced change in LTP
−Removed: Note that AßOs disrupted normal LTP findings, but that pre-incubation with ACU3B3 prevented that disruption.
−Removed: Prevention of toxic effects of AßOs on calcium homeostasis
−Removed: Exposure to ACU3B3 has been shown to prevent calcium overload in cortical neuronal cultures induced by direct application of syn-AßOs (Figure 9).
−Removed: Disruptions in calcium homeostasis that cause cellular dysfunction have been implicated in a number of disease states, including myocardial infarction and stroke.
−Removed: Further, AßOs have been shown to cause disruption of calcium homeostasis, and thus, restoration of intracellular calcium to normal levels could serve as a functional indicator of potential treatment effect in AD.
−Removed: Multiphoton microscopy was used to examine the relationship of syn-AßO and neuronal calcium homeostasis in vitro (Figure 9).
−Removed: Direct application of syn-AßOs elicited calcium elevations in cortical neuronal cultures.
−Removed: Prior exposure to antibodies ACU3B3 and 3D6 prevented this calcium elevation (Figure 9).
−Removed: These results demonstrate that syn-AßOs induce elevated concentrations of intracellular neuronal calcium and that ACU3B3 prevented the syn-AßO-induced calcium overload.
−Removed: Effect of ACU3B3 on calcium homeostasis
−Removed: The relationship of syn-AßO and neuronal calcium homeostasis in the presence and absence of ACU3B3 was studied in primary cultures of transgenic APP-PS1 mouse cortical neurons.
−Removed: Multiphoton microscopy was used to obtain images of neuronal cultures at 12-14 days in vitro, or DIV, or 21 DIV.
−Removed: Cortical regions were identified and reimaged before and after topical applications of syn-AßOs to allow comparison of resting calcium within the same neuronal compartments.
−Removed: After baseline calcium was obtained, the cultures were treated with antibody-immunodepleted syn-AßOs (1 mL of 3 nM syn-AßOs with 9 µg of antibody) or syn-AßOs alone for 45 minutes.
−Removed: The cultures were then re-imaged in the same areas in the dish.
−Removed: Taken together, these studies show that ACU3B3 prevents the toxic effect of AßOs on calcium homeostasis.
+Added: These data demonstrate the specificity of sabirnetug for oligomers versus monomers, and also demonstrate a range of oligomers that are bound by sabirnetug.
+Added: 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.
+Added: Based on these and other data, we believe that sabirnetug can target therapeutically relevant AßOs in the brain of early AD patients.
In Vivo Pharmacology
−Removed: In order to understand the effects of ACU193 in intact animals, we performed behavioral studies in transgenic mice with genetic alterations that overproduce a mutant amyloid precursor protein that forms amyloid plaques.
+Added: 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.
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.
−Removed: The Phase 1 clinical trial includes doses in the range used in these nonclinical studies.
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).
5 unchanged sentences
Prior to dosing, Thy1-hAPP/SL mice showed increased activity in the activity chamber compared to wild-type mice.
−Removed: After treatment with ACU3B3, Thy1-hAPP/SL mice activity fell to a level
−Removed: comparable to wild-type mice, particularly activity in the center of the test arena (Figure 11A).
+Added: 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]).
Similar effects of ACU3B3 were found with changes in Y-maze behavior (Figure 11[B]) and passive avoidance (Figure 11[C]).
16 unchanged sentences
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.
−Removed: The range of doses used in these nonclinical studies are expected to be covered in INTERCEPT-AD.
Pharmacokinetics and Pharmacodynamics
−Removed: ACU193 has demonstrated favorable pharmacokinetics and pharmacodynamics based on a number of nonclinical studies.
−Removed: ACU193 could be detected in plasma, CSF, and brain tissue of Tg2576 mice, rats, dogs, and rhesus monkeys following IV injection.
−Removed: Penetration of ACU193 into the brain was demonstrated by direct measurements of brain levels in Tg2576 mice, rats, and dogs, and by measurements of CSF levels in rats and rhesus monkeys.
−Removed: Brain levels were approximately 0.02% of plasma levels and CSF levels ranged from 0.05 to 0.15% of plasma levels, showing penetration of ACU193 into the brain.
−Removed: Toxicokinetic data collected as part of GLP toxicity studies in Sprague Dawley rats and cynomolgus monkeys showed clearance of 1 to 3 mL/h/kg and terminal half-life of approximately seven days.
−Removed: Brain penetration and in vivo binding of ACU193 was explored in seven-month-old Tg2576 mice dosed intravenously with 2, 10 and 50 mg/kg of ACU193 or hu3D6 (bapineuzumab), and perfused brain tissue was collected 24 hours after dosing for analysis.
−Removed: A dose dependent increase in brain levels of ACU193 (Figure 14A) and ACU193/AßO complex (Figure 14B) was demonstrated, with a minimum effective dose for target engagement of 10 mg/kg.
−Removed: Levels of ACU193 and AßO/ACU193 complexes in the brain 24 hours following IV dosing in seven-month-old Tg2576 mice (n = 4/cohort)
−Removed: These results show ACU193 can penetrate the blood-brain barrier and bind endogenous AßOs.
−Removed: Additionally, a study of pharmacokinetics in CSF was conducted in rhesus monkeys.
+Added: A study of pharmacokinetics 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.
−Removed: As shown in Figure 15, the concentrations of ACU193 in CSF should provide adequate target engagement with dosing every four weeks.
−Removed: Comparison of ACU193 levels in rhesus CSF to CSF Levels of AßO in human AD patients
−Removed: Following two doses of 20 mg/kg ACU193 CSF concentrations were sufficient to provide target engagement at 28 days.
+Added: As shown in Figure 14, the concentrations of sabirnetug in CSF should provide adequate target engagement with dosing every four weeks.
+Added: 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.
+Added: Comparison of sabirnetug levels in rhesus CSF to CSF Levels of AßO in human AD patients
+Added: Following two doses of 20 mg/kg sabirnetug CSF concentrations were sufficient to provide target engagement at 28 days.
An estimate of 1 fmole/mL for oligomer concentration is conservative given that it is based on AßOs consisting of trimers.
Safety Profile
−Removed: GLP studies using IV administration of ACU193 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.
+Added: 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.
In Sprague Dawley rats, no adverse findings were noted.
−Removed: In the 14-week study in cynomolgus monkeys, doses of 60, 300, or 600 mg/kg/dose ACU193 once every two weeks were administered.
−Removed: Three animals administered the highest 600 mg/kg/dose were sacrificed early for humane reasons on Days 43 or 60 due to ACU193-related, anaphylactoid-type reactions.
+Added: In the 14-week study in cynomolgus monkeys, doses of 60, 300, or 600 mg/kg/dose sabirnetug once every two weeks were administered.
+Added: 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.
Thus, the 300 mg/kg/dose is considered the NOAEL for cynomolgus monkeys.
−Removed: The NOAELs of 300 mg/kg and 250 mg/kg compare favorably to the highest dose of ACU193 being used in our Phase 1 clinical trial (60 mg/kg).
−Removed: Based in part on binding to AßOs rather than amyloid plaque, ACU193 has the potential to have a lower rate of ARIA than plaque-clearing anti-amyloid antibodies.
−Removed: Additionally, ACU3B3 showed no apparent increased risk of microhemorrhage when administered in vivo for three months in aged Tg2576 mice, as compared with 3D6, a plaque binding antibody used as a positive control.
−Removed: With regard to effector function and possible inflammatory effects generally, ACU193 is an IgG2 subclass antibody which has limited inflammatory effector function signaling compared to other IgG subclasses.
+Added: The NOAELs of 300 mg/kg and 250 mg/kg compare favorably to the highest dose of sabirnetug that was used in our Phase 1 clinical trial (60 mg/kg) and the doses chosen for our Phase 2 clinical trial (30 and 50 mg/kg).
+Added: With regard to effector function and possible inflammatory effects generally, sabirnetug is an IgG2 subclass antibody which has limited inflammatory effector function signaling compared to other IgG subclasses.
Combination Potential
−Removed: While we believe ACU193, if successful, will likely be a foundational treatment for people with early AD, it also could be used as part of a combination treatment regimen.
−Removed: The pathology of AD is complex, and many experts in the field expect that combination therapy using drugs with different mechanisms of action, such as tau, immune modulation, glial cells such as microglia and astrocytes, and growth factors, will ultimately prove most successful, similar to cutting edge approaches used in oncology.
−Removed: In addition, because symptomatic treatments, such as memantine and cholinesterase inhibitors, affect neurotransmitter systems rather than the underlying AD pathology, we believe that it is likely that they will be used together with disease-modifying treatments.
+Added: While we believe sabirnetug, if successful, will likely be a foundational treatment for people with early AD, it also could be used as part of a combination treatment regimen.
+Added: The pathology of AD is complex, and many experts in the field expect that combination therapy using disease-modifying drugs with different mechanisms of action, such as tau, immune modulation, glial cells such as microglia and astrocytes, and growth factors, will ultimately prove most successful, similar to cutting edge approaches used in oncology.
+Added: In addition, because symptomatic treatments, such as memantine and cholinesterase inhibitors, affect neurotransmitter systems rather than the underlying AD pathology, we believe that they can be used together with disease-modifying treatments.
Manufacturing
We do not currently own or operate facilities for product manufacturing, storage and distribution, or testing.
−Removed: We contract with third parties for the manufacture of ACU193.
+Added: We contract with third parties for the manufacture of sabirnetug.
Because we rely on contract manufacturers, we employ personnel with extensive technical, manufacturing, analytical and quality experience.
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Our systems and our contractors are required to be in compliance with these regulations, and compliance is assessed regularly through monitoring of performance and a formal audit program.
−Removed: Our current supply chains for ACU193 involve several manufacturers that specialize in specific operations of the manufacturing process, including raw materials manufacturing, drug substance manufacturing and drug product manufacturing.
−Removed: We currently operate under work order programs for ACU193 with master services agreements in place that include specific supply timelines, volume and quality specifications.
+Added: Our current supply chains for sabirnetug involve several manufacturers that specialize in specific operations of the manufacturing process, including raw materials manufacturing, drug substance manufacturing and drug product manufacturing.
+Added: We currently operate under work order programs for sabirnetug with master services agreements in place that include specific supply timelines, volume and quality specifications.
We believe our current manufacturers have the scale, the systems, and the experience to supply our currently planned clinical trials.
−Removed: We face competition from several different institutions, including pharmaceutical and biotechnology companies, research institutions, governmental organizations and universities developing novel therapies for AD.
−Removed: We believe that the key factors affecting the clinical and commercial success of ACU193 will include safety profile, efficacy, cost, method of administration, level of marketing activity, insurance reimbursement and intellectual property protection.
−Removed: If approved, ACU193 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.
−Removed: ACU193 may compete with one or more potentially disease-modifying therapeutics that target Aß or amyloid plaques, the most advanced of which are Biogen Inc.’s Aduhelm (aducanumab), which was given accelerated approval by FDA in June 2021, and Eisai’s Leqembi (lecanemab), which was given accelerated approval by FDA in January 2023.
−Removed: FDA issued a complete response letter to Eli Lilly and Company in January 2023 for the accelerated approval submission of donanemab.
−Removed: Eisai filed for full approval of Leqembi in January 2023;
−Removed: however, Biogen has not filed for full approval of Aduhelm.
−Removed: Centers for Medicare and Medicaid Services (CMS) have stated they would not reimburse for a drug given an accelerated approval by FDA for Alzheimer’s disease outside of a clinical trial.
−Removed: Roche Holding AG (gantenerumab) announced negative results from their Phase 3 study in November 2022, and Eli Lilly and Company (donenamab) is anticipated to complete its Phase 3 study in 2023.
−Removed: Other companies known to be developing therapies with Aß, AßO-, and amyloid plaque-related targets include AltPep Corporation, Alzheon, Inc., Alzinova AB, Chugai Pharmaceutical Co.
−Removed: Ltd., Cognition Therapeutics, Inc., Grifols, S.A., KalGene Pharmaceuticals, Inc., Neurimmune AG, Novartis AG, ProMIS Neurosciences, Inc., Prothena Biosciences, Inc., Vaxxinity, Inc., Vivoryon Therapeutics N.V.
−Removed: and Wren Therapeutics, Inc.
−Removed: Additionally, ACU193, 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., Biohaven Pharmaceuticals, Inc., Cassava Sciences, Inc., Denali Therapeutics, Inc., Johnson & Johnson (including Janssen, its wholly-owned subsidiary) and Takeda Pharmaceutical Co.
−Removed: Percent Slowing of Cognitive/Functional Decline*
−Removed: Measured Outcome** solanezumab
−Removed: (Phase 3) Aduhelm
−Removed: (Phase 3) Aduhelm
−Removed: (Phase 3) lecanemab
−Removed: (Phase 3) donanemab
−Removed: ADAS-cog -11 % -27 % -12 % -26 % -39 %
−Removed: ADCS-ADL -15 % -40 % -18 % -37 % -23 %
−Removed: CDR-SB -15 % -23 % 2 % -27 % -23 %
−Removed: MMSE -13 % -15 % 3 % N.A.
−Removed: iADRS -11 % N.A.
−Removed: * Percent Slowing= [1- [(endpoint score-baseline score)active/(endpoint score-baseline score)placebo]]*100%*(-1)
−Removed: Alzheimer’s Disease Assessment Scale – Cognitive Subscale
−Removed: Alzheimer’s Disease Cooperative Study – Activities of Daily Living
−Removed: Clinical Dementia Rating – Sum of Boxes
−Removed: Mini-Mental State Examination
−Removed: Integrated Alzheimer’s Disease Rating Scale
−Removed: ENGAGE Post-Protocol Version 4 – patients who received at least 14 doses of 10 mg/kg, High Dose cohort achieved 27% improvement on CDR-SB compared to placebo.
−Removed: A potential limitation of the amyloid plaque-targeting antibodies under development is an adverse effect known as ARIA.
−Removed: ARIA has two different forms, ARIA-E, or cerebral edema, formerly called vasogenic edema, and ARIA-H, or cerebral microhemorrhages.
−Removed: While the mechanism of ARIA is not known with certainty, the prevailing theory is that ARIAs are related to the presence of amyloid plaques around blood vessels in the majority of people with AD, a condition known as cerebral amyloid angiopathy.
−Removed: It is generally believed that the removal of these amyloid plaques by the antibody can result in small hemorrhages, or ARIA-H.
−Removed: ARIA-H occurs in individuals with untreated AD and its occurrence is increased in individuals treated with antibodies that target amyloid plaques.
−Removed: Increased ARIA-H is correlated with worsening cognition.
−Removed: In contrast to ARIA-H, ARIA-E is hypothesized to result from the leakage of fluid from the blood vessels into the interstitial spaces in the brain, causing an effusion or edema, ARIA-E.
−Removed: ARIA-E, in particular, is sometimes associated with symptoms that include worsening of cognition, headache, gait disturbance and seizures, which can be severe enough to lead to hospitalization.
−Removed: ARIA-E usually resolves weeks to months following the cessation of treatment.
−Removed: In clinical trials for anti-Aß/plaque mAbs, surveillance MRI scans are required to detect asymptomatic ARIA.
−Removed: Table 2 below illustrates the rates of ARIA observed in Phase 2 or 3 studies for the most advanced mAbs.
−Removed: Percent of ARIA Events for Anti-Aß/plaque mAbs*
−Removed: Targeting Aẞ Monomers Targeting Amyloid Plaques Targeting Protofibrils
−Removed: EXPEDITION 3 (Phase 3) Aduhelm
−Removed: EMERGE (Phase 3) Aduhelm
−Removed: ENGAGE (Phase 3) donanemab
−Removed: (Phase 2) Leqembi
−Removed: lecanemab (Phase 3)
−Removed: PC Treated PC Low High PC Low High PC Treated PC Treated
−Removed: ARIA-E 0.2% 0.1% 2.2% 26.2% 34.4% 3.0% 25.6% 35.7% 0.8% 27.5% 1.7% 12.6%
−Removed: ApoE e4 carriers 1.9% 29.8% 42.5% 2.4% 28.7% 41.8% 3.6% 44.0% 2.3% 15.8%
−Removed: ApoE e4 non-carriers 2.9% 18.1% 17.9% 4.3% 17.5% 27.7% 0.3% 5.4%
−Removed: Any ARIA E or H 10.3% 32.8% 41.2% 9.8% 30.7% 40.3% 8.0% 38.9% 9.5% 21.5%
−Removed: PC = Placebo, Low = Low Dose;
−Removed: High = High Dose
−Removed: * Shows the absence of ARIA after treatment with antibodies targeting Aß monomers (solanezumab) in comparison to the increasing presence of ARIA after treatment at increasing dose levels with antibodies targeting amyloid plaques (aducanumab, BAN2401, and donanemab), indicating that ARIA results from the removal of amyloid plaques around blood vessels and likely does not result from treatment with antibodies that target Aß monomers.
−Removed: AD Product Candidates and Target Selectivity and ARIA Profile
−Removed: Target Selectivity+ ARIA
−Removed: Product Candidate Amyloid plaque Aß
−Removed: oligomers Lower rate of
−Removed: ACU193 x untested x ✓
−Removed: Leqembi lecanemab ✓
−Removed: Aduhelm aducanumab ✓
−Removed: solanezumab* x
−Removed: gantenerumab ✓
−Removed: crenezumab* ✓
−Removed: bapineuzumab* ✓
−Removed: * Phase 3 discontinued for primary AD indication
−Removed: + There have been no comprehensive head-to-head clinical trials between any of the product candidates listed above.
+Added: In June 2021, the FDA granted approval for Biogen’s Aduhelm® (aducanumab) under the FDA’s Accelerated Approval Pathway, or AAP.
+Added: Aduhelm was the first new AD product approval since 2004 and the first approved disease-modifying product.
+Added: 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.
+Added: The CED limits reimbursement of anti-amyloid antibodies, including Aduhelm, to placebo-controlled clinical trials.
+Added: In May 2022, Biogen announced its decision to eliminate substantially all commercial support for Aduhelm in the U.S.
+Added: and withdrew its marketing application for Aduhelm in Europe.
+Added: In January 2024, Biogen announced its decision to discontinue the development and commercialization of Aduhelm.
+Added: In September 2022, Eisai announced results from its Leqembi® (lecanemab) Phase 3 CLARITY-AD trial.
+Added: Leqembi is a recombinant humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble (protofibrils) and insoluble (plaque) forms of amyloid beta.
+Added: 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.
+Added: In January 2023, the FDA granted approval for Leqembi under the AAP based on results of its Phase 2 study.
+Added: In July 2023, the FDA approved the supplemental Biologics License Application, or sBLA, supporting the approval of Leqembi.
+Added: Also in July 2023, CMS announced it would cover Leqembi when a physician and care team participates in a CMS-facilitated registry.
+Added: 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.
+Added: In January 2023, the FDA issued a complete response letter to Eli Lilly and Company for the accelerated approval submission of donanemab.
+Added: In May 2023, Eli Lilly announced results from its donanemab Phase 3 TRAILBLAZER-ALZ 2 trial.
+Added: Donanemab is an immunoglobulin gamma 1 (IgG1) monoclonal antibody that specifically targets deposited amyloid plaque.
+Added: 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.
+Added: Eli Lilly expects regulatory action from the FDA on donanemab in 2024.
+Added: 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.
+Added: We face competition from several different institutions, including pharmaceutical and biotechnology companies, research institutions, governmental organizations and universities developing novel therapies for AD.
+Added: 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.
+Added: 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.
+Added: 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.
+Added: 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.
+Added: and Wavebreak Therapeutics, Inc.
+Added: 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.
+Added: Lundbeck A/S, Lighthouse Pharma, Roche Holding AG, and Takeda Pharmaceutical Co.
Additional Treatment Modalities
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Collaboration Agreement with Merck
−Removed: 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 ADDL, which agreement was amended and restated in October 2006.
+Added: 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.
−Removed: During the collaboration, Merck developed ACU193, an ADDL
−Removed: antibody, and intellectual property related to ACU193 was filed by Merck.
+Added: During the collaboration, Merck developed sabirnetug, an ADDL antibody, and intellectual property related to sabirnetug was filed by Merck.
In 2011, Merck elected to voluntarily terminate the collaboration agreement.
−Removed: Pursuant to the surviving provisions of the agreement, effective upon termination of the collaboration, Merck granted us an exclusive, perpetual, irrevocable, royalty-free, worldwide license, with right to sublicense, under Merck’s interest in the patent rights and know-how necessary for the research, development, manufacturing or commercialization of ADDL antibodies, ADDL antigens or products, including ACU193.
+Added: Pursuant to the surviving provisions of the agreement, effective upon termination of the collaboration, Merck granted us an exclusive, perpetual, irrevocable, royalty-free, worldwide license, with right to sublicense, under Merck’s interest in the patent rights and know-how necessary for the research, development, manufacturing or commercialization of ADDL antibodies, ADDL antigens or products, including sabirnetug.
License Agreement with Lonza
−Removed: On November 2, 2022, the Company entered into a License Agreement (the “Lonza License Agreement”) with Lonza Sales.
−Removed: Under the terms of the Lonza License Agreement, Lonza granted the Company a worldwide non-exclusive license to use Lonza’s glutamine synthetase gene expression system to manufacture and commercialize ACU193 (the “Product”).
+Added: On November 2, 2022, the Company entered into a License Agreement, or the Lonza License Agreement, with Lonza Sales AG, or Lonza.
+Added: Under the terms of the Lonza License Agreement, Lonza granted the Company a worldwide non-exclusive license to use Lonza’s glutamine synthetase gene expression system to manufacture and commercialize sabirnetug, or the Lonza Product.
Pursuant to the Lonza License Agreement, we paid Lonza an upfront fee of 1.0 million Swiss Francs.
−Removed: 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 Product, which include (i) a royalty of less than 1.0% on net sales where Lonza manufactures the 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 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 Product.
−Removed: These payment obligations would expire ten years from the first commercial sales of the Product in such country of sale.
+Added: 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.
+Added: These payment obligations would expire ten 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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The Lonza License Agreement also contains customary representations, warranties, indemnification and other obligations of the Company and Lonza.
+Added: Halozyme License Agreement
+Added: 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.
+Added: 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.
+Added: Halozyme will also be the Company’s exclusive supplier of clinical and commercial supplies of the API for Halozyme’s PH20 product.
+Added: Pursuant to the Halozyme License Agreement, the Company paid Halozyme a seven figure upfront payment for the license to Halozyme’s technology.
+Added: Additionally, the Company will make milestone payments tied to achievement of certain development and commercialization milestone events with respect to the Halozyme Product, as well as milestone payments based on achievement of certain net sales levels of the Halozyme Product.
+Added: The Company will also make single-digit royalty payments based on worldwide net sales of the Halozyme Product.
+Added: The Halozyme Agreement includes customary termination rights, representations and warranties, covenants and indemnification obligations for a transaction of this nature.
Intellectual Property
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We require our employees, consultants, scientific advisors and contractors to enter into confidentiality agreements prohibiting the disclosure of confidential information and requiring disclosure and assignment to us of the ideas, developments, discoveries and inventions important to our business.
−Removed: The main form of commercial exclusivity for our product candidate, ACU193, is expected to come from biologic regulatory exclusivity.
−Removed: We expect that once approved by regulatory agencies, ACU193 will receive the benefit of 12 years of market exclusivity in the U.S.
+Added: The main form of commercial exclusivity for our product candidate, sabirnetug, is expected to come from biologic regulatory exclusivity.
+Added: 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.
−Removed: We have an exclusive license grant from Merck to patents claiming the composition and method of use of our product candidate, ACU193.
+Added: We have an exclusive license grant from Merck to patents claiming the composition and method of use of our product candidate, sabirnetug.
The license grant arose from our collaboration agreement with Merck to research, discover, and develop technology related to ADDLs.
−Removed: During our collaboration, ACU193, an ADDL antibody, was developed and intellectual property was filed by Merck.
−Removed: In 2011, the collaboration agreement terminated and Merck exclusively licensed to Acumen, Merck’s interest in patent rights claiming ADDL antibodies, including ACU193, ADDL Antigens and/or Products to Acumen.
−Removed: In the nine years subsequent to the termination of the collaboration with Merck, Acumen has controlled and directed and continues to control and direct prosecution of the licensed ACU193 patent portfolio.
−Removed: Acumen has also paid for and continues to pay all costs and fees associated with the prosecution and maintenance of the licensed ACU193 patent portfolio.
+Added: During our collaboration, sabirnetug, an ADDL antibody, was developed and intellectual property was filed by Merck.
+Added: In 2011, the collaboration agreement terminated and Merck exclusively licensed to Acumen, Merck’s interest in patent rights claiming ADDL antibodies, including sabirnetug, ADDL Antigens and/or Products to Acumen.
+Added: In the nine years subsequent to the termination of the collaboration with Merck, Acumen has controlled and directed and continues to control and direct prosecution of the licensed sabirnetug patent portfolio.
+Added: Acumen has also paid for and continues to pay all costs and fees associated with the prosecution and maintenance of the licensed sabirnetug patent portfolio.
As of March 20, 2024, Acumen licenses from Merck one issued U.S.
−Removed: 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, ACU193.
+Added: 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.
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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.
−Removed: 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.
+Added: 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
+Added: 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.
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• approval by an institutional review board, or IRB, or independent ethics committee at each clinical site before the trial is commenced;
−Removed: • performance of adequate and well-controlled human clinical trials in accordance with Good Clinical Practice, 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;
+Added: • 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;
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Clinical trials are conducted under protocols detailing, among other things, the objectives of the study, the dosing procedures, subject selection and exclusion criteria, and the parameters and criteria to be used in monitoring safety and effectiveness.
−Removed: A separate submission to the existing IND must be made for each successive clinical trial conducted during product development and for any protocol and
−Removed: subsequent protocol amendments.
+Added: A separate submission to the existing IND must be made for each successive clinical trial conducted during product development and for any protocol and subsequent protocol amendments.
Furthermore, an independent IRB for each site proposing to conduct the clinical trial must review and approve the plan for any clinical trial and its informed consent form before the clinical trial begins at that site, and must monitor the study until completed.
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.
−Removed: 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, 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.
+Added: 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.
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.
+Added: 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.
+Added: 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.
+Added: 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.
+Added: 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.
+Added: FDA has not yet published new or revised draft guidance.
For purposes of BLA approval, human clinical trials are typically conducted in three sequential phases that may overlap or be combined:
21 unchanged sentences
Before approving a BLA, the FDA will typically inspect the facility or facilities where the product is manufactured.
−Removed: 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.
+Added: The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance
+Added: with cGMP 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.
20 unchanged sentences
Fast Track designation, Breakthrough Therapy designation, and priority review do not change the standards for approval but may expedite the development or approval process.
−Removed: 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.
+Added: Even if a product candidate qualifies for one or more of these
+Added: 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
19 unchanged sentences
There also are continuing, annual program fees for any marketed products.
−Removed: 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 cGMP.
+Added: 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.
Changes to the manufacturing process are strictly regulated, and, depending on the significance of the change, may require prior FDA approval before being implemented.
25 unchanged sentences
In addition, government proposals have sought to reduce the 12-year reference product exclusivity period.
−Removed: 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 litigation.
+Added: 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
As a result, the ultimate impact, implementation, and regulatory interpretation of the BPCIA remain subject to significant uncertainty.
Other Healthcare Laws
−Removed: 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 and may constrain the financial arrangements and relationships through which we research, as well as, sell, market and distribute any products for which we obtain marketing approval.
−Removed: Such laws include, without limitation, federal and state anti-kickback, fraud and abuse, false claims, data privacy and security and physician and other health care provider transparency laws and regulations.
−Removed: The laws that will affect our operations include, but are not limited to:
+Added: 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.
+Added: 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.
+Added: Such laws include, without limitation, the following, some of which may apply to our operations only if and when we have a marketed product:
• the federal Anti-Kickback Statute, which prohibits, among other things, individuals or entities from knowingly and willfully soliciting, receiving, offering or paying any remuneration (including any kickback, bribe or rebate), directly or indirectly, overtly or covertly, in cash or in kind in return for, or to induce, either the referral of an individual, or the purchase, lease, order or arrangement for or recommendation of the purchase, lease, order or arrangement for any good, facility, item or service for which payment may be made, in whole or in part, under a federal healthcare program, such as the Medicare and Medicaid programs.
The term “remuneration” has been broadly interpreted to include anything of value.
+Added: A person does not need to have actual knowledge of this statute or specific intent to violate it in order to have committed a violation.
Although there are a number of statutory exceptions and regulatory safe harbors protecting some common activities from prosecution, the exceptions and safe harbors are drawn narrowly;
• the federal civil and criminal false claims laws, including, without limitation, the federal False Claims Act, or FCA, which prohibit, among other things, individuals or entities from knowingly presenting, or causing to be presented, to the federal government, claims for payment or approval that are false or fraudulent or knowingly making a false statement to avoid, decrease or conceal an obligation to pay money to the federal government.
−Removed: 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 federal False Claims Act;
+Added: 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;
1 unchanged sentence
Similar to the federal Anti-Kickback Statute, a person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation;
−Removed: • HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act and their implementing regulations, also imposes obligations, including mandatory contractual terms, on “covered entities,” including certain healthcare providers, health plans, healthcare clearinghouses, and their respective “business associates,” that create, receive, maintain or transmit individually identifiable health information for or on behalf of a covered entity as well as their covered subcontractors, with respect to safeguarding the privacy, security and transmission of individually identifiable health information, as well as analogous state
−Removed: and foreign laws that govern the privacy and security of health information in some circumstances, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts;
−Removed: • the federal transparency laws, including the federal Physician Payments Sunshine Act, which requires certain manufacturers of drugs, medical devices, biologicals and medical supplies for which payment is available under Medicare, Medicaid or the State Children’s Health Insurance Program, with specific exceptions, to report annually to the Centers for Medicare and Medicaid Services, or CMS, information related to:
−Removed: (i) payments or other “transfers of value” made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), other healthcare professionals (such as physician assistants and nurse practitioners) and teaching hospitals, and (ii) ownership and investment interests held by physicians and their immediate family members;
−Removed: • analogous state and foreign laws and regulations;
−Removed: state laws that require manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers, marketing expenditures or drug pricing;
−Removed: state laws that require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government, or that otherwise restrict payments that may be made to healthcare providers;
−Removed: and state and local laws that require the registration of pharmaceutical sales representatives.
−Removed: Because of the breadth of these laws and the narrowness of the statutory exceptions and regulatory safe harbors available, it is possible that some of our business activities could be subject to challenge under one or more of such laws.
+Added: • HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, and their implementing regulations, also imposes obligations on “covered entities,” including certain healthcare providers, health plans, healthcare clearinghouses, and their respective “business associates,” if those business associates create, receive, maintain or transmit individually identifiable health information for or on behalf of a covered entity as well as the business associates’ covered subcontractors, with respect to safeguarding the privacy, security and transmission of individually identifiable health information, as well as analogous state and foreign laws that govern the privacy and security of health information in some circumstances, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts;
+Added: • the FDCA, which, among other things, strictly regulates drug product and medical device marketing, prohibits manufacturers from marketing such products for off-label use and regulates the distribution of samples;
+Added: • 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;
+Added: • federal and state consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm consumers;
+Added: • 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;
+Added: • 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.
+Added: 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.
3 unchanged sentences
Coverage and Reimbursement
−Removed: In the United States and in other countries, patients who are provided medical treatment for their conditions generally rely on third-party payors to reimburse all or part of the costs associated with their treatment.
−Removed: Adequate coverage and reimbursement from governmental healthcare programs, such as Medicare and Medicaid, and commercial payors is critical to new product acceptance.
−Removed: Thus, even if a product candidate is approved, sales of the product will depend, in part, on the extent to which such product will be covered by third-party payors, such as federal, state, and foreign government healthcare programs (e.g., Medicare, Medicaid, TRICARE), commercial insurance and managed healthcare organizations, and the level of reimbursement for such product by third-party payors.
−Removed: Third-party payors determine which products and procedures they will cover and establish reimbursement levels.
−Removed: These third-party payors are increasingly reducing reimbursements for medical products, drugs and services.
−Removed: In addition, the U.S.
−Removed: government, state legislatures and foreign governments have continued implementing cost-containment programs, including price controls, restrictions on coverage and reimbursement and requirements for substitution of generic products.
−Removed: Reimbursement by a third-party payor may depend upon a number of factors, including the third-party payor’s determination that a procedure is safe, effective and medically necessary;
+Added: 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.
+Added: In the United States, no uniform policy of coverage and reimbursement for drug products exists among third-party payors.
+Added: Therefore, coverage and reimbursement for drug products can differ significantly from payor to payor.
+Added: 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.
+Added: Third-party payors are increasingly challenging the prices charged, examining the medical necessity, and reviewing the cost-effectiveness of medical products and services and imposing controls to manage costs.
+Added: Coverage and reimbursement by a third-party payor may depend upon a number of factors, including the third-party payor’s determination that a procedure is safe, effective and medically necessary;
appropriate for the specific patient;
3 unchanged sentences
and neither cosmetic, experimental nor investigational.
−Removed: In order to secure coverage and reimbursement for any product that might be approved for sale, we may need to conduct expensive pharmacoeconomic studies in order to demonstrate the medical necessity and cost-effectiveness of our products.
−Removed: Adoption of price controls and cost-containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures, could further limit sales of any product.
−Removed: Decreases in third-party reimbursement for any product or a decision by a third-party payor not to cover a product could reduce physician usage and patient demand for the product and also have a material adverse effect on sales.
+Added: 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.
+Added: These studies will be in addition to the studies required to obtain or maintain regulatory approvals.
+Added: 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.
+Added: 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.
+Added: 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.
+Added: 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
+Added: 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.
+Added: Moreover, a third-party payor’s decision to provide coverage for a product does not mean that an adequate reimbursement rate will be approved.
+Added: 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.
+Added: A pharmaceutical company may also have to offer discounts or rebates to private third party payors to obtain favorable coverage.
+Added: Adequate third-party reimbursement may not be available to enable a company to realize an appropriate return on an investment in product development .
+Added: The containment of healthcare costs has become a priority of federal and state governments, and the prices of products have been a focus in this effort.
+Added: Governments have shown significant interest in implementing cost-containment programs, including price controls, restrictions on reimbursement and requirements for substitution of generic products.
+Added: Adoption or enhancement of price controls and cost-containment measures could further limit a company’s revenue generated from the sale of any approved products.
+Added: Coverage policies and third-party payor reimbursement rates may change at any time.
+Added: Even if favorable coverage and reimbursement status is attained for one or more products for which a company receives regulatory approval, less favorable coverage policies and reimbursement rates may be implemented in the future.
Healthcare Reform
−Removed: In March 2010, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act, each as amended, collectively known as the ACA, was enacted, which substantially changed the way healthcare is financed by both governmental and private insurers, and significantly affected the pharmaceutical industry.
−Removed: The ACA contains a number of provisions, including those governing enrollment in federal healthcare programs, reimbursement adjustments and changes to fraud and abuse laws.
−Removed: For example, the ACA:
−Removed: • increased the minimum level of Medicaid rebates payable by manufacturers of brand name drugs from 15.1% to 23.1% of the average manufacturer price;
−Removed: • required collection of rebates for drugs paid by Medicaid managed care organizations;
−Removed: • required manufacturers to participate in a coverage gap discount program, under which they must agree to offer 70 percent 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;
−Removed: • imposed a non-deductible annual fee on pharmaceutical manufacturers or importers who sell “branded prescription drugs” to specified federal government programs.
−Removed: Since its enactment, there have been executive, judicial and Congressional challenges to certain aspects of the ACA, and we expect there will be additional challenges and amendments to the ACA in the future.
−Removed: On June 17, 2021 the U.S.
−Removed: Supreme Court dismissed a challenge on procedural grounds that argued the ACA is unconstitutional in its entirety because the “individual mandate” was repealed by Congress.
−Removed: Thus, the ACA will remain in effect in its current form.
−Removed: Prior to the U.S.
−Removed: Supreme Court ruling, on January 28, 2021, President Biden issued an executive order that initiated a special enrollment period from February 15, 2021 through August 15, 2021 for purposes of obtaining health insurance coverage through the ACA marketplace.
−Removed: The executive order also instructed certain governmental agencies to review and reconsider their existing policies and rules that limit access to healthcare, including among others, reexamining Medicaid demonstration projects and waiver programs that include work requirements, and policies that create unnecessary barriers to obtaining access to health insurance coverage through Medicaid or the ACA.
−Removed: It is possible that the ACA will be subject to judicial or Congressional challenges in the future.
−Removed: It is also unclear how other such challenges and the healthcare reform measures of the Biden administration will impact the ACA or our business.
−Removed: Other legislative changes have been proposed and adopted since the ACA was enacted, including aggregate reductions of Medicare payments to providers of 2% per year, which began in 2013, and due to subsequent legislative amendments to the statute, will remain in effect through fiscal year 2030, with the exception of a temporary suspension from May 1, 2020 through March 31, 2022 due to the COVID-19 pandemic.
−Removed: Under current legislation the actual reduction in Medicare payments will vary from 1% in 2022 to up to 3% in the final fiscal year of this sequester.
−Removed: Additionally, on March 11, 2021, President Biden signed the American Rescue Plan Act of 2021 into law, which eliminates the statutory Medicaid drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single source and innovator multiple source drugs, beginning January 1, 2024.
+Added: 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.
+Added: These reform initiatives, if implemented, could impact our ability to sell a product candidate profitably if and when approved for marketing.
+Added: 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;
+Added: 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;
+Added: increased the minimum Medicaid rebates owed by most manufacturers under the Medicaid Drug Rebate Program;
+Added: extended the Medicaid Drug Rebate program to utilization of prescriptions of individuals enrolled in Medicaid managed care organizations;
+Added: subjected manufacturers to new annual fees and taxes for certain branded prescription drugs;
+Added: 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.
+Added: More generally, the ACA expanded health care coverage through Medicaid expansion and the implementation of the “individual mandate” for health insurance coverage.
+Added: Beyond the ACA, there have been ongoing health care reform efforts.
+Added: Drug pricing and payment reform was a focus of the Trump Administration and has been a focus of the Biden Administration.
+Added: 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.
+Added: 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.
+Added: 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.
+Added: The focus on health care reform, including reform of drug pricing and payment, has continued in the wake of the IRA.
+Added: 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.
+Added: Healthcare reform efforts have been and may continue to be subject to scrutiny and legal challenge.
+Added: For example, with respect to the ACA, tax reform legislation was enacted that eliminated the tax penalty established for individuals who do not maintain mandated health insurance coverage beginning in 2019 and, in 2021, the U.S.
+Added: Supreme Court dismissed the latest judicial challenge to the ACA brought by several states without specifically ruling on the constitutionality of the ACA.
+Added: 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.
+Added: Pursuant to court order, the removal was delayed and subsequent legislation imposed a moratorium on
+Added: implementation of the rule until January 2032.
+Added: As another example, the IRA drug price negotiation program has been challenged in litigation filed by various pharmaceutical manufacturers and industry groups.
Moreover, there has recently been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in several Congressional inquiries, proposed and enacted legislation and executive orders issued by the prior presidential administration designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drug products.
Individual states in the United States have also become increasingly active in implementing regulations designed to control pharmaceutical product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.
+Added: General legislative cost control measures may also affect reimbursement for our product candidates.
+Added: The Budget Control Act, as amended, resulted in the imposition of reductions in Medicare (but not Medicaid) payments to providers in 2013 and will remain in effect into 2032 unless additional Congressional action is taken.
+Added: Any significant spending reductions affecting Medicare, Medicaid or other publicly funded or subsidized health programs that may be implemented and/or any significant taxes or fees that may be imposed on us could have an adverse impact on our results of operations.
+Added: Adoption of new legislation at the federal or state level could affect demand for, or pricing of, any future products if approved for sale.
+Added: We cannot, however, predict the ultimate content, timing or effect of any federal and state reform efforts.
+Added: There is no assurance that federal or state health care reform will not adversely affect our future business and financial results.
Employees and Human Capital Resources
2 unchanged sentences
As of March 20, 2024, we had 52 employees, 51 of which were full time.
−Removed: Of the 40 employees, there were 11 in research and development and six in general and administrative functions.
+Added: Of the 52 employees, there were 36 in research and development and 16 in general and administrative functions.
We also utilized consultants in various roles related to research and development and general and administrative functions.
11 unchanged sentences
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.