Multiple new Alzheimer’s treatments, progress in the fight against ALS and novel approaches in neuropsychiatry. 

All three developments add up to what analysts say could be a “paradigm-shifting” year for the neuroscience field.

In that regard, the New Year looks poised to kick off at a fever pitch, beginning with a decision date for Eisai/Biogen’s lecanemab on Friday, January 6. 

The Food and Drug Administration is expected to grant accelerated approval for the Alzheimer’s drug, after full results from a Phase 3 trial mirrored an earlier topline reveal, bolstering analysts’ confidence in its efficacy and safety.

As previously reported, lecanemab met the primary endpoint in the trial, dubbed Clarity-AD, with a treatment difference of 0.45 on a major outcome measure called CDR-SB. The data were aired at the Clinical Trials on Alzheimer’s disease (CTAD) conference in San Francisco in November. 

‘Positive energy’ in Alzheimer’s

“We expect the positive energy and excitement from CTAD 2022 to continue,” wrote analysts from SVB Securities in a forward-looking note to investors about the CNS field. “After lecanemab’s positive CLARITY-AD data announced earlier this fall, most physicians agree that Abeta does contribute to Alzheimer’s progression and that lecanemab should be the first disease-modifying agent to be widely available to Alzheimer’s patients.” 

The investment bank, along with many other industry watchers, also has its eye on potential updates to the Alzheimer’s drug reimbursement picture. Right now, Medicare only pays for anti-amyloid antibody therapies for patients enrolled in randomized clinical trials, thanks to an April decision prompted by the 2021 approval of Biogen Alzheimer’s drug Aduhelm. 

The limits, largely in line with a draft ruling issued by the Centers for Medicare and Medicaid Services last January, also apply to forthcoming drugs in the same class. But with lecanemab targeting full approval in the second half of 2023, the analysts predict that CMS’s decision might be due for an update.

If CMS reconsiders its National Coverage Determination on the anti-Abeta class of monoclonal antibodies, it “could enable widespread transformation in the standard of care for Alzheimer’s patients,” the SVB team wrote.

Agents in this class must also navigate reimbursement for the related diagnostic testing needed to verify the presence of amyloid, something which is required for treatment. Last week, several outlets reported, CMS delayed the release of coverage for amyloid PET scans, saying it wants to review the Phase 3 data published by Eiasi/Biogen for lecanemab.

Another catalyst to keep an eye out for is the release of pivotal data from Eli Lilly’s Phase 3 TRAILBLAZER-2 study involving donanemab in early Alzheimer’s, due in the second quarter. Donanemab, molecularly similar to lecanemab (and with similar efficacy), is under review for a possible accelerated approval, so the data take on added significance.

“We also expect multiple data points from pipeline candidates with non-Abeta targeting mechanisms, as physicians are now looking to evaluate which combinations of approaches should be used alongside Abeta targeting therapies to maximize treatment effect and further alter the disease course,” the SVB analysts pointed out.

New ALS mechanisms 

The September approval of Amylyx’s Relyvrio for ALS certainly was a highlight for the field. The third drug approved for the disease, it was the first to demonstrate a statistically significant functional benefit among subjects taking the therapy in a clinical trial. 

Relyvrio’s green light followed a tortuous regulatory process, during which the FDA’s external advisors literally reversed course and voted that the agency should grant approval to what’s become the third ALS drug. 

The patient community, meanwhile, is contending with the drug’s $158,000 per year price tag, set by Amylyx following approval. It’s led to headaches in the form of insurance delays or denials, and sometimes exorbitant out-of-pocket expenses.

The SVB analysts say they have their eye on Relyvrio’s launch for a couple of other reasons. The confirmatory PHOENIX study, expected in 2024, “could be negative” or show numerical (but not statistically significant) improvements in function and survival, they wrote. That, in turn, “could reduce physician and patient confidence for the drug.”

What’s more, competitors could enter the market sooner than anticipated if regulatory agencies accelerate approvals of other candidates in late-stage trials, the analysts speculate.

Still, the next 12 months could bring more progress on the ALS front in the form of drugs with new mechanisms of action. For one, an FDA advisory committee is scheduled to meet in the first half of the year about the pending approval for Biogen’s tofersen in SOD1-ALS.

MM+M readers will recall that the SOD1 type is the form that eventually claimed the life of medical communications legend Lisa Stockman-Mauriello last year. Stockman-Mauriello advocated for expanded access to tofersen for patients with the SOD1 mutation and for future clinical trials to include a parallel expanded-access program.

Further out on the horizon, other pivotal ALS-related study readouts expected include Seelos’ SLS-005 and Prilenia’s pridopidine data from the HEALEY platform study, and Sanofi/Denali’s SAR443820/ DNL788 in the pivotal HIMALAYA study in late 2023/early 2024.

In addition, as noted by the SVB team, more targeted therapies are being explored for a genetic form of ALS with mutations in C9orf72, from the likes of Wave, Alector and Transposon. The three are developing assets aimed at this rare form of the disease, with data expected from mid-to-late 2023.

Neuropsychiatry’s novel approaches

Joining ALS and Alzheimer’s with meaningful data in store for next year is the neuropsychiatry field. 

Take major depressive disorder (MDD), where the therapeutic paradigm continues to advance with the recent approval of Axsome Therapeutics’ rapid-acting combo med Auvelity.

Forthcoming MDD-related catalysts include a third-quarter FDA decision for Biogen/Sage’s zuranolone as well as anticipated data for Relmada’s REL-1017. Both of these agents are angling to become part of what SVB termed “a new wave of novel-mechanism, rapid-acting antidepressants that physicians and patients are excited about.”

Additionally, in post-traumatic stress disorder and obsessive compulsive disorder, two other areas of unmet need, firms exploring novel approaches range from Jazz Pharma, Aptinyx and Lundbeck, to Biohaven, respectively. 

Then there are clinical readouts which SVB flags as important for the neuropsychiatry space, but may not be market-moving in and of themselves: 

• Karuna Therapeutics’ EMERGENT-3 study of KarXT in schizophrenia is expected in the first quarter. As the third pivotal study for this novel antipsychotic, the trial is likely to yield more supportive data. However, the company’s two previously positive trials could form the basis of a regulatory submission, which could come mid-2023. 
• Intra-Cellular’s Phase 3 “403” study of Caplyta in MDD and borderline personality disorder patients with mixed features is also expected in the first quarter. Positive data could have implications for label expansion, as well as potential readthrough to adjunctive MDD studies reading out in 2024. Although, the investment bank doesn’t expect the same sales inflection seen with Caplyta’s earlier label expansion into bipolar disorder.