A once-daily add-on therapy for Parkinson's disease (PD) used in Europe for years has now gained clearance in the U.S. with FDA approval of Ongentys (opicapone). The drug, an improvement upon generics in its class, will be sold by Neurocrine Biosciences Inc. The medicine, a catechol-O-methyltransferase (COMT) inhibitor first approved by the EMA in 2016, extends the half-life of levodopa, increasing doses of which are required to achieve motor control as PD progresses. Portugal-based Bial-Portela & Ca SA, from which Neurocrine licensed North American rights to the drug, will receive a $20 million award from its partner.

Shares of San Diego-based Neurocrine (NASDAQ:NBIX), a neuroscience company focused on treating movement disorders, rose about 3% by late morning following the approval.

U.S. pricing and availability of the Ongentys have yet to be set. Though not disclosing an exact figure, Neurocrine CEO Kevin Gorman told BioWorld that it will be less that the specialty pharma-type pricing he has seen with some other recent PD drugs, which have exceeded that group's typical $670-plus monthly cost.

"Not all high-priced drugs are important drugs, and not all important drugs need to be high-priced," Gorman said, adding that he wants Ongentys to be "as widely affordable as possible to the Parkinson's community."

The launch will be delayed until at least later this year, dependent on the course of the COVID-19 pandemic and Bial's ability to adequately supply commercial inventories.

Neurocrine's top commercial product is Ingrezza (valbenazine), a vesicular monoamine transporter (VMAT) 2 that, in April 2017, became the first FDA-approved therapy for tardive dyskinesia. Since then, it has faced competition from Teva Pharmaceutical Industries Ltd.’s Austedo (deutetrabenazine) and disappointment in a failed bid to expand its application to Tourette syndrome, an indication in which Austedo also failed. Despite those challenges, sales of Ingrezza reached $753 million in 2019 and are projected by analysts to break through the $1 billion mark this year. Neurocrine also receives royalties from its partnership with Abbvie Inc. on the endometriosis pain drug Orilissa (elagolix).

U.S. sales of Ongentys are likely to be smaller, though exact figures on historic sales are hard to come by, since Bial is privately held. But it fits well with Neurocrine's sales force, a team of about 300 representatives who already call on psychiatrists and neurologists to sell Ingrezza and are already working with doctors who treat PD.

Potential safety advantage

The standard-of-care treatment for PD is a combination of levodopa and carbidopa, but as the disease progresses, patients become less sensitive and responsive to levodopa, leading to increased periods of "off time," PD-speak for the return of tremor, rigidity and bradykinesia that are primary symptoms of PD.

COMT inhibitors, such as Tasmar (tolcapone, Bausch Health Companies Inc.), Comtan (entacapone, Novartis AG and Orion Corp.) and Ongentys, help restore that responsiveness, though to varying degrees and not without trade-offs. Tolcapone is a more potent inhibitor of COMT than entacapone, both in the periphery and central nervous system, according to an assessment of the class in the EMA's 2016 assessment report on Ongentys. But "due to an increased risk of hepatic toxicity with tolcapone, its use is limited to fluctuating patients who have failed other therapies or are intolerant to entacapone, which is currently the standard COMT inhibitor used in PD, according to the assessment.

Ongentys, which will be available in 25-mg and 50-mg doses in the U.S., has managed to present a strong safety profile and, in the pivotal BIPARK-1 and BIPARK-2 trials, reduced the amount of off-time and increased on-time for PD patients, Neurocrine's chief medical officer, Eiry Roberts, told BioWorld.

A 50-mg dose of Ongentys was found to be superior to placebo in reducing off time by 63.8 min./day and 54 min./day in the two phase III trials, without increasing on-time-with-dyskinesias. Also, in BIPARK-1, the same dose was found to be noninferior to Comtan, with a mean difference in change from baseline in time in off state of 26.2 min.

Pooled safety data from the BIPARK-1 and BIPARK-2 studies indicated that the most common adverse reactions across all patients treated with Ongentys (incidence at least 4% and greater than placebo) were dyskinesia, constipation, blood creatine kinase increase, hypotension/syncope and weight decrease.

Real-world experience with the drug gathered by Bial in Europe has been even better, Roberts said, producing evidence that it's possible to switch from other treatments to opicapone, which "is encouraging for patients, given that many need to try different treatments during the course of their disease’s progression," she said.

Eiry emphasized the value of once-daily dosing for patients, who with entacapone need to take the medicine every time they take levodopa, something that some patients do up to five times daily. "Even with that, there is a very rapid wearing off of the effect," she said, a situation that can leave them facing difficulties with movement in the middle of the night and early morning.

That the most commonly-used COMT inhibitors were first approved nearly 20 years ago means prescribers have been able to achieve substantial familiarity with them. But demand for novel agents and combinations has continued. That has led to the development of multiple new therapies, such as Orion and Novartis' Stalevo, a single-tablet combination of entacapone, levodopa and carbidopa, for the treatment of PD. Different L-dopa preparations, dopamine agonists and monoamine oxidase inhibitors such as selegiline and rasagiline are also on offer. New adjunctive agents for both motor and non-motor symptoms have also emerged, such as safinamide and Gocovri (amantadine, Adamas Pharmaceuticals Inc.), adding another layer of complexity to the treatment algorithm, according to Cortellis.

Parkinson's disease is the second most common neurodegenerative disorder in the U.S. after Alzheimer's disease.

In light of the COVID-19 pandemic, Ongentys will likely be launched in the second half of this year, Gorman said. Many of the neurologists, their nurses, and other staff that would normally be treating PD patients are helping out at hospitals with COVID-19 patients. "It's an important drug for their patients, but there really is an immediacy to what they're trying to deal with, with the pandemic."

At the end of 2019, Neurocrine had about 700 full-time employees. With a substantial balance sheet, anchored by nearly $1 billion in cash, Gorman said the company is in a good place. By year-end, if things go well, it will have three approved drugs in four different indications – a PDUFA date for Orilissa in uterine fibroids is set for midyear – three different drugs in pivotal phase III programs, and five other medications in phase II.