Trevi Therapeutics Inc. said a new $50.5 million series C financing led by New Enterprise Associates will help it advance the development of Nalbuphine ER, a twice-daily oral opioid in development for the treatment of two forms of severe itching. The round included new investors Lundbeckfonden Ventures, Omega Funds and Aperture Venture Partners, along with TPG Biotech, Trevi's largest investor and the leader of its $12.8 million series A in December 2012 and $25 million series B round in June 2014.

Taken together with a $50 million investment in itch-focused Menlo Therapeutics Inc. announced earlier this week, Trevi's new financing makes it a hot week for itch, or pruritus, a condition with two high-profile forms: prurigo nodularis (PN), a rare skin condition characterized by hard crusty lumps that itch intensely, and uremic pruritus (UP), a larger itching malady associated with kidney dialysis. Without any FDA-approved therapies, pruritus has long been underserved by antihistamines and corticosteroids, a situation that could begin to change if Trevi or its competitors succeed in trials to come. (See BioWorld, July 19, 2017.)

President and CEO Jennifer Good told BioWorld she expects to get Nalbuphine ER back into the clinic for a 200-patients PN trial during the first half of 2018, with a readout anticipated sometime during the second half of 2019. The company will also run an open-label extension study, as it did with its phase II study. "We'll circle back with UP once we get PN rolling along," she said.

Nalbuphine got its start at Penwest Pharmaceuticals Co., where Trevi co-founders Good and Thomas Sciascia worked on the executive team, and was eventually developed and sold by Penwest acquirer Endo International plc as Nubain (nalbuphine hydrochloride), an intravenously administered drug. Since then, Trevi has made substantial investments in developing its ER formulation, work that has helped it amass a protective estate of 10 issued patents related to both the drug's formulation and method of treatment. (See BioWorld Today, Aug. 11, 2010.)

Thanks to Nubain's earlier approval and well-known profile, when Trevi goes to the FDA, it will be able to seek 505(b)(2) approvals for itching related to PN or, later, itching related to UP.

"I don't think the FDA is going to be interested in giving a chronic pruritus label, because there's just so many underlying medical issues going on in these patients," Good said.

In October 2016, New Haven, Conn.-based Trevi announced phase II trial results in reduced itch intensity and other supporting efficacy endpoints in patients with PN, as well as a statistically significant reduction in itch intensity in a phase II/III trial in UP.

The phase II PN trial included 62 participants and tested Nalbuphine ER tablets dosed twice daily at 90 mg and 180 mg in PN. The main outcome variables were responder analyses of the proportion of patients with at least a 30 percent or 50 percent reduction in their seven-day worst-itch intensity Numerical Rating Score (NRS) from baseline to completion of treatment at week 10.

The proportion of patients in the 180-mg arm meeting 50 percent responder criteria at week 10 or last observed visit (mITT population with n=18) approached statistical significance (p=0.083) and for patients who completed treatment, met statistical significance (p=0.028).

The mean change in worst itch NRS was additionally evaluated, and the mITT population of the 180-mg arm as compared to placebo approached statistical significance (p=0.083) as well.

The company also recently completed a one-year open-label trial in PN in which Nalbuphine ER was well-tolerated and all patients who completed dosing showed evidence of lesion healing.

Where Trevi's story goes next will, of course, depend on the outcome of trials ahead. But Good noted that there's a lot of strategic interest in itch.

"If we do a good job, run a good trial and get good data, that may be an obvious value creation path," she said. "I think there's a likely scenario for M&A here if we can deliver some good studies." Though it's a different company, indication and drug, it's worth noting that NEA and Lundbeckfond invested in U.K.-based dermatology company Ziarco Pharma Ltd. ahead of Novartis AG snapping it up late last year.

In connection with the financing, David Meeker, former CEO of Sanofi/Genzyme, will join Trevi's board as chairman. NEA's Ed Mathers, Mette Kirstine Agger, of Lundbeckfond, and Otello Stampacchia, of Omega Funds will also join the board.