Top 10 SMA Stories of 2020

SMA News Today brought you daily coverage of the latest scientific findings, treatment developments, and clinical trials related to spinal muscular atrophy (SMA) throughout 2020.

We look forward to reporting more news to patients, family members, and caregivers dealing with SMA during 2021.

Here are the top 10 most-read articles of 2020, with a brief description of what made them relevant for the SMA community.

No. 10 — “ZPR1 Protein May Be New Potential Therapeutic Target for SMA, Preclinical Study Suggests”

Researchers in the U.S. found that increasing the levels of ZPR1 — a protein found in low levels in SMA patients — improved growth, muscle strength, motor function, and survival in a mouse model of the disease. Further analyses in cells from the mouse model and SMA patients revealed that ZPR1 directly promotes the production of survival motor neuron (SMN), the protein lacking in SMA, lessening SMA-associated accumulation of DNA damage and subsequent nerve cell loss. These findings point to ZPR1 as a potential new therapeutic target for SMA, but further studies are needed to better understand its mechanisms of action and to test several methods of increasing its levels.

No. 9 — “Guidance on Zolgensma in Europe Notes Lack of ‘Evidence’ for Broad Use”

Nearly two months after Zolgensma’s approval in Europe for treating almost all SMA types in children weighing up to 21 kilograms (about 46 pounds) — which may cover those up to age 5 — a panel of European experts issued a consensus statement stressing that trial evidence of its benefits was lacking for those beyond early infancy. Therefore, data on its use in the broader population needs to be collected and, in the meantime, treatment decisions need to be made on a case-by-case basis, panel members noted. The statement also offered general guidelines covering many aspects of Zolgensma treatment, including patient selection — which has to consider additional factors besides the traditional SMA types, safety considerations, and long-term monitoring.

No. 8 — “Protest Secures Spinraza for All SMA Patients in Romania”

In the beginning of the year, we reported the success of an October 2019 protest by adults with SMA requesting that all SMA patients in Romania be given free access to Biogen’s Spinraza (nusinersen) — the first disease-modifying therapy approved for all SMA patients. While the therapy was approved in the European Union in May 2017, health authorities in each member state decide whether to include it in their public health programs, where patients can access the treatment at low or no cost. By the time of the protest, many children and all adults with SMA in the country were still waiting to gain access to the therapy. A universal coverage agreement between Romania’s National Health Insurance Agency, Biogen, and the company’s European partner, Ewopharma, was reached in December 2019.

No. 7 — “Novartis to Open, at FDA Request, New Trial of Zolgensma for Older Patients”

In September, Novartis announced its plans to launch a new clinical trial evaluating AVXS-101, administered directly into the spinal canal (intrathecal injection), in older SMA patients. AVXS-101 is approved as Zolgensma when given through an into-the-vein (IV) infusion. The therapy’s intrathecal administration is favored for those beyond toddler age, as it is thought to better target motor neurons — the specialized nerve cells that control voluntary movements and are progressively lost in SMA. The decision followed the U.S. Food and Drug Administration (FDA) request for an additional trial to further support the regulatory submission for intrathecal administration, as well as the therapy’s benefits in older patients. Findings from this future trial will complement existing data from the Phase 1 STRONG trial (NCT03381729) in SMA type 2 children up to 5 years old, which was placed on an FDA partial hold in October 2019 due to concerning side effects seen in a primate study. According to Novartis, the upcoming trial cannot include U.S. sites until the hold on STRONG is lifted.

No. 6 — “Spinraza-Zolgensma Combination Well-tolerated in Children with SMA Type 1, Study Shows”

Researchers in the U.S. reported the cases of five children with type 1 SMA who were treated with both Zolgensma and Spinraza. While both treatments work to restore the levels of the SMN protein, they do so through different mechanisms. Zolgensma, a one-time gene therapy developed by AveXis (a Novartis’ subsidiary now known as Novartis Gene Therapies), uses a modified and harmless virus to deliver a healthy copy of SMN1, the mutated gene in SMA that contains the instructions to produce SMN, to cells. Spinraza, given directly into the spinal canal every four months, targets SMN2, a backup gene that can partially compensate for the loss of SMN1-derived SMN.

Four children received the gene therapy after initiating Spinraza treatment and at older ages than those evaluated in Zolgensma’s clinical trials. One child received Zolgensma first, followed by Spinraza, and was the only one to receive the gene therapy within the age range studied in clinical trials. Data showed that combining both therapies was generally well-tolerated, while sustaining the children’s motor improvements. Of note, results also suggested that older patients may be at a higher risk of developing gene therapies’ known side effects, such as liver dysfunction and low platelet counts.

No. 5 — “Risdiplam Use ‘Meaningful’ to Broadest SMA Group Ever in Clinical Trial, Genentech Exec Says”

In a February interview, Susan Begelman, MD, a vice president at Genentech, discussed the promising results of the Phase 2/3 SUNFISH trial (NCT02908685) evaluating Evrysdi — then known as risdiplam — in the broadest range of SMA patients, by age and disability level, yet enrolled in a clinical trial. In SUNFISH’s second part, 180 wheelchair-bound SMA type 2 or 3 patients, ages 2 to 25, were randomly assigned to either oral Evrysdi (whose optimal dose was determined in the trial’s first part) or a placebo, once daily for one year. More than 30% of the participants were at least 12 years old, had severe scoliosis, or had severe disability — features that would typically make patients ineligible for an SMA clinical trial, Begelman emphasized.

One-year data showed that the therapy led to sustained increases in SMN levels and “clinically meaningful” improvements. These were represented mainly by motor function gains in the youngest age group (2–5 years old) and stabilization in the oldest group (ages 18 to 25). All participants were given the option to continue being treated with Evrysdi for an additional year.

No. 4 — “Risdiplam Continues to Show Promise for Treating SMA, Data Show”

Consistent with the results from SUNFISH’s second part, two-year data from its first part showed that Evrysdi treatment sustainably raised SMN levels and significantly improved motor function in children and young adults with types 2 and 3 disease, compared with SMA’s natural course. After an initial 12-week, dose-finding phase, all 51 ambulatory (able to walk) and non-ambulatory patients enrolled in part 1 had been moved to Evrysdi’s optimal dose — focused on achieving a sustained twofold increase in SMN levels. In addition, preliminary one-year data from the open-label Phase 2 JEWELFISH trial (NCT03032172) showed that the therapy safely and effectively increased SMN levels in SMA type 1, 2, and 3 patients, ages 6 months to 60 years, who were previously treated with other disease-modifying therapies.

No. 3 — “18 States in US Screening Newborns for SMA as Efforts Continue for More, MDA Says”

By February 2020, 18 states were screening newborn babies for SMA, while others had begun pilot screening or were considering doing so. SMA was first nominated to be included in the Recommended Uniform Screening Panel in November 2008, but was only officially added in July 2018. Notably, since newborn screening has considerable costs, each state decides whether to screen for each of the 35 diseases included in the panel, either by legislative action or a governor issuing an executive order. The 18 states with SMA screening programs at the time of the article’s publication are Colorado, Connecticut, Indiana, Kansas, Kentucky, Maryland, Massachusetts, Minnesota, Missouri, Mississippi, New Hampshire, New York, Pennsylvania, Utah, Vermont, West Virginia, Wisconsin, and Wyoming.

No. 2 — “FDA Approves Risdiplam, as Evrysdi, 1st Oral Treatment for All SMA Types”

In August, the FDA approved Evrysdi as the first oral and at-home treatment for adults and children 2 months of age and older with all types of SMA. The decision made Evrysdi the third SMA disease-modifying treatment to become available since 2016. Developed by Roche and Genentech in collaboration with PTC Therapeutics and the SMA Foundation, Evrysdi is a small molecule designed to boost SMN production in cells throughout the body (including not only motor neurons but also cells in other tissues and organs) by targeting the backup gene SMN2. The FDA’s decision was based on top-line data from the ongoing Phase 2/3 FIREFISH (NCT02913482) and SUNFISH trials. Of note, FIREFISH’s top-line data included 41 type 1 infants, ages 1 to 7 months. Both trials met their main and most secondary goals, showing that one year of Evrysdi’s use resulted in significant improvements in motor milestones in babies with type 1 SMA, and in motor function in children and young adults with types 2 and 3 disease.

No. 1 — “Roche Starts Global Early Access Program for SMA Therapy Risdiplam in Europe”

Our most-read article of 2020 concerned Roche’s launch of a worldwide early access program for Evrysdi in January, which started by making the therapy immediately available to European patients with SMA type 1, the disease’s most serious form. This type of program is meant to provide access to therapies not yet approved for commercial use to people with life-threatening or seriously debilitating conditions and an unmet medical need. Evrysdi was expected to also become available to those with type 2 disease upon Roche’s filing of an application to the European Medicines Agency seeking Evrysdi’s approval, which was accepted in August and is currently being reviewed by the agency. The program was meant to start in other countries that also reached an early access agreement with Roche.

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At SMA News Today we hope these stories and our reporting throughout 2021 help to better inform and improve the lives of everyone affected by SMA.

We wish all our readers a happy 2021.