Allergan needs a win with rapastinel, while Lundbeck’s chief exec faces her second clinical challenge.
Welcome to your weekly digest of approaching regulatory and clinical readouts. After a tough 2018 Allergan needs some good news, and it will soon find out if its depression project rapastinel will provide it. Three phase III trials of the project are due to yield topline data in the first half of this year.
Rapastinel targets the NMDA receptor, making it similar to Johnson & Johnson’s ketamine enantiomer esketamine. The J&J candidate is under US review with a PDUFA date of May 2019, though continuing US government shutdown could put approval in doubt.
Although the two projects are often mentioned in the same breath they act differently: rapastinel is a partial agonist of the NMDA receptor, while esketamine blocks it. This way, Allergan hopes, its project might not have the same psychomimetic effects as ketamine and, to a lesser extent, esketamine.
Dissociation – becoming less aware of one’s surroundings – has been seen with the J&J project. Allergan will want to show a safety edge with rapastinel, but stronger efficacy versus esketamine would not go amiss either. Still, Bernstein analysts only give rapastinel a 50% chance of success.
The three phase III trials of rapastinel test the project on top of standard antidepressants in patients with a partial response to the existing drugs. The primary endpoint of all three is change in Montgomery-Asberg depression rating scale (MADRS) at three weeks.
Esketamine itself had mixed results in its pivotal programme: the Transform-2 trial met its primary endpoint, but Transform-3 and Transform-1 did not. Across the three studies, which tested esketamine on top of an oral antidepressant, the reduction in MADRS score at four weeks was 3.2-4.1 points.
Allergan is also developing an oral NMDA modulator, AGN-241751, but this has only just entered phase II. The company, which faced calls for a break-up last year, needs a nearer-term boost, and with 2024 sales forecasts of $505m rapastinel is its biggest pipeline hope.
|Selected upcoming rapastinel phase III readouts|
|Name||Setting||Trial ID||Primary completion|
|RAP-MD-01||Adjunctive therapy||NCT02932943||Nov 2018|
|RAP-MD-02||Adjunctive therapy||NCT02943564||Nov 2018|
|RAP-MD-03||Adjunctive therapy||NCT02943577||Nov 2018|
|RAP-MD-06||Long-term safety study, adjunctive therapy||NCT03002077||Nov 2018|
|RAP-MD-04||Adjunctive therapy, relapse prevention||NCT02951988||Sep 2019|
|RAP-MD-99||Adjunctive or monotherapy||NCT03668600||Feb 2021|
|RAP-MD-33||Monotherapy, relapse prevention||NCT03614156||Jul 2021|
|Source: EvaluatePharma, Clinicaltrials.gov.|
The two upcoming phase III readouts for Lundbeck’s antipsychotic Rexulti in bipolar mania might not be game changing: there are already approved drugs for this indication, and existing off-label use of antipsychotics is being fuelled by increasing genericisation.
Still, the data will be interesting as they represent the second clinical stock catalyst for Lundbeck’s new chief executive, Deborah Dunsire. The first was the failure of Lu AF35700 in treatment-resistant schizophrenia, and drove shares down almost 30%.
Some analysts do not think that success in bipolar mania will add materially to Rexulti sales, but the downside risk of a second negative trial readout is substantially greater given the lack of other catalysts.
The two bipolar trials have enrolled 322 and 333 patients, the active cohorts given 2-4mg of Rexulti for 21 days, with a six-month follow-up. The primary endpoint is change in the Young-mania rating scale, and a key secondary endpoint is clinical global impression-bipolar (CGI BP) severity-of-illness score in mania.
Even if there is improvement in severity of illness, success in bipolar mania will at best be a nice-to-have addition to Rexulti’s current uses in schizophrenia and major depressive disorder, according to analysts at Leerink.
A more exciting event for Lundbeck will be whether Rexulti can have an impact on agitation in Alzheimer’s disease, where Bernstein analysts reckon success could add $1bn of sales. However, previous data have been mixed.
For now, if Rexulti does not deliver the goods in the more immediate bipolar indication, the market could seize it as an opportunity to punish the stock further.
|Selected upcoming Rexulti phase III readouts|
|Setting||Trial ID||Data due|
|Bipolar manic episodes||NCT03259555||Q1 2019|
|Bipolar manic episodes||NCT03257865||Q1 2019|
|Source: EvaluatePharma, Clinicaltrials.gov.|