GPR139

Shares of Neurocrine Biosciences saw a modest 5% bump on Tuesday after revealing that its experimental treatment for major depressive disorder (MDD) met the primary and key secondary endpoints in the Phase II SAVITRI study. It’s the second company to post positive MDD data in as many weeks. Intra-Cellular’s stock rose as much as 28% after its Caplyta (lumateperone) succeeded in a Phase III trial as adjunctive therapy to antidepressants. The atypical antipsychotic reduced Montgomery Åsberg Depression Rating Scale (MADRS) total score by 4.9 points more than placebo at week six.Neurocrine’s NBI-1065845, a once-daily oral AMPA positive allosteric modulator, also led to statistically significant improvements in MADRS total score versus placebo in patients with MDD who have not benefited from treatment with at least one antidepressant.The company did not disclose the specific dose that achieved the primary endpoint, but said that at day 28, the investigational drug demonstrated a 4.3-point lower score than placebo. By day 56, the gap had widened to 7.5 points in favour of NBI-1065845.With an adverse event profile similar to placebo – and headaches as the most common side effect – the candidate also appeared to meet a safety bar set by Morgan Stanley analysts, who previously predicted that the Phase II results could set up NBI-1065845 as a competitor to Johnson & Johnson’s ketamine derivative Spravato (esketamine), “but with improved tolerability.”In a Phase III trial reported last year, nearly half the patients with treatment-resistant MDD who had received the pharma’s eskatamine nasal spray reported dizziness, and about a third experienced nausea and dissociation.Neurocrine gained an exclusive licence to NBI-1065845, along with six other antipsychotics, as part of a broad 2020 deal with Takeda. The AMPA-targeting treatment’s clinical success comes roughly six months after a separate ex-Takeda programme failed in a Phase II trial to treat MDD patients with anhedonia.Under the deal terms, Neurocrine and Takeda have an agreement to equally split profits for NBI-1065845 as well as NBI-1065846 (TAK-041/zelatriazin), a small-molecule agonist of GPR139, though the Japanese pharma can opt out and instead receive development and commercial milestone payments.

Shares in Neurocrine Biosciences fell 6% to $105 in after-hours trading in the aftermath of the news. Neurocrine Biosciences delivered a double dose of bad news after markets closed Thursday, revealing the failures of phase 2 proof-of-concept trials of an epilepsy candidate and a Takeda-partnered psychiatry program. The San Diego-based biotech picked up the psychiatry candidate, NBI-1065846, from Takeda in 2020 as part of a multi-asset deal worth $120 million upfront. Neurocrine began a phase 2 clinical trial of the molecule the following year, enrolling patients with anhedonia—the inability to feel pleasure—in major depressive disorder on the strength of evidence that agonism of GPR139 may improve outcomes. That hypothesis crumbled under the glare of a midphase trial. The study missed its primary endpoint, which looked at the change in anhedonia severity on Day 57. And, while Neurocrine is yet to share data publicly, it has seen enough internally to halt development of the once-weekly oral drug candidate. The setback still leaves Neurocrine with opportunities to deliver a return on its investment in the Takeda programs. The partners are continuing to collaborate on clinical-phase treatments for major depressive disorder and cognitive impairment associated with schizophrenia. Neurocrine is still digging into the implications of the failure of its other candidate, NBI-921352. The asset, a NaV 1.6 inhibitor that Neurocrine licensed from Xenon Pharmaceuticals for $50 million upfront, failed to meaningfully reduce seizure frequency in a phase 2 dose finding study in adults with focal onset seizures (FOS). The failure prompted Neurocrine to halt plans to develop the molecule in FOS. A study of the candidate in SCN8A-developmental epileptic encephalopathy is continuing while Neurocrine checks whether the FOS data have any implications for the ongoing trial. The SCN8A study is scheduled to finish early next year. Work on a preclinical Nav1.2/1.6 inhibitor is continuing under the alliance between Neurocrine and Xenon.  Shares in Neurocrine fell 6% to $105 in after-hours trading in the aftermath of the news. The biotech’s prospects are more closely tied to the commercial performance of the blockbuster Ingrezza and work to bring crinecerfont to market than either of the failed midphase programs. Mizuho Securities analyst Uy Ear called the results disappointing, but the firm had low confidence going into the readout and had forecasted modest sales for the assets. While NBI-1065846 still has potential in SCN8A, Ear noted that the ultra-rare disease has a patient population of about 800 worldwide. 

Neurocrine Biosciences announced Friday that two drug candidates separately partnered with Takeda and Xenon Pharmaceuticals missed the mark in a pair of Phase II studies. "We are disappointed with the outcome of these studies, but remain fully committed to finding new treatment options for patients living with serious neurological and neuropsychiatric disorders, including epilepsy and major depressive disorder (MDD)," stated Eiry Roberts, chief medical officer at Neurocrine.According to the company, a dose-finding study of the selective NaV 1.6 inhibitor NBI-921352 failed to meaningfully reduce seizure frequency when used as adjunctive therapy in adults with focal onset seizures (FOS), so it is scrapping the programme on which it was collaborating with Xenon. Neurocrine said it will review data from the FOS trial to determine any potential implication for its ongoing study in SCN8A-developmental epileptic encephalopathy. It continues to advance a preclinical dual NaV1.2/1.6 inhibitor as part of its 2019 epilepsy collaboration with Xenon.Meanwhile, a second compound dubbed NBI-1065846 did not meet its primary endpoint in the placebo-controlled TERPSIS study involving MDD patients with anhedonia. The GPR139 agonist, also known as TAK-041, is partnered with Takeda as part of deal potentially worth close to $1.9 billion. There are no plans to continue developing NBI-1065846. However, Neurocrine said the companies continue to collaborate on several programmes, including NBI-1065845 for the treatment of inadequate response to MDD treatment, as well as luvadaxistat for cognitive impairment associated with schizophrenia. Both are in Phase II, while another asset, NBI-1070770, is in Phase I testing for MDD.Failures could 'stunt momentum'The trial results "remind us of the riskiness of Neurocrine's broader pipeline," commented BMO Capital Markets analyst Evan Seigerman, noting that the failures are "likely to stunt momentum."Meanwhile analysts at Morgan Stanley said the results for NBI-1065846 were "not a surprise to us or many investors, as anhedonia in MDD has been a challenging indication." However, they said they had been "optimistic that NBI-921352 would read out positively as there was biologicrationale - selectivity to Nav1.6 - to believe it could work." Still, while the analysts expect Neurocrine shares will face headline risk in the near term, they think "it should be limited."Neurocrine recently reported two positive Phase III readouts for its oral CRF1 antagonist crinecerfont in congenital adrenal hyperplasia, including in adult and paediatric patients.