- The results of Parts B and C of the DEVOTE study confirm the clinical benefit of higher doses of nusinersen (50/28 mg) in both previously treated and untreated nusinersen patients.
- The dosage regimen tested also shows faster slowing of neurodegeneration, as measured by neurofilament levels.
- Biogen plans to file registration applications for approval of higher doses of nusinersen worldwide
Biogen announced detailed results from Parts B and C of the Phase 2/3 DEVOTE study, evaluating the safety and efficacy of an investigational regimen of higher doses of nusinersen in spinal muscular atrophy (SMA), showing benefit in both previously treated and untreated nusinersen patients with SMA with onset in infancy or later.
The investigational higher dosing regimen of nusinersen involves faster saturation doses (two 50 mg doses 14 days apart) and higher maintenance doses (28 mg every 4 months) compared to the approved nusinersen dosing regimen. The data underscore the potential of this investigational treatment regimen at higher doses to address unmet needs for SMA treatment.
"What's striking is that the higher dosing regimen reduces neurofilament levels faster, which means it slows neurodegeneration faster. We know how important this is in people living with SMA. Over time, we are seeing evidence of the benefits of higher doses of nusinersen in all phenotypes of SMA." - said Dr. Thomas Crawford, co-director of the Muscular Dystrophy Association clinic at Johns Hopkins Medicine. "Despite administering a significantly higher dose of the drug, the higher dosing regimen appears to have a consistent safety profile with the approved 12-mg regimen."
DEVOTE is a three-part study that included 145 participants of different ages and with different types of SMA. The pivotal Part B cohort (n=75) achieved its primary endpoint, in which untreated, symptomatic infants who received the higher dosing regimen achieved significantly greater improvement in motor function, as measured by the Children's Hospital of Philadelphia Infant Neuromuscular Impairment Test (CHOP-INTEND), compared to the pre-specified matched sham treatment group from the phase 3 ENDEAR trial (+15.1 vs -11.1, P<0.0001).
In addition to primary comparisons of the higher-dose regimen with the matched sham treatment group, analyses comparing it with the approved 12-mg dose regimen were also conducted, although these did not have adequate statistical power to detect significant differences between the groups. Despite the relatively small study size, secondary analyses consistently favored the higher-dose group in all comparisons with the sham treatment group and in almost all comparisons with the 12 mg regimen. Detailed results include:
- The higher-dose regimen led to a 94% reduction in plasma neurofilament light chains (NfL), a marker of neurodegeneration, from baseline to day 183, compared to a 30% reduction in the sham treatment control group (p<0.0001). In addition, a faster reduction in NfL levels was observed with the higher dosing regimen, with greater reductions observed on day 64 (p = 0.0050), compared to the 12 mg dose.
- On day 302, participants receiving the higher dose showed a 19.6-point improvement from baseline in the CHOP-INTEND score, compared to a 21.6-point improvement with the 12 mg dose (mean least squares difference: -1.94; p=0.8484). On Day 302, the higher-dose regimen showed a mean improvement in the change in section 2 of the Hammersmith Infant Neurological Examination (HINE-2) compared to the 12 mg regimen (mean least squares difference: 0.58; p=0.1734).
- The higher dosing regimen reduced the risk of death or permanent ventilation by 67.8% compared to the sham treatment regimen (HR: 0.322; nominal p=0.0006) and 29.9% compared to the 12 mg regimen (HR: 0.701; p=0.2775). A similar pattern was observed for overall survival, as well as other major events such as hospitalizations and major respiratory events.
- In the Part B cohort including participants with later disease onset, participants receiving the higher drug dose (n=16) achieved numerically greater improvements in motor function scores, including the Hammersmith Functional Motor Scale - Expanded (HFMSE) and Revised Upper Limb Module (RULM) scales on Day 302. Day, compared to the 12 mg group (n=8) in the DEVOTE study, and at Day 279 compared to the pre-specified matched 12 mg (n=32) and sham treatment(n=16) control groups from the CHERISH study.
Also presented are preliminary results from Part C (n=40) of the DEVOTE study, in which a diverse group of participants aged 4-65 switched to a higher dosing regimen (a single 50 mg dose followed by a 28 mg maintenance regimen) after a median of 3.9 years on the approved 12 mg regimen. Participants experienced improved motor function after switching to the new regimen, with a mean increase of 1.8 points on the HFMSE scale and 1.2 points on the RULM scale from baseline at Day 302.
In all parts of the DEVOTE study, the higher dosing regimen was generally well tolerated and showed a safety profile similar to the approved 12 mg regimen. For the 12 mg dose, the most common adverse events (AEs) were respiratory tract infections, fever, constipation, headache, vomiting and back pain. The frequency of AEs in the DEVOTE study was similar in all nusinersen treatment arms. The number of adverse events leading to withdrawal and death occurred only in the untreated Part B cohort and was 20% (10), 24% (6) and 55% (11) in the 50/28 mg, 12 mg and matched sham arms, respectively.
"While we have seen tremendous progress in improving the lives of people with SMA over the past decade, there are still unmet needs and we can do more to meet the full range of needs and goals in our community," said Kenneth Hobby, president of Cure SMA. "The results of the DEVOTE study are promising and show the potential to make additional significant advances that can further improve motor function, which impacts the daily living activities of all people living with SMA."
Biogen plans to submit registration applications to regulatory authorities around the world for the nusinersen treatment regimen at the higher 50/28 mg dose. Nusinersen is currently sold in more than 71 countries at the approved dose of 12 mg.
Source: press release
