In 2016, the first treatment for spinal muscular atrophy (SMA) was approved. Seven years on, there are just five marketed drugs for the indication according to GlobalData’s Pharmaceutical Intelligence Centre. More treatments are effective in type 1 SMA but those diagnosed with type 2 or 3 continue to struggle to access treatment. Those with Kennedy’s disease, known as Spinal and Bulbar Muscular Atrophy (SBMA), have no effective treatments that have been approved.

GlobalData is the parent company of the Clinical Trials Arena.

Significant progress has been made over the past seven years but it remains difficult for patients to receive treatment for the disease due to inaccessibility. Are any trials looking to combat the unmet needs for patients, including lack of access to treatment?

Apitegromab could improve symptoms when combined with SMN2 therapies

The Phase III SAPPHIRE trial (NCT05156320) is investigating the pipeline drug apitegromab in development by Scholar Rock. The trial, which commenced in November 2021, is a double-blind, placebo-controlled trial to evaluate the efficacy and safety of apitegromab (SRK-015) in patients who have later-onset SMA receiving background nusinersen or risdiplam therapy. The trial started several months after the US Food and Drug Administration (FDA) granted Fast Track designation for the drug in March 2021 after successful trials in type 1 patients. The trial will complete in June 2024.

It is under development for the treatment of type 2 and type 3 SMA and is administered intravenously. The drug candidate blocks the activation of latent myostatin with the aim of improving patients’ motor function. Myostatin is a member of the TGF beta superfamily of growth factors expressed primarily in skeletal muscle cells to inhibit muscle growth.

Dr Rose Joachim, director of Neurology at GlobalData, says that the different MOA that apitegromab offers in the SAPPHIRE trial could assist type 2 and 3 patients with very limited treatment options. “We have two SMN2 regulators on the market and in this study, they're studying apitegromab on top [of those therapies] trying to get even stronger of a response by targeting a different mechanism. It’s definitely exciting,” Joachim says.

Dr Sharon Hesterlee, executive vice president and chief research officer of the Muscular Dystrophy Association, believes apitegromab will work well with an SMN2 regulator due to the treatments having different targets. “I think it's interesting to see these myostatin inhibitors coming because that's a really novel approach to complement what you're doing in the cell itself.” Hesterlee explains.

While Dr Leigh Ramos-Platt notes that this drug will be used to complement current therapies. She is the medical director of the Muscular Dystrophy Association Neuromuscular Clinic at Children’s Hospital Los Angeles, one of the sites where Scholar Rock is conducting this trial. “While the SMN2 up regulators can be helpful with preventing them from progressing further, we do need something to help patients get better. That’s what we are looking at in this trial,” Ramos-Platt says.

Are researchers close to finding a functional cure?

Novartis is nearing the end of its Phase III STEER trial of onasemnogene abeparvovec, marketed under the name Zolgensma. It is a randomised, sham-controlled, double-blind study (NCT05089656) to evaluate the efficacy and safety of intrathecal OAV101 in type 2 SMA patients who are 2 to 18 years of age, treatment-naive, sitting, and never ambulatory. The trial is due to end on 31 July 2024.

Onasemngene abeparvovec is a gene therapy administered intrathecally intended for patients with inherited mutations affecting the SMN1 gene. These patients have either been diagnosed with SMA type 1 or have up to three copies of another gene known as SMN2. If proven efficacious, this trial will allow the treatment to be used in type 2 patients.

Joachim says that onasemngene abeparvovec appears to offer something close to functional cure but the real question is the longevity. Joachim explains, “I think it is a functional cure in [the] infantile [SMA] patients that it's [used in] treating right now so to be able to expand that to older patients, that would be really revolutionary for sure.”

Ramos-Platt says that this trial will hopefully address a big unmet need of Zolgensma. “The unmet need right now is in the US cap for this is at two years of age. Once patients are over two years of age, they cannot receive this gene therapy,” Ramos-Platt says. “It’s already approved in other countries but it's based on weight so even then, once you hit a certain weight, you can't get it. This trial is looking at dosing in older, heavier patients.”

Nusinersen is being tested at higher doses – will it remain safe and tolerable?

The DEVOTE study (NCT04089566) by Biogen is investigating the clinical efficacy of Spinraza (nusinersen) administered intrathecally at higher doses to subjects with SMA, measured by change in Children's Hospital of Philadelphia - Infant Test of Neuromuscular Disorders (CHOP- INTEND) total score. The study will also examine its safety and tolerability.

The Phase II/III DEVOTE trial is due to end on 3 April 2024 and is a randomised, parallel assignment, global, double-blind, active-controlled, open label, pivotal, three-part, sequential assignment, dose escalation, treatment and multi-centre study. Nusinersen was approved for use in December 2016, becoming the first approved drug to treat SMA. Despite the drug being approved for seven years, investigators continue to test it to see how effective it can be for different patient groups and in different doses.

Joachim says that this could help patients but only if having a higher dose continues to be safe and well tolerated. “It could definitely be helpful to patients if it's found that it's safe to be administering that higher dose,” Joachim believes. “Some years ago, numerous physicians [interviewed by GlobalData] were a little bit unhappy with the efficacy of Spinraza, but potentially increasing the dose could improve outcomes.”

Ramos-Platt adds: “Patients get dosed every four months, it doesn't sound like it's a lot, but if you look at that over a lifetime, that's a lot of intrathecal injections. So this particular trial is trying to address one, can we give patients that are older a higher dose so that they don't feel that we're off effect before their next dose is due?”

“The other thing that they're also trying to answer is that can we make it less frequent? Which would be a lot easier for families.”

Asthma medication could help resolve symptoms of Kennedy’s disease

A Phase II study (EudraCT-2017-005103-27) being conducted by the University of Padova in Italy is investigating the efficacy and safety of clenbuterol. The drug was approved for asthma patients in 1980 and is marketed as Monores but now, investigators are testing the pill in SBMA patients. A pilot study conducted in 2013, which involved 16 SBMA patients, showed that clenbuterol appeared to improve stamina levels in people with SBMA. The Phase II study is due to end on 8 November 2023.

Joachim says that due to there being no treatment for Kennedy’s disease, it is good to see something being tested that could improve symptoms. “There're several studies where they've looked at using clenbuterol and [assessed] its effects of halting muscle wasting,” Joachim explains. “There's just absolutely nothing for Kennedy's disease so anything that could help improve quality of life and slow progressive loss of muscle strength would be really, really helpful.”

While Hesterlee says: “They haven't been incredibly effective in most disorders where they've been tried but it doesn't mean that they wouldn't work in SBMA. If it's effective, that would be of course fantastic for those patients, particularly since it's a drug that should not be too expensive.”

Why is the clinical landscape so limited for the treatment of SMA?

There does seem to be more hope for patients with SMA as more trials are being conducted however, it continues to be difficult for researchers to conduct SMA trials for a number of factors given a myriad of reasons.

“This is a rare disease so sometimes that slows development as well, because the patient population isn't that big,” Joachim declares. “I think that it was probably hard to first understand the mechanisms to target but now they're kind of just building on that. After the first drug was approved in 2016 they really just started to build on that.”

As well as this, Hesterlee explains that she believes it took some time after the first few drugs hit the market for pharmaceutical companies to work out whether there was still unmet need but that development is now picking up again. “The first drugs were so effective, so people were waiting to see what the unmet need was and whether there was room to do drug development around that space,” Hesterlee says. “Now we might start seeing more because usually, you see a strong follow on if you get an approval. But I think overall, understanding if there is still unmet need was important.”