The systemic nature and high specificity of risdiplam — an oral treatment under review in the U.S. to possibly treat all types of spinal muscular atrophy (SMA) — are key to its effectiveness and favorable safety profile.
In an interview with SMA News Today, Paulo Fontoura, MD, PhD, global head of neuroscience and rare disease clinical development for Roche, discussed risdiplam’s potential and likely reasons for its reported success in a broad range of SMA patients whether defined by disease type, age, or disability level.
Risdiplam — developed by Roche and Genentech in collaboration with PTC Therapeutics and the SMA Foundation — works by correcting an event, called alternative splicing, that limits to between 10% and 15% the amount of functional SMN that a second survival motor neuron gene, called SMN2, produces.
Alternative splicing allows for a single gene to give rise to many different proteins. Much like in a recipe, adding or removing certain key ingredients — in this case, pieces of genetic information called exons — can change what results: the messenger RNA (mRNA) and final protein. (mRNA is a molecule derived from DNA and used as a template for protein production.)
In SMN2, this splicing event results in the exclusion of exon 7 from most mRNA molecules this gene produces, resulting in a shorter, poorly working SMN protein. By correcting SMN2’s splicing, risdiplam prevents exon 7 deletion from this gene’s mRNA and “restores” the production of a functional SMN protein.
Available clinical data to date — from the Phase 2/3 SUNFISH (NCT02908685) and FIREFISH (NCT02913482) trials — show that risdiplam has a very favorable safety profile. They also, respectively, show that its use significantly improves motor function in infants with type 1 SMA, and in children and young adults with SMA types 2 and 3.
Together, these trials involved more than 200 people with SMA types 1, 2, and 3, ages 1 month to 25 years old.
SUNFISH details yet to come …
While still not disclosing the risdiplam dose used in SUNFISH — the first placebo-controlled trial to include SMA types 2 and 3 patients ages 2 to 25 — Fontoura noted that it was adjusted to different age groups due to differences in metabolism and weight.
SUNFISH findings released thus far showed that motor function improvements were more pronounced in younger patients (2–5 years old) than in older ones (18–25 years old). Young adults mainly showed stabilization in their motor abilities.
That is “expected and totally in line with data which is already out there for other [therapies],” as “the expectations for treatment benefit are also different” between children who are still growing and gaining in motor milestones and those who are not. In older patients, a main treatment goal is to prevent further loss of motor function, or stability.
Detailed results on motor benefits with risdiplam’s use in all age ranges were expected to be presented at the 2020 American Academy of Neurology (AAN) annual meeting, set to open April 25 in Toronto. But AAN was canceled due to the COVID-19 pandemic, a first in the conference’s 72-year history.
“As soon as we have a venue that we know we can present those data in, we’re going to come forward,” Fontoura said.
Roche also plans to evaluate whether SMN protein or other blood biomarker levels associate with improved motor function in SMA patients. If so, they could be used to monitor or predict treatment outcomes.
SMN levels in healthy people “fluctuate a lot,” challenging the definition of a “normal level that we need to target,” Fontoura said. So researchers have focused on differences in SMN levels before and after treatment, aiming to see at least a two-fold increase. Such a rise in protein levels was found to be “very directly correlated with a massive increase in survival” in animal models.
So far, patients treated with risdiplam have shown a three-fold mean increase in blood SMN levels, with many of them achieving up to a six-fold increase, the neurologist added.
Risdiplam’s effectiveness, however, can also be assessed by measuring the levels of the normal SMN mRNA against the shorter version (without exon 7). According to Fontoura, virtually no levels of the shorter SMN mRNA were detected in most treated patients — at all dose levels studied — highlighting that SMN2 was largely producing only normal SMN mRNA.
SMN protein levels measured in the blood are considered to reflect those present in the brain and spinal cord, he emphasized, as risdiplam’s oral administration — it’s a liquid taken by mouth daily — provides for systemic (bodywide) distribution with an equal “penetration” between brain and peripheral tissues.
… but oral benefits a likely plus
Risdiplam’s systemic nature is a key feature when treating a disease that affects not only the central nervous system (CNS; brain and spinal cord), but also peripheral tissues, such as muscle, the neuromuscular junction — the point of contact where a motor nerve cell reaches and communicates with a muscle cell — and the heart, bones, and liver.
“The systemic distribution of risdiplam is an important feature of this [therapy]. It certainly … contributes to the efficacy, because we know that the defect in the gene product affects multiple tissues beyond the CNS.”
Still, “it’s hard to separate what comes from one [CNS] or the other [peripheral tissues], because we measure motor function as an outcome, and motor function is dependent on all of them … intact neurons, intact neuromuscular junction, and intact muscles,” Fontoura added.
He expects that the importance of rising SMN levels in peripheral tissues will likely become more evident as long-term data on risdiplam use is available.
Safety continues to be favorable. “The really key thing around safety is the specificity” of a therapy, meaning a lack of off-target effects. Risdiplam has a high specificity to SMN2, affecting only a small number of other genes.
FOXM1, a gene involved in the regulation of cell division, was the company’s main safety concern, Fontoura said, as high levels of risdiplam affected FOXM1 splicing, resulting in the production of a protein that halts cell division.
Based on this, “a very, very strict monitoring program, both preclinically and in the clinic,” was developed to ensure that risdiplam at ideal doses would be below that troublesome threshold and not affect cell division.
“At the therapeutic value that we have studied, where you see clinical benefits, you really see no impact in those issues,” Fontoura said.
The U.S. Food and Drug Administration (FDA)’s decision on risdiplam is now expected on or before Aug. 24, a three-month delay necessitated by the agency recently asking that SUNFISH top-line data be included in its ongoing review.
Risdiplam is also now under review by regulatory agencies in Indonesia, Taiwan, Chile, Brazil, South Korea, and Russia.
Filing of a similar marketing application is imminent in China, and expected around mid-year to the European Medicines Agency and other health agencies.
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