Biogen at WMS 2024: Stephanie Fradette from Biogen in an Illuminating Dialogue Exchange with PharmaShots

Shots:

Biogen recently shared findings from the P-II/III DEVOTE study, which investigated the safety and efficacy of a higher dose regimen of Spinraza for the treatment of spinal muscular atrophy (SMA)

Stephanie Fradette, Head of Neuromuscular Development Unit at Biogen, joins PharmaShots for a stimulating conversation on Biogen's groundbreaking presentation at World Muscle Society 2024.

Stephanie highlights the primary and secondary outcomes showing benefits in both individuals previously treated and treatment-naïve to nusinersen with infantile-onset or later-onset SMA.

Saurabh: Would you like to share the study design of DEVOTE? 

Stephanie: DEVOTE is a Phase 2/3 randomized, controlled study designed to evaluate the safety, tolerability, pharmacokinetics and efficacy of a novel dosing regimen of nusinersen (comprised of two 50 mg doses 14 days apart, and higher maintenance regimen, 28 mg, every 4 months) in treatment-naïve and previously treated participants with spinal muscular atrophy (SMA).

The study enrolled 145 participants across ages and SMA types at approximately 42 sites around the world. DEVOTE was a multi-part study including an open-label safety evaluation cohort (Part A), a double-blind, active control randomized treatment cohort (Part B) in treatment-naïve infantile-onset (pivotal) and later-onset participants, and an open-label cohort to assess the safety and tolerability of transitioning participants from the currently approved dose of SPINRAZA to the higher dose regimen (Part C).

The study was powered to assess the efficacy of the higher dose regimen (50/28mg) relative to a prespecified, matched subset of the sham control group from the Phase 3 ENDEAR study in the treatment-naïve, infantile-onset cohort (Part B). ENDEAR is one of the two pivotal studies that formed the basis of regulatory approval for SPINRAZA® 12 mg. A total of 75 infantile-onset participants were randomized 2:1 to receive the higher dose (50/28mg) or approved (12/12mg) regimen. Though not powered to detect statistically significant differences, supportive analyses were also conducted to compare these two dosing regimens.

In the Part B later-onset cohort, 24 treatment-naïve participants were enrolled and randomized 2:1 to receive the higher dose (50/28mg; n=16) or approved (12/12mg; n=8) regimen. Though not powered to demonstrate statistically significant differences, supportive analyses were conducted to compare these two groups, as well as the 50/28mg group relative to prespecified, matched subsets of the sham and 12/12mg groups from the Phase 3 CHERISH study.

Part C enrolled 40 participants aged 4 to 65 that were transitioned to the higher dose regimen following a median of 3.9 years on the approved 12/12mg regimen of nusinersen.

More information about the DEVOTE study (NCT04089566) is available at clinicaltrials.gov.

Saurabh: How did the high dose Nusinersen perform as compared to the previously indicated 12mg dose in terms of neurofilament reduction? 

Stephanie: In the Part B infantile-onset cohort, the higher dose regimen led to a 94% reduction in plasma neurofilament light chain (NfL) from baseline to Day 183, compared to a 30% reduction in the matched sham control group (p<0.0001). Consistent with the more rapid loading period, the 50/28mg regimen led to faster slowing of neurodegeneration as shown by greater reductions in plasma NfL at Day 64 as compared to the 12 mg regimen (p=0.0050). Similarly in the treatment-naïve later-onset cohort, the 50/28mg regimen led to more rapid lowering of plasma NfL.

Saurabh: Are there any safety issues associated with high dosage that were not observed in the ENDEAR trial? What were the adverse effects observed during DEVOTE? 

Stephanie: In DEVOTE, the investigational higher dose regimen was generally well tolerated and showed a safety profile broadly consistent with that of then approved 12 mg regimen. Most adverse events (AEs) were mild to moderate and assessed as not related by the investigator.

In the high dose group, the most common AEs were events commonly seen in children with SMA or in the general population, or events associated with the LP procedure. In infantile onset, the most common AEs were respiratory failure, fever, respiratory infections (including URIs, pneumonia) and COVID 19. In Part B later-onset, the most common AEs were procedural headache, procedural pain, cough, diarrhea, nasopharyngitis, rhinorrhea, tonsillitis, URIs and vomiting.

In Part B infantile-set, aspiration pneumonia was more frequently (at least >5% difference) observed in high dose infantile-onset participants, compared to historical matched sham-treated participants from ENDEAR. These events were assessed as unrelated by the investigators.

Saurabh: What primary and secondary outcomes did you target in patients administered with the higher dose? 

Stephanie: As noted above, the study was powered to assess the efficacy of the higher dose regimen (50/28mg) relative to a prespecified, matched subset of the sham control group from the Phase 3 ENDEAR study in the treatment-naïve, infantile-onset cohort (Part B).

The primary endpoint was the change from baseline to Day 183 in the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) score in the Part B infantile-onset participants randomized to the 50/28mg regimen (n=50), as compared to the matched sham control group (n=20). In addition to the primary comparisons of the higher dose regimen to the matched sham group, analyses comparing to the approved 12 mg regimen were also performed, though not adequately powered to detect significant differences between these groups. These secondary analyses compared:

The higher dose regimen and the matched sham control group in infantile onset participants across Hammersmith Infant Neurological Examination (HINE) Section 2, neurofilament, event free survival, and survival.

The higher dose regimen and the approved 12 mg dose in infantile-onset participants across CHOP-INTEND, HINE-2, neurofilament, event free survival, and survival.

Saurabh: What patients' unmet needs is DEVOTE trial targeting through the introduction of a high dose Nusinersen? 

Stephanie: While there has been remarkable progress in the treatment of SMA, we do not have a cure today and there remains significant unmet need for additional efficacy. The novel, higher dose regimen for nusinersen is more than double the currently approved dose and combines an increased dose with a faster loading schedule, delivering more drug with the first dose than is delivered throughout the entire two-month loading period with the approved regimen. The more rapid loading period led to a faster slowing of neurodegeneration. Over time, the higher dose regimen led to meaningful clinical benefit in both treatment-naïve and previously treated patients across the disease spectrum.

Over the past eight years, SPINRAZA has impacted thousands of lives for the better and we are excited by the opportunity to further address remaining unmet need.

Should the higher dose regimen be approved, we will work tirelessly with the community and expert treating physicians to bring this advancement to patients around the world.

Saurabh: Can you elaborate the improvements achieved in motor function by administering a higher dosage? 

Stephanie: Detailed results from the Part B infantile-onset, treatment-naïve cohort include:

On the primary endpoint, the 50/28mg group achieved a significantly greater improvement (15.1-point improvement) on CHOP-INTEND from baseline to Day 183 as compared to the matched sham group (an 11.1-point worsening) (p<0.0001).
Over 302 days, the 50/28mg group improved by an average of 19.6 points on CHOP-INTEND and 5.9 points on HINE-2.
Importantly, the higher dose regimen reduced the risk of death or permanent ventilation by 67.8% relative to sham (HR: 0.322; nominal p=0.0006) and 29.9% relative to the 12 mg regimen (HR: 0.701; p=0.2775). A similar pattern was observed for overall survival, as well as other relevant events such as hospitalizations and serious respiratory events.

In the Part B later-onset cohort, participants receiving the higher dose regimen (n=16) achieved numerically greater improvements on motor function assessments including the Hammersmith Functional Motor Scale – Expanded (HFMSE) and the Revised Upper Limb Module (RULM) at Day 302 over the 12 mg group (n=8) in DEVOTE, and at Day 279 as compared to pre-specified matched 12 mg (n=32) and sham control groups (n=16) from the Phase 3 CHERISH study, the other pivotal study that formed the basis of regulatory approval for SPINRAZA® 12 mg.

In Part C, participants (n=40) experienced functional improvements after transitioning to the 50/28mg regimen after a median of 3.9 years on the approved regimen, with mean increases of 1.8 points on HFMSE and 1.2 points on RULM from baseline at Day 302.

Image Source: Canva

About the Author:

Stephanie Fradette

As Head of Neuromuscular Development at Biogen, Fradette oversees the company’s research and development of treatments for neuromuscular diseases.