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).
ZOLGENSMA
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.
RISDIPLAM
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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