by William Newton in Texas

Alkermes’ ALKS-3831 for schizophrenia and bipolar disorder has evoked mixed expert forecasts for how a Food and Drug Administration (FDA) Advisory Committee (AdCom) meeting on 9 October could interpret Phase III weight gain data.

The AdCom will likely question whether or not ALKS-3831, a formulation of samidorphan and generically available olanzapine, provided a clinically meaningful reduction in the common weight gain side effect versus olanzapine. Members could raise concerns over the lack of clinically significant differentiation in the lipid and glycemic parameters between ALKS-3831 and olanzapine, which was the comparator in the Phase III ENLIGHTEN-2 study (NCT02694328), as well as the high drop-out rate and the number of missing weight assessments in the same study. These objections could influence the AdCom’s recommendations and the subsequent FDA regulatory decision.

However, the primary weight change endpoints, which were met in the ENLIGHTEN-2 trial, were designed based on preliminary discussions between Alkermes and the FDA with the understanding ALKS-3831 would be approved if it achieved these endpoints without any added toxicity.

ALKS-3831 has a Prescription Drug User Fee Act (PDUFA) date of 15 November. The FDA is not obligated to follow the recommendation of an AdCom, although it commonly does.

Although Alkermes primarily studied patients with schizophrenia during clinical development, the company submitted pharmacokinetic bridging data comparing ALKS-3831 to olanzapine in patients with bipolar I disorder as part of its New Drug Application (NDA), according to a January company press release. Experts said they expect approval for the bipolar indication if the drug is approved for schizophrenia, citing olanzapine’s existing use in both indications. The upcoming AdCom will also consider the potential clinical risks of the interaction between samidorphan in ALKS-3831 and opioids, according to a 21 August company press release.

If ALKS-3831 is approved, many olanzapine prescribers would attempt to switch their patients to ALKS-3831 when possible. Payer barriers such as stringent prior authorisation and copayment requirements could dramatically reduce the actual market uptake. Analysts forecast peak sales of $364m in 2026. Alkermes has a market cap of $2.59bn.

An Alkermes spokesperson declined to comment, citing ongoing regulatory conversations and sent a link to a public press release.

Questions over ENLIGHTEN-2 weight, metabolic data

AdCom members will likely scrutinise the clinical meaningfulness of the weight gain benefit shown in ENLIGHTEN-2, experts said. The trial’s primary endpoint of weight gain of 10% or more of baseline body weight after six months was seen in 29.8% of patients on olanzapine compared to 17.8% on ALKS-3831, and patients on olanzapine had a 57% higher mean percent weight change than patients on ALKS-3831 after six months (Correll, et al. [2020] American Journal of Psychiatry, 177 (8), pp. 1–11).

For some AdCom members, the credibility of the weight gain benefit will likely be undermined by the lack of differentiation in baseline metabolic parameters between the two arms, said Dr William Carpenter, professor of psychiatry, University of Maryland, College Park. These included measures of cholesterol, triglycerides, glucose, insulin and haemoglobin A1c (HbA1c) levels. However, the six-month study could be too short to show differences in glycemic and lipid parameters, which means some AdCom members could view the weight gain improvement in ALKS-3831 as a likely precursor to longer-term metabolic improvements, Carpenter and the source added.

AdCom members will also likely be concerned about how the study chose not to measure blood pressure data, as high blood pressure is a highly common adverse effect of antipsychotic drugs, a biostatistician said. The trial also replaced 500 missing body weight datapoints with estimates, which may not have been made within the optimal standard error, he said. The 561-patient trial had a cumulative dropout rate of 36%.

Additionally, AdCom members will likely question whether mean percentage weight change is a useful primary endpoint given the large study size and variation in baseline body weight among patients, Carpenter and the biostatistician said. Patients in the olanzapine group had a mean baseline body weight of 77.6kg, while patients in the ALKS-3831 group had a mean body weight of 77.17kg with standard deviations of 13.47 and 13.69 respectively.

For the trial’s secondary endpoint, ENLIGHTEN-2 showed 42.7% patients on olanzapine compared to 27.5% on ALKS-3831 gained more than 7% of their baseline body weight, which Alkermes referred to as clinically significant weight gain in a June company presentation. This 7% change in baseline body weight is consistent with the parameter used in the most recent scientific literature on clinically meaningful weight gain, said Dr Matcheri Keshavan, professor of psychiatry, Harvard Medical School, Cambridge, Massachusetts. As a result, AdCom members would likely accept the statistically significant improvement demonstrated in this secondary endpoint, he said.

The source agreed, noting while Alkermes expected a greater weight gain improvement, the FDA will likely approve the treatment because ENLIGHTEN-2 demonstrated a statistically significant weight gain improvement without any added toxicity. Adverse events were reported in 82.2% of the olanzapine group and 74.1% of the ALKS-3831 group with the most commonly reported adverse event being weight increase. There were no deaths reported, and severe adverse events occurred in 2.5% of patients on olanzapine and 3.6% of those on ALKS-3831.

The other Phase III, ENLIGHTEN-1 (NCT02634346), which measured both olanzapine and ALKS-3831 against a placebo, established ALKS-3831’s similar efficacy profile to olanzapine and showed it is superior to placebo in the primary outcome of change from baseline in Positive and Negative Syndrome Scale (PANSS) total score at week four. Its addition of established noninferiority to an existing approved treatment is unlikely to be questioned by the AdCom or the FDA, experts said.

High uptake if no reimbursement roadblocks

If it is approved and there are no significant payer barriers to prescribing ALKS-3831 in outpatient settings, it will likely see strong market uptake due to the widespread popularity of olanzapine, experts and the source said. In addition to its schizophrenia and bipolar indications, it would likely see off-label use for a number of early signs of psychosis, for which olanzapine is commonly prescribed, Carpenter added.

However, payers are more likely to enforce prior authorisation protocols, requiring patients to have failed on olanzapine and to have known risk factors for obesity-related complications, before starting ALKS-3831, the payer consultant said. Insurers will likely place ALKS-3831 in the copayment tier of 20%–30%, he added. Because ENLIGHTEN-2 only demonstrated a weight gain benefit without significant changes to most metabolic parameters, most payers will likely view ALKS-3831 as providing only a lifestyle benefit, which payers typically do not fully reimburse, the consultant said. Analysts estimate the drug will have a list price of up to $1,200, while olanzapine can retail for under $10 with the use of coupons.

Still, pressure from prescribing physicians or any data, tying olanzapine-related weight gain to serious, long-term consequences could cause payers to remove financial barriers to prescribing ALKS-3831, the consultant said. Postmarketing study data could play an important role in this determination, he added.

William Newton is a Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.