Cure SMA conference – Roche fights back against Spinraza

Roche’s quiet discontinuation of olesoxime, a spinal muscular atrophy project it gained when it bought Trophos, showed how tough it had become to compete against Biogen/Ionis’s Spinraza, which in 2016 became the first disease-modifying treatment for this disorder.

Still, presentations from Roche and Cytokinetics over the weekend show that industry has not given up yet. Indeed, the early Roche efficacy data – covering RG7916, an SMA asset it licensed from PTC Therapeutics – have already been hailed by analysts as making this project “maybe better than Spinraza”.

PTC stock, resurgent over the past two years as the group overcomes its Duchenne muscular dystrophy disappointment, opened up 30% this morning.

The results came from the first part of the open-label Firefish trial of RG7916, an SMN splicing modifier that now has the generic name risdiplam. By Bernstein analysts’ reckoning the most exciting aspect of the presentation at the Cure SMA conference was video footage of three infants with SMA being able to sit unassisted for 10-15 seconds.

On a stricter scientific basis presenters boasted of risdiplam’s ability to raise Chop-Intend scores, a measure of motor milestone development in SMA; median increases were 5.5 points at two months, 12.5 at four months, and 14 at six months. The efficacy was backed with the claim that treated subjects saw up to a 6.5-fold increase in the SMN protein whose low levels cause SMA.

Bernstein said the data compared favourably to Chop-Intend increases seen with Spinraza – 3, 8 and 10 points at these respective times. The analysts even argued that the numbers were comparable to Spinraza’s biggest threat, Novartis’s AVXS-101, which has generated increases of 10, 15 and 19 points.

Oral advantage?

As important as these cross-trial comparisons might be the fact that risdiplam is orally delivered.

Spinraza and AVXS-101, an antisense and gene therapy respectively, are expected to yield 2024 sales of $2.1bn and $1.6bn, according to EvaluatePharma sellside consensus (Avexis buy endorses gene therapy and gives Biogen a headache, April 9, 2018).

Bernstein, which has been negative on Spinraza for some time, wrote that the threat of pills was underappreciated by investors, and said long-term Spinraza forecasts would come down. If this comes to pass it would represent a significant coup for Roche, which until last month had boasted two SMA projects – risdiplam and the Trophos-derived olesoxime.

However, it ditched the latter citing “many difficulties ... focused on [its] formulation”, and the emergence of an effective SMA treatment, presumably Spinraza. The Swiss group, which had bought Trophos in 2015 for €120m up front, revealed the discontinuation in a low-key announcement to a UK SMA patient group.

The same patient group yesterday described as encouraging data revealed over the weekend by a rival company, Cytokinetics. These results, also presented at the Cure SMA conference, concerned reldemsetiv (CK-2127107), a Troponin activator partnered with Astellas.

However, the data are somewhat equivocal, and Cytokinetics cautions that they come from a hypothesis-generating phase II trial. Reldemsetiv is designed to improve muscle endurance, so it is not strictly speaking disease-modifying, hence the company’s use of the surrogate six-minute walk distance (6MWD) as an endpoint.

Two doses, 150mg and 450mg, were tested, and numerical 6MWD increases were seen versus placebo for both, at four and eight weeks. However, only the higher group, and only at week four, showed a benefit that might meet statistical significance, yielding a nominal p value of 0.0037.

Cytokinetics said the data showed a dose-dependent increase, and hailed them as the first backing for a muscle-directed therapy in SMA. As reldemsetiv is orally dosed it could, along with risdiplam, represent another challenge to complex systemic drugs – assuming that longer-term data bear out the initial efficacy hints.

To contact the writer of this story email Jacob Plieth in London at [email protected] or follow @JacobPlieth on Twitter