The chief medical officer of Scholar Rock described how the investigational apitegromab aims to fill some of the current unmet needs for patients with spinal muscular atrophy.
This is a 2-part interview. To view part 1, click here.
Originally published in April 2021, results from the phase 2 TOPAZ clinical trial (NCT039215128) further demonstrated apitegromab’s (SRK-015; Scholar Rock) proof-of-concept as a treatment for patients with spinal muscular atrophy (SMA). A majority of the 23 patients (57%; n = 13) with ambulatory type 3 SMA who received a 20-mg/kg dose monotherapy of apitegromab in conjunction with nusinersen (Spinraza; Biogen) across cohort 1 maintained or improved their motor function, as reflected by a greater than 0-point change from baseline in Revised Hammersmith Scale. Additional improvements in Hammersmith Functional Motor Scale Expanded (HFMSE) scores were displayed in cohort 2, which included 14 patients with type 2 and nonambulatory type 3 treated with 20-mg/kg apitegromab.
Apitegromab, a muscle-directed therapy, is differentiated from the approved SMN upregulators by acting as a complementary treatment. The therapy has previously received fast track and prime designations from the FDA and is set to undergo a phase 3 study later this year.
Yung Chyung, chief medical officer, Scholar Rock, told NeurologyLive that although these SMN therapies offer a chance for patients to achieve meaningful motor functional gains, there are many individuals who have missed their ideal treatment window. On a new segment of NeuroVoices, Chyung details why a complementary approach with apitegromab can alter and improve the SMA treatment landscape, the upcoming phase 3 trial, and why early administration of therapy is crucial for this patient population.
Yung Chyung, MD: The advent of SMN upregulated therapies undoubtedly represents an important advance in the treatment of SMA. With that said, the main benefit of such therapies in most patients appears to be to stabilize the disease by preventing further deterioration of motor neurons. When initiated very early in life, these therapies can offer a chance for patients to achieve meaningful motor functional gains. For many individuals with SMA, that early intervention window has already passed. In such individuals, the main benefit at that point is to keep the motor function from declining further.
Given that most patients are already suffering from substantial motor function deficits at the time of diagnosis, there’s a big need here to address this challenge. Even for patients who started SMN therapies earlier in life, the treatments appear to be far from curative. There continues to be an important unmet need. That’s why we believe the treatment landscape needs an entirely distinct but complementary approach, namely muscle-directed therapy. This is where apitegromab has the potential to make a difference by aiming directly at the muscle. Our hypothesis is that apitegromab may complement the disease-stabilizing effects of SMN therapies and drive improvements in motor function rather than just prevent decline.
The good news here is that there is progress on earlier diagnosis, as well as the advent of newborn screening. These are important measures to get patients identified earlier so that intervention can happen quicker, at an earlier stage of life. With that being said, unfortunately for a majority of patients living with SMA today, they don’t have that opportunity to have that earlier intervention because the diagnosis already happened. Our hope and aspiration is to make a difference for patients who have already passed the intervention window, as well as looking forward to the future to have an impact on for newly diagnosed patients who are in that early intervention setting.
I’m not a clinician taking care of patients with SMA, but we’re working with clinicians, investigators, physical therapists, and the patient community towards improving the treatment landscape and trying to develop novel therapies. Along those lines, it’s important to think about the full spectrum and broad nature of SMA. There are different types of SMA with different age ranges. There are patients who are identified and diagnosed earlier, for which they have the opportunity to have early intervention, and then there’s individuals for which the diagnosis happened later. The goal here, as a community, is to see what we can do to make a difference for all patients with SMA.
We are indeed excited about the progress of apitegromab and plan to proceed to a phase 3 trial. We envision a randomized, double-blind, placebo-controlled trial that would investigate apitegromab as an add-on to background SMN upregulated therapies such as nusinersen or risdiplam. At this stage, we think it would be in a type 2 and non-ambulatory type 3 SMA population. The Hammersmith scale, specifically HFMSE, would make sense to use as the primary efficacy end point given that it is validated in SMA, clinically meaningful, and has served as an important efficacy measure in prior phase 3 trials in SMA. The HFMSE was the primary efficacy measure for the non-amateur cohorts in the TOPAZ trial. Now, these development plans, including the phase 3 trial design, are subject to regulatory feedback. As things get more finalized, our intention is to provide an update, so please stay tuned.
We’re enthusiastic about the potential of apitegromab and our phase 3 trial will be aimed at robustly investigating that potential. The overall approach will be subject to regulator feedback. We are quite encouraged by the recognition of the persistent unmet medical need in SMA by regulators, as evidenced by the receipt of fast track and prime designations from the FDA for apitegromab. We should note that while our current plans are focused on type 2 and non-ambulatory type 3 population, we do believe there is broad potential for apitegromab in SMA, such as in type 1 SMA. We will continue to look further into the ambulatory type 3 SMA data from the TOPAZ trial as we believe there’s a potential signal there. There’s a lot of work ahead of us, but we’re excited about the progress and look forward to finding updates as they become available.