The FORWARD-5 study was the third and final Phase III efficacy study initiated by Alkermes to investigate ALKS-5461 in Major Depressive Disorder (MDD) patients. However, in January 2016 the company had reported this drug failed to meet the primary endpoints of its first two Phase III studies, the FORWARD-3 and FORWARD-4 trials, reporting no significant benefits of ALKS-5461 treatment compared with placebo.

In October 2013, this potential first-in-class drug was granted Fast Track designation (FTD) by the FDA for the adjunctive treatment of MDD in patients with an inadequate response to standard antidepressant therapies. This status will both facilitate and expedite the FDA developmental and regulatory review process for ALKS-5461, given it aims to fill an unmet medical need. As such, Alkermes will now look to hold a meeting with the FDA to discuss the next steps in the regulatory process for ALKS-5461. GlobalData anticipates ALKS-5461 entering the US market in early 2018.

Major depressive disorder

MDD is one of the most common psychiatric diseases worldwide, with patients typically experiencing long terms of depressed mood, loss of interest and enjoyment, fatigue and reduced energy levels, changes in cognitive function, anxiety, and suicidal ideation. The current treatment options tend to rely on selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs); however, these antidepressants are not ideal, as approximately one third of patients do not demonstrate any remission of symptoms. Patients who do not respond to two or more antidepressant therapies are referred to as “treatment-resistant,” and ALKS-5461 is aimed towards providing a therapy for these patients.

ALKS-5461 is a fixed-dose combination product composed of samidorphan, a proprietary opioid modulator that acts as a strong selective antagonist of the µ-opioid receptor, with buprenorphine, a κ-opioid receptor antagonist and a partial µ-opioid receptor agonist. Buprenorphine has been shown to have rapid and significant antidepressant effects in MDD patients, even in those refractory to therapy; however, its use has been limited to date due to the risk of abuse and addiction. The combination with samidorphan is intended to yield a novel, potentially non-addictive, opioid modulator. Indeed, in December 2015, Alkermes announced positive topline results from a supportive human abuse potential study with ALKS-5461, and observed a statistically significant and meaningful reduction in abuse potential with ALKS-5461 treatment, compared to buprenorphine alone.

FORWARD clinical program

Alkermes’ FORWARD clinical program evaluated ALKS-5461 in three core Phase III efficacy studies, as well as in additional supportive studies to evaluate the long-term safety, dosing, pharmacokinetic profile, and human abuse potential. Based on information gained from the failed FORWARD-3 and FORWARD-4 Phase III efficacy studies, patient enrollment in FORWARD-5 was increased and the statistical analysis plan was updated. Despite these amendments delaying the study’s overall completion, Alkermes’ decision seems to have been justified, given the positive efficacy ultimately demonstrated. Alkermes has stated that it will look to utilize the results from the FORWARD-5 study and a previously completed Phase II clinical trial, as well as supportive data from FORWARD-4, to provide efficacy data for ALKS-5461 to the FDA.

Key opinion leaders (KOLs) interviewed as part of GlobalData’s MDD PharmaPoint report were initially optimistic about the potential of ALKS-5461 prior to the disappointing efficacy shown in the FORWARD-3 and FORWARD-4 studies. While ALKS-5461 does have a novel mechanism of action that is expected to provide benefit to MDD patients, KOLs explained that patient uptake may be negatively impacted as a result of its previous Phase III outcomes. Furthermore, ALKS-5461 is likely to find itself under greater competition compared with other emerging pipeline therapies that have demonstrated more robust efficacy in treatment-resistant MDD patients, such as Janssen’s esketamine, or Allergan’s rapastinel. KOLs also remained concerned about the risk of dependency due to its action through the opioid system; however, these concerns may already be mitigated through the demonstrated supportive clinical data showing that there was no difference in abuse potential between ALKS-5461 and placebo.

Related report

PharmaPoint: Major Depressive Disorder – Global Drug Forecast and Market Assessment to 2025
Major depressive disorder (MDD) is one of the most common psychiatric diseases worldwide. It is characterized by single or recurrent major depressive episodes (MDEs), where patients can typically experience periods of depressed mood, loss of energy, abnormal cognition, anxiety and suicidal ideation. Similar to other neuropsychiatric disorders, MDD has a multifaceted and varied etiology, and remains poorly understood.