Upcoming events – A double date with destiny for Alkermes

Alkermes’ two most advanced pipeline assets must prove their worth in the coming months: ALKS 5461 by persuading an FDA panel, and ALKS 3831 by succeeding in phase III.

Welcome to your weekly digest of approaching regulatory and clinical readouts. The FDA convening a joint meeting of two different advisory committees – those on psychopharmacologic drugs and drug safety and risk management – can mean only one thing: opioids.

The two-for-the-price-of-one meeting on November 1 will evaluate ALKS 5461, a potential adjunct therapy for major depressive disorder developed by Alkermes. This is a combination of buprenorphine and samidorphan, and with opioids viewed with a great deal of suspicion owing to their addictive qualities the panellists will scrutinise the data from numerous phase III trials for any suggestion of dependence or withdrawal.

They will also be looking for definitive signs of efficacy, and looking hard. The pivotal programme for ’5461 comprises the Forward-3, 4 and 5 studies, only one of which was positive (Alkermes might finally move Forward, October 21, 2016). Alkermes received a refusal-to-file letter in April, but somehow got the FDA to accept its filing a month later.

It is possible that Alkermes is not fully confident of approval. The company began a new phase III study, ALK5461-217, in June 2017 and yet another, 218, in August this year. Presumably these trials are too recent to have yielded data in time for inclusion in the FDA filing.

Analysts from Stifel give ’5461 a 30% chance of approval based on the current dataset, and quote a physician as saying that, even though abuse liability has not cropped up in trials so far, the breadth of concern surrounding the opioid epidemic could work against chances of approval.

Sales forecasts are modest, at $234m in 2024, according to EvaluatePharma consensus.

Phase III trials of ALKS 5461 in major depressive disorder

Status

Name

N

Completion date

Trial ID

Recruiting

ALK5461-217

450

Aug 2021

NCT03188185

Recruiting

ALK5461-218

250

Jul 2021

NCT03610048

Completed

Forward-1/ALK5461-210

66

Sep 2014

NCT02085135

Completed

Forward-2/ALK5461-208

1,486

Nov 2017

NCT02141399

Completed

Forward-4/ALK5461-205

385

Dec 2015

NCT02158533

Completed

Forward-3/ALK5461-206

447

Dec 2015

NCT02158546

Completed

Forward-5/ALK5461-207

407

Sep 2016

NCT02218008

Source: EvaluatePharma, clinicaltrials.gov.

Slim chance?

Alkermes might have a better pipeline hope in the schizophrenia candidate ALKS 3831, whose 2024 revenues are forecast at $419m by the sellside, as compiled by EvaluatePharma. This project, a combination of samidorphan and the generic antipsychotic olanzapine, trails ’5461, with a pivotal US study soon to report topline data. Following the uninspiring results from a previous trial Alkermes will need a slam-dunk.

Full data from the earlier trial, Enlighten-1, show that ALKS 3831 hit the primary efficacy endpoint with a significant improvement versus placebo on the positive and negative syndrome scale after four weeks' treatment. It showed similar efficacy to the active comparator, olanzapine monotherapy.

But the project was unable to avoid the one side-effect it was intended not to cause: weight gain. This is a problem with olanzapine, which was included in Enlighten-1 to provide a comparison. Indeed, more patients gained more weight with ’3831 than with olanzapine.

Enlighten-1 data

 

Placebo

ALKS 3831

Olanzapine

No of patients

112

124

120

Change from baseline in PANSS total score*

-17.5

-23.9

-22.8

     Change vs placebo

 

-6.4

-5.3

     P value

 

<0.001

0.004

No of patients whose weight increased (%)

4 (3.0)

25 (18.7)

19 (14.3)

Ave increase in weight (kg)

0.2

3.0

2.4

*Primary endpoint. Source: Alkermes investor presentation.

Enlighten-2, which ought to read out by the end of the year, does not assess ’3831’s efficacy, which Alkermes apparently regards as proven. Instead the six-month trial focuses solely on the combo’s effect on patients’ weight, compared with placebo and olanzapine alone.

Its co-primary endpoints are the percent change from baseline in body weight and the proportion of patients who gain at least 10% of their baseline weight. The project's prospects rely on it clearly surpassing olanzapine on these measures, since without a weight gain advantage there is no reason to switch to Alkermes’s therapy from a cheaper generic.

The Stifel analysts give Enlighten-2 a 50% probability of showing a small improvement in weight gain but a more compelling benefit on weight-gain outliers. Whether this will be enough for the FDA, let alone payers, is a question for another day.

Phase III trials of ALKS 3831 in schizophrenia

Status

Name

N

Completion date

Trial ID

Completed

Enlighten-1

 403 

May 2017

NCT02634346

Active, not recruiting

Enlighten-2

561

Nov 2018

NCT02694328

Source: EvaluatePharma, clinicaltrials.gov.

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