Approaches and targets for depression and other mental health illnesses have remained stagnant for decades. With several readouts for novel therapies on the horizon, that could be changing.
The psychiatric space is drawing significant interest as late-stage readouts for novel depression treatments glitter just on the horizon—with many experts hoping that a precision medicine approach is on the cusp of proving its worth.
Though the market is saturated with generic selective serotonin reuptake inhibitor (SSRI) and serotonin-norepinephrine reuptake inhibitor (SNRI) drugs—the go-to treatments for depression—studies show that a large portion of the population is depressed. An estimated 21 million, or 8.3% of adults in the U.S. had at least one major depressive episode in 2021.
Yet, according to Amit Etkin, CEO of Alto Neuroscience, there is hope ahead. “We’re in this period of a lot of readouts, new drugs and the potential for a very different set of antidepressants [on the market] five years from now,” he told BioSpace.
Etkin noted that assets now in development rely on different mechanisms and targets than the antidepressants currently on the market. “There’s no appetite for developing things that are similar to what we’ve had before,” he said.
Some of these novel therapies are tested on only a subset of patients within a given diagnosis, moving forward a precision approach that experts say could move the needle on the standard of care.
“While there are lots of medications out there, we have not solved depression,” Steve Butts, CEO of Arrivo BioVentures, told BioSpace. Many recent approvals in the psychiatric space have been “polished up versions of older medications. We are getting closer to personalized medicine with this”—something he noted is crucial for both the industry and patients.
Precision Psychiatry Comes Into Focus
The success rate for psychiatric drugs is the lowest among non-oncology indications with a 6.2% chance of approval. Even successful drugs in the category have a small effect size, and according to Etkin, solely employing novel mechanisms has so far not improved things on that front. He’s hoping precision medicine will.
Etkin sees a stark division between a “traditional all-comer” strategy and a precision approach to psychiatric drug development. Historically, trials have included all patients within a diagnosis, such as major depressive disorder (MDD). With a precision approach, companies have the opportunity to understand the underlying biology of psychiatric disorders, “using something other than just the diagnosis” to select patients for trials and targeting the patient population expected to respond better to the therapeutic.
Both Alto and Johnson & Johnson’s Janssen are taking a precision approach to depression.
Janssen is sectioning out its trial participants based on specific symptoms. Its orexin antagonist, seltorexant, is in a Phase III study for MDD patients suffering from insomnia, while aticaprant, a kappa-opioid receptor (KOR) antagonist, is in a Phase III study targeting MDD patients with anhedonia. Both studies are projected to read out this year.
Alto is using clinical biomarkers to select patients for trial participation. Depending on the trial, the biotech chooses participants based on cognitive tests or EEG measures to indicate the underlying biology of each patient’s brain.
In December 2023, the company shared a positive readout from ALTO-300 in patients bearing a specific EEG-based biomarker. Results from the trial showed that patients with the biomarker saw a greater drop in their Montgomery–Åsberg Depression Rating Scale (MADRS) score than patients without the biomarker profile. In January 2023, a study of another candidate, ALTO-100, showed 61% of biomarker-defined patients had a clinical response to the treatment versus only 33% of comparators without the biomarker.
Meanwhile, Arrivo is developing a novel therapeutic for depression with an epigenetic mechanism. Its SP-624 activates SIRT6, an enzyme that works through several inflammatory pathways and is essential to epigenetic regulation of gene expression, mitochondrial health and DNA repair.
In a Phase I trial, the company realized its asset alleviates depression symptoms preferentially in females. Butts said this discovery is a strong step forward toward understanding the underlying biological basis for why this psychiatric disorder manifests so differently in males and females.
New Mechanisms Drive Investments
The neuropsychiatric space has been gaining traction as “success builds on success,” Butts said, pointing to the recent $14 billion acquisition of Karuna Therapeutics and its schizophrenia asset, KarXT, by Bristol Myers Squibb. BMS is already seeing a return on its investment as Phase III data in April showed significant and sustained symptom improvement in patients taking KarXT.
If approved, KarXT would be the first new class of medicine for schizophrenia in over 50 years, Karuna founder and Chief Operating Officer Andrew Miller told BioSpace in a previous interview. The M1/M4-preferring muscarinic agonist is being reviewed by the FDA with an action date of September 26.
Another recent deal in the schizophrenia space came last December, when AbbVie dropped $8.7 billion to acquire Cerevel Therapeutics, picking up its late-stage, next-generation antipsychotic emraclidine. The asset is a positive allosteric modulator of the muscarinic M4 receptor being tested in schizophrenia and Alzheimer’s disease psychosis.
“Those kinds of [deals] help the rest of our industry,” Butts said.
On the depression front, Neurocrine Biosciences revealed positive data from a Phase II study of a Takeda-partnered asset targeting the AMPA receptor in patients who don’t benefit from current antidepressants. Graig Suvannevejh, senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas, told BioSpace that while the Phase II data were good, the effect will now need to be repeated in a larger Phase III study.
KOR antagonists have also caught the eye of pharma. In addition to Janssen’s aticaprant, Neumora Therapeutics’ navacaprant is in a Phase III study for MDD. Navacaprant is being tested as a monotherapy, potentially making it a good option for patients who want to avoid the “troublesome side effects” of current antidepressants, Suvannavejh said.
Finding the right novel targets for each unique patient population is going to end up being one of the “more productive tensions in our field as we see these readouts happening,” Alto’s Etkin said. “New mechanisms and a new approach in orientation—other areas of medicine have done quite a bit, but we’ve just not seen that historically in psychiatry.”
Novel mechanisms also stand a better chance for reimbursement, Suvannevejh noted. With multiple generic SSRI and SNRI drugs available, insurers are less likely to cover the cost of a drug with a similar mechanism, he said. “The worst thing that can happen is that you spend 10 years getting your drug approved,” only to have insurance refuse to pay for it, Suvannevejh explained. “Payers will pay for novelty and innovation.”
Kate Goodwin is a freelance life science writer based in Des Moines, Iowa. She can be reached at kate.goodwin@biospace.com and on LinkedIn.
