Risdiplam Showing Potential to Raise SMN Protein to Healthy Levels in SMA Babies and Adults, PTC Says in Interview

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by Emma Yasinski |

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Preliminary data from two ongoing clinical trials into risdiplam (RG7916) — a potential oral therapy for all types of spinal muscular atrophy — support its considerable promise, with treated babies now able to “roll, sit, kick … things that they [otherwise] never do,” the CEO of PTC Therapeutics said in an interview.

Data collected through Sept. 7 and presented at the recent Annual Congress of the World Muscle Society in Argentina showed that this small molecule raised the median CHOP INTEND score of 14 type 1 SMA infants in the open-label Phase 2/3 FIREFISH (NCT02913482) study by four points, from 37.5 at six months after the start of treatment to 41.5 at eight months.

“SMA type 1 babies never naturally achieve a score of 40 or greater,” Stuart Peltz, the company’s CEO, said in the interview with SMA News Today. “What we’ve shown so far … is that there’s a significant number of patients who were able to actually gain developmental milestones that they didn’t have previously. … improvements and the milestones [that] are probably the biggest achievements.”

Those milestones include babies, ages 1 to 7 months at study start, who can reach for things and lift their heads, and six who were even able to sit — three without support. Equally impressive, none have lost the ability to swallow, and none required a tracheostomy or permanent ventilation. Some of these patients are now about 2 years old.  

“In real life, what matters is what these babies are able to do,” added Nikolai Naryshkin, PTC’s vice president of biotechnology. “These are real-world functions that really matter to both patients and their families.” (Under a 2011 licensing agreement, Roche is leading work on risdiplam in partnership with PTC and the SMA Foundation.)

Data from a separate Phase 2/3 trial in type 2 and 3 patients ages 2 to 25, called SUNFISH (NCT02908685), also showed increases — a median of three points — in the Motor Function Measure 32 (MFM-32) scale over the course of a year. These findings in 30 patients were from data collected through July  6.

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“Three points can be quite significant,” Peltz said, adding that as the disease progresses, patients usually drop by one point each year. Just being able to move your hands to your head or brush your teeth “brings a sense of independence … that can have a more profound effect than you might think on a person.”

One patient, he said, spoke of wanting simply to lift his hand “several inches” higher, because “that could be the difference in whether you could feed yourself or not.”

Improvements were, as expected, more distinctly evident in younger than older SUNFISH patients.

“You’re always better off treating younger than older, because with time … the amount of muscle you have is less and less,” Peltz said. “In progressive neuromuscular diseases, the earlier you intervene, the easier you can see improvements in patients.”

The 51 people enrolled in the dose-ranging first part of SUNFISH were a “broad range” of types 2 and 3, and included many who were non-ambulatory and five with severe scoliosis. Those continuing or brought into the trial’s pivotal part two will be more homogeneous in terms of disability, Peltz said.

Aiming to correct splicing, a gene’s job

SMA is a genetic disorder, where the survival motor neuron (SMN) gene produces little or no SMN protein. The act of creating a protein begins with the gene encoding a string of pre-messenger RNA, which is edited to remove some unwanted sections through a process called splicing. Messenger RNA (mRNA) then comes in and uses the spliced gene to finish the job. But the dysfunctional SMN gene splices the pre-mRNA poorly, so that little functional SMN protein develops, and muscles atrophy.

Risdiplam, a once-a-day liquid treatment that can be taken by mouth or through a feeding tube, modifies the way the pre-mRNA is spliced, helping to produce more copies of working SMN protein.

“Always in our target plan was to have an orally bioavailable small molecule” for ease of administration and because a small molecule can reach tissue anywhere — both inside and outside the central nervous system — crucial in a disease like SMA that affects muscle throughout the body, said Peltz, who founded PTC  in 1998 after years spent teaching RNA biology at Rutgers University in New Jersey.

He was approached by the SMA Foundation at a muscular dystrophy meeting in 2004, and asked if his company might be “interested in studying and doing things in SMA.”

Work began on what would become risdiplam in 2006, Peltz and Naryshkin said. The foundation pitched in with financial support, tools ranging from animal models and cell lines to disease natural history, and expertise both in SMA biology and the “patient voice and perspective.”

As a small molecule, risdiplam penetrates the blood-brain barrier to reach the central nervous system — the brain and spinal cord — and circulates to tissues elsewhere via the bloodstream. While the central nervous system is where the disease exerts its most profound effects, “we knew that it was a muscle disease, a nerve disease, liver, bone,” Peltz said. “So to have something that was oral that would distribute to all the tissues was important.” 

In part one of FIREFISH, 21 infants were given ascending doses of risdiplam daily for four weeks. PTC said the most effective doses were 0.08mg/kg for infants 6 months and younger, and 0.2mg/kg for those older than 6 months. Treatment was well-tolerated with no child withdrawing from the study for safety reasons, although serious adverse events were reported in 10 infants — traced to the underlying disease — two of which were fatal.

Its purpose was to determine safety, but researchers looked for signs of efficacy as well. Along with the improved CHOP INTEND scores, the babies achieved several motor milestones not seen in the natural progression of SMA — assessed through the Hammersmith Infant Neurological Examination (HINE) Module 2 — such as kicking (seven infants), sitting with or without support (six; three unsupported), holding their head upright (six), and rolling to the side (four).

Sitting without assistance for at least five seconds is a primary measure of treatment effectiveness in part two of the study, now underway and enrolling another 40 infants, 1 to 7 months, at sites in the U.S., across Europe, Canada, Brazil, and Asia (more information can be found here). All will be treated for 24 months at those optimal doses.

“Why we know the drug is demonstrating clinical benefit is because they’re now performing developmental functions that, in the absence of treatment, they’d never be able to do,” Peltz said. “That’s why we’re so excited about this.”

In SUNFISH’s dose-testing part one, 51 SMA type 2 or 3 children and young adults with a wide range of functional abilities were randomized to increasing doses of risdiplam or placebo for 12 weeks. Among the 30 patients whose data were presented at the Muscle Society meeting, 14 were treated at the optimal 5 mg dose that is being used in part two, and 21 with a lower dose.

A large majority, 76.5%, in the younger age group (2-11 years old) showed improvements upon treatment in MFM-32 scores — which measures 32 tasks focused on upper and lower limb strength, and hand, finger and neck muscle strength — compared with 46.2% in the older group (ages 12-25).

“They’re all moving in the right direction,” Naryshkin said.

Importantly, pooled data showed that blood levels of this key muscle protein reached or surpassed those “in the range of healthy adult subjects” after four weeks of risdiplam treatment, and in SUNFISH patients treated at optimal dose, this increase has been maintained over one year. Rising SMN protein levels also were observed independent of a patient’s number of SMN2 gene copies.

Now at one year of treatment, the 168 patients participating in SUNFISH continue to tolerate risdiplam well, with none withdrawing due to safety concerns. In part one, 90.2% reported adverse events, PTC noted, but all “were generally reflective of the underlying disease.”

Researchers in this and other studies also observed sustained increases in the amount of functional SMN protein in patients’ blood after one year, regardless of disease type. This biomarker represents not only the amount of properly spliced SMN protein in the blood, but, PTC believes, the amount likely to be found in the brain.

Blood levels “gave us a biomarker,” Peltz said. “We can take blood out and see that the SMN transcript was spliced in blood, and then — in all the animal models — we showed that what you saw in the blood was what you saw in the brain.”

New trials for potential ‘best-in-class’ therapy

The company is readying eligible patients for two newer trials — the yet-to-open RAINBOWFISH in pre-symptomatic SMA type 1 infants, and the 24-month JEWELFISH (NCT03032172) safety study, enrolling SMA type 2 or 3 infants to adults, 6 months to 60 years old, including those who took part in earlier studies into SMN2-targeting therapies like Spinraza (nusinersen) — or used Spinraza after its approval— and investigational treatments like olesoxime (TRO19622,) which Roche pulled from development after disappointing trial results this year.

Risdiplam is intended to be a monotherapy, but PTC is open to using it to supplement other treatments, if all continues to go well in these pivotal trials. AveXis‘ SMA gene therapy, AVXS-101, now up for approval to treat type 1 babies by regulatory authorities in the U.S, Europe, and Japan, in particular may be “potentially complementary to risdiplam/maintenance therapy.”

And as an oral liquid, risdiplam may hold advantages over Spinraza, the first disease-modifying treatment approved in 2016 for all SMA types, which is administered by spinal infusion (intrathecal injection).

It will stand on its own if approved, Peltz and Naryshkin stressed. “What we’ve done and shown so far is … increases in [SMN] protein levels once patients start taking risdiplam, as measured in the blood,” meaning a bodywide rise. All in all, Peltz added, a sign that “bodes very well for [risdiplam] to have the potential to be best-in-class.”