Data at the World Muscle Society meeting this week were always going to make for uncomfortable reading for Biogen and Ionis. Competitors are advancing with potentially more effective and more convenient projects than the groups’ antisense spinal muscular atrophy therapy Spinraza, Biogen’s most important sales growth driver.
A gene therapy from Novartis is yielding stellar efficacy and survival data in this childhood disease, for instance. However, gene therapies pose their own questions over convenience and affordability, meaning that perhaps the biggest threat to Biogen comes from Roche/PTC Therapeutics’ risdiplam (RG7916).
World Muscle data have confirmed that risdiplam is a very viable asset. This oral SMN2 splicing modifier seems to induce stronger responses than Spinraza in patients with SMA type 1, the most severe form of the condition.
Roche’s SMA type 1 trial is called Firefish, and the group said yesterday that three of 14 enrolled infants had been able to sit unassisted at eight months post treatment. Though the data are very encouraging it is not entirely clear whether this finding substantially improved on an earlier look at the results.
Back in June, three of 21 subjects were said to have achieved the same milestone at six months. This metric will ultimately form the primary endpoint of the study, measured from the trial’s 40-patient, pivotal second stage.
Many sellside analysts leapt to Biogen’s defence and pointed to evidence showing that Spinraza has also generated much stronger results when given to much younger babies. Stiefel, for example, accepted that risdiplam now looked approvable, but said it by no means had best-in-class efficacy.
True, cross-trial comparisons should be made with caution, and the timing of treatment post-birth is a confounding factor: Roche probably benefited from treating infants earlier in its study. But it seems evident that on the unassisted sitting measure and others risdiplam looks stronger than Spinraza in its equivalent SMA type 1 study, Endear.
Throw in the fact that risdiplam is oral while Spinraza must be injected into the spine, and it is easy to see why the Roche project is considered a threat for the longer term.
|SMA type 1 trials|
|Phase III Endear study, 12mth post treatment||Firefish study, after 9.5mth exposure to treatment||Str1ve study, cohort 2, 24mth post treatment|
|Event-free survival||61% (n=80)||90% (n=21)||100% (n=15)|
|Rolling||10% (n=73)||29% (n=14)||75% (n=12)|
|Sitting unassisted||8% (n=73)||21% (n=14)||92% (n=12)|
|Standing assisted||1% (n=73)||0% (n=14)||17% (n=12)|
|Chop-Intend responders, >4 points, at 6mth||71% (n=73)||93% (n=14)||Not reported|
|Source: World Muscle presentations, sellside notes.|
Of course all this could be rendered moot in type 1 patients if AVXS-101, the gene therapy Novartis acquired as part of its $8.7bn takeover of Avexis, reaches the market.
New data at the conference confirmed the remarkable profile of this asset. 100% of 15 subjects enrolled into Novartis’s pivotal Str1ve study were reported to be alive at 24 months; the comparator numbers from Biogen and Roche, at shorter follow-up, are 61% and 90% respectively.
Even more striking was the independent sitting metric, which for the subjects treated with Novartis’s gene therapy amounted to 92%. With the caveat that gene therapies represent entirely separate economic propositions, and that to justify their price long-term evidence needs to be presented showing that they have true, curative potential, it is hard not to see AVXS-101 as a game-changer.
Novartis also seems to be challenging Roche’s risdiplam on its own turf, with its in-house oral SMN2 splicing modifier branaplam. Data for this are early, however, with World Muscle hearing only of changes in Chop-Intend, an SMA outcome score, correlating with dose. Five of 13 branaplam-treated subjects have died, the rest remaining on therapy for 28-33 months.
Either way, unless a serious safety issue emerges it seems likely that SMA type 1 patients will soon have a highly effective gene therapy option – at least in countries where this is available. That would leave agents like Spinraza, risdiplam and branaplam fighting over less severely ill patients.
Here the agents’ comparative effectiveness is much less clear, but the convenience of each one will matter much more. On the upside for Biogen/Ionis, risdiplam is not forecast to reach the market until 2021. But the writing could be on the wall for Spinraza, and Biogen’s decision to keep investing in its SMA pipeline is surely an admission of this.