Spinal muscular atrophy (SMA) patients treated with SPINRAZA (nusinersen) have experienced stabilised or improved motor function, contrary to the natural course of the degenerative disease, Biogen and Ionic Pharmaceuticals have announced. This is the end of study result from CHERISH, the phase three study comparing the use of nusinersen with a sham control for the treatment of late onset 5q SMA, recently published in The New England Journal of Medicine.
SMA is an autosomal recessive neuromuscular disease – it is a debilitating and life-threatening rare disease, and the leading genetic cause of death in infants. As spinal muscular atrophy is progressive, patients decline over time, with increasingly debilitating symptoms, affecting sufferers’ ability to move, swallow, and ultimately breathe.
The majority of individuals treated with nusinersen in the CHERISH study, however, demonstrated benefits in upper limb and general motor function, including crawling and standing without support.
Eugenio Mercuri (U.O.C. Neuropsichiatria Infantile, Policlinico Universitario “A. Gemelli”, Rome, Italy), lead investigator of the study, comments, “The publication of CHERISH study results in The New England Journal of Medicine emphasises nusinersen’s meaningful motor function and upper limb improvements [from baseline] in individuals with later-onset SMA rarely seen in the natural course of the disease, which is typically a continued decline in motor function over time.”
“During the study, some individuals treated with nusinersen achieved motor milestones including crawling or standing with assistance, or saw a stabilisation or slowing of disease progression. We also saw an improvement [from baseline] in upper limb function, including raising objects.”
The pre-specified CHERISH primary endpoint was improvement in motor function, as defined by change from baseline in the Hammersmith Functional Motor Scale-Expanded (HFMSE). The HFMSE is a validated tool specifically designed to assess motor function in individuals with SMA. The final analysis demonstrated a highly statistically significant and clinically meaningful improvement in motor function in individuals treated with nusinersen vs. the sham control, as observed by the treatment difference of 4.9 points in the mean change from baseline to month 15 in the HFMSE score (p=0.0000001). A treatment difference of three and above is clinically significant.
When measuring changes from baseline, individuals who received nusinersen (n=84) achieved a 3.9 point mean improvement at month 15, while individuals who were not on treatment (n=42) experienced a mean decline of 1.0 point. Primary end point results of the end of study analysis were consistent with the interim analysis.
Alfred Sandrock, executive vice president and chief medical officer at Biogen, says, “As the first and only approved treatment of SMA, the data published in The New England Journal of Medicine continue to underscore the benefit of nusinersen to individuals with later-onset SMA. The CHERISH data are part of the largest clinical development programme to date for the treatment of SMA. The programme in its entirety shows that nusinersen has the potential to positively impact the motor function of children with SMA regardless of the age or stage of their disease.”
Data from the other endpoints analysed, including attainment of new motor milestones and upper limb motor function, were consistently in favour of individuals who received treatment and were considered clinically significant. Upper limb function, as measured by the Revised Upper Limb Module (RULM), improved in individuals treated with nusinersen (4.2 points). The RULM is an important measure of motor function in non-ambulatory individuals.
Nusinersen demonstrated a favourable benefit-risk profile. Safety data were consistent with those expected in the general SMA later-onset population and in individuals undergoing lumbar puncture and were similar to those reported in an open-label study in later-onset SMA.
Frank Bennett, senior vice president of research and leader of the neurological disease franchise at Ionis, explains, “The CHERISH data published today, together with the results from the phase three ENDEAR study in individuals with infantile-onset SMA, which were published last November in The New England Journal of Medicine, emphasises the therapeutic potential of nusinersen in individuals with SMA. We believe the fact that both nusinersen pivotal studies have been published in a prestigious journal is a testament to the robustness of our SMA clinical development programme.”
Following the positive interim analysis, Biogen ended the CHERISH study early so all participants could have the option to received nusinersen in the SHINE open-label extension study. In addition to SHINE, Biogen continues to collect and evaluate data to provide a deeper understanding of the efficacy and safety of nusinersen across 5q SMA populations. The nusinersen clinical development programme includes more than five years of data and is the largest body of evidence for an interventional approach in SMA.
End of study results from ENDEAR, the phase three nusinersen study for the treatment of infantile-onset SMA, were published in the 2 November 2017 issue of The New England Journal of Medicine.