Zolgensma

Pharmacotherapeutic group: Other drugs for disorders of the musculo-skeletal system, ATC code: M09AX09 Mechanism of action Onasemnogene abeparvovec is a gene therapy designed to introduce a functional copy of the survival motor neuron gene (SMN1) in the transduced cells to address the monogenic root cause of the disease.‍‍‍‍‍‍​​​‍​​​​​​ By providing an alternative source of SMN protein expression in motor neurons, it is expected to promote the survival and function of transduced motor neurons. Onasemnogene abeparvovec is a non-replicating recombinant AAV vector that utilizes AAV9 capsid to deliver a stable, fully functional human SMN transgene. The ability of the AAV9 capsid to cross the blood brain barrier and transduce motor neurons has been demonstrated. The SMN1 gene present in onasemnogene abeparvovec is designed to reside as episomal DNA in the nucleus of transduced cells and is expected to be stably expressed for an extended period of time in post-mitotic cells. The AAV9 virus is not known to cause disease in humans. The transgene is introduced to target cells as a self-complementary double-stranded molecule. Expression of the transgene is driven by a constitutive promoter (cytomegalovirus enhanced chicken-β-actin-hybrid), which results in continuous and sustained SMN protein expression. Proof of the mechanism of action has been supported by non-clinical studies and by human biodistribution data. Clinical efficacy and safety AVXS-101-CL-303 Phase 3 study in patients with Type 1 SMA AVXS-101-CL-303 (Study CL-303) is a Phase 3 open-label, single-arm, single-dose study of intravenous administration of onasemnogene abeparvovec at the therapeutic dose (1.1 × 10 14 vg/kg). Twenty-two patients were enrolled with Type 1 SMA and 2 copies of SMN2. Before treatment with onasemnogene abeparvovec, none of the 22 patients required non-invasive ventilator (NIV) support, and all patients could exclusively feed orally (i.e., did not need non-oral nutrition). The mean Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) score at baseline was 32.0 (range, 18 to 52). The mean age of the 22 patients at the time of treatment was 3.7 months (0.5 to 5.9 months). Of the 22 enrolled patients, 21 patients survived without permanent ventilation (i.e., event-free survival) to ≥10.5 months of age, 20 patients survived to ≥14 months of age (co-primary efficacy endpoint), and 20 patients survived event-free to 18 months of age. Three patients did not complete the study, of which 2 patients had an event (death or permanent ventilation) leading to 90.9% (95% CI: 79.7%, 100.0%) event-free survival (alive without permanent ventilation) at 14 months of age, see Figure 1. Figure 1 Time (months) to death or permanent ventilation pooled from onasemnogene abeparvovec IV studies (CL-101, CL-302, CL-303, CL-304-2 copy cohort) PNCR = Pediatric Neuromuscular Clinical Research natural history cohort NeuroNext = Network for Excellence in Neuroscience Clinical Trials natural history cohort For the 14 patients in Study CL-303 that achieved the milestone of independent sitting for at least 30 seconds at any visit during the study, the median age when this milestone was first demonstrated was 12.6 months (range: 9.2 to 18.6 months). Thirteen patients (59.1%) confirmed the milestone of independent sitting for at least 30 seconds at the 18-month visit (co-primary endpoint, p<0.0001). One patient achieved the milestone of sitting independently for 30 seconds at 16 months of age, but this milestone was not confirmed at the Month 18 visit. The video-confirmed developmental milestones for patients in Study CL-303 are summarised in Table 4. Three patients did not achieve any motor milestones (13.6%) and another 3 patients (13.6%) achieved head control as the maximum motor milestone before the 18 months of age final study visit. Table 4 Median time to video documented achievement of motor milestones Study CL-303 Video documented milestone Number of patients achieving milestone n/N (%) Median age to the milestone achievement (months) 95% Confidence interval Head control 17/20* (85.0) 6.8 (4.77, 7.57) Rolls from back to sides 13/22 (59.1) 11.5 (7.77, 14.53) Sits without support for 30 seconds (Bayley) 14/22 (63.6) 12.5 (10.17, 15.20) Sitting without support for at least 10 seconds (WHO) 14/22 (63.6) 13.9 (11.00, 16.17) * 2 patients were reported to have Head Control by clinician assessment at baseline. One patient (4.5%) could also walk with assistance at 12.9 months. Based on the natural history of the disease, patients who met the study entry criteria would not be expected to attain the ability to sit without support. In addition, 18 of the 22 patients were independent of ventilatory support at 18 months of age. Motor function improvements were also observed as measured by the CHOP-INTEND, see Figure 2. Twenty-one patients (95.5%) achieved a CHOP-INTEND score ≥ 40, 14 patients (63.6%) had achieved a CHOP-INTEND score ≥ 50, and 9 patients (40.9%) had achieved a CHOP-INTEND score ≥ 58. Patients with untreated SMA Type 1 almost never achieve a CHOP-INTEND score ≥ 40. Motor milestone achievement was observed in some patients despite plateauing of CHOP-INTEND. No clear correlation was observed between CHOP-INTEND scores and motor milestone achievement. Figure 2 CHOP-INTEND motor function scores - Study CL-303 (N=22) AVXS-101-CL-302 Phase 3 study in patients with Type 1 SMA AVXS-101-CL-302 (Study CL-302) is a Phase 3, open-label, single-arm, single-dose study of intravenous administration of onasemnogene abeparvovec at the therapeutic dose (1.1 × 10 14 vg/kg). Thirty-three patients were enrolled with Type 1 SMA and 2 copies of SMN2 . Before treatment with onasemnogene abeparvovec, 9 patients (27.3%) reported ventilatory support and 9 patients (27.3%) reported feeding support. The mean CHOP-INTEND score of the 33 patients at baseline was 27.9 (range, 14 to 55). The mean age of the 33 patients at the time of treatment was 4.1 months (range, 1.8 to 6.0 months). Of the 33 enrolled patients (Efficacy Completers population), one patient (3%) was dosed outside of protocol age range and was therefore not included in the intent-to-treat (ITT) population. Of the 32 patients in the ITT population, one patient (3%) died during the study, due to disease progression. Of the 32 patients in the ITT population, 14 patients (43.8%) achieved the milestone of sitting without support for at least 10 seconds at any visit up to and including the 18 month visit (primary efficacy endpoint). The median age when this milestone was first achieved was 15.9 months (range, 7.7 to 18.6 months). Thirty-one patients (96.9%) in the ITT population survived without permanent ventilation (i.e., event-free survival) to ≥ 14 months of age (secondary efficacy endpoint). The additional video-confirmed developmental milestones for patients in the Efficacy Completers population in Study CL-302 at any visit up to and including the 18 month visit are summarised in Table 5. Table 5 Median time to video documented achievement of motor milestones in Study CL-302 (Efficacy Completers population) Video documented milestone Number of patients achieving milestone n/N (%) Median age to the milestone achievement (months) 95% Confidence interval Head control 23/30* (76.7) 8.0 (5.8, 9.2) Rolls from back to sides 19/33 (57.6) 15.3 (12.5, 17.4) Sits without support for at least 30 seconds 16/33 (48.5) 14.3 (8.3, 18.3) * 3 patients were reported to have head control by clinician assessment at baseline. One patient (3%) achieved the motor milestones of crawling, standing with assistance, stands alone, walking with assistance, and walking alone all by the age of 18 months. Of the 33 enrolled patients, 24 patients (72.7%) achieved a CHOP-INTEND score ≥ 40, 14 patients (42.4%) achieved a CHOP-INTEND score ≥ 50, and 3 patients (9.1%) achieved a CHOP-INTEND score ≥ 58 (see Figure 3). Patients with untreated SMA Type 1 almost never achieve a CHOP-INTEND score ≥ 40. Figure 3 CHOP-INTEND motor function scores in Study CL-302 (Efficacy Completers population; N=33)* AVXS-101-CL-101 Phase 1 study in patients with Type 1 SMA The results seen in Study CL-303 are supported by study AVXS-101-CL-101 (Study CL-101) a phase 1 study in patients with Type 1 SMA, in which onasemnogene abeparvovec was administered as a single intravenous infusion in 12 patients from 3.6 kg to 8.4 kg (0.9 to 7.9 months of age). At 14 months of age, all treated patients were event-free; i.e. survived without permanent ventilation, compared to 25% in the natural history cohort. At the end of the study (24 months post-dose), all treated patients were event-free, compared to less than 8% in the natural history, see Figure 1. At 24 months of follow up post-dose, 10 out of 12 patients were able to sit without support for ≥ 10 seconds, 9 patients were able to sit without support for ≥ 30 seconds and 2 patients were able to stand and walk without assistance. One out of 12 patients did not achieve head control as the maximum motor milestone before the age of 24 months. Ten of 12 patients from Study CL-101 continue to be followed in a long-term study (for up to 6.6 years after dosing) and all 10 patients were alive and free of permanent ventilation as of 23 May 2021. All patients have either maintained previously attained milestones or gained new milestones such as sitting with support, standing with assistance and walking alone. Five of the 10 patients received concomitant nusinersen or risdiplam treatment at some point during the long-term study. Maintenance of efficacy and achievement of milestones can therefore not be solely attributed to onasemnogene abeparvovec in all patients. The milestone of standing with assistance was newly acquired by 2 patients who had not received nusinersen or risdiplam at any point prior to the time this milestone was achieved. AVXS-101-CL-304 Phase 3 study in patients with pre-symptomatic SMA Study CL-304 is a global, Phase 3, open-label, single-arm, single-dose study of intravenous administration of onasemnogene abeparvovec in pre-symptomatic newborn patients up to 6 weeks of age with 2 (cohort 1, n=14) or 3 (cohort 2, n=15) copies of SMN2 . Cohort 1 The 14 treated patients with 2 copies of SMN2 were followed to 18 months of age. All patients survived event-free to ≥ 14 months of age without permanent ventilation. All 14 patients achieved independent sitting for at least 30 seconds at any visit up to the 18 months of age visit (primary efficacy endpoint), at ages ranging from 5.7 to 11.8 months, with 11 of the 14 patients who achieved independent sitting at or before 279 days of age, the 99th percentile for development of this milestone. Nine patients achieved the milestone of walking alone (64.3%). All 14 patients achieved a CHOP-INTEND score ≥ 58 at any visit up to the 18 months of age visit. No patients required any ventilatory support or any feeding support during the study. Cohort 2 The 15 treated patients with 3 copies of SMN2 were followed to 24 months of age. All patients survived event-free to 24 months of age without permanent ventilation. All 15 patients were able to stand alone without support for at least 3 seconds (primary efficacy endpoint), at ages ranging from 9.5 to 18.3 months, with 14 of the 15 patients who achieved standing alone at or before 514 days of age, the 99th percentile for development of this milestone. Fourteen patients (93.3%) were able to walk at least five steps independently. All 15 patients achieved a scaled score of ≥ 4 on Bayley-III Gross and Fine Motor Subtests within 2 standard deviations of the mean for age at any post-baseline visit up to 24 months of age. No patients required any ventilatory support or any feeding support during the study. COAV101A12306 Phase 3 study in patients with SMA weighing ≥ 8.5 kg to ≤ 21 kg Study COAV101A12306 is a completed, Phase 3, open-label, single-arm, single-dose, multi-centre study of intravenous administration of onasemnogene abeparvovec at the therapeutic dose (1.1 × 10 14 vg/kg) in 24 paediatric patients with SMA weighing ≥ 8.5 kg to ≤ 21 kg (median weight: 15.8 kg). The patients ranged in age from approximately 1.5 to 9 years at the time of administration. Patients had 2 to 4 copies of SMN2 (two [n=5], three [n=18], four [n=1] copies). Before treatment with onasemnogene abeparvovec, 19/24 patients had previously received nusinersen for a median duration of 2.1 years (range, 0.17 to 4.81 years), and 2/24 patients had previously received risdiplam for a median duration of 0.48 years (range 0.11 to 0.85 years). At baseline, patients had a mean Hammersmith Functional Motor Scale - Expanded (HFMSE) score of 28.3 and a mean Revised Upper Limb Module (RULM) score of 22.0. In addition, all patients demonstrated the milestones of head control and sitting with support, twenty-one were able to sit without support, and six demonstrated the highest possible achievable milestones of standing alone and walking alone. At Week 52, the mean change from baseline in overall HFMSE total score was 3.7 (18/24 patients). The mean increase in overall RULM total score was 2.0 (17/24 patients) at Week 52. Four patients achieved new developmental milestones. Milestones observed at the baseline visit were maintained to Week 52 for the majority of patients. Two patients who did not demonstrate previously achieved developmental milestones showed improvement in the HFMSE score from baseline to Week 52. Onasemnogene abeparvovec has not been studied in patients with a bi-allelic mutation of the SMN1 gene and only one copy of SMN2 in clinical studies. The licensing authority has deferred the obligation to submit the results of studies with onasemnogene abeparvovec in one or more subsets of the paediatric population in spinal muscular atrophy for the granted indication (see section 4.2 for information on paediatric use).