FDA warning letter to IONIS-TTRrx trial site hits Ionis stock

FDA
The warning letter relates to platelet monitoring in patients taking Ionis' IONIS-TTRrx.

The FDA has sent a warning letter to a trial site studying Ionis Pharmaceuticals’ IONIS-TTRrx. The letter relates to an investigator-sponsored trial, not Ionis’ phase 3 study, but the regulator’s criticism of the site’s compliance with platelet-monitoring requirements has raised broader worries about the real-world viability of the antisense drug.

In the warning letter, FDA inspectors outline the faults they found with an independent trial Merrill Benson, M.D., is running at Indiana University to assess the effect of IONIS-TTRRx in patients with familial amyloid cardiomyopathy. During visits to the site late last year, FDA inspectors found fault with Benson’s monitoring of platelet counts. In a breach of the protocol, two patients' platelets weren't checked for about three weeks.

The lapse is noteworthy because of the importance of platelet monitoring to the prospects of the drug and other antisense therapies. Studies of IONIS-TTRRx and volanesorsen, another antisense drug in development at Ionis’ subsidiary Akcea Therapeutics, have seen low platelet levels, raising concerns of a classwide side effect.

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Ionis implemented new platelet-monitoring procedures last year to mitigate the risk. The lapse in monitoring at Benson’s site identified by the FDA is from around the time Ionis learnt of the link between volanesorsen and low platelet levels and adopted the new monitoring program. Ionis is presenting the warning letter as a result of this transition period and Benson’s subsequent failure to send FDA an adequate response to the issues they raised. Others took a bleaker view.

Publication of the warning letter wiped 6% off Ionis’ share price and prompted Piper Jaffray analyst Joshua Schimmer to cut his target for the stock from $66 to $51. Schimmer’s concern, which was echoed by more sanguine analysts at Leerink, relates to what Benson’s inability to comply with the protocol means for IONIS-TTRrx commercially. As Schimmer put it: “If a study center can't adhere to strict monitoring of platelets, then how can this be expected in the real-world setting?”

Benson’s site is closely involved with the development of IONIS-TTRrx and, as such, is likely to be better placed than a real-world healthcare setting to understand and comply with the protocol. Ionis is using Benson’s site in its phase 3 trial of IONIS-TTRrx. And it has cited Benson’s trial when discussing the prospects of the drug in patients with TTR-related amyloid cardiomyopathy.

If weekly monitoring is impractical for healthcare sites, it could dampen the prospects of multiple antisense drugs. However, there is a counterargument that such extrapolation of the impact of the warning letter is a stretch. Benson’s site failed to comply with a recently adopted process. But the fact that inspectors visiting in October and November only found fault with practices in May and June suggests compliance improved. And Ionis said the site passed its own audits as part of the phase 3 trial.

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