Durability Seen With Novartis, Roche SMA Therapies Heading For Market
Executive Summary
Novartis and Roche have announced additional interim clinical data as their candidate spinal muscular atrophy therapies near the marketplace.
Clinical data to support the use of novel spinal muscular atrophy (SMA) therapies under development by Novartis AG and Roche were highlighted during this week’s American Academy of Neurology (AAN) meeting in Philadelphia, PA, and are likely to be crucial for informing patients and physicians about the drugs’ effects when they reach the market and start to compete with Biogen Inc.’s already marketed antisense SMA therapy, Spinraza (nusinersen).
Commercially, sales of new SMA therapies could be significant, with those of Novartis’s intravenous formulation of the SMA gene therapy Zolgensma (onasemnogene abeparvovec-xioi, AVXS-101), possibly reaching between $500m and $1.3bn, Deutsche Bank analysts estimate in a 6 May note. The size of the opportunity will depend on price, which for Zolgensma could be around $2m per patient, and the breadth of the label, for example type 1 only or including all three types of SMA.
Compelling initial data were also presented on use of an intrathecal formulation of Zolgensma in older, type 2, patients, suggesting that Novartis’s gene therapy could be as effective as Spinraza, and be of benefit in a larger population of type 2/3 patients, the analysts say. The use of Zolgensma in catch-up patients could also add significantly to revenues.
Credit Suisse analysts noted that treatment results with intrathecal Zolgensma seemed to compare favorably with those reported in Biogen’s Spinraza CHERISH Phase III study, and they also reckon that Roche’s investigational oral therapy, risdiplam, could account for around 30% of patients with type 2 SMA when it is launched, with Zolgensma becoming the standard of care in newborn and young type 2 SMA patients. They believe risdiplam will be used in patients unable to receive a gene therapy like Zolgensma, or who have an incomplete or waning therapeutic response.
That said, there have been concerns about serious adverse events associated with Zolgensma (see sidebar).
These concerns may dampen initial enthusiasm for new therapies. Currently, Biogen’s Spinraza is the market leader in SMA therapies, with Spinraza sales of $518m in the first quarter of 2019. (Also see "Biogen Stays Steady As Alzheimer’s Programs Falter" - Scrip, 24 Apr, 2019.)
There are just under a dozen candidate SMA therapies in clinical trials, according to the drug development database, Biomedtracker. (Also see "Scrip's Guide To Spinal Muscular Atrophy Therapies" - Scrip, 1 Mar, 2019.)
Four-Year Results
At the AAN meeting, no decline in the therapeutic effect four years after an intravenous single-dose of Novartis’s investigational SMA type 1 gene therapy, Zolgensma was reported from the Phase I START study.
In cohort 2 of the START study in patients with SMA type 1 who began to exhibit symptoms before six months of age, all 12 patients given therapeutic doses of Zolgensma were alive and free from permanent ventilation for breathing at the 24-month study close-out time point. 11 of the 12 patients could hold their head erect for more than three seconds and sit without support for more than five seconds, nine patients could sit without support for more than 30 seconds, two patients could stand alone, two could walk with assistance, and two could walk alone, at the 24-month time point.
Ten patients were enrolled in a follow-up study, and at a mean time since treatment of 3.7 years, all patients had maintained the motor function and milestones gained during the initial 24-month study, Novartis noted. Three patients had also started other therapies, but the decision was not due to loss of motor function, the company added.
Zolgensma is being developed by the Novartis subsidiary, AveXis Inc., in collaboration with Genethon, and has been granted a priority review by the US FDA, with regulatory action anticipated in this month; the drug is expected by Novartis to receive approval in Japan and the EU later this year.
Roche’s Oral Therapy
Roche described promising clinical data for its oral survival motor neuron-2 (SMN2) splicing modifier, risdiplam, in patients with type 1, 2 and 3 SMA during the AAN meeting. Among 17 infants taking part in the dose-finding part 1 of the pivotal FIREFISH study and receiving the selected therapeutic dose, seven were able to sit without support for at least five seconds, 11 were able to sit (with or without support), nine achieved upright head control, and one was able to stand, after 12 months of risdiplam therapy. (Also see "Roche Makes Case For Its Oral SMA Drug Risdiplam As Filings Beckon" - Scrip, 6 Feb, 2019.)
Three infants suffered fatal complications of their disease after one, eight and 13 months of treatment, but none of these events was attributed by the investigator to risdiplam. The most common side effects were fever (52.4%), upper respiratory tract infections (42.9%), diarrhea (28.6%), vomiting (23.8%), cough (23.8%), pneumonia (19%) and constipation (19%).
In a second clinical study, SUNFISH, in patients aged 2-25 years with types 2 or 3 SMA, initial signs of efficacy were reported in part one of the study in 51 patients, including an improvement of at least three points on the MFM32 scale in 58% of patients at the 12-month study time point. Adverse events reported included fever (41%), cough (33%), vomiting (29%), with the most serious adverse event being two cases of pneumonia.
Roche says it will make regulatory filings with the US FDA and the EU’s EMA in the second half of 2019 for risdiplam, which is being jointly developed by Roche, PTC Therapeutics Inc. and the patient group, the SMA Foundation.