Successes in Parkinson’s dyskinesia are so rare that their occurrence is greeted with celebration even if – as happened with Adamas Pharmaceuticals yesterday – the feat is achieved with a reformulation of an old drug for the condition.
That drug is amantadine, approved decades ago despite offering a limited benefit as well as unwanted side effects. Adamas’s extended-release formulation is based on the premise that once-daily dosing can get around many of these problems, and yesterday’s phase III success puts the group ahead of a rival approach in development by a private company, Osmotica.
The positive phase III data with Adamas’s formulation, ADS-5102, were greeted with an 83% share price uplift in the company’s stock, which since July had fallen precipitously along with many other biotechs. The faith of IPO investors has been rewarded, with the shares now standing 137% above their float price in April 2014.
In Parkinson’s patients dyskinesia – characterised by uncontrollable, jerky movements – is caused by long-term use of levodopa, which despite having this side effect remains the mainstay treatment.
Adamas has been rewarded for its smart design of ADS-5102’s phase III study, Ease Lid, as well as for pinpointing amantadine’s drawbacks: Adamas claims that CNS side effects are caused not by amantadine’s absolute levels in the blood but by the speed at which these are reached. In contrast ADS-5102 is absorbed more slowly, with maximum concentration achieved many hours after dosing.
All endpoints hit
Ease Lid had set improvement in UDysRS score at 12 weeks as its primary endpoint, and once-daily ADS-5102 at 340mg hit this, with a 23% reduction versus placebo being highly statistically significant (p=0.0009).
This was not without adverse events: those of a severe grade were seen in four placebo and 17 active drug recipients, while serious grade events occurred in three placebo and seven active recipients. Four placebo and 13 ADS-5102 patients discontinued owing to adverse events.
All four secondary endpoints were also hit. In 2013 Adamas reported positive results from the phase II/III Eased trial in which 340mg and 420mg doses of ADS-5102 significantly improved UDysRS over eight weeks versus placebo (Therapeutic focus – Treating dyskinesia proves as elusive as Parkinson’s itself, October 25, 2013).
So far ADS-2102 has been neck and neck with Osmotica’s Osmolex ER (OS-320), a once-daily amantadine formulation that has US orphan drug status. This is in two phase III studies, one of which, testing 240mg and 320mg amantadine doses and also looking at UDysRS score as primary endpoint, is to be completed this month.
If the Ease Lid data have allowed Adamas to jump ahead then it is possible that Osmotica’s recent merger with Vertical/Trigen Holdings, a private equity-owned generics company, could further slow progress of Osmolex ER. Meanwhile, many other Parkinson’s dyskinesia projects have either stalled or failed in development and been quietly dropped.
Adamas says it will discuss the Ease Lid data with the US FDA with a view to making a regulatory filing. The group has some choices to make, but surely its $103m of third-quarter cash will not allow it to bring ADS-5102 to market alone.
Knowing big pharma’s aversion to licensing in assets that are mere reformulations, an equity raise looks like the likeliest outcome for Adamas.
|ADS-5102||Adamas||Ease Lid||121 pts; all endpoints hit||NCT02136914|
|ADS-5102||Adamas||Ease Lid III||72 pts; ends Jan 2016||NCT02274766|
|ADS-5102||Adamas||–||Open-label safety trial||NCT02202551|
|Osmolex ER||Osmotica||Allay-Lid II||162 pts; ends Dec 2015||NCT02153632|
|Osmolex ER||Osmotica||Allay-Lid I||162 pts; ends Sep 2016||NCT02153645|