A Two-Part, Open-Label Study to Investigate the Single-Dose Pharmacokinetics of MK-8931 When Administered to Subjects With Mild and Moderate Hepatic Insufficiency

This study consists of Part I and an optional Part II. The purpose of Part I is to compare the plasma pharmacokinetics of verubecestat (MK-8931) following administration of a single oral dose of 40 mg MK-8931 to participants with moderate hepatic insufficiency (HI) to that of healthy matched controls. An interim safety and pharmacokinetic analysis on the basis of Part I will be performed in order to support the decision to continue with the optional Part II. If a decision to continue with Part II is made, participants with mild HI will be enrolled to receive a single oral dose of 40mg MK-8931. If any healthy participants from Part I do not meet the matching criteria for Part II additional healthy participants will be enrolled.

Start Date11 Oct 2016

Sponsor / Collaborator

Merck Sharp & Dohme Corp.

NCT01953601

/ TerminatedPhase 3

A Phase III, Randomized, Placebo-Controlled, Parallel-Group, Double-Blind Clinical Trial to Study the Efficacy and Safety of MK-8931 (SCH 900931) in Subjects With Amnestic Mild Cognitive Impairment Due to Alzheimer's Disease (Prodromal AD)

This study consists of two parts, Part 1 and Part 2. Part 1 assesses the efficacy and safety of verubecestat (MK-8931) compared with placebo administered for 104 weeks in the treatment of amnestic mild cognitive impairment (aMCI) due to Alzheimer's Disease (AD), also known as prodromal AD. Participants are randomized to receive placebo, or 12 mg or 40 mg verubecestat, once daily. The primary study hypothesis for Part 1 is that ≥1 verubecestat dose is superior to placebo with respect to the change from baseline in the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB) score at 104 weeks. Participants completing Part 1 may choose to participate in Part 2, which is a long term double-blind extension to assess efficacy and safety of verubecestat administered for up to an additional 260 weeks. In Part 2, all participants receive either 12 mg or 40 mg verubecestat, once daily.

Start Date05 Nov 2013

Sponsor / Collaborator

Merck Sharp & Dohme Corp.

ACTRN12612000869875

/ SuspendedPhase 2/3

An Efficacy and Safety Trial of MK-8931 in Subjects with Mild to Moderate Alzheimer’s Disease

Start Date10 Dec 2012

Sponsor / Collaborator

Merck Sharp & Dohme Corp.

100 Clinical Results associated with Verubecestat

100 Translational Medicine associated with Verubecestat

100 Patents (Medical) associated with Verubecestat

115

Literatures (Medical) associated with Verubecestat

01 Jan 2026·PROTEOMICS

Elenbecestat and Compound 89 Potently Inhibit BACE1 but Not BACE2 When Subchronically Dosed in Non‐Human Primates

Article

Author: Hyakkoku, Kana ; Yoshimura, Akimasa ; Lichtenthaler, Stefan F. ; Schmidt, Andree ; Horiguchi, Naotaka ; Müller, Stephan A. ; Ito, Mana ; Tschirner, Sarah K.

ABSTRACT:

The β‐secretase BACE1 (β‐site amyloid precursor (APP) cleaving enzyme 1) is a major drug target for Alzheimer's disease (AD), as it catalyzes the first step in amyloid β (Aβ) generation, but has additional substrates and functions, in particular in the brain. Several advanced clinical trials with BACE1 inhibitors were stopped because of an adverse event, a mild cognitive worsening. The underlying mechanism is not yet known but may result from co‐inhibition of the BACE1‐homolog BACE2. While a cerebrospinal fluid (CSF) biomarker for measuring BACE2 activity is not yet established, VCAM‐1 has been suggested as such a biomarker, but has not yet been tested upon prolonged dosing in vivo. Using CSF pharmacoproteomics and a subchronic dosing paradigm in non‐human primates, we demonstrate that compound 89, a BACE inhibitor not yet tested in humans, and the clinically tested drug elenbecestat inhibit BACE1 in vivo, with little or no effect on BACE2, as seen with a reduction of substrates of BACE1, but not of the BACE2 substrate VCAM‐1. As a control, verubecestat, which inhibits both BACE2 and BACE1, reduced CSF abundance of BACE1 substrates as well as of VCAM‐1. This study demonstrates the suitability of VCAM‐1 as a pharmacodynamic biomarker for measuring BACE2 target engagement in CSF.

01 Dec 2025·Alzheimers & Dementia

Predicting differential effects of sex on therapeutic benefit and limitations in Alzheimer’s disease drug development using animal models

Review

Author: Rizzo, Stacey J Sukoff

Abstract:

Background:

There has been an overwhelming need to increase the predictive validity of preclinical studies for safety and efficacy in Alzheimer’s disease (AD) using animal models; and importantly to inform differential therapeutic benefits and limitations across sexes. The Preclinical Testing Core (PTC) of the MODEL‐AD consortium has established resources for the research community for unbiased screening of potential therapeutics with prioritization of translational outcome measures, and powered to detect effects of sex in mouse models.

Methods:

For each potential drug being evaluated, the PTC selects a mouse model specific to the compound’s mechanism of action being investigated that best recapitulates the human disease signature and biology, and that can enable and inform translational in vivo target engagement and a pharmacokinetic (PK) and pharmacodynamic (PD) relationship. All studies not only include both males and females, but are powered to detect effects of sex. Initial PK studies capture a broad dose range which are used to inform differential PK/PD across sex, such that the experimental design for long‐term chronic studies captures sex‐specific target engagement and exposure levels. Compounds advancing through the pipeline that have been de‐risked and demonstrate pharmacodynamic effects that may predict efficacy can be advanced to more sophisticated cognitive studies including translational touchscreen platforms that can be also employed similarly in non‐human primates. This screening strategy has been used to characterize a variety of mechanisms of action in 5XFAD mice including the small molecules levetiracetam and verubecestat, and the murinized/chimeric monoclonal antibody aducanumab.

Results:

Using the unbiased and rigorous screening approaches of the PTC, we have identified divergent effects of sex on PK measures (including plasma and brain exposures), efficacy (e.g., amyloid lowering) and behavioral effects (including side‐effects) in all compounds tested. These data in the mice were consistent with clinical data demonstrating differential effects of sex on therapeutic benefits and limitations reported for each of these compounds

Conclusions:

Using rigorous and unbiased screening approaches that are powered to detect effects of sex in animal models can be used to predict differential effects of sex on therapeutic benefit and limitations of novel compounds being investigated for the treatment of AD.

01 Dec 2025·Alzheimers & Dementia

APP and DNA damage create a feedforward loop that contributes to Alzheimer's disease pathogenesis

Article

Author: Ma, Fulin ; Brenner, Eliana ; Herrup, Karl ; Kingston, Rody

Abstract:

Background:

Alzheimer's disease (AD) has a typical age of onset exceeding 65 years. The amyloid precursor protein (APP) has occupied a central position in the pathophysiological description of AD. Unfortunately, Aβ‐independent roles for the full‐length APP protein in AD are relatively understudied. Our work begins from the perspective that APP is a damage‐response protein that is elevated after a variety of different stresses.

Method:

Immunocytochemistry was performed on mouse brain or on dissociated cultures of neurons. We tracked DNA damage with 53BP1, 𝛾‐H2AX, or the TUNEL reaction. Lentiviruses over expressing human APP is also used.

Result:

We demonstrate that neuronal excitation in vitro leads not only to DNA damage but also to a rapid increase in APP message and protein. Induction of DNA damage alone is sufficient to induce APP expression. This can be shown either by directly inducing DNA damage with etoposide in vitro or indirectly by inhibiting DNA repair – a prominent phenotype of the Atm ‐/‐ mouse. We find that an increase in APP is sufficient in and of itself to cause DNA damage. In APP overexpressing AD mouse models DNA damage is significantly increased. In vitro, infection of cultures of wild type neurons with lentiviruses that overexpress APP also led to significant DNA damage. We applied a BACE1 inhibitor (verbecestat) or a γ‐secretase inhibitor L685458 to block the production of Aβ. The results appeared to support a key role for Aβ since both inhibitors completely blocked the APP‐induced DNA damage response. However, application of oligomeric Aβ directly to neurons resulted in no significant increase in DNA damage. This led to the realization that verubecestat and L685458 would also both inhibit the production of the APP intracellular domain (AICD).

Conclusion:

The findings offer a potential linkage between DNA damage, a hallmark of aging, and APP, a hallmark of AD. The linkage between APP and DNA damage appears to be bi‐directional and paints the picture of a pathway with the potential to become a dangerous feed‐forward loop. Our findings reveal a novel role for full length APP in AD pathogenesis through its relationship with DNA damage.

News (Medical) associated with Verubecestat

18 Aug 2023

·www.prnewswire.com

Insights Into the Global Alzheimer's Disease Market, 2023-2032 - Eli Lilly's Donanemab Poised as Front-Runner for 2024 Market Debut, Set to Rival Biogen and Eisai's LEQEMBI in Emerging Therapy Arena

DUBLIN, Aug. 18, 2023 /PRNewswire/ -- The "Alzheimer's Disease - Market Insight, Epidemiology And Market Forecast - 2032" report has been added to ResearchAndMarkets.com's offering. This report delivers an in-depth understanding of the Alzheimer's disease historical and forecasted epidemiology as well as the market trends in the United States, EU4 (Germany, France, Italy, and Spain) and the United Kingdom, and Japan. The market report provides current treatment practices, emerging drugs, market share of individual therapies, and current and forecasted 7MM Alzheimer's disease market size from 2019 to 2032. The report also covers current Alzheimer's disease treatment practices/algorithms and unmet medical needs to curate the best opportunities and assess the market's potential. Key Highlights The diagnosed prevalence of Alzheimer's disease has been increasing in the US due to the increasing geriatric population and disease awareness. Advancements in disease pathophysiology understanding have led to the discovery of novel signaling pathways, due to which various diagnostic tools have evolved that have revolutionized disease diagnosis. The current treatment regime is mostly symptomatic, slows disease progression, and helps improve quality of life. It is not curative and is a mix of non-pharmacological and pharmacological approaches. The major bottleneck in understanding Alzheimer's market is that despite an extremely vibrant pipeline, assessing drugs' potential to enter the market is difficult due to high failure rates. Many therapies like gantenerumab, dabigatran, and verubecestat were unable to move past the trial phase. Approval of disease-modifying novel anti-amyloid biologics, with targeted mechanisms of action, has led to significant improvements from the traditional symptomatic treatment regime. ADUHELM (aducanumab) by Biogen and Eisai, the first available disease-modifying treatment to address Alzheimer's pathology by targeting amyloid ? plaques, has still not received traditional approval in the US and is rejected in Europe and Japan. In July 2023, the US FDA converted Biogen and Eisai's other amyloid beta-protein inhibitor- LEQEMBI's (lecanemab) accelerated approval to a traditional one after a confirmatory trial demonstrated a 27% reduction in cognitive decline. This marks a major milestone and is a forward-looking step in addressing the unmet needs of patients with early Alzheimer's. The approval garners well for Biogen and Eisai, keeping them in a profitable position, ensuring a first-mover advantage in the market, and helping them drive past the ADUHELM stumble. There are hopes that it will be Eisai and Biogen's blockbuster product. This is further supplemented by a CMS go-ahead with Medicare covering the therapy for Alzheimer's appropriate patient segment. This will facilitate reimbursement for and access to LEQEMBI. However, certain Medicare requirements and drug labels' risk warnings and infusion-center bottlenecks could potentially weigh on drug sales, at least in the near term. The testing requirement for a genetic mutation is another hurdle. In 2022, the market size of Alzheimer's disease was highest in the US among the 7MM countries, accounting for approximately USD 1,751.7 million. It is expected to increase by 2032. Acetylcholinesterase inhibitors, donepezil, rivastigmine, and galantamine, have comparable efficacy and are widely used to treat mild-to-advanced stages of Alzheimer's disease, but their benefit-risk ratio is still being debated. NMDA antagonist, memantine, slows symptom progression in individuals with moderate to severe Alzheimer's disease but is also associated with side effects like dizziness, confusion, etc. Emerging therapies by Anavex Life Sciences, Alzheon, Athira Pharma, Annovis Bio, Eli Lilly, BioVie, AB Science, Novo Nordisk, Cassava Sciences, TauRx Therapeutics, KeifeRx, AriBio, Cerecin, Eisai, others are in late stages of development and have the potential to create a positive shift in the Alzheimer's market. Eli Lilly's donanemab (LY3002813), an FDA-designated product, is projected to be the first emerging therapy to enter the market by 2024. It will compete with Biogen and Eisai's LEQEMBI. With the therapy lowering the risk of progression by 39%, it is projected to have a slow-medium uptake. High costs will translate to higher revenue, and despite few safety concerns, the drug is anticipated to perform well during the forecast period. Alzheimer's Disease Epidemiology As the market is derived using a patient-based model, the Alzheimer's disease epidemiology chapter in the report provides historical as well as forecasted epidemiology segmented by total diagnosed prevalent cases of Alzheimer's disease, age-specific cases of Alzheimer's disease, gender-specific cases of Alzheimer's disease, and severity-specific cases of Alzheimer's disease in the 7MM covering the United States, EU4 countries (Germany, France, Italy, and Spain) and the United Kingdom, and Japan from 2019 to 2032. In 2022, the total diagnosed prevalent cases of Alzheimer's disease were estimated to be approximately 15,083,370 cases in the 7MM. These cases are projected to increase at a CAGR of 2.4%. In the US, there were approximately 41% diagnosed prevalent cases of Alzheimer's disease in 2022, which is expected to increase during the forecast period. In 2022, among the 7MM, Japan accounted for the second-highest diagnosed prevalent cases of Alzheimer's disease, contributing nearly 26%, while the UK accounted for the least with nearly 4% of the total diagnosed prevalent cases. Japan accounted for 3,954,710 diagnosed prevalent cases of Alzheimer's disease. In 2022 the age-specific distribution of the disease suggests that the age cohort of 75-84 years accounted for the majority, nearly 51% of the cases, followed by =85 (32%), 65-74 (14%), and <_5 years="years" /> As per estimates based on this epidemiology model for Alzheimer's disease, the gender distribution of the disease suggests a female predominance across the 7MM, with approximately 5,024,849 male and 10,058,521 female cases in the 7MM in 2022. According to estimates based on this epidemiology model for Alzheimer's, in Japan, in 2022, there were approximately 2,324,183, 826,139, 517,671, and 286,716 cases of MCI, mild, moderate, and severe dementia, which are expected to increase during the study period. Alzheimer's Disease Drug Chapters The drug chapter segment of the Alzheimer's disease report encloses a detailed analysis of Alzheimer's disease - currently used drugs and mid-stage (Phase II and Phase I) pipeline drugs. It also helps understand the Alzheimer's disease clinical trial details, expressive pharmacological action, agreements and collaborations, approval and patent details, advantages and disadvantages of each included drug and the latest news and press releases. Marketed Drugs ADUHELM (aducanumab): Biogen and Eisai In June 2021, Biogen and Eisai's ADUHELM (aducanumab) received accelerated approval from the US FDA for the treatment of people living with early Alzheimer's disease, including people with mild cognitive impairment due to Alzheimer's disease, making it the first available disease-modifying treatment to address Alzheimer's disease pathology by targeting amyloid ? plaques. However, the drug is not globally accessible, as it did not receive approval by the EMA or MHLW, and the Alzheimer's community is still awaiting further trial data to support its approval. It exerts its mechanism of action by crossing the blood-brain barrier and selectively targeting and binding aggregated soluble oligomers and insoluble fibril conformations of A? plaques in the brain. LEQEMBI (lecanemab): Biogen and Eisai Biogen and Eisai's LEQEMBI (lecanemab) is a humanized IgG1 monoclonal antibody directed against aggregated soluble (protofibrils) and insoluble forms of A?. In July 2023, the US FDA granted it traditional approval after a confirmatory trial verified the clinical benefit. It is the first amyloid beta-directed antibody, targeting the disease process, to be converted from accelerated to traditional approval for treating people with mild Alzheimer's disease and mild cognitive impairment due to Alzheimer's disease. An application to the European Medicines Agency (EMA) for approval of lecanemab in the EU has been submitted and it is also designated for priority review by the Japanese Ministry of Health, Labour, and Welfare. Emerging Drugs NE3107: BioVie NE3107, being developed by BioVie, is an oral, small molecule, blood-brain permeable, anti-inflammatory, insulin sensitizer that binds to extracellular signal-regulated kinase (ERK) and selectively inhibits inflammation. NE3107 inhibits extracellular ERK/NFkB activation and TNF production stimulated by inflammatory mediators, such as lipopolysaccharide, and inhibits NFkB activation and TNF production. BioVie is also developing a drug for treating Parkinson's disease, multiple myeloma, and prostate cancer. The company is currently conducting Phase III trials to treat mild to moderate Alzheimer's disease. Donanemab (LY3002813): Eli Lilly Donanemab (LY3002813), being developed by Eli Lilly and Company, is a humanized IgG1 monoclonal antibody N3pG, developed from mouse mE8-IgG2a that identifies and destroys A? proteins, excess abnormal proteins that bind together to create brain plaques in Alzheimer's disease patients. The rationale behind donanemab is that targeting deposited plaque itself is necessary to clear existing amyloid burden from the brain rather than merely prevent the deposition of new plaques or the growth of existing plaques. Given via the IV administration route, its Phase III trial was recently completed. The confirmatory Phase III TRAILBLAZER-ALZ 2 trial is ongoing, with topline data read-out expected in Q2 2023, and will form the basis of donanemab's application for traditional approval. Drug Class Insights Pharmacological therapies such as acetylcholinesterase inhibitors and NMDA receptor antagonists, and recently, more targeted amyloid beta-proteins inhibitors are the available therapies for Alzheimer's. The approved acetylcholinesterase inhibitors, donepezil, rivastigmine, and galantamine have comparable therapeutic effects. These are recommended to treat mild-to-advanced stages of Alzheimer's, yet their benefit-risk ratio is still being debated. They work by inhibiting the activity of acetylcholinesterases, thus increasing the levels of acetylcholine in the brain, and improving cognitive symptoms. The NMDA antagonist, memantine, is recommended for moderate to severe Alzheimer's and slows disease progression. It is not typically used as a first-line treatment for mild Alzheimer's. In Alzheimer's NMDA receptors are activated by the neurotransmitter glutamate. This overstimulation leads to nerve cell damage and cognitive decline. Memantine blocks the excessive activity of glutamate, regulating the neurotransmitter's effect. Biogen and Eisai's ADUHELM (aducanumab) and LEQEMBI (lecanemab) are two amyloid beta inhibitors that are approved by the US FDA for early Alzheimer's. These are a class of drugs that target and reduce the production, aggregation, or accumulation of amyloid beta protein in the brain. These aim to slow down or potentially halt the progression of Alzheimer's disease. Though there has been considerable research and development in the area of amyloid beta-protein inhibitors, the results have been mixed. The complex nature of Alzheimer's disease and the involvement of multiple pathological processes make it a challenging condition to target with a single therapy. Alzheimer's Disease Market Outlook The current treatment is symptomatic and works by modulating the activity of brain neurotransmitters, such as acetylcholine, serotonin, noradrenaline, glutamate, and dopamine. Due to the associated side effects, personalizing the treatment and considering patients' comorbidities is important. Acetylcholinesterase inhibitors and NMDA receptor antagonists have been available for over a decade. Their effectiveness is modest, temporary, and needs to be regularly re-evaluated. They have demonstrated symptomatic benefits but are associated with side effects. With improved understanding, a pathological cascade of amyloid-? deposition, tau-hyperphosphorylation, neurofibrillary tangle formation, inflammation, and synaptic and cell loss has been well documented. Biogen and Eisai have developed ADUHELM (aducanumab) and LEQEMBI (lecanemab) as anti-amyloid therapies. Of these former could not get traditional approval, but recently LEQEMBI received US FDA approval. Hopefully, it will change the market dynamics and make Biogen and Eisai key players. This approval of a disease-modifying therapy is a ray of hope for many early-stage Alzheimer's patients. But a testing requirement on the drug's prescribing label could be a potential hurdle. The FDA recommends doctors test patients for a genetic mutation known as ApoE4 before starting treatment. The current market has been covered by the symptomatic treatment that includes different pharmacological agents used across the 7MM, which presents minor variations in the overall prescription pattern. ADUHELM, LEQEMBI, galantamine, rivastigmine, donepezil, memantine, and combination (memantine with acetylcholinesterase inhibitors) are the major drugs considered for symptomatic treatment in the forecast model. Key players like Anavex Life Sciences, Alzheon, Athira Pharma, Annovis Bio, Eli Lilly, BioVie, AB Science, Novo Nordisk, Cassava Sciences, TauRx Therapeutics, KeifeRx, AriBio, Cerecin, Eisai, and others are evaluating their lead candidates in different stages of clinical development. They aim to investigate their products for the treatment of Alzheimer's Disease. The total market size of Alzheimer's disease in the 7MM was approximately USD 3,460.6 million in 2022 and is projected to increase during the forecast period (2023-2032). According to the publisher's estimates, among the 7MM, the US had the largest market share in Alzheimer's disease, with a revenue of USD 1,751.7 million in 2022. This will increase significantly due to increasing awareness and launch of the emerging therapies. The total market size of Alzheimer's disease in EU4 and the UK was approximately 23.0% of the total market revenue for the 7MM. Among EU4 and the UK countries, Germany accounted for the maximum market size in 2022, while the UK occupied the bottom of the ladder. In the 7MM, cholinesterase inhibitors and NMDA receptor antagonists accounted for USD 3,210.9 million and USD 245.0 million in 2022. Among cholinesterase, donepezil had the highest share (among all the therapies), with nearly 54% of the total revenue in the class, while rivastigmine generated USD 946.1 million in 2022. According to the publisher's estimates, Biogen and Eisai's LEQEMBI, which received approval from the US FDA in July 2023, though may have a humble start, is projected to grow substantially during the forecast period, providing the company a substantial advantage in the biologic pie of the Alzheimer market. Various therapies like Anavex Life Sciences's ANAVEX2-73 (blarcamesine), Alzheon's ALZ-801 (valiltramiprosate), Athira Pharma's fosgonimeton (ATH-1017), Annovis Bio's buntanetap, Eli Lilly's donanemab (LY3002813), BioVie's NE3107, Cassava Sciences' simufilam (PTI-125), and TauRx Therapeutics' hydromethylthionine mesylate (TRx0237) among others are anticipated to enter the market during the forecast period. Eli Lilly's donanemab (LY3002813), an FDA-designated product, is projected to enter the market by 2024. An amyloid ? protein inhibitor, it will compete with Biogen and Eisai's LEQEMBI. With excellent efficacy, wherein the therapy reduced the risk of progression by 39%, it is projected to have a slow- medium uptake. The high costs will translate to high revenue, and it will attain its peak by the seventh year. Despite a few safety concerns, the drug will perform well during the forecast period. NE3107, simufilam (PTI-125), ANAVEX2-73 (blarcamesine), and ALZ-801 (valiltramiprosate) are next in line with projected entry by 2025. Alzheon's ALZ-801, another FDA-designated product, has demonstrated excellent efficacy in its trial, but high doses and long treatment duration may affect its potential. With a slow-medium uptake, it will attain its peak share by the eighth year. Alzheimer's Disease Drugs Uptake This section focuses on the uptake rate of potential drugs expected to be launched in the market during 2019-2032. For example, Annovis Bio's buntanetap, a translational inhibitor of neurotoxic aggregating proteins, with an anticipated entry by 2027 in the US, is predicted to have a slow-medium uptake during the forecast period. Pipeline Activities The report provides insights into therapeutic candidates in Phase II and Phase I. It also analyzes key players involved in developing targeted therapeutics. Development Activities The report covers information on collaborations, acquisitions and mergers, licensing, and patent details for emerging therapies for Alzheimer's disease. KOL Views To keep up with current market trends, we take KOLs and SMEs' opinions working in the domain through primary research to fill the data gaps and validate our secondary research. Industry Experts contacted for insights on the Alzheimer's disease evolving treatment landscape, patient reliance on conventional therapies, patient therapy switching acceptability, and drug uptake, along with challenges related to accessibility, including Medical/scientific writers, Medical Professionals, Professors, Directors, and Others. This analysts connected with 50+ KOLs to gather insights; however, interviews were conducted with 15+ KOLs in the 7MM. Centers like Southern Illinois University School of Medicine, the University of Washington, the University Hospital of Tours, Navarra Institute for Health Research, the University of Tokyo School of Medicine, and the National Center of Neurology and Psychiatry were contacted. Their opinion helps understand and validate current and emerging therapy treatment patterns or Alzheimer's disease market trends. This will support the clients in potential upcoming novel treatments by identifying the overall scenario of the market and the unmet needs. Physician's View According to the primary research analysis, LEQEMBI's approval will change the treatment regime and market dynamics for Alzheimer's. Though not curative, this first approved disease-modifying therapy garners well for early Alzheimer's patients, as it delays the progression. Though the drug has potential, there are certain hurdles, like testing requirements on the drug's prescribing label and risk warning, which push one to keep caution. The results in delaying disease progression have done well, and awareness needs to be generated to ensure drug usage. Qualitative Analysis The publisher performs Qualitative and market Intelligence analysis using various approaches, such as SWOT and Conjoint Analysis. In the SWOT analysis, strengths, weaknesses, opportunities, and threats in terms of disease diagnosis, patient awareness, patient burden, competitive landscape, cost-effectiveness, and geographical accessibility of therapies are provided. These pointers are based on the Analyst's discretion and assessment of the patient burden, cost analysis, and existing and evolving treatment landscape. Conjoint Analysis analyzes multiple emerging therapies based on relevant attributes such as safety, efficacy, frequency of administration, route of administration, and order of entry. To analyze the effectiveness, drug-attributed analysis is calculated from scores based upon changes from baseline in ADCS-ADL, ADAS-Cog, and Clinical Dementia Rating, among others. The therapies' safety is evaluated wherein treatment-related adverse events, serious adverse events were majorly observed, besides the occurrence of amyloid-related imaging abnormalities. It sets a clear understanding of the side effects posed by the drug in the trials. In addition, the scoring is also based on the route of administration, order of entry and designation, probability of success, and the addressable patient pool for each therapy. According to these parameters, the final weightage score and the ranking of the emerging therapies are decided. Market Access and Reimbursement In April 2022, CMS released its final national coverage determination decision memorandum on Medicare coverage for approved mAbs as a treatment for Alzheimer's. CMS issued a two-track decision that differentiates Medicare coverage for mAbs based on whether they receive from the US FDA: Accelerated approval based on surrogate endpoints or traditional approval based on clinical endpoints. In July 2023, the US FDA approved the sBLA supporting the traditional approval of LEQEMBI 100 mg/mL injection for IV use. Following FDA's traditional approval Medicare will cover the therapy for appropriate patients. This will facilitate reimbursement for and access to LEQEMBI across a broad range of healthcare settings in the US. The report provides detailed insights on the country-wise accessibility and reimbursement scenarios, cost-effectiveness scenarios, programs making accessibility easier and out-of-pocket costs more affordable, insights on patients insured under federal or state government prescription drug programs, etc. Key Topics Covered 1. Key Insights 2. Report Introduction 3. Alzheimer's Disease Market Overview at a Glance 4. Methodology of Alzheimer's Disease Epidemiology and Market 5. Executive Summary of Alzheimer's Disease 6. Key events 7. Disease Background and Overview 8. Patient Journey of Alzheimer's Disease 9. Epidemiology and Patient Population 10. Marketed Drugs 11. Emerging Therapies 12. Alzheimer's Disease: The Seven Major Market Analysis 13. KOL views 14. SWOT Analysis 15. Unmet Needs 16. Market Access and Reimbursement 17. Appendix A selection of companies mentioned in this report includes: AB Science AgeneBio Alzheon Anavex Life Sciences Annovis Bio AriBio Athira Pharma BioVie Cassava Sciences Cerecin Eisai Eli Lilly KeifeRx Neurim Pharmaceuticals/Syneos Health Novo Nordisk TauRx Therapeutics For more information about this report visit About ResearchAndMarkets.com ResearchAndMarkets.com is the world's leading source for international market research reports and market data. We provide you with the latest data on international and regional markets, key industries, the top companies, new products and the latest trends. Media Contact: Research and Markets Laura Wood, Senior Manager [email protected] For E.S.T Office Hours Call +1-917-300-0470 For U.S./CAN Toll Free Call +1-800-526-8630 For GMT Office Hours Call +353-1-416-8900 U.S. Fax: 646-607-1907 Fax (outside U.S.): +353-1-481-1716 Logo: SOURCE Research and Markets

Drug ApprovalPhase 2Phase 3Breakthrough TherapyAccelerated Approval

09 Aug 2022

·www.biopharmadive.com

A biotech startup gives Merck its next shot at Alzheimer’s

Merck & Co. is buying into another Alzheimers drug, this time through a backloaded deal with Boston-based Cerevance.Under the terms of the deal, Merck will take over one research program and collaborate with Cerevance to identify new protein targets in the brain.Cerevance will get $25 million upfront and could receive up to $1.1 billion more if it hits certain development and commercial milestones. Reaching those milestones is highly uncertain Alzheimers drug development is notoriously difficult and nearly every single treatment tested for the disease has failed. Pharmaceutical companies, including Merck, have kept looking, given the diseases devastating impact and wide prevalence.Founded in the U.K. in 2016, Cerevance focuses on central nervous system and neurodegenerative diseases. Its lead drug candidate targets Parkinson's disease and in March, the company reported results from a Phase 2 clinical trial. In 2019, it brokered a deal with Takeda to pursue central nervous system disease targets and to develop drugs for gastrointestinal disorders. But the company has also zeroed in on dementia and Alzheimers, too.When Cerevance entered discussions with Merck in early 2022, the big pharma company was impressed with its drug discovery platform, which employs machine learning to identify new neurological disease targets, said Craig Thompson, who joined Cerevance as its CEO in April.There's a lot of disease areas to find something for but this continually impacts more people as the population continues to age, Thompson said. More than 6 million Americans are affected by Alzheimers, according to data from the Alzheimers Association.Cerevance uses tissue from 24 brain banks to study how neurodegenerative diseases progress. By isolating specific cells in both healthy and diseased brain tissue samples, researchers can look for particular proteins and examine biological pathways that are harder to see in mice or with stem cells. The companys platform allows it to search for promising targets in mature brain cells, even those that are expressed at lower levels and might otherwise go undetected with other methods.Cerevances target does not appear to be amyloid, the sticky protein thats drawn the interest of Alzheimers drug developers for decades, but Thompson declined to specify what its pursuing instead.There is a novel target identified for the discovery-stage program; however, we will also explore targets not yet identified, he saidTakedaand venture capital firm LightstoneVentures launched Cerevance with a $36 million Series A round. Its most recent funding was a $65 million Series B round in 2020 from investors that included Bill Gates and GV.The alliance with Cerevancerepresents a new foray into Alzheimers drug development for Merck. Its last high-profile effort ended in 2017,when it halted study of a drug called verubecestat after trial monitors determined there virtually no chance of finding a positive clinical effect.“Merck did not respond to a request for comment.Most Alzheimers drugs have, in one way or another, been designed to clear amyloid protein from the brain. But again and again, treatments from companies including Merck, Roche, Eli Lilly and AstraZeneca have failed in late-stage testing.In June 2021, the Food and Drug Administration controversially granted Biogen accelerated approval for its Alzheimer's drug Aduhelm, which had delivered contradictory results in late-stage clinical trials. Aduhelm is meant to slow the cognitive and physical decline that occurs in Alzheimer's patients by targeting amyloid.Biogens partner Eisai has put another amyloid-targeting Alzheimer's drug called lecanemab in front of the FDA this year, as has Lilly with its candidate, donanemab. '

Accelerated ApprovalCollaborate

09 Aug 2022

·www.biospace.com

Merck Returns to Alzheimer’s Disease with $1.1B Cerevance Pact

Courtesy of Tada Images/Getty Images With an investment valued at up to $1.1 billion, Merck is diving back into Alzheimer’s research through a collaboration with Cerevance. Using Cerevance’s proprietary Nuclear Enriched Transcript Sort sequencing (NETSseq) technology platform, the two companies have partnered to identify new targets for the treatment of Alzheimer’s disease (AD). On Tuesday morning, the two companies announced the collaboration, which includes the out-licensing of one discovery-stage program to Merck. For privately-held Cerevance, the partnership comes months after the company posted positive mid-stage data in another neurological disease space, Parkinson’s. That study, which assessed the oral compound CVN424, showed that treatment with the drug developed through the NETSseq platform was able to reduce the “OFF” times for Parkinson’s patients. “OFF” refers to the occasions when Parkinson’s patients experience disease symptoms despite being on medication. CVN424 was developed to target GPR6, a G-coupled protein receptor. That receptor was targeted after the NETSseq platform determined it was highly expressed in striatal medium spiny neurons in the indirect pathway of the basal ganglia circuit. The technology platform is capable of profiling neuronal and glial cell populations at unprecedented depths. It’s that deep analysis that Merck is banking on to find a new treatment option for Alzheimer’s, particularly following the setbacks of the amyloid-beta approaches to treating the disease. Craig Thompson, chief executive officer of Cerevance, said the collaboration with Merck is continued validation of the company’s proprietary NETSseq technology. In an interview with BioSpace, Thompson, who was appointed to the role of CEO earlier this year, said Cerevance began discussing potential collaborations in the CNS space following the release of the positive Phase II Parkinson’s data. Merck was one of the companies that expressed significant interest in the data generated by NETSseq and its potential in Alzheimer’s disease, which has repeatedly proven to be a complex disease to target with therapeutics. Merck Takes Another Shot at Alzheimer's For Merck, delving back into Alzheimer’s comes several years after the pharma giant experienced setbacks with experimental β-site amyloid-precursor-protein-cleaving enzyme (BACE) inhibitors. In 2018, the company’s BACE inhibitor verubecestat failed in a Phase III Alzheimer’s trial. An external Data Monitoring Committee halted that study of patients with prodromal Alzheimer’s disease early after an interim safety analysis. One year prior, a Phase II/III study of verubecestat in mild-to-moderate Alzheimer’s disease was also halted following the recommendation of an external data monitoring committee that said there was “virtually no chance of finding a positive clinical effect.” Thompson, who worked at Merck for 12 years earlier in his career, said he was thrilled the pharma giant was interested in working with Cerevance, mainly because he is highly familiar with the “scientific rigor” the larger company employs in its development programs. “It gave me a lot of joy that they found the NETSseq program,” he said. Cerevance's Novel NETSseq Platform Over the next three years, the two companies aim to discover potential new targets for therapeutic approaches through the NETSseq platform, which was developed at Rockefeller University. The NETSseq program enabled researchers to comprehensively pro brain cell types, including both neurons and glial cells. Using the program, Cerevance has been able to isolate specific cell populations in brain tissue samples, revealing biological pathways that underlie neurodegenerative and psychiatric diseases that have proven to be difficult to see in animal models or differentiated human stem cells, Thompson said. The technology platform will allow Merck and Cerevance to take a “fresh approach” to Alzheimer’s. They hope the collaboration will reveal novel therapeutic targets that can slow or inhibit disease progression. Jason M. Uslaner, vice president and head of neuroscience discovery at Merck Research Laboratories, said progress in the understanding of the biology of neurodegenerative diseases has revealed new mechanisms for potential therapeutic intervention. “We look forward to advancing the discovery program as well as taking advantage of the NETSseq platform to identify new targets with the team at Cerevance,” Uslaner said in a statement. Under the terms of the deal, Merck provided Cerevance with $25 million upfront, including the in-licensing of the early-development asset. Cerevance will be eligible for development and commercial milestone payments that total approximately $1.1 billion. Should any product from the collaboration become commercialized, Cerevance will also be eligible for potential royalties on sales. Merck isn’t the only big pharma company to partner with Cerevance. Three years ago, Cerevance and Japanese pharma powerhouse Takeda partnered on a collaboration to tackle gastrointestinal disorders that have their roots in the central nervous system. It is believed that some cell types found in the brain can impact the development of GI diseases.

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100 Deals associated with Verubecestat

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KEGG	Wiki	ATC	Drug Bank
D10739	Verubecestat	-	DB12285

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Indication	Highest Phase	Country/Location	Organization	Date
Mild cognitive disorder	Phase 3	-	Merck Sharp & Dohme Corp.	05 Nov 2013
Alzheimer Disease	Phase 3	-	Merck Sharp & Dohme Corp.	05 Nov 2013

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01739348 (EPOCH, Pubmed \| Alzheimers Res Ther) Manual	Phase 3	Alzheimer Disease	1,957	Verubecestat 12mg	qnykuuislj(xjrcdcbfxb) = wiwqjgcsnv yccjkirvsy (ndcgvxcyzu ) View more	Negative	07 Aug 2019
				Verubecestat 40mg	qnykuuislj(xjrcdcbfxb) = uruezyulte yccjkirvsy (ndcgvxcyzu ) View more
NCT01953601 (APECS, AAIC2019) Manual	Phase 3	Alzheimer Disease	963	Verubecestat 12 mg	outsxbzade(uxknarwsir) = mwgiudbwpc agcdpiwydw (itprddnxlc, 0.32) View more	Positive	01 Jul 2019
				Verubecestat 40 mg	outsxbzade(uxknarwsir) = qvljufccpz agcdpiwydw (itprddnxlc, 1.10) View more
NCT01953601 (MK-8931-019 \| 8931-019 \| APECS, CTgov)	Phase 3	Alzheimer Disease \| Mild cognitive disorder	1,454	Verubecestat 12 mg (Parts 1 and 2) (Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2))	zmivpwkpnw(ncsjojcewq) = rnvahvsakw etfyrjyque (sgdakgnpua, wukgsbuvwm - tiubiokuza) View more	-	17 May 2019
				Verubecestat 40 mg (Parts 1 and 2) (Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2))	zmivpwkpnw(ncsjojcewq) = reyisubxrg etfyrjyque (sgdakgnpua, nwzrqxsrln - fpgtvupdnn) View more
NCT02910739 (CTgov)	Phase 1	Alzheimer Disease \| Mild cognitive disorder	16	MK-8931 (Part I: MK-8931 40 mg in Moderate HI Participants)	kwqmibiqym(pmtulitsjl) = xrpuucllpn kcrxteleqn (loyjverbzi, lwpcepyywx - rbhborxwrm) View more	-	01 Oct 2018
				MK-8931 (Part I: MK-8931 40 mg in Healthy Participants)	kwqmibiqym(pmtulitsjl) = cigpaeoltc kcrxteleqn (loyjverbzi, dklchxpsge - ponnolcild) View more

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