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US FDA approves world's most expensive drug Zolgensma one-time treatment for SMA

ZOLGENSMA logoSwiss drugmaker Novartis has received US approval for its spinal muscular atrophy gene therapy Zolgensma® (onasemnogene abeparvovec-xioiT) for the treatment of pediatric patients less than 2years of age with spinal muscular atrophy (SMA) with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene). The one time treatment drug is priced at a record $2.125m. Novartis executives have defended the price, saying a one-time treatment is more valuable than expensive long-term treatments that cost several hundred thousand dollars a year.

Zolgensma® is designed to address the genetic root cause of SMA by providing a functional copy of the human SMN gene to halt disease progression through sustained SMN protein expression with a single, one-time intravenous (IV) infusion. Zolgensma represents the first approved therapeutic in a proprietary platform to treat rare, monogenic diseases using gene therapy.

The therapy uses a virus to provide a normal copy of the SMN1 gene to babies born with a defective gene and is delivered by infusion. Novartis said it has so far treated more than 150 patients with Zolgensma. Zolgensma according to Novartis is a near-cure for SMA if delivered soon after birth although current available data extends only to four years post therapy. European and Japanese approvals of the drug is expected laster this year.

The competitor drug Biogen’s Spinraza, was first approved treatment for SMA in 2016, but requires infusion into the spinal canal every four months and is priced at around $750,000 for the initial year and $375,000 annually thereafter.

SMA is a severe neuromuscular disease characterized by the loss of motor neurons leading to progressive muscle weakness and paralysis. SMA is caused by a genetic defect in the SMN1 gene that codes SMN, a protein necessary for survival of motor neurons.The incidence of SMA is approximately 1 in 10,000 live births and it is the leading genetic cause of infant mortality. The most severe form of SMA is Type 1, a lethal genetic disorder characterized by rapid motor neuron loss and associated muscle deterioration, resulting in mortality or the need for permanent ventilation support by 24 months of age for more than 90 percent of patients if left untreated.

The efficacy of Zolgensma® in pediatric patients less than 2 years of age with SMA with bi-allelic mutations in the SMN1 gene was evaluated in STR1VE, an open-label, single-arm clinical trial (ongoing), and in START, an open-label, single-arm, ascending-dose clinical trial (completed). Patients experienced onset of clinical symptoms consistent with SMA before 6 months of age. All patients had genetically confirmed bi-allelic SMN1 gene deletions, 2 copies of the SMN2 gene, and absence of the c.859G>C modification in exon 7 of SMN2 gene (which predicts a milder phenotype). All patients had baseline anti-AAV9 antibody titers of <= 1:50, measured by ELISA. In both trials, Zolgensma® was delivered as a single-dose intravenous infusion.

Efficacy was established on the basis of survival, and achievement of developmental motor milestones such as sitting without support. Survival was defined as time from birth to either death or permanent ventilation. Permanent ventilation was defined as requiring invasive ventilation (tracheostomy), or respiratory assistance for 16 or more hours per day (including noninvasive ventilatory support) continuously for 14 or more days in the absence of an acute reversible illness, excluding perioperative ventilation. Efficacy was also supported by assessments of ventilator use, nutritional support and scores on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND). CHOP-INTEND is an assessment of motor skills in patients with infantile-onset SMA.

The ongoing clinical trial, STR1VE, enrolled 21 patients (10 male and 11 female) with infantile-onset SMA. Before treatment with Zolgensma, none of the 21 patients required non-invasive ventilator (NIV) support, and all patients could exclusively feed orally (i.e., no need for non-oral nutrition). The mean CHOP-INTEND score at baseline was 31.0 (range 18 to 47). All the patients received 1.1 × 10[1][4] vg/kg of Zolgensma. The mean age of the 21 patients at the time of treatment was 3.9 months (range 0.5 to 5.9 months).

As of the March 2019 data cutoff, 19 patients were alive without permanent ventilation (i.e., event-free survival) and were continuing in the trial, while one patient died at age 7.8 months due to disease progression, and one patient withdrew from the study at age 11.9 months. The 19 surviving patients who were continuing in the trial ranged in age from 9.4 to 18.5 months. By the data cutoff, 13 of the 19 patients continuing in the trial reached 14 months of age without permanent ventilation, one of the study's co-primary efficacy endpoints. In addition to survival, assessment of the other co-primary efficacy endpoint found that 10 of the 21 patients (47.6%) achieved the ability to sit without support for >= 30 seconds between 9.2 and 16.9 months of age (mean age was 12.1 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, and only approximately 25% of these patients would be expected to survive (i.e., being alive without permanent ventilation) beyond 14 months of age. In addition, 16 of the 19 patients had not required daily NIV use.

Comparison of the results of the ongoing clinical trial to available natural history data of patients with infantile-onset SMA provides primary evidence of the effectiveness of Zolgensma.

The completed clinical trial, START, enrolled 15 patients (6 male and 9 female) with infantile-onset SMA, 3 in a low-dose cohort and 12 in a high-dose cohort. At the time of treatment, the mean age of patients in the low-dose cohort was 6.3 months (range 5.9 to 7.2 months), and 3.4 months (range 0.9 to 7.9 months) in the high-dose cohort. The dosage received by patients in the low-dose cohort was approximately one-third of the dosage received by patients in the high-dose cohort. However, the precise dosages of Zolgensma received by patients in this completed clinical trial are unclear due to a change in the method of measuring Zolgensma concentration, and to decreases in the concentration of stored Zolgensma over time. The retrospectively-estimated dosage range in the high-dose cohort is approximately 1.1 × 10[1][4] to 1.4 × 10[1][4] vg/kg.

By 24 months following Zolgensma® infusion, one patient in the low-dose cohort met the endpoint of permanent ventilation; all 12 patients in the high-dose cohort were alive without permanent ventilation. None of the patients in the low-dose cohort were able to sit without support, or to stand or walk; in the high-dose cohort, 9 of the 12 patients (75.0%) were able to sit without support for >= 30 seconds, and 2 patients (16.7%) were able to stand and walk without assistance. Comparison of the results of the low-dose cohort to the results of the high-dose cohort shows a dose-response relationship that supports the effectiveness of Zolgensma®.

Limitation of Use:

The safety and effectiveness of repeat administration of Zolgensma have not been evaluated. The use of Zolgensma in patients with advanced SMA (e.g., complete paralysis of limbs, permanent ventilator-dependence) has not been evaluated.

Important Safety Information

Acute Serious Liver Injury
Acute serious liver injury and elevated aminotransferases can occur with Zolgensma. Patients with pre-existing liver impairment may be at higher risk. Prior to infusion, assess liver function of all patients by clinical examination and laboratory testing (e.g., hepatic aminotransferases [aspartate aminotransferase and alanine aminotransferase], total bilirubin and prothrombin time). Administer systemic corticosteroid to all patients before and after Zolgensma infusion. Continue to monitor liver function for at least 3 months after infusion.

Thrombocytopenia
Transient decreases in platelet counts, some of which met the criteria for thrombocytopenia, were observed at different time points after Zolgensma infusion. Monitor platelet counts before Zolgensma infusion and on a regular basis afterwards.

Elevated Troponin-I
Transient increases in cardiac troponin-I levels (up to 0.176 mcg/L) were observed following Zolgensma infusion in clinical trials. The clinical importance of these findings is not known. However, cardiac toxicity was observed in animal studies. Monitor troponin-I before Zolgensma infusion and on a regular basis for at least 3 months afterwards.

Adverse Reactions
The most commonly observed adverse reactions (incidence >=5%) were elevated aminotransferases and vomiting. Full prescribing information is available at https://www.avexis.com/content/pdf/prescribing_information.pdf

Source: Novartis

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