Sunovion Pharmaceuticals Inc.'s $624 million cash buyout of Cynapsus Therapeutics Inc. puts premium firepower behind the race for a drug to treat off episodes in Parkinson's disease (PD) and brings aboard an on-demand, sublingual candidate "well matched to patients' symptoms," Antony Loebel, Sunovion's chief medical officer, told BioWorld Today.

"Sometimes, these episodes are predictable, and the medication can be used in those cases to prevent the onset or the worsening," he said, while in other instances, off periods "are erratic or unpredictable, and in those cases, it's also particularly important to have an on-demand option that can be easily utilized and have rapid effect."

Sunovion is paying $40.50 per share to take over Cynapsus in a deal cleared by the boards of both companies. Shares of Cynapsus (NASDAQ:CYNA) closed Thursday at $39.70, up $21.34 or 116.2 percent.

The arrangement provides Sunovion, of Marlborough, Mass., with APL-130277, an FDA fast-tracked form of apomorphine for which Cynapsus planned an NDA filing in the first half of next year. Although an injectable form of the drug is available as Apokyn from US Worldmeds LLC, an under-the-tongue form should provide an important advantage in PD. Off episodes are described as periods when oral levodopa has not taken effect or has worn-off, and PD symptoms have worsened.

"We sometimes compare [APL-130277] to the Listerine strip – it looks similar to that," Loebel said, adding that the drug works in "five to 10 minutes" after applying. At present, "virtually all" PD patients take Sinemet (carbidopa/levodopa, Merck & Co. Inc.), he said, though the standard treatment is "not fully effective, and for many patients it becomes less effective over time. Patients either experience a loss of effectiveness of levodopa," in which case their symptoms recur and worsen, or "sometimes, there is even excessive amounts of dopamine in the brain, which results in dyskinesia, hallucinations and some other problems," he said. Sunovion plans to "follow the schedule and program" outlined by Cynapsus for the compound, and upon closing the deal intends to wrap up the research "as expeditiously as possible. Sunovion is very well placed to manage the development," he added, given the firm's "heritage of successful commercialization of products in the area of neurology as well as psychiatry. We think this product will fit very well into our portfolio."

Zacks analyst Anita Dushyanth said in a report that, "while [injected] apomorphine has been the Holy Grail in treating advanced PD patients, the high cost of the drug, the necessity of co-therapies for prevention of side effects and the subcutaneous administration has restricted its use. Besides attracting new patients to the sublingual formation, APL-130277 could widen the use per patient as it is definitely user friendly and less painful" than shots, she noted.

CYNAPSUS VOTING AHEAD

About 1 million of the U.S. adult population and an estimated 6 million people worldwide suffer from PD, and Toronto-based Cynapsus' survey conducted in 2012 explored the market potential for its drug. Some 40 percent of PD patients experience at least one off episode or two hours of such periods cumulatively per day, which equates to a target patient population of around 400,000. According to the poll of neurologists and movement disorder specialists, eligible patients can be categorized into three segments: about 20 percent are considered mild (one off episode per day), about 55 percent fall into the moderate slot (two episodes per day), and about 25 percent could be called advanced (three or more). Cynapsus is taking aim at the whole range.

"Since every PD patient's range of symptoms is unique, they require different treatment regimens," analyst Dushyanth said, so patients with mild symptoms may administer one sublingual strip per day, while a patient experiencing severe symptoms may require three to five strips. PD worsens with time; increased doses need to be taken as symptoms become more troublesome. "High insurance premiums are imposed on patients taking expensive drugs," of course, but "in order to address this broad spectrum of patient audience and bring financial relief to them, Cynapsus is planning to price APL-130277 attractively to make it accessible and affordable" by comparison to the injectable, she said.

Cynapsus has asked doctors and insurance payers for their opinions, discovering "a potential favorable pricing environment and high acceptance [about 90 percent] for reimbursement," Dushyanth said. "Roughly 75 percent of the responders were willing to reimburse at an average wholesale price equal to the apomorphine injection, if clinical trials demonstrated substantial benefit over the injectable apomorphine." The non-narcotic morphine derivative "acts as a potent dopaminergic agonist," she said. "Since hepatic metabolism prevents its effectiveness when dosed orally, subcutaneous injection has been set as the gold standard for maximum effectiveness," deployed either intermittently or continuously to help in managing sudden and/or unexpected off episodes. But injections can be difficult for some patients experiencing severe tremor or dyskinesia during off periods.

This is where APL-130277 comes in. Cynapsus near the end of 2011 finished its all-stock acquisition of Hamilton, Ontario-based Adagio Pharmaceuticals Ltd., which terminated a 2010 license option agreement between the two companies for APL-130277 and put the drug in the hands of Cynapsus, along with Adagio's related intellectual property for the drug. Under the terms, Adagio shareholders stood to receive shares of Cynapsus based on APL-130277 development milestones. Sunovion's buyout of Cynapsus means a payment of C$2.5 million (US$1.9 million) to former Adagio shareholders.

The takeover is expected to close in the fourth quarter of 2016, which is the third quarter of Sunovion's fiscal year, through a plan of arrangement under the Canada Business Corporations Act that calls for approval by at least two-thirds of the votes cast by Cynapsus shareholders and warrant-holders, who will be voting together as a single class at a special meeting. Agreements in support of the deal have been signed by all directors and officers of Cynapsus and the company's largest shareholder, representing about 18.3 percent of the Cynapsus securities that are entitled to vote. Full details will be disclosed in about two weeks, the companies said.

NEURODERM ON THE MARCH IN EU

Another player in the space is Acorda Therapeutics Inc., of New York, which has an inhaled form of levodopa, CVT-301, which is expected to finish its phase III trial in off PD episodes by the end of this year, with an NDA filing expected in the first quarter of 2017. Acorda gained the compound in its $525 million buyout of Chelsea, Mass.-based Civitas Therapeutics Inc. in October 2014 and enrolled the first patient in the pivotal phase III trial the following December. (See BioWorld Today, Sept. 25, 2014, and Dec. 11, 2014.)

Designed as a self-administered rescue treatment, CVT-301 showed efficacy in a phase IIb trial as an on-demand, adjunctive treatment to boost levodopa levels as needed. It is formulated by way of Arcus technology, which consists of a reusable, pocket-sized, breath-activated inhaler, and has shown a statistically significant reduction vs. placebo according to the Unified Parkinson's Disease Rating Scale Part III motor score (p < 0.001), without dyskinesia during "on" periods. The CVT-301 inhaler also was shown to be easily self-administered by patients during the off state.

Piper Jaffray analyst David Amsellem was cautious about the Acorda drug's chances, given that "regulatory hurdles for inhalation products for non-pulmonary conditions are high. Management was fairly sanguine regarding the safety profile of CVT-301," he wrote in a September research report, and he conceded that, "at first glance, safety appears to check out fine: the rate of adverse events (AEs) was similar across the active drug and placebo arms in the phase IIb study, and there were no serious AEs. In our view, pulmonary AEs and lung function will be the paramount considerations" for regulators, he wrote. "Though there were no changes in lung function in patients on active drug, there were four cases of cough (vs. one case in the placebo arm). In a general sense, we would take a cautious approach. In our view, the FDA looks at these products something like this: 'You are putting something in the lungs that does not need to be there, so it had better be squeaky clean from a pulmonary safety perspective.'"

Also posting news recently in PD was Rehovot, Israel-based Neuroderm Ltd., which last week started enrolling PD patients in a phase III trial called iNDiGO with its drug-device combo ND0612L, a low-dose, continuous, subcutaneously delivered levodopa/carbidopa liquid formulation. The study is a 16-week, international, multicenter, randomized, double-blind, placebo-controlled, parallel group experiment designed to compare the efficacy, safety and tolerability of continuous subcutaneous infusion of adjunct ND0612L therapy with oral standard-of-care and placebo in patients who suffer from motor fluctuations despite optimized standard-of-care therapy. Patients will be randomized to receive either continuous subcutaneous infusion of ND0612L or a placebo, replaced every 24 hours during the 16-week treatment period. The primary endpoint is the change from baseline to week 16 in the mean percentage of off time, based on patients' home diary assessments. While the original trial design anticipated enrolling 200-240 patients, the company has dropped the number to 150 following sample-size calculations using expected treatment effect and variability, as well as those observed in a previous trial. Last May, the FDA lifted a clinical hold that was blocking progress with two PD therapies, ND0612H and ND0612L. Holding up the trials was an agency request to review data related to the candidates' subcutaneous delivery devices: belt-mounted pumps, the Crono Twin ND and Crono ND. (See BioWorld Today, May 11, 2015.)

In June, the other candidate, ND0612H, achieved comparable pharmacokinetics (PK) to Duodopa (carbidopa/levodopa enteral suspension, Abbvie Inc.) in a head-to-head European pilot comparison trial. "Neuroderm now plans to initiate a definitive PK study by year end which, together with safety data could enable an EU filing for PD," wrote Jefferies analyst Peter Welford in a report, calling the route "a lower risk and perhaps expedited path to the EU market, with U.S. FDA requiring phase III efficacy trials." He reiterated his "buy" rating "still assuming a conservative 40 percent worldwide probability of success." Duodopa, available in the EU since 2014, is infused directly into the small intestine. It was approved in the U.S. as Duopa in January 2015.

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