The chief medical officer of Scholar Rock provided background on the company’s investigational SMA treatment and its clinical benefit when applied with nusinersen (Spinraza; Biogen).
Despite the utilization of SMN upregulators in the treatment paradigm, spinal muscular atrophy (SMA) remains a debilitating disease for patients. Apitegromab, a muscle-directed therapy developed by Scholar Rock, demonstrated its ability to improve motor function in both ambulatory and nonambulatory type 2 and 3 SMA in the recently concluded phase 2 TOPAZ clinical trial (NCT0392158).
In the non-ambulatory cohort of patients on background nusinersen started earlier in life, treatment with apitegromab 20 mg/kg led to sizable increases in Hammersmith Functional Motor Scale Expanded (HFMSE). In the non-ambulatory cohort of patients on background nusinersen started later in life (≥5 years of age), treatment with apitegromab 20 mg/kg led to an increase in HFMSE, contrasting with declines experienced on average by this patient population without treatment.
Prior to treatment with apitegromab, investigators documented that nusinersen did not increase HFMSE on average in children who initiate treatment after the age of 5 years. Of the pooled populations, 7 of 35 patients (20%) gained at least 1 World Health Organization (WHO) motor milestones following 12 months of apitegromab treatment, including 1 patient who gained 3 milestones and 1 who gained 2.
Yung Chyung, MD, chief medical officer, Scholar Rock, sat down with NeurologyLive on a new iteration of NeuroVoices to provide further background on the results, the unique study design, and apitegromab’s mechanism of action. He also provided perspective on the unmet needs of patients with type 2 and 3 SMA and the need to continue research in this area.
Yung Chyung, MD: Our vision for apitegromab and SMA is to address the persistent unmet medical need despite the advent of SMA regular therapies. To do this, we are aiming to improve motor function when added on top of such therapies. Towards the end, we were very excited by the TOPAZ results, which we believe illustrates the transformative potential apitegromab has, particularly in the type 2 and nonambulatory type 3 SMA populations. More specifically, we looked at 2 different nonambulatory cohorts. The first looked at individuals who had previously been started on background nusinersen earlier in life as well as those who started later in life.
The primary efficacy measure was the Hammersmith scale, which previously served as the primary end point for a phase 3 nusinersen trial as well. This scale is important, clinically meaningful, and validated outcome measure for SMA. Across the nonambulatory populations, the TOPAZ trial observed meaningful increases in the mean change from baseline to Hammersmith scale. Notably, the majority of patients in the non-ambulatory cohorts experienced increases in their Hammersmith score with subsets of individuals achieving sizable increases. We also observed a potential signal for clinical effect in the ambulatory type 3 care. All in all, we’re quite enthusiastic about advancing our program with apitegromab in SMA and further investigating the efficacy and safety of this molecule towards our aspiration of transforming the care of patients with SMA.
The therapeutic hypothesis here is not to replace or compete with SMN regular therapies. Instead, the goal is to complement the primarily disease stabilizing effects of SMN regulators by aiming to drive motor function improvements through apitegromab and help address the severe functional deficits that patients still suffer despite SMN regulated therapies. Given that nusinersen was the only SMN therapy generally available at the time of TOPAZ trial enrollment, we decided to use that therapy for our study. With that being said, our therapeutic hypothesis is that apitgromab has the potential to be added on top of any SMN regulator, as an orthogonal and complimentary approach. Our intention is to broadly explore apitegromab on top of any SMN regulator including nusinersen, risdiplam (Evrysdi; Genentech), and eventually gene therapy, and not limit such exploration to nusinersen alone.
Broadly speaking, many diseases involve complex biologies with very severe disease manifestations. To tackle these challenging problems, it makes sense that the overall research and development field is heading towards these integrative approaches where it’s not just 1 therapeutic tool by itself. It’s taking a combination or add on approach to tackling these difficult challenges. We think it’s part of a broader movement in the next wave of therapeutic strategies to address these serious illnesses.
Apitegromab is aimed as a muscle directed therapy intended to complement SMN regulated treatment by seeking to improve motor function rather than just merely prevent further decline. Mechanistically, apitegromab blocks the activation of late myostatin with a goal of increasing fast twitch fiber function in skeletal muscle. Just as background, fast twitch fibers are important for motor tasks involving short term versus long-term strength and are directly relevant to SMA. In SMA, there is prominent fast twitch fiber atrophy which in turn is associated with severe motor functional impairment.
There is another important feature of apitegromab for which were still developing and investigating beyond just efficacy, which is myostatin selectivity. Myostatin is structurally similar to other proteins in the body that may modulate entirely unrelated biologies such as activin, GDF11, and BMP9. We hypothesize that this activity may help mitigate the potential for off-target effects. We also believe it’s particularly important given that many patients with SMA are children and given that muscular directed therapy will probably need to be chronic.
There is a very high unmet medical need in this population despite the availability of SMN regulated therapy. Overall, we estimate that type 2 nonambulatory and type 3 SMA population represents approximate two-thirds of the current prevalence of SMA. To illustrate the persistent functional deficits for this population, in TOPAZ, despite having been on nusinersen for an average of roughly 2 years prior to enrollment, the mean Hammersmith scale scores for the non-ambulatory cohorts were in the low to mid-20s out of a maximum possible score of 66. It’s important to emphasize that the 66-point maximum score on this Hammersmith scale is not representative of the performance of an Olympic athlete, but rather at the level at which a healthy toddler can perform. More specifically, this scale evaluates various motor functional tasks that may seem rather basic but could have profound impact on what your daily living may be. For example, being able to raise your hand to your head may mean the difference in being able to comb your hair or not. Being able to turn to your side while lying down has the potential to be the difference between a caregiver having to go in multiple times a night to turn the child from side to side to avoid bed sore formation and getting an uninterrupted night’s sleep. This is why we believe even a 1-point gain on the scale has the potential to make a meaningful difference for individuals with SMA, let alone a 3-point, 5-point, or 10-point increase.
Transcript is edited for clarity. For more segments of NeuroVoices, click here.