Investors and others in the field of Parkinson's disease (PD) are weighing the odds of two major players in treating "off" episodes: Sunovion Pharmaceuticals Inc. with apomorphine sublingual film (APL-130277), for which the FDA set Tuesday as the PDUFA date; and Acorda Therapeutics Inc., of Ardsley, N.Y., preparing to launch Inbrija (levodopa inhalation powder) this quarter. Off periods are times when PD symptoms return because of low dopamine levels between doses of oral carbidopa/levodopa.

Marlborough, Mass.-based Sunovion gained its PD compound in the $635 million buyout of Cynapsus Therapeutics Inc., and saw the purchase validated with the success of a pivotal phase III trial about a year ago. The drug showed a statistically significant mean reduction in off episodes as measured by a commonly used assessment of motor function in Parkinson's patients, meeting the trial's primary endpoint. The study also met its key secondary endpoint, showing that a statistically significant greater percentage of people treated with the drug had a patient-rated full "on" response vs. those in the placebo group. (See BioWorld, Jan 31, 2018.)

Apomorphine is the only molecule approved for on-demand, intermittent treatment of off episodes for advanced PD patients, but in the U.S. it is currently approved only as a subcutaneous injection, sold as Apokyn from US Worldmeds LLC. Sunovion's sublingual formulation is designed to offer a new option that can be used first thing in the morning, and up to five times throughout the day. In August 2016, the FDA granted it fast track status. Sunovion is a subsidiary of Sumitomo Dainippon Pharma Co. Ltd.

Acorda, of Ardsley, N.Y., came by its therapy via the 2014 $525 million cash buyout of Civitas Therapeutics Inc., just as the latter was about to price its IPO. The acquirer already has marketed products Ampyra (dalfampridine) to improve walking in patients with in multiple sclerosis, Zanaflex (tizanidine hydrochloride) to manage spasticity and Qutenza (capsaicin) to manage postherpetic nerve pain, plus a half-dozen candidates in a range of neurological and related conditions. With the purchase of Civitas, of Chelsea, Mass., Acorda took aboard the global rights to Inbrija, then known as CVT-301. (See BioWorld Today, Sept. 25, 2014.)

The approval of Inbrija in December laid to rest worries by company backers that the drug-device combo might become snagged at the FDA. The NDA had been accepted in February, but the agency later said it needed more time to sort through the updated package regarding chemistry, manufacturing and controls (CMC) after the company, answering a request from the FDA, submitted more CMC info. In late August 2017, regulators had delivered a refusal to file letter to Acorda on Inbrija that included questions about when the manufacturing site would be ready for inspection and about the drug's master production record.

That's all behind Acorda now, and details laid out in the scientific paper showed how Inbrija 84 mg significantly improved motor function at 30 minutes during off periods in people with PD, the study's primary endpoint. Onset of action was seen as early as 10 minutes and the reduction at 30 minutes proved to hold at 60 minutes. Multiple secondary endpoints were supportive of the primary endpoint, the company noted.

Opinion sharply divided

Data from the study, called Span-PD, were first presented at the 2017 International Congress of Parkinson's Disease and Movement Disorders, so it was the The Lancet's accompanying editorial that got more attention. The author lauded inhaled levodopa for its promise but also pointed out the four-point efficacy delta on the Unified Parkinson's Disease Rating Scale-3 measure turned up smaller than the phase II seven-point difference, and the study did not hit statistical significance in total time of the off state. The time to onset of action rang the bell at 30 minutes, but the difference was minimal at 20 minutes; the effect also was statistically significant at 10 minutes but modestly, while patients are eager to switch to an on state as soon as they can. The author mentioned often that a higher dose might have been more effective, and suggested that trials underestimated adverse events, pointing out also that the experiment didn't include patients with severe dyskinesia.

What does it mean? Jefferies analyst Michael Yee conceded that the editorial "marginalizes the overall profile" of Inbrija, which may imply that would-be buyers are less interested. Acorda paid a relatively small price for Civitas, and "a sale at 50 percent premium is only $1.2 billion, after years of running the whole phase III [program] and finally getting [the drug] approved." Yee said he believes Acorda may want to sell, "because it will be a long process to ramp and build, and selling this from a small biotech is not optimal use of capital for a $300-500 million product, whereas a large company would be far more levered to tuck it into an existing salesforce."

Acorda "has previously said it regularly explores all options to maximize shareholder value," he wrote in a Jan. 18 report.

H.C. Wainwright analyst Raghuram Selvaraju said trends favor an Acorda sale, citing "entities' recent voracious appetite for PD-focused firms," as shown by such deals as Sunovion's Cynapsus takeover and the 2017 move by Mitsubishi Tanabe Pharma Corp. to snatch Israel-based Neuroderm Ltd., the developer of a belt-worn pump for the continuous delivery of liquid levodopa/carbidopa to treat severe PD, for $1.1 billion in cash or $39 per share. The proposed acquisition of Celgene Corp. by Bristol-Myers Squibb Co. "also underscores, we think, the fact that acquirers are being opportunistic in the current market environment" and "the favorable label for Inbrija could prove critical in tipping the balance towards a purchase of Acorda," he wrote in a Jan. 14 report. (See BioWorld, July 25, 2017.)

Approval of Sunovion's therapy seems mostly expected, though what happens afterward in the PD off landscape remains a topic of debate. "Acorda bulls say the apomorphine class has had a turbulent history, whereas bears say APL-130277 should work 24/7 vs. Inbrija, which might have lesser efficacy in the mornings," wrote Jefferies' Yee, adding that the Sunovion therapy "is meant for acute use rather than chronic use, which would naturally confer a better safety profile."

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