[Editor’s note: This is the third in a series of articles on Zolgensma and treatments for SMA, the issues they raise, and possible discoveries to come, all drawn from recent interviews with neurologists and researchers involved in this work. Others in this series can be found here.
SMA News Today is also interested in speaking with families of children treated with Zolgensma in its approved form, using intravenous injection, to share their experiences and opinions with our readers. If you or those you know are open to this interview, please contact us at [email protected]]
Parents of children born with spinal muscular atrophy are among those most riveted by news of a gene therapy for this devastating neuromuscular disease. But what options exist, and which might open in a not-too-distant future, for all those older than 2 years old — who cannot yet use Zolgensma as approved?
“This certainly has been a very exciting time … for potentially intervening early” and altering the disease’s course in babies, John Brandsema, MD, a pediatric neurologist at the Children’s Hospital of Philadelphia (CHOP), said in an interview with SMA News Today.
“Whether there might be potential to further expand the label” to treat other SMA groups, he added, need wait until “there’s more experience on the research side either in patients who are older or at a different [disease] stage.”
One alternative, however, has been around for a few years now.
Spinraza (nusinersen, by Biogen) is a spinal infusion therapy that works as an SMN2 splicing modifier, enabling that gene to create a full-length and functional SMN protein, preventing the progressive loss of motor nerve fibers that results in ever more extensive muscle weakness and atrophy (shrinkage).
It became the first disease-modifying SMA treatment approved by the U.S. Food and Drug Administration just days before Christmas in 2016, followed by the European Medicines Agency in June 2017. Regulatory agencies in Australia, Canada, and Japan, among others, also came to support its use.
These approvals cover all SMA patients, regardless of disease type, and repeat reports on its clinical use — as well as continuing trial data — support its effectiveness and safety in infants, children, and adults.
Zolgensma (onasemnogene abeparvovec-xioi), developed first by AveXis and now by Novartis (which acquired AveXis in 2018), is the second such therapy, and said to be a one-time treatment. Its viral transporter contains a working copy of the SMN1 gene, which is rendered non-functional by mutations in most SMA patients, to restore healthy SMN protein levels.
It’s in testing in a range of SMA patients, from presymptomatic newborns to — importantly — type 2 children up to 5 years old. Results from this currently recruiting clinical trial, known as STRONG (NCT03381729) and due to conclude in September 2020, are expected to inform REACH, a future trial in patients up to age 18.
Risdiplam, a potential oral therapy
Looming among SMA treatment possibilities is a liquid medicine — risdiplam — advancing in clinical trials for types 1, 2, and 3 and intended to be swallowed or given through a feeding tube once daily.
Should a gene therapy’s gains eventually show some wear, say as someone treated in infancy reaches adulthood, “then coming back with risdiplam later on” would “definitely [be] an option” of interest, said Arthur Burghes, PhD, a researcher at The Ohio State University College of Medicine and professor of biological chemistry and pharmacology.
Because, he added, if risdiplam wins approval, “then you have a drug compound that can be relatively easily administered to adults.”
Developed by Roche and Genentech in collaboration with PTC Therapeutics and the SMA Foundation, risdiplam, like Spinraza, is aimed at increasing the ability of the SMN2 gene to generate a full-length SMN protein in motor neurons, specialized cells that control muscle contraction. Without this boost, SMN2 mostly produces an unstable and shorter-than-usual form of SMN, the protein severely lacking in SMA patients.
As such, risdiplam — again like Spinraza — is a splicing modifier, meaning it can change the way pre-messenger RNA (mRNA) molecules — those generated from DNA before protein production — are spliced or “edited” to generate full-length mRNA and a working SMN protein.
The European Medicines Agency granted risdiplam priority medicines, or PRIME, status in December 2018, assisting its development, based on the positive findings of two Phase 2/3 trials: FIREFISH (NCT02913482), an open-label study, and SUNFISH (NCT02908685), which includes a placebo group. The FDA earlier designated risdiplam an orphan drug, a move that also speeds clinical work.
One-year results from FIREFISH — a two-part trial initially in 21 babies enrolled at 1 to 7 months with SMA type 1 — showed crucial one-year benefits in 18 children, including no one moving to permanent ventilation and all preserving the ability to swallow. A majority, 85%, were able to eat orally. (Three of these 21 infants died of causes unrelated to treatment.)
A four-point or higher improvement in CHOP-INTEND scores — a measure of motor abilities — was also seen in 86% of this group compared with the study’s start (baseline). Among 17 infants given the higher and therapeutic dose, seven were able to sit without support for at least five seconds, 11 were able to sit with or without support, and nine could hold their heads upright with control. One was able to stand.
FIREFISH, which enrolled another 41 infants for its confirmatory part two, is expected to conclude in September 2020.
“By being able to sit upright, you’re also able to move your arms, perhaps eventually feed yourself. That’s a critical milestone,” Susan Begelman, vice president for the Rare Disease and Neuroscience Medical Unit, U.S. Medical Affairs at Genentech/Roche, said in an interview at a May scientific conference.
Interim results from SUNFISH, also a two-part trial but in a “broad range” of type 2 or type 3 patients ages 2 to 25, showed a more than two-fold increase in median SMN protein blood levels after one year over pretreatment levels, and three-point improvements in motor function (using the Motor Function Measure-32 scale) in 58% of the 43 patients who could be evaluated at that one-year mark.
Three-point gains were seen in 71% of younger patients (up to age 11), and in 42% of those ages 12 to 25.
SUNFISH has enrolled 231 patients in total, and is set to be completed in July 2020.
JEWELFISH (NCT03032172), a safety and tolerability study, is now recruiting up to 180 type 2 or 3 patients, 6 months to 60 years, who took part in the Phase 1 MOONFISH (NCT02240355) study or were previously treated with Spinraza, Zolgensma, or olesoxime.
Although designed to stand alone, risdiplam’s developers are open to alternatives. “The potential for combination therapies is on everyone’s mind: healthcare providers certainly, certainly ours,” Begelman said. “But that would have to be studied.”
Muscle builders and an oral DMT
SRK-015, Scholar Rock’s investigational therapy for muscle strength, is now in a proof-of-concept Phase 2 trial (NCT03921528), called TOPAZ, in type 2 and 3 patients, ages 2 to 21, that’s enrolling at its two U.S. sites.
The therapy, given orphan drug status by regulatory authorities in both the U.S. and EU, is a man-made antibody engineered to block the activation of latent (immature) myostatin, a negative regulator of muscle mass that’s largely found in skeletal muscle cells. When active, Myostatin is known to inhibit muscle growth, and lowering its activity levels is associated with greater muscle mass and strength.
Also targeting muscle function is Cytokinetics‘ reldesemtiv. Results from an exploratory Phase 2 trial (NCT02644668) showed gains in exercise capacity and respiratory muscle strength in reldesemtiv-treated patients with SMA types 2–4, given one of two doses (150 mg and 450 mg) compared with placebo.
Reldesemtiv, granted orphan drug designation by the FDA, is a selective fast skeletal muscle troponin activator intended to slow calcium release from fast skeletal muscle fibers and improve muscle contraction. As such, it’s meant to complement existing SMA treatments, and is also being studied to possibly treat amyotrophic lateral sclerosis (ALS).
Novartis has another potential disease-modifying treatment making its way through testing: the oral SMN2 splicing modifier LMI070 (branaplam).
A Phase 1/2 open-label trial (NCT02268552) is now assessing the safety, tolerability, pharmacological properties, and efficacy of LMI070 in up to 44 type 1 infants, newborns to 6 months old. The trial, which is recruiting at sites across Europe, is expected to conclude in July 2020.