AveXis‘ gene therapy AVXS-101, now under review for approval to treat infants with spinal muscular atrophy (SMA) type 1 in the U.S. and Europe, may be truly “transformative,” said Kenneth Hobby, president of the patient advocacy group Cure SMA.
Trial data in this patient group “shows that a one-time dose of gene therapy has the potential for a transformative impact on this life-threatening disease. SMA type I is the most common and most severe form, and, if not treated, is often fatal within two years of life,” Hobby said in an email reply to SMA News Today.
Cure SMA, which first moved to support the therapy development in 2010, reported the two regulatory filings on its website Thursday. A pre-application review period was also initiated in Japan.
AveXis is requesting that its AVXS-101 applications be accepted, and reviewed for approval, for intravenous (IV) therapy delivery in infants up to 9 months old. Older patients and those with SMA types 2 and 3 may be the subject of future filings.
The U.S. Food and Drug Administration (FDA) will decide whether to accept the Biologics License Application within two months. All three regulatory agencies are expected to reach final decisions by or in mid-2019.
“We are excited and grateful that these families will have another treatment option available to them,” Hobby said. “Our sense of satisfaction comes from seeing families affected by SMA, who were once given few or no options, standing on the cusp of a time in which they will have multiple options for therapy — and will be able to choose the one that best fits their own goals and needs.”
“These breakthroughs,” he added, “have truly changed, and, in many cases, saved lives.”
If approved, a pending hurdle will be access to the therapy — the costs of treatments for rare diseases such as SMA are beyond the reach of most families without insurance coverage, company-run assistance programs, or a national willingness to bring them into public health plans. And a gene therapy that might be, especially in infants treated early in the disease course, a treatment close to a cure could be quite costly indeed.
Hobby noted that Cure SMA does not and cannot determine the cost of care. But working with stakeholders — pharmaceutical and health insurance companies, as well as clinicians — to ensure that financial concerns are not an obstacle to timely and appropriate treatment “is part of our mission.”
Cure SMA and the rare disease community have been concerned with the high cost of care for SMA patients for decades, which increases exponentially with disease progression, he added. Likely increases in pediatric care costs with the advent of new therapies has led to “a significant expansion of Cure SMA’s advocacy efforts focused specifically on access.”
“Our role has been to work directly with federal and state governments and commercial payers to advocate for favorable coverage decisions,” ensuring full access to therapies, treatments, and devices. “We will continue to do so alongside our families,” Hobby said.
Potential ‘one-time therapy’
AVXS-101 is designed to deliver a functional copy of the SMN1 gene to motor neurons, which control muscle contraction. SMN1 is defective in SMA patients and leads to lower levels of a working SMN protein. This results in the loss of motor nerve cells, progressive muscle weakness, and atrophy.
The gene therapy uses a modified, harmless viral vector called an adeno-associated virus (AAV), previously shown to cross blood vessels and get into muscles. AAV9, the specific AAV subtype in AVXS-101, is able to reach cells in the brain and spinal cord “at unprecedented levels, in ways we had never seen before,” Brian Kaspar, chief scientific officer at AveXis, said in a February interview with SMA News Today.
Data supporting the regulatory applications draw on the company’s open-label, dose-escalation Phase 1 study (NCT02122952) exploring the safety, tolerability and efficacy of two doses of AVXS-101, delivered intravenously (IV) in 15 babies with SMA type 1.
Type 1 is the most severe and common type of SMA. Symptoms appear between birth and 6 months of age, and are characterized by an inability to raise the head, to sit upright without support, or to breathe, cough or swallow normally.
The 15 infants enrolled were not older than 9 months (first nine) and 6 months (the last six) at the time of vector infusion. Three received the lower dose (6.7E13 vg/kg), while 12 were given the proposed therapeutic dose (2.0E14 vg/kg).
All had the SMN1 gene’s exon deleted in both copies, or alleles. Exons are the bits of DNA with information to generate proteins. They also had two copies of the SMN2 gene, which produces an unstable and shorter version of the SMN protein.
The trial evaluated treatment safety over two years, with efficacy assessed in January 2017 as the patients reached 13.6 months old.
“At 13.6 months of age from birth, only 25% of children survive event-free,” Sukumar Nagendran, former chief medical officer for AveXis, said of SMA’s natural history. “And at 20 months, only 8% survive event-free.”
In contrast, 100% survival was noted in toddlers given AVXS-101 at 20 months of age, and with unheard-of improvements at the higher dose, including an ability to sit 30 seconds or longer unassisted, to roll over, and, in some cases, to walk.
Babies on the lower dose also showed improved motor control. “All remarkable, transformative clinical outcomes,” Nagendran said.
“I think this really is a one-time therapy,” Kaspar added.
Data presented at the 2018 American Academy of Neurology (AAN) Annual Meeting in April showed continued survival and motor function benefits at 24 months post-treatment, including head control in 11 children. Ten of the 15 could sit unassisted for at least five seconds, nine for at least 10 seconds, and eight for 30 seconds or more.
None of the children had progressed to permanent ventilation, 11 were being fed orally, and eight were able to speak.
Mean age at the last follow-up was 27.8 months for children receiving the higher dose, and 30.7 months for those on the lower dose. The therapy continued to show a positive safety profile, with no new treatment-related safety or tolerability concerns identified.
“The IV clinical trial data shows that a one-time dose of gene therapy has the potential for a transformative impact on this life-threatening disease,” Hobby said.
Children in the pivotal Phase 1 trial moved into the long-term safety extension study, called START (NCT03421977), that opened in August 2017. This trial intends to examine the children annually for up to 15 years.
AVXS-101 is now being tested in type 1 children younger than 6 months in the STR1VE Phase 3 trial (NCT03306277), assessing the treatment’s effectiveness and safety.
Preliminary STR1VE results also presented at AAN showed benefits with no serious adverse events. In the six babies who had received AVXS-101, mean CHOP-INTEND scores — which assess movement ability — rose by an average of 7.8 one month after dosing. Two months later, half of these patients had improved 17.3 points. None required respiratory or nutritional support.
Two other trials of AVXS-101 as an IV therapy are underway:
- The SPR1NT (NCT03505099) Phase 3 study in pre-symptomatic infants with SMA types 1, 2, and 3
- The STR1VE-EU (NCT03461289) Phase 3 trial, which is the European equivalent of STR1VE in the U.S.
Intrathecal (IT, through the spinal canal) administration of AVXS-101 in older patients is also intended or starting to be evaluated in:
- STRONG (NCT03381729), a Phase 1 study in SMA type 2 patients up to 60 months of age
- REACH, set to open in 2019, for patients with SMA types 1-3 ages 6 months to 18 years, including those ineligible for other trials.
Cure SMA looks forward to continued development of this spinal canal delivery, “which may allow older patients to receive the treatment as well,” Hobby said. “We look forward to positive results from these trials, and expect that data will support a filing for IT delivery in 2020.”
The company expects to present broad AVXS-101 data at the AAN meeting set for May.
‘Unparalleled’ progress, with more to come
Disease-modifying therapies for SMA are rather recent arrivals.
Progress in the field since, marked by the filings for AVXS-101, has been “unparalleled,” Hobby said.
He mentioned other potential options now in clinical testing, including Genentech/Roche’s oral small molecules RG7916 and olesoxime, and muscle therapies from Cytokinetics/Astellas, and from Scholar Rock (SRK-015). Nearly a dozen other potential treatments are in preclinical studies, Hobby added.
Hobby attributed the existence and speed of these advances to the efforts of the SMA community at large.
“The passion, dedication, and unity of our community is also unparalleled, and it is their commitment that has enabled us to reach this exciting and hopeful time,” Hobby said. “We also thank the many dedicated scientists, researchers and pharmaceutical partners for their tireless work in developing innovative treatments for SMA.”