close

Clinical Trials

Date: 2019-01-05

Type of information: Presentation of results at a congress

phase: 1-2

Announcement: presentation of results at the 22nd Annual Meeting of the American Society of Gene and Cell Therapy

Company: Audentes Therapeutics (USA - CA)

Product: AT132

Action mechanism:

  • gene therapy. XLMTM is caused by mutations in the MTM1 gene, which encodes myotubularin that plays an important role in the development, maintenance and function of skeletal muscle cells. AT132 is comprised of an AAV8 vector containing a functional copy of the MTM1 gene. Multiple studies in animal models of XLMTM have demonstrated that a single administration of AT132 improved disease symptoms and survival rates, with no significant AT132-related adverse events or safety findings. In one study these effects have lasted more than four years to date. Audentes is developing AT132 in collaboration with Genethon.

Disease: X-Linked Myotubular Myopathy (XLMTM)

Therapeutic area: Rare diseases - Genetic diseases - Neuromuscular diseases

Country: USA

Trial details:

  • ASPIRO is designed as a multicenter, multinational, open-label, ascending dose study to evaluate the safety and preliminary efficacy of AT132 in approximately 12 XLMTM patients less than five years of age. The study is expected to include nine AT132 treated subjects and three delayed-treatment concurrent control subjects. Primary endpoints include safety (adverse events and certain laboratory measures) and efficacy (assessments of neuromuscular and respiratory function). Secondary endpoints include the burden of disease and health related quality-of-life, and muscle tissue histology and biomarkers. The primary efficacy analysis is expected to be conducted at 12 months, with interim evaluations expected to be conducted at earlier time points. After the primary 12-month assessment, subjects are expected to be followed for another four years to assess long term safety, durability of effect and developmental progression. (NCT03199469)
  • In addition to ASPIRO, the clinical development program for AT132 includes RECENSUS, a retrospective medical chart review, INCEPTUS, a clinical assessment and Phase 1 / 2 run-in study. The primary objectives of INCEPTUS are to characterize the disease course and natural history of children with XLMTM, assess the burden of disease on XLMTM patients and caregivers, identify subjects for potential enrollment in ASPIRO, and serve as a longitudinal baseline and within-patient control for ASPIRO.

Latest news:

  • • On May 1, 2019, Audentes Therapeutics announced new positive data from ASPIRO, the Phase 1/2 clinical trial of AT132 for the treatment of X-linked Myotubular Myopathy (XLMTM). The data have been presented at the 22nd Annual Meeting of the American Society of Gene and Cell Therapy by Perry B. Shieh, M.D., Ph.D., Associate Professor of Neurology, University of California Los Angeles and Principal Investigator for ASPIRO. Data Summary: The newly reported data include safety and efficacy assessments for 11 patients enrolled in ASPIRO as of the April 8, 2019 data cut-off date, including 48 weeks of follow-up for seven patients enrolled in Cohort 1 (1x1014 vector genomes per kilogram (vg/kg); six treated and one untreated control) and 24 weeks of follow-up for four patients in Cohort 2 (3x1014 vg/kg; three treated and one untreated control). Key assessments include neuromuscular function as measured by both improvements in the CHOP INTEND score and the achievement of motor milestones; respiratory function as measured by improvements in maximal inspiratory pressure (MIP) and reduction in ventilator dependence; and vector copy number, mRNA, protein expression and histological improvement as assessed via muscle biopsy. Efficacy: Rapid CHOP INTEND improvements have been achieved and maintained in both dose cohorts, and the majority of patients have demonstrated progressive attainment of motor developmental milestones, such as head control, sitting unassisted, crawling, standing with support and initiating stepping movements. Patients receiving AT132 have achieved reductions in ventilator dependence not previously observed in chronically ventilated patients with neuromuscular disorders. Reduction of ventilator dependence is an endpoint considered to be correlated with survival. Four patients were successfully weaned off of ventilation by the 48-week timepoint, with all other treated patients demonstrating sustained and clinically meaningful reductions in ventilator use. Muscle biopsy data show robust dose-dependent transduction, transcription and protein expression. All biopsies show marked improvement in histopathological markers of disease, with a trend toward continued improvement in the Cohort 1 patient samples from 24 to 48-week timepoints, and evidence of more rapid pathological improvement by week 24 in the Cohort 2 biopsy samples. Safety: AT132 has been generally well-tolerated and has shown a manageable safety profile across both dose groups. There have been no possibly or probably treatment-related serious adverse events (SAEs) reported in Cohort 1 since the scientific update in May 2018. There have been eight possibly or probably treatment-related SAEs reported in Cohort 2. All SAEs have been successfully managed and patients have shown no evidence of clinical compromise. Results to date indicate no clinically meaningful differences in the safety and tolerability profile of AT132 between the 1x1014vg/kg and 3x1014vg/kg dose cohorts. Next steps in the AT132 development program include selection of the optimal dose in the ASPIRO study, planned to occur in the second quarter of 2019, and further interactions with the FDA and EMA, planned to occur in the third quarter of 2019, to present this most recent data update and gain further alignment on the license application submission pathways for AT132 in the United States and Europe.
  •  • On January 31, 2019, Audentes Therapeutics provided an update following the receipt of minutes from its Regenerative Medicine and Advanced Therapy (RMAT)/Type B meeting with the FDA held in December 2018, regarding the company's lead gene therapy candidate, AT132, for the treatment of X-linked Myotubular Myopathy. The goal of the meeting was to review nonclinical, clinical, and chemistry, manufacturing, and controls (CMC) data generated to date in the AT132 program, and to align with the FDA on program next-steps to enable submission of a Biologics License Application (BLA) for AT132. Following the meeting, Audentes is proceeding with its previously announced plan to enroll an additional 3-5 patients in Cohort 2 of ASPIRO, the Phase 1/2 study of AT132. Optimal dose selection is expected to occur in the second quarter of 2019, after the evaluation of the six-month biopsy results from the first three patients dosed in Cohort 2. Subsequent to the determination of the optimal dose, Audentes plans to provide an updated data package to FDA to facilitate final agreement on the path to BLA submission. Audentes also received preliminary feedback on its CMC characterization and validation plans and will submit the requested information to the Investigational New Drug (IND) application on a continuing basis. In pursuit of global regulatory approvals for AT132, Audentes also initiated discussions with the European Medicines Agency (EMA) in the fourth quarter of 2018 under the recently granted Priority Medicines (PRIME) designation. In the first quarter of 2019, Audentes anticipates receiving scientific advice from the EMA that will begin to define the path toward submission of a European Marketing Authorization Application. • On October 5, 2018, Audentes Therapeutics announced  the presentation of new interim data from ASPIRO, the Phase 1/2 clinical trial of AT132 for the treatment of X-linked Myotubular Myopathy (XLMTM)at the 23rd International Annual Congress of the World Muscle Society. The newly reported data include follow-up assessments ranging from 4 to 48 weeks for the eight patients enrolled in ASPIRO to date, including the seven patients enrolled in Cohort 1 (1x1014 vg/kg; six treated and one untreated control) and one patient enrolled to date in Cohort 2 (3x1014 vg/kg).  Key assessments include neuromuscular function as measured by CHOP INTEND; respiratory function as measured by maximal inspiratory pressure (MIP) and ventilator dependence; and vector transduction, transgene expression and histological improvement as assessed via muscle biopsy.  All treated patients continue to show meaningful improvements in neuromuscular and respiratory function, with no new treatment-related SAEs reported since the last scientific update in May 2018 .
  • Data Summary
  • Safety: AT132 has been well tolerated with a manageable safety profile to date at doses up to 3x1014 vg/kg.  There have been no treatment-related SAEs reported since the last scientific update in May 2018 .
  • Efficacy: thepresentation provides incremental new CHOP INTEND and ventilator dependence data for all patients; MIP data for Patients 2, 5, 6, 7, and 8; and week 24 biopsy data for Patient 5.
  • Data continue to show significant improvements in neuromuscular and respiratory function as assessed via CHOP INTEND and MIP in all treated patients, including the Cohort 2 sentinel patient.  All treated patients in Cohort 1 have shown significant reductions in ventilator use, and three patients have now achieved ventilator independence.
  • Week 24 muscle biopsies show evidence of highly efficient tissue transduction as indicated by vector copy number and robust myotubularin protein expression as assessed by Western blot.  Histological analyses also show significant improvements in myofiber size, nuclear peripheralization and organelle localization.
    Summary Table of Key Baseline and Follow-up Assessments 
    Demographics Neuromuscular Assessment Respiratory Assessments Biopsy
    Age at Baseline (Years) CHOP INTEND at Baseline CHOP INTEND at Last Report (Max Score=64) ?  From Baseline MIP at Baseline (cm H2O) 2 MIP at Last Report (cm H2O) 2 ?  From Baseline Ventilator Status at Baseline Ventilator Use at Baseline (hrs per day) Ventilator Use at Last Report (hrs per day) ?  From Baseline (hrs per day) VCN per diploid genome MTM1 expression vs. Normal 4
    Cohort 1 (1x1014vg/kg) Patient 1 0.8 29 56 (Wk 48) +27 (93%) 33 89 (Wk 24)3 +56 (170%) BiPAP 12 hrs. 0 (Wk 48) -12 hrs. 6.2 (Wk 24) ~120%
    Patient 2 4.1 45 64 (Wk 48) +19 (42%) 44 112 (Wk 48) +68 (155%) Invasive 22 hrs. 6 (Wk 48) -16 hrs. 7.1 (Wk 24) ~250%
    Patient 3 2.6 34 34 (Wk 36) 0 (0%)1 26 70 (Wk 24) +44 (170%) Invasive 24 hrs. 0 (Wk 40) -24 hrs. 2.7 (Wk 24) ~80%
    P. 4 (Control) 4.0 49 47 (Wk 36) -2 (-4%) 58 46 (Wk 24) -12 (-21%) BiPAP 12 hrs. 12 (Wk 36) 0 hrs. NA 5 NA 5
    Cohort 1 Expansion Patient 5 1.0 36 53 (Wk 24) +17 (47%) 14 78 (Wk 24) +64 (457%) Invasive 24 hrs. 12 (Wk 24) -12 hrs. 2.2 (Wk 24) ~52%
    Patient 6 0.8 39 52 (Wk 16) +13 (33%) 35 87 (Wk 12) +52 (149%) Invasive 24 hrs. 0 (Wk 20) -24 hrs. NA 6 NA 6
    Patient 7 0.8 43 53 (Wk 16) +10 (23%) 29 68 (Wk 12) +39 (134%) Invasive 23.5 hrs. 10 (Wk 20) -13.5 hrs. NA 6 NA 6
    Cohort 2 (3x1014vg/kg) Patient 8 1.2 36 55 (Wk 4) +19 (53%) 31 67 (Wk 4) +36 (116%) Invasive 22.5 hrs. 23.3 (Wk 4) +0.8 hrs. NA 6 NA 6
    MIP = Maximal Inspiratory Pressure; Ventilator Use = Ventilator Dependence Over Prior 24 hours; VCN = Vector Copy Number
    1. Patient 3 was fitted with a temporary halo traction device for treatment of preexisting scoliosis at the time of his week 36 visit, impeding his ability to complete the full CHOP INTEND assessment. As of the 24-week assessment, Patient 3 had achieved a 41% improvement in CHOP INTEND from baseline.
    2. >80 cmH20 is considered in the normal range for healthy children less than five years of age.
    3. Unable to collect data at week 48 due to lack of cooperation by the patient.
    4. Protein expression numbers may change in future presentations as Audentes is currently titrating the standard and extending the linear range of the assay.
    5. Control patients are not treated until the optimal dose has been selected. Once treated, biopsies are conducted at baseline, week 24 and week 48 post treatment.
    6. The longest duration of follow-up for Patients 6, 7 and 8 is 16 weeks. Post treatment biopsies will be conducted at week 24 and week 48.
    The independent Data Monitoring Committee (DMC) has reviewed the preliminary safety and efficacy data from the Cohort 2 sentinel patient and has recommended continuing with enrollment of the remaining three patients in Cohort 2, which is expected to commence in the coming weeks.  In addition, with the goal of gaining alignment with the FDA and the EMA on the potential registration pathway for AT132 under its Regenerative Medicine Advanced Therapy (RMAT) and Priority Medicines (PRIME) designations, Audentes plans to hold initial discussions with both regulatory bodies beginning in the fourth quarter of 2018. • On May 16, 2018, Audentes Therapeutics announced continuing positive data from the first dose cohort of ASPIRO, a Phase 1 / 2 clinical trial of AT132 in patients with X-Linked Myotubular Myopathy (XLMTM). The data were presented during an oral presentation at the 21st annual meeting of the American Society of Gene and Cell Therapies in Chicago.
  • The interim data includes safety and efficacy assessments as of May 12, 2018 for the first dose cohort of ASPIRO, comprised of six AT132-treated patients dosed at 1x1014 vector genomes (vg) per kilogram (kg), and one delayed-treatment concurrent control patient. Individual patient follow-up ranged up to 24 weeks.
  • Safety Summary: There have been a total of 24 adverse events (AEs) reported in ASPIRO, six of which were determined to be serious adverse events (SAEs). One of the six SAEs occurred in Patient 4, the delayed treatment concurrent control patient, who was hospitalized for gastroenteritis at week 10. The patient has recovered and the event was determined to be not treatment-related. The remaining five SAEs occurred in Patient 3. The first was a hospitalization for pneumonia two weeks post study drug administration (not treatment-related); the next three were a series of related SAEs that occurred seven weeks post study drug administration and included hospitalization for a gastrointestinal infection during which the patient experienced elevated creatine kinase (CK) and troponin levels suggestive of myocarditis (probably treatment-related). These events have been controlled with treatment, and cardiac function has not been compromised. The final SAE in Patient 3 was a hospitalization at week 21 for monitoring of atrial tachycardia, deemed possibly treatment-related. Patient 3 was noted to have experienced an episode of tachycardia prior to enrollment in ASPIRO. Patient 1 experienced three non-serious AEs that were determined to be possibly treatment-related, including mild, clinically asymptomatic exacerbation of pre-existing hyperbilirubinemia (resolved) and mild unspecific abnormalities in liver ultrasound and proteinuria (resolved). Patient 2 experienced four non-serious AEs determined to be probably treatment related, including clinically asymptomatic hyperbilirubinemia; and liver enzyme and CK elevations which have been controlled by extended steroid coverage. There have been an additional 11 non-serious AEs in ASPIRO, all determined to be not treatment-related. There have been no significant treatment-related adverse events identified to date in Patients 5 through 7, referred to as the Cohort 1 expansion patients.
  • Efficacy Summary: The key assessment of neuromuscular function is the CHOP-INTEND scale, in which a maximal score of 64 reflects the level of neuromuscular function that a healthy baby is expected to approach by three to six months of age. Additional analyses to be reported based on longer term follow-up include the Motor Function Measure (MFM-20) and Bayley-III™ scales of infant and toddler development. Motor developmental milestones are derived from each of the neuromuscular assessments.
  • Patient Interim Data Summaries:
  • Patient 1: data set includes assessments through week 24 timepoint
  • Age 0.8 years at baseline
  • BiPAP of 12 hours per day at baseline, now ventilator independent since week 16
  • CHOP-INTEND increased from 29 at baseline to 64 at week 24, an increase of 121%
  • MIP increased from 33 cmH20 at baseline to 89 cmH20 at week 24, an increase of 170%
  • No age-appropriate first-year motor milestones were achieved at the baseline assessment. By week 12, Patient 1 had acquired several age appropriate skills, including the ability to control head movements, roll over by himself and sit unassisted for > 5 seconds, and maintained these skills through week 24. Physicians and caregivers have reported additional observations in Patient 1 at week 24, including the ability to feed orally, stand with support and increased loudness of vocalization.
  • Patient 2: data set includes assessments through week 24 timepoint
  • Age 4.1 years at baseline
  • Invasive ventilation 22 hours per day at baseline, decreased to 12 hours per day at week 24
  • CHOP-INTEND increased from 45 at baseline to 59 at week 24, an increase of 31%
  • MIP increased from 44 cmH20 at baseline to 104 cmH20 at week 24, an increase of 136%
  • No age-appropriate first-year motor milestones were achieved at the baseline assessment. By week 12, Patient 2 had acquired several skills, including the ability to control head movements, roll over by himself and sit unassisted for > 5 seconds, and maintained these skills through week 24.
  • Physicians and caregivers have reported additional observations in Patient 2 at week 24, including standing with support, scooting and crawling, and increased loudness of vocalization.
  • Patient 3: data set includes efficacy assessments through week 12 timepoint
  • Age 2.6 years at baseline
  • Invasive ventilation of 24 hours per day at baseline, no change at week 12
  • CHOP-INTEND increased from 34 at baseline to 43 at week 12, an increase of 26%
  • MIP increased from 26 cmH20 at baseline to 48 cmH20 at week 12, an increase of 85%
  • No age appropriate first-year developmental milestones were achieved at the baseline assessment or by week 12
  • Physicians and caregivers have reported increased loudness of vocalization and trunk strength at week 12
  • Patient 4 (Delayed-treatment concurrent control): includes assessments through week 24 timepoint
  • Age 4.0 years at baseline
  • BiPAP was 12 hours per day at baseline, no change at week 24
  • CHOP-INTEND was 49 at baseline, no change at week 24
  • MIP decreased from 58 cmH20 at baseline to 46 cmH20 at week 24, a decrease of 21%
  • First-year developmental milestones of head control and sitting unassisted for > 5 seconds were noted at baseline, but only head control was maintained at week 24
  • Patient 5: data set includes assessments through week four timepoint
  • Age 1.0 year at baseline
  • Invasive ventilation of 22.7 hours per day at baseline
  • CHOP-INTEND increased from 36 at baseline to 50 at week four, an increase of 39%
  • MIP increased from 14 cmH20 at baseline to 33 cmH20 at week four, an increase of 136%
  • Patient 6: data set includes assessments through week four timepoint
  • Age 0.8 years at baseline
  • Invasive ventilation of 24 hours per day at baseline, 21 hours per day at week four
  • CHOP-INTEND increased from 39 at baseline to 43 at week four, an increase of 10%
  • MIP improved 35 cmH20 at baseline to 63 cmH20 at week one, an increase of 80
  • Patient 7: data set includes only baseline assessments
  • Age 0.8 years at baseline
  • Invasive ventilation of 23.5 hours per day at baseline
  • CHOP-INTEND was 43 at baseline
  • MIP was 29 cmH20 at baseline
  • Audentes is currently completing analysis of the muscle biopsies gathered from initial Cohort 1 patients. These data, along with the safety and efficacy assessments from all patients, will be reviewed with the independent Data Monitoring Committee to inform decisions regarding dose escalation. Audentes expects to provide an update on these plans in the third quarter of 2018.
  • • On January 4, 2018, Audentes Therapeutics announced positive interim data from the first dose cohort of ASPIRO, a Phase 1 / 2 clinical trial of AT132 in patients with X-Linked Myotubular Myopathy (XLMTM).  The interim data includes safety and efficacy assessments for the first dose cohort of ASPIRO, comprised of three AT132-treated patients dosed at 1x1014 vector genomes (vg) per kilogram (kg), and one delayed-treatment control patient. As of December 21, 2017, individual patient follow-up ranged from 4 to 12 weeks.
  • Safety Summary: There have been a total of six adverse events (AEs) reported in ASPIRO, two of which were determined to be serious adverse events (SAEs). Both SAEs occurred in Patient 3, the first of which was a hospitalization one week post-administration due to pneumonia and was deemed not treatment-related. Patient 3 was also hospitalized at week 7 post-administration due to a gastrointestinal infection and elevated troponin levels, the latter of which was deemed probably treatment-related and is responding to treatment with intravenous steroid administration and supportive care.
  • Of the four non-serious AEs, two have been determined to be probably or possibly treatment-related. Patient 1 experienced a mild, clinically asymptomatic exacerbation of a preexisting elevated bilirubin level, which was deemed possibly treatment-related and resolved with treatment. Patient 2 experienced a clinically asymptomatic elevation in liver enzyme levels toward the end of the protocol-specified prednisolone weaning period, which was deemed to be probably treatment-related and was controlled by extending the duration of steroid coverage.Efficacy Summary : The key assessment of neuromuscular function in this first data set from Cohort 1 is the CHOP-INTEND scale, in which a maximal score of 64 reflects the level of neuromuscular function that a healthy baby is expected to approach by 3-6 months of age. Additional analyses to be reported based on longer term follow-up include the MFM-20 and Bayley-III™ scales of infant and toddler development (fine and gross motor function). Motor developmental milestones are captured within each of the neuromuscular assessments.
  • The key assessment of respiratory function in this first data set from Cohort 1 is a measurement of maximal inspiratory pressure (MIP), for which values ? 80 cmH20 are considered normal in healthy children less than 5 years of age. Additional analyses to be reported based on longer term follow-up include measurement of maximal expiratory pressure (MEP), time per day on invasive ventilatory support (tracheostomy) or non-invasive respiratory support (BiPAP), and for those patients who are on 24-hour continuous ventilatory support, an assessment of ability to maintain adequate respiratory function while off a ventilator, termed "respiratory sprinting."
  • Patient Interim Data Summaries:
  • Patient 1: data set includes assessments through week 12 timepoint
  • Age 0.8 years (9 months) and on 12 hours of BiPAP per day at baseline
  • CHOP-INTEND increased from 29 at baseline to 56 at week 12
  • MIP increased from 33 cmH20 at baseline to 80 cmH20 at week 12
  • No age-appropriate first-year motor milestones were achieved at the baseline assessment; by week 12, Patient 1 had acquired several age appropriate skills, including the ability to control head movements, roll over by himself and sit unassisted for > 5 seconds Patient 2: data set includes assessments through week 8 timepoint
  • Age 4.1 years and on 17 hours of invasive ventilation per day at baseline
  • CHOP-INTEND increased from 45 at baseline to 56 at week 8
  • MIP increased from 44 cmH20 at baseline to 77 cmH20 at week 4
  • Patient 3: data set includes assessments through week 4 timepoint
  • Age 2.6 years and on continuous (24-hour) invasive ventilation at baseline
  • CHOP-INTEND did not change meaningfully from 34 at baseline to 36 at week 4
  • MIP increased from 26 cmH20 at baseline to 44 cmH20 at week 4
  • Patient 4 (delayed-treatment control): data set includes assessments through week 4 timepoint
  • Age 4.0 years and on 12 hours of BiPAP per day at baseline
  • CHOP-INTEND did not change meaningfully from 49 at baseline to 46 at week 4
  • MIP at baseline was 58 cmH20; MIP was not assessed at week 4 per protocol
  • Physicians and caregivers have reported progressive qualitative improvements in disease severity in all treated patients. Ventilator settings (pressure, rate and volume of mechanical ventilation) have been reduced in Patients 1 and 2. All treated patients have demonstrated improvements in airway clearance control, including swallowing and coughing, which is critical to preventing aspiration. By way of example, at baseline Patient 1 required suctioning of the oro-pharyngeal cavity several times per hour, and by week 12 he required no suctioning. In addition, investigators report anecdotally that all treated patients have increased limb and trunk strength, which is an early indicator of gross motor function improvement, and that the velocity and accuracy of their movements have increased. Caregivers also report that patients have increased vocalization, improving their ability to communicate.
  • Audentes is currently reviewing the interim efficacy and safety data with the independent Data Monitoring Committee of ASPIRO prior to initiating enrollment and dosing of the next cohort. Audentes plans to provide the next update on interim data from ASPIRO in the second quarter of 2018.
  • • On September 21, 2017, Audentes Therapeutics announced it has commenced dosing of patients in ASPIRO, a Phase 1 / 2 clinical trial of AT132 for the treatment of X-Linked Myotubular Myopathy (XLMTM).Preliminary data from ASPIRO is expected to be available in the fourth quarter of 2017.
  • • On April 3, 2017, Audentes Therapeutics announced that the FD has cleared the investigational new drug (IND) application for AT132, its gene therapy product candidate to treat X-Linked Myotubular Myopathy (XLMTM). The IND is now active and Audentes plans to initiate ASPIRO, the multicenter, multinational, open-label, ascending dose Phase 1 / 2 clinical study of AT132.
 

Is general: Yes