Crenezumab

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.

Company describes new biomarker and cognitive treatment effects that support continued development of pepinemab in Mild Cognitive Impairment and Mild Dementia due to Alzheimer’s diseaseROCHESTER, N.Y., Oct. 31, 2024 (GLOBE NEWSWIRE) -- Vaccinex (Nasdaq: VCNX) today provided an update on new clinical findings from its SIGNAL-AD Phase 1b/2 trial of pepinemab antibody in Alzheimer’s disease. Vaccinex recently announced positive results of the phase 1b/2 study of its lead product, pepinemab, in early stages of Alzheimer’s disease (AD). The purpose of this report is to share additional data demonstrating stage-specific biomarker and cognitive effects starting with Mild Cognitive Impairment (MCI), the very earliest diagnostic stage of AD, and following through to progression to later stages of mild dementia. Currently approved treatments for AD are designed to reduce expression of Abeta amyloid and appear to modestly slow cognitive decline. The Vaccinex strategy is to intervene early to block astrocyte activation and associated inflammation with pepinemab so as to potentially achieve greater reduction in overall disease activity. We report today that expression of plasma GFAP and p-tau 217 biomarkers appears to increase predominantly during MCI and that this is inhibited by pepinemab treatment. Glial Fibrillary Acidic Protein (GFAP) is a well-characterized marker of increasing astrocyte reactivity, and p-tau 217 is a peptide fragment of toxic “tau tangles” that accumulate in neurons during disease progression. In the absence of effective treatment, patients typically progress to mild dementia, which approximately corresponds to Mini-Mental State Examination (MMSE) scores of 22-26 . We report that pepinemab treatment at this stage may slow further cognitive decline as evidenced by strong treatment trends for multiple different cognitive measures. In further support of potential treatment benefit, we performed a proteomic analysis of Cerebrospinal Fluid (CSF) from patients treated with pepinemab or placebo. The results identified several proteins that have been previously reported to increase during normal AD progression but are here shown to be inhibited by pepinemab treatment. These constitute additional disease-associated biomarkers whose inhibition, we believe, further supports the benefit of pepinemab treatment. Finally, investors will be aware of concerns regarding damage to vascular integrity of brain tissue and the risk of inflammation and hemorrhage due to treatment with antibodies to Abeta amyloid. We have not seen evidence of such effects for treatment with pepinemab antibody. On the contrary, employing a human Brain-Chip model, we were able to demonstrate that damage caused by toxic aggregates of alpha synuclein can be inhibited or reversed by treatment with pepinemab. The results of similar analysis of damage caused by Abeta amyloid in the presence or absence of anti-Abeta antibody will be reported soon. Treatment with aSyn fibrils disrupted vascular integrity of brain chip (blue) compared to untreated control (black)Concurrent pepinemab treatment significantly inhibited effects of aSyn (green closed squares)Delayed pepinemab treatment significantly reversed effects of aSyn (green open squares) Continued Pepinemab Development The Company views the results of this AD study in the context of its larger previous randomized phase 2 study in Huntington’s disease (HD), which showed highly significant beneficial effects of pepinemab treatment on HD-specific biomarkers and measures of cognition. The immediate goal of the SIGNAL-AD study was to determine whether effects are consistent in another very prevalent neurodegenerative disease. Further, we report a new finding that pepinemab can inhibit or reverse the damaging effects of alpha synuclein, a key constituent of Lewy bodies that are characteristic of Neuronal Synuclein Diseases including Dementia with Lewy Bodies and Parkinson’s disease, as well as being expressed in ~50% of Alzheimer’s Disease cases. This not only extends the potentially beneficial treatment effects of pepinemab but may also greatly expand the application of this drug to other prevalent neurological diseases. In terms of current clinical development, we believe the most productive path forward is to treat patients with MCI or mild dementia due to AD with pepinemab with the aim of slowing or preventing disease progression and the emergence of additional pathogenic mechanisms. The Company plans to continue partnering discussions for continued development of pepinemab in AD, HD and potentially other neurodegenerative diseases. Forward Looking Statements To the extent that statements contained in this letter are not descriptions of historical facts regarding Vaccinex, Inc. (“Vaccinex,” “we,” “us,” or “our”), they are forward-looking statements reflecting management’s current beliefs and expectations. Such statements include, but are not limited to, statements about the use and potential benefits of pepinemab treatment in patients with AD and HD; the potential and prospects for continuing late stage development of pepinemab, including as part of a prospective partnership; and other statements identified by words such as “believe,” “being,” “will,” “appear,” “expect,” “ongoing,” “potential,” “promising,” “indicate,” “suggest,” “apparent”, and similar expressions or their negatives (as well as other words and expressions referencing future events, conditions, or circumstances). Forward-looking statements involve substantial risks and uncertainties that could cause the outcome of our research and pre-clinical development programs, clinical development programs, future results, performance, or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, uncertainties inherent in the execution, cost and completion of preclinical studies and clinical trials, risks related to reliance on third parties, that interim and preliminary data may not be predictive of final results and does not ensure success in later clinical trials, uncertainties related to regulatory approval, risks related to our dependence on our lead product candidate pepinemab, the possible delisting of our common stock from Nasdaq if the Company is unable to regain and sustain compliance with the Nasdaq listing standards, and other matters that could affect our development plans or the commercial potential of our product candidates. Except as required by law, the Company assumes no obligation to update these forward-looking statements. For a further discussion of these and other factors that could cause future results to differ materially from any forward-looking statement, see the section titled “Risk Factors” in our periodic reports filed with the Securities and Exchange Commission and the other risks and uncertainties described in the Company’s annual year-end Form 10-K and subsequent filings with the SEC. Investor ContactElizabeth Evans, PhDChief Operating Officer, Vaccinex, Inc.(585) 271-2700eevans@vaccinex.com A photo accompanying this announcement is available at https://www.globenewswire.com/NewsRoom/AttachmentNg/775d3ef7-a1e1-41c0-9f61-c7f4ddec61b5