2024 Highlights the Rollercoaster That Is Neuro

From the FDA approval of Bristol Myers Squibb’s Cobenfy as the first new schizophrenia treatment in more than three decades to the failure of Sage Therapeutics’ dalzanemdor in three neurodegenerative diseases, it has been a year of sweet triumph and crushing disappointment for neuroscience drug developers—largely reflecting the reality of these confounding conditions.

Perhaps it’s just my fascination with neuro—which despite (or maybe because of) its challenges, has long captured my attention—but I believe some of 2024’s most compelling storylines have come from this space. There was the battle between BMS’ and AbbVie’s multibillion dollar neuro acquisitions from last December—Karuna vs. Cerevel in the schizophrenia space—which resulted in spectacularly different outcomes. And then there was the approval of Eli Lilly’s donanemab (Kisunla), the first anti-amyloid competitor in Alzheimer’s for Eisai and Biogen, which discontinued Aduhelm this January after securing Leqembi’s approval in 2023. Now, Kisunla and Leqembi are rolling out as the amyloid hypothesis still faces doubt.

Given the nature of neurological diseases and biopharma’s myriad bids to solve them, these soap opera storylines are to be expected, and even encouraged, as it cumulatively means more progress for intractable, often fatal, diseases.

One of the highest highs this year was the FDA’s late September approval of Cobenfy, which served as indisputable validation for BMS’ $14 billion acquisition of Karuna. Less than two months later, however, AbbVie’s emraclidine—a lead asset in the pharma’s nearly $9 billion buyout of Cerevel—failed to show efficacy in two registration-style Phase II trials for schizophrenia.

Two parallels are noteworthy here. The first, of course, pertains to the business strategy, with both pharma companies scooping up the assets in multibillion dollar acquisitions in the same month. Cobenfy proved its worth with promising Phase III results in April and secured FDA approval in late September—35 years to the day after the last novel drug was approved for schizophrenia.

The second likeness between Cobenfy and emraclidine is the science that underlies them: both drugs belong to the muscarinic class. Muscarinic receptors play a role in the pathology of schizophrenia, and the space has caught fire of late with several companies developing therapeutic candidates. Cobenfy’s approval portended success for the drug class, and AbbVie seemed close on BMS’ heels with emraclidine.

But there is a difference between the two assets: Cobenfy targets both the M1 and M4 receptors, while emraclidine only targets M4. “There’s been a longstanding thesis that M1 may contribute to efficacy on cognition,” Stifel analysts noted. The way these two assets performed, it certainly seems like that could be the case.

Schizophrenia may have stolen the show in the latter part of 2024, but we must not forget that early in the second half, Alzheimer’s researchers and patients celebrated the approval of Kisunla—the third anti-amyloid antibody to hit the market in the past four years. But as is almost always the case in Alzheimer’s, there were also several failures.

November was a particularly bad month for the space—and again, for AbbVie. On Nov. 25, Alector announced that its AbbVie-partnered investigational antibody AL002 failed to significantly slow clinical progression in patients with Alzheimer’s disease. The flop triggered a layoff of approximately 17% of the biotech’s workforce. The same day, Cassava Sciences revealed that its controversial Alzheimer’s candidate simulfilam failed to meet all pre-specified co-primary, secondary and exploratory biomarker endpoints in a Phase III trial. The result follows allegations of “data manipulation” related to the drug.

In amyotrophic lateral sclerosis (ALS), meanwhile, the FDA approvals of Amylyx’s Relyvrio in 2022 and Biogen’s Qalsody in 2023 generated momentum, but not three months into 2024, Amylyx announced that Relyvrio failed the Phase III PHOENIX trial. The drug was approved based on results from the Phase II CENTAUR trial, in which it extended median survival by more than 10 months compared with placebo. Talk about a rollercoaster ride for Amylyx co-CEOs Josh Cohen and Justin Klee. To their credit, the duo had vowed to pull the drug from the market if PHOENIX was not successful, and in April they made good on this promise. This, in itself, gets my vote for one of 2024’s top stories.

“Given the high unmet medical need that still exists in mental illness and devastating diseases like Alzheimer’s disease and ALS, we’ll continue to look to industry to come up with great innovation when it comes to new mechanisms of action, therapeutic modalities and approaches, as well as use of novel endpoints and novel clinical trial design,” Graig Suvannevejh, senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas, told BioSpace in an email.

Looking more widely across the industry, there are plenty more examples of the trials and tribulations that plague this area of drug development. Sage Therapeutics, for example, has been riding one of the park’s darker rollercoasters. The biotech’s shares have lost more than 90% of their value over the past year and a half, thanks in large part to a hat trick of mid-stage flops. In April, dalzanemdor failed to show efficacy against Parkinson’s disease; it then failed in Alzheimer’s and Huntington’s—the final blow that prompted the company to discontinue the asset’s development.

Sage’s downward spiral began in August 2023 when it—along with partner Biogen—won FDA approval for Zurzuvae in postpartum depression (PPD) but failed to secure the regulator’s nod for major depressive disorder (MDD), a much larger indication that has had its fair share of misses lately. Earlier this month, Relmada Therapeutics halted two Phase III trials of its MDD candidate REL-1017 after a futility analysis, leading the company to consider “strategic alternatives.” And in October, Alto Neuroscience reported that a trial of ALTO-100 failed to improve symptoms in a Phase II trial.

“We are disheartened by the results from this study as the unmet need in this patient population is immense,” Alto CEO Amit Etkin said in a statement at the time. Indeed, between 10% and 30% of MDD patients do not respond to typical antidepressant treatments.

On a high note, rare, neurological diseases enjoyed a moment in 2024. In March, Orchard Therapeutics won approval for Lenmeldy, the first gene therapy for metachromatic leukodystrophy (MLD), a rare and heritable metabolic disease that can cause organ damage and neurological issues, in pediatric patients. Then, in September, patients with Niemann-Pick disease type C saw the approval of the first treatments for the ultra-rare and progressive neurodegenerative disease as the FDA greenlit IntraBio’s Aqneursa just days after Zevra Therapeutics’ Miplyffa. Yet another rare disease that scored a victory this year is Duchenne muscular dystrophy (DMD), with Sarepta Therapeutics’ Elevidys securing a label expansion to treat patients who are at least 4 years old, regardless of whether they can walk. This was despite the gene therapy’s failiure to meet the primary efficacy endpoint in its confirmatory trial.

Finally, despite Sage’s recent failure, the Huntington’s space is beginning to see some real traction. Prilenia Therapeutics, Wave Life Sciences and uniQure are all eyeing paths to approval of therapies that could address the disease’s underlying cause. Investment is ticking up as well. This year, Novartis committed up to $2.9 billion in a deal with PTC Therapeutics for a Huntington’s drug, just months after inking an up to $1.3 billion deal with Voyager Therapeutics to develop gene therapies for the disease and spinal muscular atrophy.

Taken together, I’d say the rollercoaster that is neuro produced more thrills than bumps in 2024—but the twists and turns are a stark reminder of just what a black box the brain is. Treatments for these diseases are truly the holy grail of biopharma, and as always, we are moving incrementally closer to answers.