First Patient Dosed in Phase 3 Trial of AVXS-101 in Presymptomatic Infants with SMA Types 1, 2 and 3

José Lopes, PhD avatar

by José Lopes, PhD |

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The first patient has been dosed in the Phase 3 clinical trial of AveXis’ gene therapy candidate AVXS-101 in presymptomatic infants with spinal muscular atrophy (SMA) types 1, 2 and 3, the company announced.

SPR1NT (NCT03505099) is an open-label, global study evaluating a one-time, intravenous AVXS-101 treatment in presymptomatic babies likely to develop SMA with deletion of both copies of the SMN1 gene and two, three, or four copies of the SMN2 gene. The study is still recruiting participants.

Scientists plan to enroll 44 babies, who must be younger than 6 weeks, or 42 days. Following a screening period and administration of AVXS-101, patients will be followed up until they are 18, 24 or 26 months old, depending on whether they have two, three, or four SMN2 copies, respectively.

AVXS-101 contains the normal version of the SMN gene, which is defective in SMA patients. Lower levels of the SMN protein lead to loss of motor neurons, nerve cells responsible for transmitting signals to muscle cells. SMN deficiency ultimately causes progressive muscle weakness and atrophy.

The SMN2 gene is an alternative source of SMN protein, but most of it is unstable and shorter than the normal version. SMA severity correlates with the number of SMN2 gene copies: The more copies a patient has, the less severe the disease will be.

“Treating SMA as early as possible is critically important in order to rescue motor neurons before they are permanently lost. SPRINT enables us to understand how intervening in pre-symptomatic infants with AVXS-101 may impact clinical outcomes, including milestone development such as functional sitting, standing without support and walking,” Sukumar Nagendran, MD, chief medical officer of AveXis, said in a press release.

“In addition to our ongoing studies in SMA Types 1 and 2, SPRINT adds to our evaluation of AVXS-101 in multiple SMA sub-types, including Type 3. We are excited by the progress made across our clinical development program as we continue toward the goal of making AVXS-101 available to the SMA community,” he said.

The treatment’s effectiveness and safety will be regularly assessed until the end of the study. Participants will then be asked to roll over into a long-term follow-up study.

Researchers will evaluate relevant clinical goals, as well as infants’ survival and the treatment’s safety. The therapeutic dose of AVXS-101 will be 1.1 x 1014 vg/kg.

Infants with different SMN2 copy numbers will be assessed separately for achievement of developmental milestones. Those with two SMN2 copies will be primarily analyzed for their ability to sit independently for at least 30 seconds up to 18 months of age.

The infants’ event-free survival at 14 months of age and their ability to maintain weight at or above the third percentile without feeding support up to 18 months of age, will also be analyzed.  An event is defined as death or dependence on breathing support for at least 16 hours per day for 14 consecutive days.

Infants with three SMN2 copies will be primarily assessed for their ability to stand without support for at least three seconds up to 24 months of age. Their ability to walk unassisted by 24 months old, defined as taking at least five steps independently with coordination and balance, will also be evaluated.

Researchers will also analyze the proportion of infants with four SMN2 copies, who do not show symptoms of SMA type 3 — based on a scaled score on Bayley V.3 Gross and Fine Motor Subtests of infant development — at 36 months of age.

Besides SPR1NT, AveXis is continuing patient enrollment for its STR1VE Phase 3 trial (NCT03306277) in the U.S. The study focuses on AVXS-101’s safety and effectiveness in children with SMA type 1 younger than 6 months.

Patient recruitment for the STRONG Phase 1 trial (NCT03381729) in children up to 60 months old with SMA type 2 is also ongoing. This study assesses treatment with AVXS-101 delivered via the spinal canal.

AveXis recently announced it will launch a European Phase 3 trial of AVXS-101 in SMA type 1 in May, called STR1VE-EU (NCT03461289). The company is also planning the REACH trial for patients with SMA types 1-3, ages 6 months to 18 years, who are ineligible for the other studies.

The SPR1NT study will be conducted in 13 countries, including sites across the U.S, as well as Australia, Belgium, Israel, Japan, Republic of Korea, Spain, Taiwan, and the U.K.

The University of Wisconsin-Madison is the only trial location already enrolling participants. For contacts and more information about patient recruitment, click here.

AveXis recently discussed the clinical program of AVXS-101 in an interview with SMA News Today.