Allergan's rapastinel fails to meet primary endpoints in Phase III depression studies

Allergan on Wednesday announced topline results from the Phase III RAP-MD-01, RAP-MD-02 and RAP-MD-03 studies of the major depressive disorder (MDD) drug candidate rapastinel, saying treatment arms did not differentiate from placebo on the primary and key secondary endpoints. Moreover, the company reported that an interim analysis of rapastinel in the RAP-MD-04 relapse prevention study suggests the primary and key secondary endpoints will not be met either.

Chief R&D officer David Nicholson stated that the company was "deeply disappointed" in the results. He said Allergan "will evaluate the impact of these data on the ongoing monotherapy MDD programme and suicidality in MDD study," and that it expects to make a decision on these programmes during the course of 2019. 

In the RAP-MD-01 and RAP-MD-03 studies, which enrolled 457 and 415 participants, respectively, patients with MDD, who had achieved no more than a partial response to ongoing antidepressant therapy given at a stable and adequate dose, were randomised to receive rapastinel or placebo. The medication was administered as a once weekly bolus intravenous injection, while patients were required to remain on their oral antidepressant therapy throughout the study. Meanwhile, the RAP-MD-02 trial, which involved 638 patients, had a similar design except that a lower rapastinel dose was also evaluated. 

Allergan noted that rapastinel was "well tolerated without any signal of psychotomimetic side effects" in all three studies, having a safety profile similar to that of placebo. The company indicated that detailed results of the trials, including RAP-MD-04 in relapse prevention, will be presented at a future research conference. 

According to the drugmaker, rapastinel has "recently been characterised as a modest and selective positive NMDA receptor modulator with a unique pharmacological mechanism of action fundamentally different from ketamine." The therapy, also known as GLYX-13, which Allergan obtained via its acquisition of Naurex in 2015, was previously granted breakthrough therapy and fast track designations by the FDA for the adjunctive treatment of MDD. 

Meanwhile, on March 5, Johnson & Johnson received FDA approval for Spravato (esketamine), the s-enantiomer of ketamine, which works on the NMDA receptor, for use in adults with treatment-resistant depression. For related analysis, see Physician Views Results: Psychiatrists outlook on esketamine mixed, though off-label ketamine use provides an interesting case study with potentially positive implications.

For further analysis, read ViewPoints: Allergan tests the limits of investor patience with depression failure.

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