Intra-Cellular Therapies’ previous success with its schizophrenia candidate ITI-007 looks like it could have been a fluke after a second phase III trial failed to show any benefit. However, the company seems to be betting that the latest result is the aberration, saying it still plans to meet the FDA to discuss the regulatory path for the drug.
This is perhaps not surprising – the group has little else in its pipeline so needs to make a success of ITI-007. Intra-Cellular is no doubt hoping that the FDA will consider its full data package and the drug’s good safety profile, but it is hard not to be sceptical about its prospects, particularly when a closer look at the previous studies shows patchy results at different doses (see table below).
The company’s shares opened down 64% this morning.
Oh no placebo
Schizophrenia is a notoriously difficult indication for drug development and, like others before it, the 5-HT2A antagonist and dopamine modulator might have been scuppered by the placebo effect.
At least that is the reason Intra-Cellular is giving for the fact that neither dose of ITI-007 evaluated in Study ’302 – 20mg or 40mg – hit the primary endpoint, change from baseline on the positive and negative syndrome scale (PANSS).
But this does not explain why Johnson & Johnson's Risperdal, an older antipsychotic and the active competitor in the trial, did show a separation from placebo at six weeks.
|Change from baseline on the PANSS total score|
|ITI-007 20mg||ITI-007 40mg||ITI-007 60mg||ITI-007 120mg||Placebo||Risperdal|
|Study ’005 (Phase II)||-||-||-13.2*||-8.3**||-7.4||-13.4*|
|*Significant vs placebo; **Non-significant vs placebo|
Intra-Cellular played up the lack of side effects with ITI-007 – in the risperidone arm these included weight gain and changes in glucose, cholesterol, triglyceride and prolactin levels. These metabolic effects can lead to diabetes in patients taking antipsychotics.
The question is whether this, along with ITI-007’s previous positive phase II and phase III data, will be enough for approval.
Both Leerink and Suntrust Robinson Humphrey analysts think not, saying that Intra-Cellular will probably need to carry out another phase III trial to support an NDA in schizophrenia. This could start next year and report top-line data in 2018.
The company will be glad that it raised cash when it could, reeling in $345m in September 2015, not long after the win in the first phase III trial, Study ’301 (Intra-Cellular’s schizophrenia success could tempt a buyer, September 17, 2015).
Even that victory is looking less emphatic in light of the latest results, though: the 40mg dose tested in Study ’301 did not lead to a significant improvement in the PANSS score at day 28. And with the phase II Study ’005 failing at 120mg, ITI-007’s dose-response will need a close look.
This could help explain why the drug remained unpartnered while other projects were being snapped up (The stakes rise for unpartnered assets, August 11, 2016). In this case the bigger players were wise to stay on the sidelines.
The $443m that Intra-Cellular had in the bank at the end of June should be enough to complete the schizophrenia programme and ongoing phase III studies in bipolar depression. But there is now a big question mark over ITI-007. The issue might not be whether Intra-Cellular can afford to carry out a new phase III trial, but whether it can afford not to.
|ITI-007-301||Phase III in schizophrenia||NCT02282761|
|ITI-007-302||Phase III in schizophrenia||NCT02469155|
|ITI-007-401||Phase III monotherapy in bipolar depression||NCT02600494|
|ITI-007-402||Phase III in combination with lithium or valproate in bipolar depression||NCT02600507|