Failure of Merck & Co’s preladenant is a visible sign of how difficult innovation in Parkinson’s disease continues to be. The New Jersey group’s pill was the most advanced product in the adenosine A2A receptor antagonist class, and one that offered hope of additional motor control to the standard treatment of levodopa but has been quietly losing steam over the past couple of years (Therapeutic focus - A2A antagonists lining up to enter final stage Parkinson's trials, April 22, 2010).
On the positive side, Kyowa Hakko Kirin has obtained Japanese approval for Nouriast, a compound that was knocked back by the FDA and no longer has a US partner. However, once-promising clinical assets from Vernalis and Sigma-Tau have been shelved, while Biotie Therapies has retained UCB as a partner for tozadenant only by promising to conduct phase III trials itself (Biotie and UCB tie the knot with pivotal trial pre-nup, February 27, 2013).
Merck says an initial review of data from three different phase III trials showed that its pill had failed to demonstrate that it improved functional status or motor skills, and as a result the company will discontinue the extension phase of these studies. The group will not pursue a regulatory filing.
Other than the Japan-approved Nouriast, preladenant, also known as MK-3814, is the most advanced A2A antagonist. Analysts had forecast a launch in 2014 and risk-adjusted sales of $136m in 2018 – a small amount when compared to Merck's forecast group sales of $40bn in 2018. Trial success would no doubt have seen expectations rise.
It will come as a bigger disappointment to Parkinson’s patients, who are in need of a treatment that can be added to L-dopa and other dopamine-replacement therapies – an old but effective approach. Their limitations become clear only with time as the effectiveness wanes – manifesting itself in “off time” with poor motor control and dyskinesia – and side effects grow, and thus it has been hoped that newer agents could be added to specialists’ armoury.
The adenosine A2A receptor regulates the release of dopamine, and thus developers hoped that it would help to reverse motor symptoms. Phase II trials of preladenant, in the hands of Schering-Plough before the combination with Merck, had shown significant reduction in off time and increases in “on time” without increasing dyskinesias at 5mg and 10mg twice-daily dosages.
Without phase III confirmation, howerver, there is no hope of winning regulatory approval. In the realm of Parkinson’s disease medicine this makes preladenant the polar opposite of Acadia Pharmaceuticals’ Parkinson’s psychosis candidate pimavanserin tartrate (ACP-103), which looks likely to be submitted to the regulator a year early thanks to persuasive phase III data.
Will big pharma return?
With Merck’s failure, the pipeline of advanced candidates has shrunk to just two: Biotie’s tozadenant (SYN-115), which it picked up in its acquisition of Synosia Therapeutics, and Vernalis’s V81444 (see table). With a strengthened UCB collaboration, Biotie now intends to start pivotal trials by mid-year, while Vernalis intends to do the same in phase II, although a spokesman told EP Vantage that trial had not started yet.
|Adenosine A2A receptor antagonist pipeline|
|SYN-115 (tozadenant)||Biotie Therapies/UCB|
|Phase I||MK-8800||Merck & Co|
In phase I, Merck has filed a pharmacokinetic trial for MK-8800, another Schering-Plough acquisition, although this is not open for recruitment, according to Clinicaltrials.gov. Meanwhile, the private Spanish biotech Palobiopharma initiated a safety, tolerability and pharmacokinetic trial of PBF-509 in November.
V8144 is a back-up compound to Vernalis's Biogen Idec-partnered vidapenant (V2006), research on which was terminated in phase II after an analysis of preclinical toxicology data. Biogen handed back rights to the A2A programme in 2011.
So far, the once-promising adenosine A2A receptor target has turned out to be a dry hole, with the exception of a single product on the market in Japan that has been denied in the US. With Merck’s failure, it appears that big pharma is gone from all late-stage studies. Work still is under way, but it will be some time before the industry gets any more clues about the promise of the class.
|Trial IDs||MK-3814 (preladenant)|