ZolgensmaSpinal muscular atrophy type 1 or patients with ≤ 3 copies of the SMN2 gene (paediatric patients weighing ≤ 21kg)
New molecular entity
Novartis Gene Therapies
Novartis Gene Therapies
Development and Regulatory status
May 21First patient treated in England with Zolgensma. Four centres have been commissioned across England to administer the treatment, Manchester University NHS Foundation Trust, Sheffield Children ´s NHS Foundation Trust, University Hospitals Bristol and Weston NHS Foundation Trust and Evelina London Children ’s Hospital (part of Guy’s and St Thomas’ NHS Foundation Trust), with agreement for Evelina London Children ’s Hospital to develop a collaborative model with Great Ormond Street Hospital for Children NHS Foundation Trust .
Mar 21NHS England agree deal with Novartis, which will allow up to 80 patients a year to benefit from single IV infusion therapy of onasemnogene abeparvovec .
Jul 20Available in France and Germany, with ~90% of patients covered through agreements already in place with sickness funds. Novartis is in discussions with all EU markets regarding its Day One access program, and have confidential agreements in place with five additional markets .
May 20AveXis has met with more than 100 stakeholder organisations across Europe to discuss their ´ Day One ´ access programme to enable rapid access with customisable options designed to work within local pricing and reimbursement frameworks. It ensures the cost of patients treated before national pricing and reimbursement agreements are in place align with the value-based prices negotiated following clinical and economic assessments. The options include: Retroactive rebates ensuring early access costs are aligned with negotiated prices following local clinical and economic assessment processes; Deferred payments and instalment options allowing reimbursement bodies to manage budget impact during the early access phase; Outcomes-based rebates negotiated following clinical and economic assessments can be applied to patients treated during the early access period; Robust training for treating institutions on administration and follow-up care; Access to RESTORE, a global registry of patients who have been diagnosed with SMA that draws upon existing country registries .
May 20The European Commission gave conditional approval to for onasemnogene for pts with SMA Type 1. 
Mar 20Recommended for conditional EU approval by CHMP - the full indication is "for the treatment of: patients with 5q spinal muscular atrophy (SMA) with a bi-allelic mutation in the SMN1 gene and a clinical diagnosis of SMA Type 1; or patients with 5q SMA with a bi-allelic mutation in the SMN1 gene and up to 3 copies of the SMN2 gene." The medicine is for single treatment only and should be administered in suitable clinical centres under the supervision of a physician experienced in the management of patients with SMA. Conditional approval indicates that approval has been granted on the basis of less data than would normally be expected and that further efficacy and safety data are expected. The conditional approval will normally be renewed until sufficient data are available to support a final authorisation decision, whether positive or negative .
Aug 19Novartis is under investigation by FDA for submitting manipulated data as part of its regulatory submission. FDA has decided to keep the drug on the market as it believes it is still "safe, pure, and potent for its approved population" .
May 19Zolgensma approved by US FDA for children <2 yrs old with SMA with bi-allelic mutations in the SMN1 gene. It will be available at a cost $2.125 million, or $425,000 per year for 5 years .
May 19In Europe, Zolgensma is being reviewed under Accelerated Assessment Procedure .
Mar 19A new market research report identifies onasemnogene abeparvovec as one of seven new drugs it believes will hit sales of $1 billion or more, the so-called “blockbuster” mark, by 2023 .
Dec 18FDA grants priority review for onasemnogene abeparvovec, which means it could be approved in May 2019 .
Nov 18Marketing authorisation applications have been made in the EU, the US, and Japan, based on the results of the PI trial and the ongoing PIII STR1VE trial. The company expects regulatory approvals in the first half of 2019 and launch mid-2019 .
Nov 18Application is being reviewed under EMA´s accelerated assessment programme .
Sep 18Filings for IV formulation now planned for 2018 .
May 18Also has breakthrough paediatric therapy and fast track designations in the US .
May 18AveXis has been acquired by Novartis who have announced plans to submit regulatory application in the EU in 2019. A new manufacturing plant is to be built in North Carolina in the US [4,5].
Sep 17Pivotal PIII US trial initiated (NCT03306277) .
Jan 17VXS 101 granted PRIority MEdicines (PRIME) status in EU. Also has orphan drug status in EU .
Oct 14Orphan status was granted in the US .
A self-complementary adeno-associated virus, serotype 9 (scAAV9) carrying the cDNA of the human survival motor neuron (SMN) gene under the control of cytomegalovirus (CMV) enhanced chicken beta-actin hybrid promoter
The estimated incidence is between 1 in 6,000 and 1 in 10,000 live births and the carrier frequency is between 1 in 40 and 1 in 60. SMA type II is the most common form; SMA type 1 (acute infantile) is the most acute form with onset before six months and median survival of 7 months, 95% die before 18 months .
Spinal muscular atrophy type 1 or patients with ≤ 3 copies of the SMN2 gene (paediatric patients weighing ≤ 21kg)
Trial or other data
Aug 22Novartis has recorded two deaths after treatment with Zolgensma. Two children in Russia and Kazakhstan died about five to six weeks after receiving Zolgensma, both dying of acute liver failure. Both had received corticosteroids to restore liver function. In Sep 21, the FDA noted that about one-third of the 500 patients who had received Zolgensma experienced a liver-related side effect .
Apr 22PIII SMART study is recruiting, including in the Great North Children´s Hospital in Newcastle, to evaluate the safety and efficacy of onasemnogene abeparvovec in children with SMA weighing ≥ 8.5 kg and ≤ 21 kg. The new clinical data will supplement emerging real-world evidence and use of this innovative therapy in the EU and Canada, where regulatory approval includes dosing guidance for babies and young children up to 21 kg. Since launch, more than half (55%) of children treated in Europe range in weight between ≥ 8.5 kg and ≤ 21 kg. According to Pediatric Neuromuscular Clinical Research (PNCR) natural history study of SMA, almost all patients under the age of five years will be under 21 kg, with some patients as old as eight years of age weighing below 21 kg. The global study is expected to enroll 24 symptomatic children with SMA across sites in Europe, North America, Australia and Taiwan, and will follow patients for a period of 12 months [33,34].
Mar 22The completed SPR1NT trial shows children with three copies of SMN2 treated presymptomatically achieved age-appropriate milestones, including standing and walking; required no ventilatory or feeding tube support; and had no serious, treatment-related adverse events. Post-hoc analyses of START, STR1VE-EU and STR1VE-US trials showed children with SMA Type 1 (n=65) achieved/ maintained important measures of bulbar function 
Jun 21Data from PIII SPR1NT study found 100% of the 14 children in the two-copy cohort treated presymptomatically could sit independently for >30 seconds. Of those, 79% were within the WHO window of expected normal development. In addition, a majority of pts went on to stand and walk independently, most within the typical range of normal development. 
Mar 21The Lancet reports in the PIII STR1VE trial (NCT03306277, n=22), onasemnogene abeparvovec showed a therapeutic benefit when administered to symptomatic patients with infantile-onset spinal muscular atrophy, compared with untreated control patients who were part of a natural history dataset .
Oct 20Interim results from the STR1VE-EU trial reported showing improvement in motor function following treatment with and most have already achieved motor milestones. Overall, 93.9% of patients were able to swallow thin liquids, and 30.3% required feeding support with 27.3% of patients required ventilatory support at baseline. At data cut-off, 97% of patients in the intent to treat population survived event free, including 93.8%, who could have reached 10.5 months of age and 56.3%, who could have reached 13.6 months of age. overall, 65.6% of patients achieved motor milestones, including 18.8% of patients could sit independently for 10 seconds, 66.7% of patients gained head control, 25% were able to roll from back to sides and one patient who could stand, crawl and walk with assistance. The mean increase in CHOP INTEND from baseline was 5.9 points (n=31) which was observed as early as at one month post-dosing, 10.1 points at 3 months (n=29) post-dosing, and 13.3 points at six months (n=27) post-dosing. Overall, 65.6% of patients enrolled in the trial achieved and maintained a CHOP INTEND score of 40 points and 37.5% were able to achieve a score of 50. In intent to treat population, 66.7% of patients were able to feed orally without need of feeding support, indicating of stabilization of disease progression .
Apr 20Phase IV long-term follow-up study (NCT04042025) is enrolling by invitation .
Jan 20UK trial sites for STRIVE-EU (NCT03461289) - GOSH, Newcastle .
Oct 19AveXis announce interim data from the P1/II STRONG study for IT administration of onasemnogene abeparvovec demonstrating older patients (≥ 2 and < 5 years) with SMA Type 2. Pts achieved mean increase of 5.9 points from baseline in HFMSE scores, nearly double the clinically meaningful threshold, at a mean duration of follow-up time of 9.3 months .
May 19New interim data from PIII SPR1NT trial presented at the 2019 American Academy of Neurology (AAN) Annual Meeting. As of March 8 2019, all patients (18/18) were alive and event-free. Among patients with two copies of SMN2 (n=8), a mean 8.9-point improvement from baseline in CHOP-INTEND was achieved 1 month post dosing, and a mean score of 8.4 points in Bayley-III Gross Motor was achieved by month 2. All patients in this group achieved or maintained a CHOP-INTEND score of 50 points, with 6 patients achieving a score of 60 points and 3 patients achieving the maximum score of 64. Patients with two copies of SMN2 reached age-appropriate motor milestones. Serious adverse events were cases of croup (n=1), lethargy (n=1), and hypercalcaemia (n=1), all of which resolved and were considered unrelated to treatment by investigators. Other observed adverse events included elevated transaminases, elevated blood creatine phosphokinase MB and elevated troponin .
May 19New interim data from PIII STR1VE trial presented at the 2019 American Academy of Neurology (AAN) Annual Meeting. As of March 8 2019, of the 20 patients who could have reached 10.5 months of age or discontinued the study prior to 10.5 months of age, 19 (95%) survived without permanent ventilation. Of the 15 patients who could have reached 13.6 months of age or discontinued the study prior to 13.6 months of age, 13 (87%) survived without permanent ventilation. CHOP-INTEND scores increased by an average of 6.9 points one month, 11.7 points three months and 14.3 points five months after gene transfer, reflecting improvement in motor function from baseline. 21/22 (95%) patients achieved a CHOP-INTEND score of ≥40. Patients treated with Zolgensma continued to gain motor milestones, with achievements babies with SMA type 1 never reach in natural history. Adverse events observed include elevated transaminases, platelet count decrease and thrombocytopenia .
Apr 19The death of a second pt, a 6 month old infant with type 1 SMA, was reported in interim data from its PIII STR1VE clinical trial of Zolgensma in Europe. Preliminary findings indicate this occurred in the context of a severe respiratory infection followed by neurological complications and was deemed possibly related to treatment. Results of an autopsy are pending .
Apr 19Novartis has shared details of an infant death in an ongoing PIII EU trial with regulatory authorities. Death was attributed to a severe respiratory infection and neurological complications. A trial investigator said the death might have been treatment-related, but autopsy results are pending. Although the death of 1 infant due to respiratory failure was reported in the STR1VE trial, that death was deemed unrelated to treatment, according to an internal investigator and an independent Data Safety Monitoring Board .
Apr 19AveXis announce interim data from PIII STR1VE trial. As of 27/9/18, 21 of 22 patients were alive and event-free (EF). Median age was 9.5 months, with 6 out of 7 patients who could have reached ≥10.5 months of age surviving EF. It was predicted that if this group had been untreated, half would either have died or required permanent ventilation by the time they were 10.5 months old .
Apr 18PIII open-label, single-arm, single-dose STR1VE EU trial (NCT03461289) planned for H1 2018 [5,6].
Apr 18PIII, open-label, single-arm SPR1NT trial (NCT03505099; AVXS101CL304) initiated to evaluate safety, survival, bulbar function in pre-symptomatic infants (age ≤6 weeks) (n=44) with spinal muscular atrophy types 1, 2 and 3 with bi-allelic deletion of SMN1 and 2, 3, or 4 copies of SMN2. The trial is enrolling patients in the US and is expected to expand to Canada, Europe (inc UK), Asia and Australia. Estimated primary completion is Oct 2020 [5,6].
Sep 17NCT03306277 is a pivotal open-label, single dose, US-based historical control trial that will enrol a minimum of 15 patients aged under 6 months with SMA type 1. Patients will have non-functional SMN 1 gene with one or two copies of functional SMN 2 gene; primary outcomes are independent sitting at 18 months age and event-free survival at 14 months, where an event is either death or need for at least 16 hours ventilator support other than psotoperatively or for acute reversible illness . Estimated primary completion is March 2020 .
Nov 16AveXis plans a pivotal trial in patients with spinal muscular atrophy type 1 in the EU, in the second half of 2017. The pivotal trial will follow a single arm design using natural history of the disease as a comparator, and will enrol approximately 30 patients. The trial was designed based on the Scientific Advice response from the Scientific Advice Working Party within the CHMP of the EMA. The CHMP additionally recommended AveXis discuss the potential for conditional marketing authorization in the future meeting with EMA .
Nov 16AveXis plans a pivotal trial in the US in patients with spinal muscular atrophy type 1 in the first of 2017. It will follow a single arm design using natural history of the disease as a comparator, and will enrol approximately 20 patients. The design of the trial was finalised based on suggestions from the Type B meeting with the US FDA. The FDA also mentioned 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. AveXis will continue discussing with the FDA regarding suitable pathways for approval of AAV9 CBA SMN1 gene therapy .
Evidence based evaluations
ZolgensmaType 2 and type 3 spinal muscular atrophy in older patients (intrathecal administration)
Novartis Gene Therapies
Novartis Gene Therapies
Development and Regulatory status
Phase III Clinical Trials
Aug 21US FDA lift the partial clinical hold on intrathecal onasemnagene clinical trials after the company presented comprehensive nonclinical toxicology data addressing the initial concerns. Trials were put on partial hold after AveXis reported dorsal root ganglia mononuclear cell inflammation associated with the treatment in preclinical animal studies. The PIII STEER trial will be initiated to assess the efficacy, safety and tolerability of intrathecal onasemnagene in treatment-naïve patients with SMA between 2 and 18 years of age. A similar late-stage trial investigating intravenous OAV-101, dubbed the SMART trial, is also underway. 
Sep 20Novartis Gene Therapies is evaluating trial design and other details and will provide an update after further discussions with regulators. The FDA request for a pivotal confirmatory study to supplement the existing STRONG data and further support the regulatory submission for AVXS-101 IT is unrelated to the partial clinical hold on AVXS-101 IT, and the new study will not be initiated in the US until the hold has been lifted by the FDA .
Sep 20Rather than accept a filing based on a PI/II trial, the FDA will require Novartis to run a pivotal PIII trial of intrathecal Zolgensma - this could push the filing to at least 2023 in the US. This is not related to the clinical hold on the STRONG trial. 
Apr 20Novartis has informed investors it will be meeting with the FDA sometime this quarter to discuss requirements for lifting the clinical hold with the agency. Depending on the outcome, the company won’t be able to file for approval until H2 2020 or possibly 2021 .
Oct 19The FDA has placed a partial clinical hold on the PI/II STRONG trial of Zolgensma intrathecal in patients with SMA type 2. The hold is a result of findings from a small, AveXis-initiated pre-clinical study in which animal findings showed dorsal root ganglia (DRG) mononuclear cell inflammation, sometimes accompanied by neuronal cell body degeneration or loss. The partial hold by the FDA does not impact marketed Zolgensma or intravenous (IV) clinical trials .
An adeno-associated virus vector-based gene therapy designed to deliver a copy of the gene encoding the human survival motor neuron (SMN) protein .
The incidence of SMA is approximately 1 in 10,000 live births. SMA is divided into subtypes based on age of onset and maximum function achieved. The onset of weakness in SMA type 2 patients is usually between 6 and 12 months .
Type 2 and type 3 spinal muscular atrophy in older patients (intrathecal administration)
Trial or other data
Dec 21PIII STEER study to evaluate the efficacy, safety and tolerability of intrathecal (IT) OAV101 in treatment naive patients with Type 2 spinal muscular atrophy (SMA) who are ≥ 2 to < 18 years of age over a 15 month trial duration is due to start (NCT05089656). The study will enroll treatment naive Type 2 SMA participants who are ≥ 2 years to < 18 years who harbor biallelic SMN1 pathogenic variants in SMN1 and 2-4 copies of SMN2. The study consists of a Screening and a Baseline Period followed by a Treatment Period 1 and Follow-up Period 1 (total of 52 weeks) and a Treatment and Follow-up Period 2 (total of 12 weeks). The total trial duration period is 64 weeks. Treatment Period 1 consists of OAV101/sham administration with in-patient hospitalization on Study Day 1, Day 2 and Day 3 (optional) (administered as a single, one-time intrathecal dose). Treatment Period 1 is followed by a 52-week out-patient Follow-Up Period 1 for safety and efficacy assessments. 125 children aged 2 to 17 years will be recruited. Primary outcome is Change from baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) total score at the end of Follow-up Period 1 in treated patients compared to sham controls in the ≥ 2 to < 18 years age group at 52 weeks; collection of these data is due to complete Jul 24 .
Feb 21PI STRONG study remains suspended .
Nov 20PI STRONG trial remains suspended after the FDA placed AVXS-101 IT administration studies on clinical hold pending further discussions regarding pre-clinical findings .
Dec 17The PI/II open-label, dose-comparison, multi-centre STRONG trial (NCT03381729) initiated in the US. The study will evaluate the safety and tolerability of intrathecal administration of onasemnogene abeparvovec-xioi in infants and children aged 6-60 months (n=51) with Spinal Muscular Atrophy type 2 with 3 copies of SMN2 and deletion of SMN1 [1,2].