Wednesday, May 8, 2019

The treatment landscape for spinal muscular atrophy,


The treatment landscape for spinal muscular atrophy, or SMA, a rare and potentially lethal genetic disease, is about to change. Until the 2016 approval of nusinersen (Spinraza) from Biogen (NASDAQ: BIIB), there were no approved medicines to help slow the progressive weakness that characterizes the disease. Infused into the spine a few times a year, for life, Spinraza has shown it works for people with multiple forms of SMA. It is now the standard of care for the disease and generated $1.7 billion for Biogen last year.

But other treatments are coming, which, as Xconomy reported last week, will present doctors and payers with tough logistical and economic questions. The two treatments under the microscope at AAN are Zolgensma, from Novartis (NASDAQ: NVS), and risdiplam, from Roche and partner PTC Therapeutics (NASDAQ: PTCT).


The gene therapy ideally would provide the same benefits as Spinraza, but through a single long-lasting infusion. The FDA could approve Zolgensma this month.

Prior to AAN, Zolgensma has shown promise in Type 1 SMA, the deadliest form of the disease, diagnosed within six months of birth. On Sunday, the Basel, Switzerland-based pharma offered more Type 1 data from the STR1VE study. But it also offered the first glimpse of studies meant to show that, like Spinraza, Zolgensma can help others with the disease as well. The STRONG study is testing Zolgensma in Type 2 patients who could sit, but not stand or walk, at the start of the study. Pre-symptomatic patients got Zolgensma in a study known as SPR1NT.

Both trials compare Zolgensma’s effects to historical data, not a placebo. Those effects are measured via tests (CHOP-INTEND, HFMSE, and Bayley-III Gross Motor Milestones) that assess physical abilities and developmental milestones. One key milestone is whether patients are alive and not using a ventilator at the age of 14 months.

Patients in STRONG were followed a median of 6.5 months after treatment, in SPR1NT, 5.4 months. At this point, neither study has lasted long enough to assess Zolgensma’s promise of a long-lasting treatment, let alone a cure. The data are being closely watched, despite not including results from the highest dose in the study. Here’s a snapshot.

STRONG: Novartis put Type 2 patients in two groups: babies six to 24 months of age, and young children two to five years old. For babies, the study’s main goal is to help them stand or walk without support for more than three seconds. For young children, the goal was a positive change on the HFMSE.

Two of the 16 babies evaluated thus far can stand without help. One of them can walk. One of the 12 young children can walk with assistance. All the patients, at minimum, maintained their abilities from the study’s start, like rolling over, controlling their head, and more. Seven of the babies and three of the young children gained an ability. All the patients are still alive, and those who have gone through HFSME evaluations have seen their scores increase.

The only serious side effects were a temporary spike in liver enzymes, a common occurrence in gene therapy trials.

SPR1NT: Novartis enrolled 18 newborn patients who had yet to show symptoms and had either two or three copies of the SMN2 gene, a predictor of disease severity. The more SMN2 genes a person has, the more mild their disease will be. (SMN stands for spinal motor neuron.)

Thus far, all 18 patients are alive. Four of eight patients with two SMN2 copies could sit independently following treatment, and one could walk. Historical data suggest these patients would never hit those goals otherwise. They also saw their CHOP-INTEND scores increase, a sign of improvement that wouldn’t be expected without treatment. No serious side effects seen were attributed to the gene therapy.

Alex Fay, a pediatric neurologist at UCSF Benioff Children’s Hospital in San Francisco, CA, cautions that it will probably take more time to “see the full range of benefit” of Zolgensma in Type 2 and 3 patients. He also notes that older patients appear more likely to have an immune defense against the treatment, which could be a problem. Still, “I think the take-home points are that gene therapy seems to be effective and safe across subtypes of early-onset SMA, efficacy appears comparable to Spinraza’s, and that there will likely be a continued role for Spinraza in treating patients with SMA,” he said after looking over the data.

Using Spinraza and Zolgensma together, particularly in pre-symptomatic patients, could be more beneficial, he adds. But combination therapy hasn’t been tested and the costs would be significant.


Like Spinraza and Zolgensma, risdiplam is meant to boost the production of the SMN protein that SMA patients lack. (Without it, motor neurons in the spinal cord waste away.)

The oral risdiplam could be more convenient. Susan Begelman, the head of medical affairs for neuroscience for Roche’s Genentech unit, notes that patients could take risdiplam on their own, and not have to go to a doctor’s office. Some SMA patients have scoliosis or spinal fusions and may not be eligible for therapy infused into the spine; some might have trouble tolerating the painful spinal taps three times a year. “This is another advantage of an oral medicine,” Begelman says.

Roche isn’t just testing risdiplam in infants, but in teenagers and adults as well. The data backing Spinraza and Zolgensma has come from younger patients.

It’s hard to compare results across trials, but until there are head-to-head studies, Spinraza and Zolgensma have set a high bar for safety and efficacy. And Roche still has a ways to go. This week’s AAN data are only from dose-finding studies, which aren’t designed to show whether the drug can change the disease. That work is now underway, with data expected later this year and in early 2020.

Here are the results from the Roche studies FIREFISH and SUNFISH.

FIREFISH: This is a study in babies one to seven months old with Type 1 SMA. Roche said, a median of 14.8 months after beginning treatment, seven of the 17 babies who got the risdiplam dose being carried forward could sit independently for at least five seconds—the main goal of the “confirmatory” portion of the trial. Additionally, 11 could sit with or without support; nine had head control; and one could stand.

Fifteen of the 17 getting the key risdiplam dose are alive. Their CHOP-INTEND scores have improved. And none have lost the ability to swallow or needed a ventilator or a tube inserted into their windpipe to help them breathe.

“It’s really encouraging how much improvement we’ve noticed in these children,” says Giovanni Baranello, a Pediatric Neurologist at the Carlo Besta Neurological Institute in Milan, Italy, and the lead investigator of the FIREFISH study.

Despite side effects including fever, respiratory tract infections, vomiting, diarrhea, and pneumonia, no patient stopped treatment, Begelman says.

SUNFISH: This study tests risdiplam in patients from two to 25 years old and have either Type 2 or 3 SMA. Some might be unable to sit, while others can walk. To judge their progress, Roche is using a neuromuscular disease test called Motor Function Measure-32.

In the dose-finding portion of its study, Roche found that 25 of 43 patients (58 percent) evaluated for at least 12 months saw their MFM-32 scores rise at least three points. (In a disease where function steadily decreases, any increase in functional score is notable.)

The benefits were less pronounced for older patients, 12 to 25 years old, which appears to jive with what’s become known about SMA; the earlier the treatment, the better the benefit. “We’ll learn as we collect more data,” Begelman says.

So will patients. Roche enrolled 180 of them in the confirmatory part of the study. Baranello is keeping an eye on what patients say about their experience—particularly the teenagers and young adults. “Ultimately they are the ones responsible for making the decision to be treated,” he says.

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