Crenezumab

PHOENIX, Nov. 14, 2024. A new Alzheimer's prevention study has received a $74.5 million five-year grant from the National Institute on Aging, part of the National Institutes of Health (NIH). The two-part study will be conducted in members of the world's largest autosomal dominant Alzheimer's disease (ADAD) kindred in Colombia who carry a genetic mutation that makes them all but destined to develop Alzheimer's and become cognitively impaired at an average age of 44. The study is led by Banner Alzheimer's Institute in Phoenix and the Neurosciences Group at the University of Antioquia (GNA) in Medellin, Colombia. It will initially aim to remove amyloid plaques as completely as possible in cognitively impaired and unimpaired carriers of the presenilin 1 (PSEN1) E280A mutation, and then evaluate different ways to stave off the recurrence of plaque deposits and other ensuing elements of the disease. Enrollment is expected to begin in the fall of 2025. The first part of the study will use Eli Lilly and Company's (Lilly) antibody therapy donanemab to remove existing plaques as completely as possible (i.e., to levels consistent with a negative amyloid PET scan). Donanemab has been shown to clear amyloid plaques and slow cognitive decline, and was recently approved by the U.S. Food and Drug Administration for use in patients with mild cognitive impairment and dementia due to Alzheimer's. The study will provide new information about the drug's safety, tolerability, and biological efficacy in the unimpaired and impaired stages of ADAD. The second part of the study will compare the following approaches in the same participants, for safety, tolerability and ability to avert amyloid plaque accumulation and other biological and clinical features of the disease: This study builds on the history, partnership, infrastructure and learnings of the original API ADAD Colombia Trial, which launched a new era in Alzheimer's prevention research when it was announced by NIH in 2012. While the investigational drug in the original trial with crenezumab failed to clear plaques or demonstrate a clinical benefit, the study introduced paradigms to speed up the evaluation of promising prevention therapies, found ways to do so in a vulnerable population in a developing country, and led to a growing number of prevention trials, some of which may find the first effective Alzheimer's prevention therapies within the next few years. Both the original and the new trial tap into GNA's identification of about 6,000 distant relatives from the Colombian PSEN1 E280A kindred, including about 1,200 who carry the ADAD-causing genetic mutation. "We are excited about the chance to advance the fight against Alzheimer's disease in partnership with our outstanding colleagues and these unique families in Colombia," said Robert Alexander, MD, the API's chief scientific officer and one of the prevention trial leaders. "This study will clarify the extent to which the antibody treatment reduces amyloid plaques in the unimpaired and impaired stages of ADAD and test different approaches to maintain low amyloid levels following plaque removal." The new study will enroll 200 cognitively unimpaired and mildly impaired mutation carriers and 40 non-carriers (who will receive placebo) from the Colombian kindred. "This trial is a testament to our dear friend and longstanding partner, Dr. Francisco Lopera, who established GNA, forged a close working relationship with API, and could not have been more committed to these families," said Eric M. Reiman, MD, executive director of Banner Alzheimer's Institute and one of the other API leaders. "He constantly said, 'My families are waiting,' and he played indispensable roles in the effort to find effective prevention therapies." "I am honored to follow in Dr. Lopera's footsteps and continue our work with API," said David Aguillón, MD, GNA's new director and principal investigator of the University of Antioquia study site. "Dr. Lopera and the Antioquia families have inspired all of us to never give up, to maintain our sense of urgency to find effective Alzheimer's prevention therapies, and to do so in ways that will help our Antioquia families." The research study is supported by grant R01AG086363 from the NIH National Institute on Aging, the lead U.S. federal agency supporting and conducting Alzheimer's disease and related dementias research. Lilly and Roche are generously donating the drug supplies that will be evaluated in this study. The study is led by Drs. Robert Alexander, Eric Reiman and Jessica Langbaum from BAI and its API; David Aguillón from the University of Antioquia; and Yakeel Quiroz from the University of Antioquia and Massachusetts General Hospital. API also received a $3 million grant from the Zurich-based NOMIS Foundation to continue to assess about 2,000 mutation carriers and non-carriers from the PSEN1 E280A kindred, provide a shared resource of longitudinal data and blood samples for the field, accelerate enrollment in the new prevention trial, and provide education and social support for the families irrespective of their participation in the study. About Banner Alzheimer's Institute Since its inception in 2006, Banner Alzheimer's Institute has sought to find effective Alzheimer's disease prevention therapies within twenty years, establish a new model of care for cognitively impaired patients and family caregivers, and forge new models of collaboration in biomedical research. It has made groundbreaking contributions to the unusually early detection, tracking, diagnosis, study and prevention of Alzheimer's disease. It includes the pioneering Alzheimer's Prevention Initiative, an extensive profile of research studies and clinical trials, comprehensive clinical, family and community service programs, leading brain imaging and blood-based biomarker research programs, and strategic partnerships with public and private research organizations around the world. About the Alzheimer's Prevention Initiative The Alzheimer's Prevention Initiative (API) is an international collaborative formed in 2009 to launch a new era of Alzheimer's prevention research. Led by Banner Alzheimer's Institute, the API conducts prevention trials in cognitively healthy people at increased risk for Alzheimer's disease. API continues to establish brain imaging, fluid biomarker and cognitive endpoints needed to rapidly test promising prevention therapies. It also leads participant recruitment registries to accelerate enrollment into Alzheimer's-focused studies. API is intended to provide the scientific means, accelerated approval pathway and enrollment resources needed to evaluate the range of promising Alzheimer's prevention therapies and find ones that work without losing another generation. For more information, go to alzheimerspreventioninitiative.com. About Grupo de Neurociencias de Antioquia Grupo de Neurociencias de Antioquia (GNA), at the University of Antioquia in Medellín, is ranked as one of the best research organizations in Colombia. For more than three decades, GNA has characterized what is now considered the world's largest population with early-onset familial Alzheimer's disease, and it continues to play pioneering roles in the effort to find effective Alzheimer's prevention therapies. GNA has also characterized large and paradigmatic populations with other forms of dementia and other neurogenetic disorders. SOURCE Banner Alzheimer's Institute Whatever your topic of interest, subscribe to our newsletters to get the best of Drugs.com in your inbox.

iStock/ bawanch This year has seen several biopharma companies drop Alzheimer’s and Parkinson’s disease programs, but experts say plenty are still chasing these multi-billion-dollar markets. There’s no question that the approvals of Eisai and Biogen’s Leqembi and Eli Lilly’s Kisunla generated momentum in the Alzheimer’s disease treatment space. However, this year has seen attrition in the pipelines for both Alzheimer’s and Parkinson’s disease. Roche in particular has parted with several assets for Alzheimer’s disease, recently terminating a partnership with UCB. This is the second Alzheimer’s cut this year for the Swiss pharma, which in January returned two failed assets to AC Immune. Several other companies, including Johnson & Johnson, Sage Therapeutics and Otsuka Pharmaceuticals, have also dropped programs targeting Alzheimer’s and/or Parkinson’s. But Graig Suvannevejh, senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas, said this is not an indication of any major shifts in the R&D landscape but rather a “coincidence.” These decisions are “really dependent on data,” he told BioSpace . Several discarded Alzheimer’s and Parkinson’s programs, including AC Immune’s crenezumab, failed to produce positive data in clinical trials. “Maybe it’s also a reflection, sometimes, of what’s happening on the competitive landscape.” In terms of anti-amyloid antibody programs, such as crenezumab, Suvannevejh noted that despite the approvals of Leqembi and Kisunla, as well as Eisai and Biogen’s Aduhelm, this class has struggled to gain traction in the market. So companies may “have an evolving view of the commercial opportunity in Alzheimer’s disease,” he said. Overall, Suvannevejh said the pipelines of companies focused on Alzheimer’s disease are “okay.” While acknowledging that large pharmaceutical companies in this space do not have the “very rich, late-stage” pipelines they had three to five years ago, he said “there’s still a presence, because it is one of the few areas that could represent easily for any drug that gets approved, at least on paper, a multi-billion-dollar annual sales potential type of product.” The Alzheimer’s treatment space is projected to be worth $15.5 billion by 2031, according to iHealthcareAnalyst. As for Parkinson’s, Suvannevejh said there are around 20 therapies on the market that address the symptoms of the disease. There currently are none, however, that are disease-modifying because the underlying cause the disease is still unclear. While alpha-synuclein is the current candidate du jour , “we don’t have data yet,” he said. The global market for Parkinson’s disease drugs is currently valued at $5.56 billion and is expected to reach $6.63 billion by 2029. Parkinson’s is “still viewed as a very big commercial opportunity,” Suvannevejh said, “but so far, it’s been equally a difficult market to tap into.” Here, BioSpace takes a closer look at four companies that have recently discontinued programs for these two intractable neurodegenerative diseases. Roche Indication: Alzheimer’s disease Assets: Bepranemab, crenezumab, semorinemab In July 2020, Roche’s Genentech inked a collaboration with UCB to develop an anti-tau antibody treatment, bepranemab (UCB0107) for Alzheimer’s disease. Roche handed over $120 million upfront to UCB, with the Belgian company eligible for $2 billion based on certain regulatory approvals and other milestones. Four years later, that partnership is over. UCB revealed Roche’s decision while announcing the acceptance of an abstract for a Phase IIa study of bepranemab at the 2024 Clinical Trials on Alzheimer’s Disease conference, saying that the rights to the program had been handed back. No further details were provided. UCB isn’t the first company to receive a return from Roche this year. In January, the pharma ended its long-term collaboration with AC Immune, handing back two Alzheimer’s assets—anti-amyloid beta antibody crenezumab and anti-tau antibody semorinemab. In 2020, topline results from a Phase II trial of semorinemab showed the candidate failed to hit its primary endpoint, as well as two secondary endpoints, while crenezumab failed Phase II and III clinical trials in 2019 and 2022, respectively, according to Fierce Biotech . Long devoted to Alzheimer’s, Roche has struggled to gain a foothold in the space. A particular blow fell when gantenerumab, an investigational antibody, failed two Phase III studies in November 2022. This was the company’s second setback that year, following crenezumab’s failure to hit its co-primary endpoints in a Phase III for people with a specific gene mutation that causes early-onset Alzheimer’s. Despite all the bumps, Roche isn’t backing away from Alzheimer’s. Two other assets, RG6289 and trontinemab, are in Phase II studies. Roche touted positive data in March 2024 from a small Phase Ib/IIa study of trontinemab, reporting “rapid and robust” amyloid plaque reduction. Johnson & Johnson Indication: Alzheimer’s disease and Parkinson’s disease Assets: Seltorexant and JNJ-0376 A week before Roche parted ways with UCB, Johnson & Johnson slashed several pipeline programs in the neurology and psychiatry spaces, including seltorexant for Alzheimer’s disease and JNJ-0376 for Parkinson’s disease. Seltorexant, a human orexin-2 receptor blocker intended for the treatment of agitation or aggression in Alzheimer’s, was being studied in a Phase II trial. While a pipeline document on J&J’s website indicates it will no longer develop the drug for this indication, it will continue to evaluate seltorexant as a treatment for major depressive disorder with insomnia symptoms. Also on the chopping block was JNJ-0376, a Phase I Parkinson’s candidate the company had previously touted in a 2023 business overview presentation as having “novel mechanisms to modify, treat and/or prevent neurodegenerative disorders.” J&J did not provide further details on this program. Sage Therapeutics Indication: Alzheimer’s disease and Parkinson’s disease Asset: Dalzanemdor It hasn’t been a good year for Sage Therapeutics’ dalzanemdor. In April, the Cambridge, Mass.–based biopharma announced it would discontinue development of dalzanemdor in Parkinson’s disease after the oral drug candidate, which is intended to treat cognitive disorders associated with NMDA receptor dysfunction, failed a mid-stage trial. In the Phase II PRECEDENT study, which included 86 patients with Parkinson’s, dalzanemdor was found to be safe, but did not show any meaningful differences over placebo in any of the exploratory endpoints, including a cognition test. Six months later, dalzanemdor suffered another defeat, missing the primary endpoint in the Phase II LIGHTWAVE study in Alzheimer’s disease. According to Sage, trial data “did not demonstrate a statistically significant difference from baseline in participants treated with dalzanemdor versus placebo” on the same cognition test. Sage will halt further development of the asset in Alzheimer’s, according to an Oct. 8 press release . Sage has one remaining shot on goal with dalzanemdor. A Phase II study of the embattled candidate is ongoing in Huntington’s disease, with early data expected later this year. Otsuka Pharmaceutical Indication: Alzheimer’s-related agitation Asset: AVP-786 The pipeline of Japanese neuro player Otsuka Pharmaceutical is one candidate lighter after AVP-786 failed to improve agitation associated with dementia due to Alzheimer’s disease in a Phase III trial. Topline Phase III results in February 2024 showed the asset, which came to Otsuka in late 2014 in the $3.5 billion acquisition of Avanir Pharmaceuticals, did not show improvement over placebo in patients’ condition. The company announced in May it would end development of AVP-786. Otsuka is still developing brexpiprazole for agitation associated with dementia due to Alzheimer’s, which has been filed with regulatory authorities in Japan, according to the company’s pipeline document . Otsuka’s current pipeline includes candidates for schizophrenia, major depressive disorder and generalized anxiety disorder, among other psychiatric diseases, but does not list any other programs for Alzheimer’s.