Why SMA Still Has an Unmet Need Despite SMN Therapies

Spinal muscular atrophy (SMA) is caused by loss-of-function mutations in the survival motor neuron 1 (SMN1) gene, and the therapies that have transformed the field — risdiplam (EVRYSDI), a small molecule splicing modifier of SMN2, and nusinersen (SPINRAZA), an antisense oligomer targeting the SMN2 gene — address that root genetic deficit directly. Yet despite the profound impact of these SMN pathway therapies, many patients with SMA type 2 and SMA type 3 continue to experience progressive muscle weakness and motor function decline.

The persistence of muscle atrophy even in patients receiving SMN therapy reveals a critical insight: correcting the SMN protein deficit upstream does not fully restore muscle mass or function downstream. Myostatin, a member of the TGF-β superfamily and a potent inhibitor of muscle growth, continues to drive muscle wasting in SMA patients regardless of SMN pathway status. This biological gap is precisely where apitegromab is designed to intervene, according to filings from PatSnap’s innovation intelligence platform.

The recognition that muscle-targeted therapy could complement SMN-directed treatment has opened a new chapter in SMA drug development — one in which Scholar Rock has established an early and defensible patent position. Understanding that position requires examining exactly what apitegromab targets and why the latent form of myostatin matters.

The Latent Myostatin Target: Scholar Rock’s Distinctive Mechanism

Apitegromab specifically binds to the activatable latent myostatin complex — also referred to in Scholar Rock’s filings as the pro/latent myostatin complex — rather than to active myostatin itself. This distinction is not merely semantic; it defines the entire therapeutic and intellectual property strategy underpinning Scholar Rock’s programme.

Myostatin is secreted as an inactive precursor. Its activation — the conversion of the latent complex into the active signalling molecule — is the rate-limiting step in myostatin-driven muscle wasting. By intervening at this activation step rather than neutralising active myostatin after the fact, Scholar Rock’s approach is designed to achieve tissue-selective inhibition. The muscle is where latent myostatin is activated and where apitegromab is intended to act, according to the company’s patent disclosures covering compositions and methods for inhibiting myostatin activation (US20220243182A1, published 4 August 2022).

“Apitegromab targets the activatable latent myostatin complex — intercepting muscle-wasting signalling at its source, before activation occurs, rather than chasing active myostatin downstream.”

This mechanistic specificity also has biomarker implications. Scholar Rock has filed a dedicated patent (US20230194565A1) covering methods for assessing the status of the myostatin signalling pathway in subjects, including methods of determining whether a subject is likely to respond to a myostatin inhibitor treatment by measuring biomarker levels in biological samples. This biomarker work suggests that Scholar Rock is building the infrastructure to support precision dosing and patient selection — a hallmark of a mature clinical programme, as tracked through PatSnap’s life sciences intelligence tools.

The specificity of the latent myostatin target also has competitive significance. Broader myostatin inhibition strategies — those targeting active myostatin or using soluble receptors — have historically been associated with off-target effects in non-muscle tissues, including bone and cardiovascular structures. Scholar Rock’s approach of intercepting the pro/latent complex before activation is presented in its patent filings as a strategy for achieving muscle selectivity, though the full clinical significance of this distinction continues to be evaluated in ongoing trials monitored by regulatory bodies including the FDA.

Mapping the Apitegromab Patent Estate

Scholar Rock has built one of the most concentrated patent estates in the muscle-targeted SMA therapy space, with filings spanning from 2020 through 2024 across both US and international (PCT) jurisdictions. Analysis of the publicly available patent record — conducted using PatSnap Eureka — reveals a multi-layered IP strategy covering the antibody itself, its methods of use in SMA, and its combination with SMN therapies.

The structure of Scholar Rock’s filings reflects a deliberate layering strategy. The foundational antibody patents (WO2020150508A1, WO2021119539A1) establish the core composition-of-matter claims for anti-pro/latent myostatin antibodies. Built on top of these are method-of-use patents specifically directed at SMA treatment (WO2021252917A1, WO2022225979A2, WO2023107895A1), and then a further layer of clinical-data-backed patents disclosing apitegromab’s use in specific patient populations — those on nusinersen or risdiplam, and treatment-naive subjects (WO2023004342A1, WO2024044679A1, WO2024044781A1). This is a classic pharmaceutical patent stacking strategy, well-documented in the broader biopharmaceutical literature tracked by organisations such as WIPO.

The most recent filings in the family — US20240327521A1 (published October 2024) and US20240228624A1 (published July 2024) — continue to extend coverage of the anti-pro/latent myostatin antibody compositions and their methods of use. This ongoing prosecution activity signals that Scholar Rock is actively defending and expanding its IP position even as it pursues regulatory approval, consistent with standard practice for rare disease programmes reviewed by bodies such as the European Medicines Agency.

Combination Strategy: Apitegromab Alongside Risdiplam and Nusinersen

The most strategically significant aspect of Scholar Rock’s apitegromab programme is its explicit positioning as a combination therapy — not a replacement for existing SMN-directed treatments. Multiple patent families filed between 2022 and 2024 disclose methods of treating SMA in subjects who are currently using SMN therapy, specifically naming nusinersen (SPINRAZA) and risdiplam (EVRYSDI) as the background treatments.

This combination positioning is commercially rational. Risdiplam and nusinersen have already achieved substantial market penetration in SMA — risdiplam as an oral daily therapy and nusinersen as an intrathecal injection. Rather than displacing these established treatments, apitegromab is designed to add a complementary muscle-targeted benefit on top of the SMN-directed effect. The patent filings covering treatment-naive subjects (those not on an SMN pathway therapy) represent an additional, though likely smaller, target population.

The mechanistic rationale for combination therapy is also embedded in the patent disclosures. Because apitegromab targets the myostatin activation pathway — a muscle-intrinsic mechanism — and SMN therapies target the motor neuron deficit, the two approaches act on different biological nodes in the SMA disease cascade. This orthogonality is the scientific basis for the combination strategy and is likely to be a central element of any regulatory submission, as drug combination frameworks are well-established in guidance from the FDA.

The combination strategy also has implications for market access and payer negotiations. If apitegromab is approved as an add-on therapy, its value proposition will need to demonstrate incremental benefit over SMN therapy alone — a higher evidentiary bar than standalone approval, but one that, if cleared, positions the drug as a standard-of-care complement rather than a niche alternative. This commercial logic is consistent with patterns observed across other combination programmes in rare disease, as documented in health technology assessment frameworks.

Beyond SMA: Muscle Wasting Indications and the Broader Pipeline

Scholar Rock’s anti-pro/latent myostatin antibody patents are not limited to SMA. The foundational composition-of-matter filings — including WO2020150508A1, WO2021119539A1, and their US counterparts — explicitly list Duchenne muscular dystrophy (DMD) and other muscle wasting disorders alongside SMA as potential indications for apitegromab.

This breadth of indication coverage in the foundational patents gives Scholar Rock optionality to pursue additional indications without requiring entirely new composition-of-matter filings. The DMD indication is particularly notable: like SMA, DMD is a rare, progressive neuromuscular disease with significant unmet need in muscle preservation, and the myostatin pathway has been studied as a therapeutic target in DMD by multiple research groups, as documented in publications indexed by NIH PubMed.

The biomarker patent (US20230194565A1) adds another dimension to the pipeline story. By developing methods to assess myostatin pathway status in individual subjects — and to determine whether a subject is likely to respond to myostatin inhibitor treatment — Scholar Rock is building the companion diagnostic infrastructure that could support patient stratification across multiple indications. This is a strategy increasingly favoured by regulators and health technology assessment bodies, as it allows more precise demonstration of treatment benefit in defined subpopulations.

For IP strategists and drug developers monitoring this space, the combination of a well-layered patent estate, a combination therapy framework, and a biomarker programme represents a sophisticated multi-pronged approach to protecting and expanding the commercial opportunity of a muscle-targeted therapy platform. The trajectory of Scholar Rock’s filing activity — accelerating from 2022 onward — suggests that the clinical and regulatory programme is generating data that is feeding directly into new IP claims, a dynamic that can be tracked in real time through tools such as PatSnap’s life sciences analytics.