Gantenerumab

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.

Roche revealed early-stage data for a new Alzheimer’s program on Wednesday as it seeks to jump back into a field littered with failures. In a 60-patient trial testing four different doses of trontinemab, researchers from Roche said the antibody removed amyloid plaque at a “rapid and robust” pace while simultaneously inducing relatively low brain swelling and bleeding side effects known as ARIA. There was also one patient death due to a large “stroke-like” brain bleed that wasn’t classified as ARIA. The program’s next steps are murky, as Roche still needs to complete the trial and its open-label extension, trontinemab program lead Luka Kulic told Endpoints News . The trial also did not measure the drug’s effects on patient cognition, which is likely what regulators would seek in a pivotal trial. But the results mark an important first step for Roche in taking another swing at Alzheimer’s following multiple Phase 3 failures of gantenerumab, an anti-amyloid antibody licensed from MorphoSys, in 2015 and 2022. The negative readouts effectively led to Roche ceding ground to the other two amyloid-targeting Alzheimer’s drugs, Eisai and Biogen’s Leqembi and Eli Lilly’s Kisunla, both of which have since won FDA approval. In the new trontinemab study, amyloid levels in patients taking the highest dose were reduced by 67% after 28 weeks compared to placebo and by 75% in the second-highest dose. Those patients also were classified as “amyloid negative” after receiving PET scans. Only one patient experienced an ARIA event, occurring in the second-highest dose cohort. Kulic said the results are the latest chapter for the amyloid hypothesis — a decades-old idea that removing such plaques in the brain can improve the hallmark cognition impairment of Alzheimer’s disease. Prior to Leqembi and Kisunla, drugmakers continuously failed to develop cognition-improving therapies, and those two approved drugs still come with considerable risk. But Kulic is hopeful that these early results can eventually translate into better data in larger studies. “We believe that we are really well on track, because trontinemab gets the [amyloid] levels below the [amyloid negativity] threshold faster than probably any other molecule that is currently out there,” Kulic said. Trontinemab is designed with what Roche calls a “Brainshuttle” module attached to the antibody, which allows it to more effectively cross the blood-brain barrier. Last year, the company reported the levels of amyloid plummeted below normal detection in 75% of patients after 28 weeks in the highest dose tested to that point.