AveXis Announces Pivotal Trial Design of SMA Type 1 Therapy Candidate

Ana de Barros, PhD avatar

by Ana de Barros, PhD |

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SMA treatment development

AveXis reported that the planned pivotal clinical trial of its gene therapy candidate AVXS-101 for spinal muscular atrophy (SMA) Type 1 will enroll about 20 patients and will have a single-arm design, with the comparator being the natural disease history.

This update follows the Type B meeting Sept. 30 with the U.S. Food and Drug Administration (FDA), and AveXis’ receipt of the meeting’s minutes. Type B meetings are routinely held at predefined endpoints between the FDA and a sponsor — in this case, AveXis. Meetings typically take place right after or before the submission of clinical data or a new drug filing.

“We believe the Type B meeting had a positive tone, with FDA offering a number of constructive suggestions which we believe will better enable implementation of a pivotal study design that is most appropriate for the patients suffering from this devastating disease,”  Sean Nolan, president and CEO of AveXis, said in a press release.

“With the feedback needed from the FDA to move forward with our pivotal trial, we plan to proceed as expeditiously as possible to begin the study in the first half of 2017,” he said.

The FDA accepted the single-arm design of the pivotal study and offered suggestions for AveXis to optimize the trial. The minutes also included a suggestion for the trial to have co-primary endpoints consisting of a measure of developmental milestone achievement (patients’ ability to sit unassisted) along with a measure of survival (such as time from birth to an “event”).

More information about the trial design is expected when the study begins, which is planned for the first half of 2017.

The pivotal clinical trial will evaluate AVXS-101’s safety, the achievement of motor milestones, and its effectiveness (defined by the time from birth to an event such as death or requiring at least 16 hours per day of breathing ventilation support for more than two weeks).

Avexis is currently conducting an open-label Phase 1 study (NCT02122952) of an intravenous injection of AVXS-101. The clinical trial enrolled 15 patients diagnosed before they were 6 months old, with two copies of the SMN2 backup gene.

Patients were divided into two cohorts: three babies, ages 6 to 7 months at time of dosing, received a low dose of 6.7 x 10^13 vg/kg (cohort 1); and 12 babies, ages 1 to 8 months at time of dosing, received 2.0 x 10^14 vg/kg (cohort 2).

Primary endpoints were safety and tolerability, and a secondary endpoint was efficacy, defined as time from birth to an event, either death or the need for at least 16 hours a day of ventilation support for 14 consecutive days.

As per data from an interim analysis reported in July, treatment with AVXS-101 demonstrated a favorable safety profile with no new treatment-related safety or tolerability concerns identified. Motor skill improvement was also seen, especially in the higher dose group who are receiving the proposed therapeutic dosing level.

Based on the pulmonary data, gene therapy appeared to improve patients’ pulmonary function, reducing the need for ventilation support and allowing patients to recover from the respiratory illnesses that often led to premature death of SMA Type 1 patients.

With regard to this study, the FDA stated:

“We strongly recommend that at the completion of the study, you request an end-of-Phase 1 meeting to evaluate the adequacy of data to support future product development, including a discussion of whether the data from the Phase 1 study might provide the substantial evidence necessary to support a marketing application.”

AveXis announced in July that the FDA had granted breakthrough therapy designated for AVXS-101 based on the preliminary clinical results from the ongoing Phase 1 trial and potentially speeding the therapy’s development. AVXS-101 was the first SMA drug to be granted breakthrough designation.

Avexis will now complete the Phase 1 trial and conduct the pivotal study. At the same time, the company will continue meeting with the FDA regarding the most expeditious pathways for FDA approval of AVXS-101.

AVXS-101 is a proprietary gene therapy candidate of a one-time, intravenous treatment for SMA Type 1, and, according to AveXis, is the only clinical-stage gene therapy in development for SMA.