Set back by dual phase III failures of a drug it had intended for treating impulsive aggression, Supernus Pharmaceuticals Inc. President and CEO Jack Khattar last February told investors he was "very conscious about the fact that we really need to reload the pipeline." Now doing just that, the company has struck an agreement with privately held Navitor Pharmaceuticals Inc. to run a joint phase II program for Navitor's mTORC1 activator, NV-5138, in treatment-resistant depression (TRD). Supernus will foot the bill. Navitor stands to earn up to $475 million if Supernus ultimately licenses or acquires the drug and the work hits certain milestones. Supernus shares (NASDAQ:SUPN) fell 0.8% Wednesday to close at $18.12.

"As a platform company, it's our intention to fully exploit the mTORC1 complex by drugging it in a number of different ways," Navitor CEO Tom Hughes told BioWorld. The Supernus deal allows it to remain focused on that mission while its partner engages with the real "depth and commitment" to a sizable and complex indication like depression, he said.

Rockville, Md.-based Supernus already has one phase II-ready candidate for depression, the selective norepinephrine reuptake inhibitor SPN-809 (viloxazine hydrochloride). Though the drug was approved and marketed for depression in Europe for many years, Supernus has primarily focused on advancing it in the guise of SPN-812, a drug for the treatment of ADHD in children and adolescents. The company has two commercial products, the CNS drugs Oxtellar XR (oxcarbazepine) and Trokendi XR (topiramate).

Under the terms of its new agreement with Navitor, Supernus will jointly conduct a phase II program for NV-5138 in TRD, for which it has agreed to pay costs of up to $50 million, plus certain costs associated with nonclinical development and formulation.

In exchange, Navitor has granted Supernus an exclusive option to license or acquire NV-5138 for all territories except greater China, prior to initiation of a phase III program. Navitor will also receive an up-front payment of $25 million, composed of a $10 million option fee and a $15 million equity investment representing about a 13% ownership in the company. Total payments, exclusive of royalty payments on net sales of NV-5138 and development costs under the agreement, have the potential to reach $410 million to $475 million, including the up-front, fees tied to the license or acquisition, and subsequent clinical, regulatory and sales milestone payments. Hughes said the deal "preserves a very healthy amount of downstream revenue" for Navitor as the drug progresses.

Supernus also has the first right of refusal for any compound with a similar mechanism of action on mTORC1 as NV-5138 in the central nervous system and the right to develop other potential applications of NV-5138, such as in the treatment of cognitive impairments or other neurological indications.

In conjunction with the equity investment, Khattar will join Navitor's board. He was unavailable to discuss the deal on April 22.

A major control point

NV-5138 is an oral small-molecule activator of mTORC1, a major control point of cellular activity, including neuronal processes tied to mood and memory. In depression, its activity is reduced, in part related to the response of the brain to stress. Born out of the work of Navitor's scientific founder, David Sabatini, NV-5138 essentially acts as if it were the amino acid leucine, but works in the brain in a way that leucine can't, Hughes explained. "It stimulates mTORC1, restores synaptic protein production in the brain" and leads to "a very rapid stimulation of dendritic spine formation, essentially demonstrating the compound allows the brain to regain that ability to make and break connections," he said.

Encouraged by animal models that showed dosing with NV-5138 translated into improvements in indicators of depressive symptoms, Navitor moved it into early clinical studies in 2018, testing a single exploratory dose of the candidate first in healthy volunteers and later in patients with TRD. In the healthy volunteers, investigators found that a single dose of NV-5138 led to signs of rapid exposure, target engagement, synaptic protein production and quantitative electroencephalogram signals of neural activation in the brain vs. placebo. In patients, a single dose led to encouraging improvements in core symptoms of depression, too, setting the stage for further clinical development. The drug has appeared safe and well-tolerated in the trials so far.

Next up, ahead of the phase II program, a multiple ascending-dose study will be run in healthy volunteers, Hughes said. Beyond that, Supernus will take the lead on communicating progress of the drug in the months to come, he said

Many avenues

Up to one-third of adults with major depression battle symptoms that don’t respond to treatment, according to a widely cited 2015 review of the subject. That has made it a hot space in CNS development, attracting a multitude of approaches, both pharmaceutical and device driven.

NMDA antagonism has been one popular approach, exemplified by programs like Axsome Therapeutics Inc.'s AXS-05. Other approaches have included triple reuptake inhibitors, such as Denovo Biopharma LLC's DB-104, a drug tested in two phase IIb TRD trials by Molecular Research Inc. following its return to the latter by Bristol Myers Squibb Co. Not all have received the warm welcome they may have hoped for, as was the case for Johnson & Johnson’s Spravato (esketamine) nasal spray, the cost effectiveness of which has been criticized by both the U.S.-based Institute for Clinical and Economic Review and the U.K.’s National Institute for Health and Care Excellence, which passed on recommending the medicine's use in the NHS, citing uncertainties over its clinical and cost-effectiveness, even as a third-line therapy.

Meanwhile, on the device front, Stanford University and Livanova plc have been exploring various avenues of attacking the illness from both within and outside the body. Stanford researchers reported earlier this month that they'd seen success in testing a transcranial magnetic stimulation for treatment-resistant severe depression, achieving a 90% remission rate for patients that put them into the nondepressed range. A double-blind, sham-controlled trial is up next to confirm the results. Meanwhile, Livanova has been testing the effectiveness of vagus nerve stimulation for tackling TRD.

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