Clinical Trials

Date: 2018-04-24

Type of information: Presentation of results at a congress

phase: 1

Announcement: presentation of results at the 2018 Annual Meeting of the American Academy of Neurology (AAN) Annual Meeting in Los Angeles

Company: Avexis (USA - TX)

Product: AVXS-101

Action mechanism:

  • gene therapy. AVXS-101 is a proprietary gene therapy candidate of a one-time treatment for SMA Type 1 and is the only clinical-stage gene therapy in development for SMA. AVXS-101 is designed to address the monogenetic root cause of SMA and prevent further muscle degeneration by addressing the defective and/or loss of the primary SMN gene. AVXS-101 also targets motor neurons providing rapid onset of effect, and crosses the blood brain barrier allowing an IV dosing route and effective targeting of both central and systemic features.

Disease: spinal muscular atrophy (SMA) Type 1

Therapeutic area: Rare diseases - Genetic diseases - Neuromuscular diseases

Country: USA

Trial details:

Latest news:

  • • On April 24, 2018, AveXis announced that it will present 24-month follow-up data from the Phase 1 trial of AVXS-101 for the treatment of spinal muscular atrophy (SMA) Type 1 at the 2018 Annual Meeting of the American Academy of Neurology (AAN) Annual Meeting in Los Angeles.
  • 24-Month Follow-Up Data from Phase 1 Trial of AVXS-101 in SMA Type 1 The following 24-month follow-up data from the Phase 1 trial will be presented during platform presentations by Samiah Al-Zaidy, MD, Co-Investigator for the trial; Linda Lowes, PhD, Director of Clinical Therapies Research and a member of the Center for Gene Therapy at the Research Institute of Nationwide Children’s Hospital; and Richard Shell, MD, member of the Section of Pulmonary Medicine at Nationwide Children’s Hospital. The Phase 1, open-label, dose-escalation trial was designed to evaluate the safety and tolerability of AVXS-101 in patients with SMA Type 1. The key measures of efficacy were the time from birth to an event and video confirmed achievement of ability to sit unassisted. Additionally, several exploratory objective measures were assessed, including a standard motor milestone development survey and CHOP INTEND. After the 24-month follow-up, to date, 11 patients have enrolled in the Long-Term Follow-Up (LTFU) trial for ongoing evaluation. Event-free Survival and Safety:  Twenty-four months following gene transfer, 15 of 15 (100%) patients were alive and without need for permanent ventilation. The median age at last follow-up was 27.8 months and 30.7 months for patients in the Cohort 2 and low-dose cohort (Cohort 1), respectively. Natural history indicates only eight percent of untreated patients with SMA Type 1 survive event-free at 20 months of age.
  • AVXS-101 appeared to have a favorable safety profile and to be generally well tolerated, with no new treatment-related safety or tolerability concerns identified at the 24-month follow-up.
    • A cumulative total of 319 AEs (five treatment-related AEs and 314 non-treatment related AEs) were reported following monitoring and source verification. Of these, 60 were determined to be SAEs and 259 were non-serious AEs.
    • As reported in 2016, one patient in Cohort 1 had a pulmonary event that required increased use of bi-level positive airway pressure (BiPAP) in advance of surgery related to hypersalivation, a condition experienced by some SMA patients; the event was determined by independent review to represent progression of disease and not to be related to the use of AVXS-101. Following surgery, the respiratory support needs decreased below event definition threshold.
    • As has been previously reported, a total of five AEs in four patients were deemed treatment-related. Of these, two were SAEs experienced by two patients, and three were non-serious AEs experienced by two patients. All consisted of clinically asymptomatic liver enzyme elevations and were resolved with prednisolone treatment. There were no clinically significant elevations of gamma-glutamyl transferase, alkaline phosphatase or bilirubin and, as such, Hy’s Law was not met. Other non-treatment-related AEs were expected and were associated with SMA.
    Treatment Durability and Motor Milestone Achievement from Long-Term Follow-Up Study:
  • Patients in Cohort 2 continued to achieve new milestones during the LTFU trial. Detailed Cohort 2 motor milestone data is included in the chart below.
    • Two additional patients achieved the ability to sit unassisted for 30 seconds or more. Eleven of 12 (92%) patients could sit unassisted.
    • Two additional patients achieved the ability to stand with assistance. Four of 12 (33%) could stand with assistance.
    • Three of four patients achieving these new milestones were on AVXS-101 alone (one sitting and two standing with assistance).
    • The oldest child from Cohort 2 at the time of last visit in the LTFU study was 46.2 months and 40.6 months post gene therapy.
    Cohort 2 Age at Gene Transfer (mos) Event-Free Survivala Event-free Survival and Motor and Other Milestones Among the 12 Patients in Cohort 2 as of December 15, 2017*
    Brings Hand to Mouth Controls Head Rolls Overb Sits with Assistance Sits Unassistedc Other Achievements
    ?5 seconds ?10 seconds ?30 seconds Speaks Swallows No NIV Use No Nutritional Supportd
    E.04 5.6 31.1 + + + + + O O + +
    E.05 4.2 28.5 + + + + + + + + + + +
    E.06 1.9 26.1 + + + + + + + + + + +
    E.07 3.6 28.1 + + + + + + O + + +
    E.08 7.9 32.4 +
    E.09 4.9 28.9 + + + + + + + + + + +
    E.10 0.9 25.3 + + + + + + + + + + +
    E.11 2.3 27.7 + + + + + + + + +
    E.12 2.6 26.8 + + + + + + + + + + +
    E.13 0.9 25.4 + + + + + + + +
    E.14 4.1 27.9 + + + + + + + + + + +
    E.15 2.1 26.3 + + + + + + + +
    Patient with Outcome (%)
    This Trial 100 % 100 % 92 % 75 % 92 % 92 % 92 % 92 % 92 % 92 % 58 % 50 %
    Natural History 8% by 20 monthse NA 0 0** 0** 0** 0** 0** NA NA NA 25% by 13 monthsf
    *At baseline, none of the patients in Cohort 2 had achieved any of the listed motor milestones except for bringing a hand to the mouth. As of December 15, 2017, the majority of these patients had reached at least one major motor milestone. No patients in Cohort 1 are listed, since none attained any motor milestones. NA denotes not available, and NIV denotes noninvasive ventilation. Plus signs indicate achievement of milestone. a. Event-free survival (the primary efficacy outcome) was defined as the age at the end of the trial at which patients were free of ventilatory support, which was defined as the need for ventilation for at least 16 hours per day for at least 14 consecutive days in the absence of acute reversible illness or perioperatively. b. According to item 20 on the Bayley Scales of Infant and Toddler Development, rolling over is defined as movement of at least 180 degrees both left and right from a position of lying on the back. c. Sitting unassisted for at least 5 seconds is in accordance with the criteria of item 22 on the Bayley Scales of Infant and Toddler Development gross motor subtest and surpasses the 3-second count that is used as a basis for sitting (test item 1) on the Hammersmith Functional Motor Scale–Expanded for SMA. Sitting unassisted for at least 10 seconds is in accordance with the criteria used in the World Health Organization Multicentre Growth Reference Study. Sitting unassisted for at least 30 seconds defines functional independent sitting and is in accordance with the criteria of item 26 on the Bayley Scales of Infant and Toddler Development gross motor subtest. d. Nutritional support refers to the placement of either a gastrostomy tube or a nasogastric tube, as determined by the preference of the parents or the primary physician. Once enrolled in the trial, all the patients who required nutritional support underwent gastrostomy-tube placement, and none were removed during the trial. e. Data are from Finkel et al. f. Defined as nasogastric tube or gastrostomy tube. Data are from Finkel et al. ** Data are from De Sanctis et al. Denotes milestone achieved during LTFU. Nutritional and Respiratory Support Patients in Cohort 2 showed a reduced need for nutritional and ventilatory support and improvement in swallowing function. According to natural history, nearly all patients with SMA Type 1 require nutritional and respiratory support by 12 months of age, and most patients are not able to swallow or speak effectively.
    • Six of seven (86%) patients in Cohort 2 that did not require feeding support before treatment continued without feeding support after treatment; seven of 10 (70%) patients that did not require BiPAP support before treatment continued without any BiPAP after treatment.
    • Eleven of 12 (92%) patients in Cohort 2 were fed orally, and six of 12 (50%) patients were exclusively fed orally; and eleven of 12 (92%) patients were able to speak.
    “The long-term follow-up data from the Phase 1 trial showed unprecedented event-free survival, continued developmental milestone achievement and long-term durability, with no new safety findings,” said Dr. Sukumar Nagendran, Chief Medical Officer of AveXis. “In aggregate, these data presented at AAN demonstrate a one-time administration of AVXS-101 appears to have a potentially clinically transformative and durable impact on patients with SMA Type 1.”
  • • On November 1, 2016, AveXis announced that the planned pivotal study of AVXS-101 in spinal muscular atrophy (SMA) Type 1 will reflect a single-arm design, using natural history of the disease as a comparator, and enroll approximately 20 patients. This update is based on the receipt of the minutes following the Type B meeting with the FDA held on September 30, 2016. In addition to evaluating safety, the planned program is expected to evaluate achievement of motor milestones, specifically patients’ ability to sit unassisted, as well as an efficacy measure defined by the time from birth to an “event,” defined as death or requiring at least 16 hours per day of ventilation support for breathing for greater than two weeks in the absence of an acute reversible illness, or perioperatively.
    • At the Type B meeting and in the meeting minutes, the FDA acknowledged the company’s rationale for a single-arm pivotal study and provided a number of constructive suggestions to help optimize such a trial design. The FDA also indicated its preference for a design with co-primary endpoints consisting of a measure of developmental milestone achievement (such as sitting unassisted) along with a clinically meaningful measure of survival (such as time to an “event” as described above). Based on FDA’s suggestions as well as other expert input, AveXis continues to evaluate a number of the details of the trial design. More specific information will be made available at the time the study is initiated, which is expected in the first half of 2017.
    With regard to the ongoing Phase 1 trial of AVXS-101, the FDA stated the following in the meeting minutes: “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.” The company’s strategy with the SMA Type 1 program is to complete the ongoing Phase 1 trial and, in parallel, execute on the single-arm pivotal trial, while continuing collaborative discussions with the FDA regarding the most expeditious pathways for FDA approval of AVXS-101.

Is general: Yes