Adamas Pharmaceuticals Inc.’s chief medical officer (CMO) Rajiv Patni told BioWorld that a full development program “just like one would do for a new chemical entity [NCE]” gets credit for the strong label – touting efficacy even during patients’ “off” times – for Gocovri (amantadine extended-release capsules), cleared by the FDA last week for levodopa-induced dyskinesia (LID) associated with Parkinson’s disease (PD).

“We did dose-finding [research], two pivotal trials, an open-label safety extension, and a battery of clinical pharmacology,” Patni said. “That’s why this is a Gocovri label. It is not a Symmetrel label. The only part of the Symmetrel label we inherit is overdose and toxicology [language], and that frankly is the only portion of the 505(b)(2) [pathway] that is relevant for us,” he said. Gocovri is “95 percent new chemical entity and 5 percent 505(b)(2),” he said. The Symmetrel version of amantadine is marketed by Endo International plc, of Dublin.

The label on Gocovri (previously known as ADS-5102) could drive a sizeable price tag, though San Diego-based Adamas so far has said only that the drug will cost somewhere in the range of $10,000 to $30,000 per year. “I’m not going to narrow it until I get the finalization of the [market] research,” said Chief Operating Officer (COO) Richard King. He told BioWorld that the firm “continue[s] to refine our thinking based upon market research and, of course, the historical investment we’ve made, and the strength of the clinical data.” Cowen and Co. analyst Ken Cacciatore said he and his consultants see a “straightforward argument for comprehensive reimbursement.”

Shares of Emeryville, Calif.-based Adamas (NASDAQ:ADMS) closed at $19.93, up $5.70, or 40 percent Friday, the first full day of trading after news of Gocovri’s clearance by U.S. regulators. (See BioWorld Today, Aug. 25, 2017.)

“Off” times are periods when standard medication may not be working well. Piper Jaffray analyst David Amsellem said in a research report that it’s “hard for us to envision significant payer hurdles for a PD product with data in its label regarding both reductions in LID and ‘off’ times (something of a sweet spot that we believe will find a receptive audience among movement-disorder specialists).”

Language on safety looks good, too, Amsellem said. Verbiage “in the Gocovri label and the label of immediate-release [IR] amantadine, in our view, should not raise concerns that Gocovri will be perceived as having a more troublesome tolerability profile compared to its predecessor. Notably, the language in the warnings and precautions section for both products appears to be similar,” as it pertains to risk of central nervous system and psychiatric side effects such as agitation, paranoid reactions, and slurred speech.

No single drug is approved in the U.S. or Europe specifically to treat LID, and Gocovri is meant to address limitations of the current formulation by achieving top concentrations of the drug in the early morning through midday, when LID can be most problematic for patients, then dropping to lower levels in the evening, potentially reducing the negative impact of amantadine on sleep. The idea is to allow for higher doses of amantadine that can be tolerated with the IR formulation, as well as making the once-nightly dosing easier to comply with.

CMO Patni noted that Gocovri “can be used with any type of levodopa-based therapy. It doesn’t have to be Sinemet (carbidopa levodopa, Merck & Co. Inc.),” and goes nicely with other dopaminergic drugs. Adamas’ goals with Gocovri were to “deliberately temper, slow down, how quickly concentrations rise in the blood and delay the time to maximum concentration.” Both targets were achieved repeatedly. “We pushed the dose,” he said. “We have a 340-mg dose of amantadine hydrochloride, which is 274 mg of amantadine,” allowing the drug to be taken at bedtime. “The initial reaction is, ‘Extended release means you take a twice-a-day or three-times-a-day drug and you make it once a day. Thank you, goodbye.’ [But] that’s not what we did.”

Head-to-head data aren’t available comparing amantadine IR with Gocovri in the population for which the latter is approved. The FDA “did not want that study done,” COO King said, but “if you look at the use of amantadine IR in this population, it’s vanishingly rare,” because the efficacy is not sufficient for patients to stay on the drug. “They’re gone by about six months in,” he said. “The benefit just isn’t there.”

Team ‘really nailed it’

Cowen’s Cacciatore modeled a price of $15,000 per year for Gocovri, and analysts at his firm “believe that anywhere within the indicated range should be reasonable and secure broad coverage/access, especially given the severe unmet need that this product addresses.” San Diego-based Acadia Pharmaceuticals Inc.’s Nuplazid (pimavanserin), for hallucinations and delusions associated with PD, goes for about $22,000 per year. “For Gocovri in LID, we estimate roughly a 15 percent-plus penetration in the treatable moderate/severe LID patient population by 2025,” Cacciatore wrote, “which would result in roughly 35,000 treated LID patients and $400 million-plus in annual sales.”

Consultants with Cowen estimated that up to 25 percent of PD patients (at least 200,000) have moderate-to-severe LID, and there are no approved therapies for the condition. Clinicians either restrict levodopa dosing – which reduces the efficacy and patients’ quality of life – or they try using off-label alternatives. The only previously approved treatment option for LID was deep brain stimulation, “which requires brain surgery, and is clearly not a viable option for the vast majority of more moderate patients,” observed Cacciatore. Gocovri is the first approved drug to demonstrate clinically meaningful reductions in both LID and “off” time.

Mizuho Securities analyst Irina Koffler also hailed the label. “We were worried about a potential complete response letter or unfavorable label previously, but the outcome came in better than expected,” with no risk evaluation and management strategies attached, and with the “on” and “off” periods covered, “including patient diary data showing about three additional hours of improved function per day, which may be well-received by doctors and payers, in our view,” she wrote in a report. “There was also no post-marketing commitment.” Adamas plans to hire 59 sales reps and six regional sales directors, which will handle the January 2018 product introduction, and the company figures it can reach 95 percent of the prescribing market.

The company is in line to collect $65 million from Healthcare Royalty for Gocovri’s approval and for the orphan drug designation.

“We designed a very focused clinical program,” Patni said. “You can have the right drug, and you can have the right dose, but you can design the completely wrong trial or execute it poorly. The team [that] we have really nailed it on all those fronts,” and the unprecedented advantage of Gocovri is “not something that the Parkinson’s community views lightly,” he said.

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