Two phase III analyses, two early terminations on positive efficacy. This is the record so far for Ionis Pharmaceuticals and its spinal muscular atrophy (SMA) project nusinersen, which showed as persuasive a benefit in the childhood onset form of the disorder as it did in infants.
The findings from the Cherish trial, announced today, put Ionis and its commercial partner Biogen in a good position to achieve a broad label on approval, should it come on schedule by May 2017. As the SMA space becomes increasingly competitive, nusinersen has a chance to establish itself as the treatment backbone for any candidates that follow.
Two for two
Cherish tested nusinersen, now dubbed Spinraza, in patients with later-onset SMA characteristic of the type 2 form of the disease. These children are born without the SMN1 gene, which encodes a protein that helps motor neurons to survive – nusinersen is an antisense oligonucleotide designed to alter the splicing of SMN2, a gene that is nearly identical, to increase its protein production.
In type 2 the symptoms appear after six months, and the life expectancy is greater than for those with the more severe type 1 disease. In type 1 nusinersen had already scored clinical success when the Endear trial read out (Ionis Endears itself to investors – and to Biogen, August 1, 2016).
Biogen and Ionis said Cherish in type 2 showed that nusinersen improved patients' Hammersmith functional motor scores by 4 points at 15 months, while patients taking placebo declined by 1.9 points, for a highly statistically significant difference.
Although the type 2 patients represent just 29% of new cases to the 58% of type 1, the longer life expectancy in type 2 means that they represent more than half of all people living with the disease. Therefore, success in the Cherish trial means that nusinersen could end up being used very broadly.
Ionis shares rose 23% in early trading today, while Biogen’s were up 6%.
Biogen has already put in place an expanded access programme for type 1 patients, and will be looking to do the same with type 2. For pharma and biotechs looking to advance follow-on agents this raises some tricky development questions.
Running placebo-controlled trials might be difficult if not impossible if all of the type 1 and 2 patients – representing an estimated 12,500 of the total 20,000 patients in the US, Europe and Japan – are eligible for an expanded access programme.
Should nusinersen receive approval on time therapies built around neuroprotection, like Trophos and Roche’s olesoxime, or muscular activation, like CK-2127107 from Cytokinetics and Astellas, could be used on top of the Ionis agent. But their pivotal trials would almost surely need to show an additional benefit over nusinersen.
On the other hand, a gene therapy like Avexis’s AVXS-101, which likewise affects the SMN gene’s ability to encode the essential proteins, does not appear to have potential to be used in conjunction with nusinersen. Avexis said the FDA had approved its design of a pivotal study that will have a single arm of 20 patients who receive AVXS-101, and that a less robust analysis involving natural history of the disease would be used.
Given the clear signals of efficacy for nusinersen, enrolment in that trial could be difficult. The lower-risk option for followers in SMA could be agents that can deliver add-on benefits, although the reward might not be what nusinersen is poised to deliver for Ionis.