Ionis safety blow boosts Alnylam

Two days ago Ionis Pharmaceuticals was in a sorry state: safety concerns with its orphan disease candidate IONS-TTRRx had scared off its partner GlaxoSmithKline and also raised questions about the rest of its pipeline.

Now, to add insult to injury, its rival Alnylam looks to be on top in the race to develop an amyloidosis therapy. The company is also in phase III with two compounds using different technology that could escape the safety worries that have hit IONS-TTRRx.

Ionis’s stock plunged 39% yesterday, while Alnylam was up 11%.

No to cardio

Glaxo had been planning to start a phase III trial of IONS-TTRRx in transthyretin (TTR) amyloid cardiomyopathy, a form of amyloidosis that involves accumulation of misfolded mutant TTR protein in the heart.

But the study, known as Cardio-TTR, was placed on hold by the FDA in April because of safety findings in the ongoing Neuro-TTR phase III trial in another form of amyloidosis, familial amyloid polyneuropathy, which affects nerve tissue.

Now Glaxo has decided not to start Cardio-TTR, at least until more data from Neuro-TTR are available. More information on the safety issue has also emerged, with Ionis reporting that cases of severe thrombocytopaenia have been seen in the Neuro-TTR study and – maybe more worryingly – in a phase III trial of another of Ionis’s projects, volanesorsen, in familial chylomicronemia syndrome.

Ionis did not say how many cases there had been or give more details on the clinical consequences, including whether any patients had died from thrombocytopaenia, which involves a decrease of platelets in the blood and can cause haemorrhage.

Class effect?

The fact that thrombocytopaenia also occurred with volanesorsen raises the question of whether this is a class effect. Ionis’s pipeline is based on antisense oligonucleotides designed to reduce the production of certain proteins – TTR in the case of IONS-TTRRx.

During a conference call to discuss the results, Ionis's chief executive, Stanley Crooke, said he was confident that this was not the case, but a class effect would be a disaster for Ionis. It could also be a boon for Alnylam, whose patisiran and revusiran work in a different way, using RNA interference technology to block TTR production.

If the problem is only linked with antisense and not RNAi therapies Alnylam will be sitting pretty in a disease that, while rare, should be lucrative. Revusiran is forecast to bring in $832m and patisiran $709m by 2022, according to EvaluatePharma sellside consensus.

However, at least one commentator is convinced that, while bad news for IONS-TTRRx and volanesorsen, the thrombocytopaenia scare might not affect the rest of Ionis’s pipeline, including its top prospect, nusinersen, in phase III for spinal muscular atrophy. This agent is administered intrathecally, so levels in the blood are insignificant.

It is also possible that the side effect will not mean the end for IONS-TTRRx and volanesorsen, but would just introduce the need for tight platelet monitoring. However, this would hit convenience and make Alnylam’s candidates more attractive.

Results from the Neuro-TTR trial, in which patients are now being more frequently monitored, are due in the first half of next year. Glaxo plans to assess these before deciding on its next steps. At best it would resume development and IONS-TTRRx would be delayed slightly – but if Glaxo pulls out of the partnership Ionis could be left on the hook for the phase III trial.

And, if more reports of thrombocytopaenia emerge, the company might want to ditch the Cardio-TTR trial and IONS-TTRRx altogether to focus on more promising assets like nusinersen.

Last year Ionis changed its name from Isis to avoid associations with the Islamist extremist group. If it hoped that this would be the end of its troubles it seems it was wrong.

To contact the writer of this story email Madeleine Armstrong in London at [email protected] or follow  @medtech_ma on Twitter