Alkermes data don’t Enlighten
The first phase III data with Alkermes’ antipsychotic ALKS 3831 do not hold much weight. The project has shown comparable efficacy with olanzapine in the Enlighten-1 trial – but for ALKS 3831 to be a commercial success it needs to avoid the weight gain associated with the older drug, and the jury is still out on this.
On a conference call to discuss the data, Alkermes executives admitted that the weight gain seen in Enlighten-1 was similar between ALKS 3831 and olanzapine, but claimed that the four-week study was too short to test this properly. Results from the six-month Enlighten-2 trial, due next year, are now even more important, but some might ask why the company did not just carry out one longer trial.
Alkermes is taking the risk of throwing good money after bad, starting two new studies this year aimed at exploring the metabolic effects of ALKS 3831. Enlighten-Early will measure weight gain versus olanzapine in young adults who are early in their illness; younger patients are more susceptible to antipsychotic weight gain, according to Alkermes’s vice-president of R&D, Elliot Ehrich.
Meanwhile, the company is also carrying out a phase I trial looking at metabolic measures including changes in blood glucose and insulin over 21 days, with results due later this year.
In Enlighten-2 and Enlighten-Early, Alkermes will want to replicate the findings of a phase II study that showed a 37% lower mean weight gain with ALKS 3831 versus olanzapine at 12 weeks.
The topline Enlighten-1 results have thrown this previous finding into doubt. ALKS 3831’s efficacy was “unambiguous”, according to Mr Ehrich – the trial met its primary endpoint, showing a statistically significant reduction from baseline in the positive and negative syndrome scale scores versus placebo, with a p value of 0.001. It also hit on its secondary endpoint, the clinical global impression – severity scale, versus placebo.
But ALKS 3831 was still linked with weight gain, although details were thin on the ground. The company would only say that this was one of the most common adverse events in Enlighten-1, and that rates of weight gain were similar between ALKS 3831 and olanzapine, which was included in the study as a positive control.
A comparable result in Enlighten-2 would destroy the case for moving patients from generic olanzapine to ALKS 3831, and therefore any chance of Alkermes finding a market. ALKS 3831 is forecast to bring in sales of $380m by 2022, according to EvaluatePharma sellside consensus.
Enlighten-2 pits ALKS 3831 against olanzapine with a primary endpoint of change in body weight, and is due to complete in February 2018.
Olanzapine is regarded as one of the most efficacious oral antipsychotics, according to Mr Ehrich, but its use has been limited by dramatic weight gain in many patients. Guidelines no longer recommend the product because of this side effect, but it remains the third most-prescribed anti-psychotic, he added.
It therefore should be enough for ALKS 3831 to show similar efficacy to olanzapine – as long as it also demonstrates a better weight-gain profile.
Alkermes’s project contains olanzapine and samidorphan, a mu opioid antagonist that the company believes should reduce the weight and metabolic consequences of the antipsychotic. Opioid antagonists have been shown to limit the reward pathway effects of eating and drinking alcohol so could help control overeating.
Enlighten-1 has not done much to support Alkermes’ theory, but the company would argue that it was not designed to. Still, investors face a nervous wait for Enlighten-2 to shed any more light on the matter.
|Study||Details||Trial ID||Data due|
|Enlighten-1||Four-week phase III trial, efficacy vs placebo, olanzapine||NCT02634346||Topline reported|
|Enlighten-2||Six-month phase III trial, weight gain vs olanzapine||NCT02694328||Feb 2018|
|Enlighten-Early||12-week phase III trial in young adults, weight gain vs olanzapine||NCT03187769||Jan 2019|
|ALK3831-A108||21-day phase I metabolic trial||NCT02922426||Aug 2017|