Positive data early next year from its pivotal study of M207, a zolmitriptan-coated microneedle patch for treating migraine, could go a long way to helping Zosano Pharma Corp. regain investor confidence after losing both its big pharma partnerships last year and watching shares plummet to a fraction of its January 2015 IPO price.

So far, all remains on track with the Zotrip study, described as registration-enabling trial, with 136 patients enrolled to date – 109 of those in the run-in phase and seven subjects randomized to treatment with M207 (formerly ZP-Triptan) or placebo. "We are pleased with enrollment to date," said President and CEO Konstantinos Alataris, who stepped into the chief executive role in January, taking over from former CEO Vikram Lamba, after being named president and chief operating officer in September.

During the company's first-quarter earnings call, Alataris told investors Zosano had sufficient funds to complete the pivotal efficacy study. As of March 31, it had about $28.4 million on the balance sheet. Additional capital likely will be required to complete a follow-up safety study, expected to start enrolling 150 patients upon completion of Zotrip. FDA guidance calls for 150 patients completing follow-up for six months and 50 patients completing 12 months of follow-up.

Assuming positive data from both trials, Zosano expects to be able to file for approval under the FDA's 505(b)(2) pathway, possibly in the third quarter of 2018, aiming to position M207 as a faster-acting triptan compared to the oral versions that have dominated the acute migraine market.

A patch formulation of 5-HT 1d receptor agonist and 5-HT 1b receptor agonist zolmitriptan, M207 comprises a 3-cm2 array of titanium microneedles attached to an adhesive patch that can deliver Zosano's drug quickly through the skin during a migraine attack. While triptans are widely used, oral versions only result in pain relief for 9 percent to 12 percent of patients at 30 minutes, and Zosano has pointed to surveys showing that faster pain relief is one of the top demands of migraine sufferers.

So far, only one triptan patch has cleared the FDA. Nupathe Inc.'s Zecuity (sumatriptan iontophoretic transdermal system) won approval in 2013, though it wasn't officially launched until the latter half of 2015 by Nupathe acquirer Teva Pharmaceutical Industries Ltd. Its commercialization was short-lived, however, with Teva voluntarily suspending sales in June due to postmarketing reports of burning and scarring. (See BioWorld Today, Jan. 22, 2013, and Jan. 9, 2014.)

An intranasal version of sumatriptan gained an FDA nod in late January. Avanir Pharmaceuticals Inc.'s Onzetra Xsail delivers a dry powder formulation of the drug via a breath-activated device.

Beyond triptans, other drug classes are finally working their way into the migraine space. Colucid Pharmaceuticals Inc., for instance, is in late-stage testing with lasmiditan, an oral drug targeting the 5-HT1F receptors expressed in the trigeminal pathway. It's performed well so far in clinical trials and its advantage could be the lack of cardiovascular risks seen with triptans, potentially setting up lasmiditan as a first-line therapy.

An oral film version of rizatriptan, developed by Redhill Biopharma Ltd., received a complete response letter (CRL) in the U.S., though it has gained approval in Europe, where it is marketed as Rizaport. And an oral, inhaled version of dihydroergotamine, formerly known as Levadex, also has struggled in the U.S. with current sponsor Allergan plc receiving a third CRL in 2014.

There's also the race to get the first calcitonin gene-related peptide (CGRP) antibody to market. A top contender, Bothell, Wash.-based Alder Biopharmaceuticals Inc. reported top-line 24-week data from its ongoing phase IIb trial showing that ALD403 extended positive results demonstrated at 12 weeks. Reported in March, those 12-week data showed the drug met both the primary endpoint, defined as a 75 percent reduction in migraine days, and the secondary endpoint of mean reduction in migraine days from baseline. (See BioWorld Today, March 29, 2016.)

Teva, of Jerusalem, Thousand Oaks, Calif.-based Amgen Inc. and Indianapolis-based Eli Lilly and Co. also are advancing CGRP-targeting drugs into late-stage development. It has emerged as the hot new target in migraine – CGRP is believed to cause vasodilation and contribute to the inflammatory response; however, drugs targeting CGRP or its receptor are expected to serve the chronic migraine market. According to a June report on Burlington, Mass.-based Colucid by Lifesci Capital analysts, a key opinion leader (KOL) noted a continued need for acute treatments. The KOL stated "that most migraine sufferers will never receive a CGRP-targeted therapy, and even those that do will still need to treat migraine episodes with an acute therapy."

SEEKING NEW PARTNERS

Zosano said a total of 360 patients are expected to be recruited in Zotrip, a double-blind, randomized, placebo-controlled trial comparing three doses of M207 (1 mg, 1.9 mg and 3.8 mg) to placebo for the treatment of a single migraine attack. Based on discussions with the FDA – and as per guidelines released by the agency in 2014 – the co-primary endpoints will be pain freedom at two hours post-dosing and freedom from each subject's most bothersome symptom at two hours post-dosing.

Specific recruitment criteria include a history of at least one year of episodic, acute migraines, with or without aura, with a screening and run-in period designed to make sure patients fit eligibility, having two to eight migraine attacks per month, documented using an electronic diary. Patients then are randomized and have eight weeks to confirm and receive blinded treatment for a single migraine attack.

Secondary endpoints include pain relief at 15 minutes, 30 minutes and two hours, plus pain freedom at 24 hours and 48 hours. The trial also will look at relief of other symptoms at two hours, including photophobia, phonophobia and nausea. A total of 35 U.S. trial sites are planned.

Zosano has not disclosed commercialization plans for M207, for which it currently retains worldwide rights.

News of the trial hasn't had much effect on the company's stock. Shares of Zosano (NASDAQ:ZSAN), which dipped in early trading Monday, ended the day at $1.74, up 45 cents, or 35 percent, though still a far cry from early 2015, when the Fremont, Calif.-based firm priced its $50 million IPO, selling about 4.5 million shares at $11 each. But at that time, the company had two promising pharma deals it inked in 2014: an agreement with diabetes specialist Novo Nordisk A/G, of Bagsvaerd, Denmark, to develop a microneedle patch version of GLP-1 analogue semaglutide for type 2 diabetes, and a deal with Lilly to develop ZP-PTH, Zosano's microneedle patch for delivering synthetic parathyroid hormone teriparatide for treating severe osteoporosis. (See BioWorld Today, Jan. 28, 2015.)

By July 2015, the Novo Nordisk deal was kaput. That agreement would have brought preclinical, clinical, regulatory and sales milestones of up to $60 million for the first product and $55 million for each additional product, plus royalties. Its termination was attributed to "strategic prioritization" at Novo Nordisk.

That was followed in September by a decision to end the Lilly agreement, in which Zosano was eligible for milestones totaling up to $300 million related to approvals of daily ZP-PTH and up to $125 million on sales milestones for that program. About that same time, Zosano decided to shift gears on that program, moving away from development of daily ZP-PTH in favor of a weekly version.

The diabetes and osteoporosis programs are at the phase II-stage. Zosano is seeking new partners for both.