• Event-free survival.

• Change from baseline in Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scores.

• Motor milestone and developmental achievements.

^{** Event defined as death or need for ≥14 days of permanent ventilatory support.}

^{** CHOP INTEND is an assessment tool designed to evaluate motor function in infants with SMA. It comprises a 0-64 scale with higher scores indicating better function.}

Inclusion criteria: 

• Genetically confirmed SMA1 diagnosis.

^{** Bi-allelic SMN1 mutations and one or two copies of SMN2.}

Exclusions criteria: 

• Genetic modifier c.859G>C in SMN2 exon 7.

• Anti-AAV9 antibody titers >1:50.

• Use of other investigational or commercial products intended for the treatment of SMA

^{** This genetic modifier predicts a milder phenotype.}

^{** Ratio excluded to prevent potential impact on therapy efficacy and risk of adverse events due to preexisting antibodies.}

(Novartis, 2023a; Novartis, 2023b; Novartis, 2023c; Stolte et al., 2022)

Procedure:

• Symptomatic patients (n=15) <9 months of age were divided into 2 cohorts—a low-dose cohort (n=3) and a high-dose cohort (n=12). 

• A single IV infusion of Zolgensma was administered.

• The low-dose (6.7 × 10¹³ vg/kg of body weight) cohort received approximately ¹⁄₃ the dosage received by the high-dose (2.0 × 10¹⁴ vg per/kg of body weight) cohort. 

Procedure:

• START participants (n=13) from the high-dose cohort (n=10) and low-dose cohort (n=3) were enrolled and studied.

• 2 patients’ families declined participation.

Procedure:

• Symptomatic patients (n=22) <6 months of age were enrolled.

• A single IV infusion of Zolgensma (1·1×10¹⁴ vg/kg of body weight - built on findings from START) was administered.

• Weekly follow-ups were conducted for 4 weeks, followed by subsequent monthly assessments until patients reached 18 months of age.

(Devi et al., 2022)

• The use of both a low-dose and high-dose cohort was beneficial, given the appropriate therapeutic dose has yet to be determined.

STR1VE:

• STR1VE was conducted in US, EU and AP - respective genetic differences amongst populations can be accounted.

• walk independently

• permanently free of ventilation if treated pre-symptom (Novartis, 2021).

·      Clinical Trial Results: The approval of Zolgensma was based on data from the ongoing Phase 3 STR1VE trial and the completed Phase 1 START trial. The clinical trials demonstrated unprecedented rates of survival, rapid motor function improvement, and durable milestone achievements. Patients in the trials showed the ability to sit without support, a milestone rarely achieved in untreated SMA patients (Day et al., 2021).

Jeffrey Wong -- Drug development & Preclinical trial

Yvonne Hew -- Clinical trials

Xinyan -- Analysis & Future outlook

• Number of participants experiencing adverse events meeting criteria such as

  --> fatality, life-threatening conditions, persistent or significant disability, congenital anomalies, hospitalization, or events requiring medical intervention.

• Adverse Events of Special Interest (AESI):

  Number of participants with identified and potential risks associated with OAV101

  --> hepatotoxicity, thrombocytopenia, cardiac adverse events, sensory abnormalities suggestive of ganglionopathy, and thrombotic microangiopathy. Assessment conducted by the investigator (Novartis, 2023).

Spinal muscular atrophy (SMA), is an autosomal recessive disease in individuals who are born without a functioning survival motor neuron one (SMN1) gene. The autosomal recessive mutation in the SMN1 gene leads to dysfunctional SMN1 proteins and decreases the total amount of functional SMN protein available (Duque et al., 2015).

SMA patients experience loss of muscle strength and paralysis because of...

• Loss of alpha motor neurons (AMNs) in the lower brainstem and spinal cord -> impaired skeletal muscle-spinal cord communication (Ogbomide et al., 2023).

1. Self complementary adeno-associated virus 9 (scAAV9)

   • Forms an intramolecular dsDNA template (McCarty, 2008)

   • Bypasses the initial DNA duplication step in the transcription process (McCarty, 2008)

2. Hybrid promoter

   • Allows for continuous expression of the SMN1 gene (Thomsen et al., 2021)

3. Functional SMN1 gene

   • Encodes human SMN1 gene

1. Intravenous injection of the scAAV9 containing human SMN1 gene (Novartis, 2023)

2. Injected scAAV9 crosses the blood brain barrier into motor neuron cells (Novartis, 2023)

3. The scAAV9 then enters the motor neuron nucleus and transducts the human SMN1 gene into the nucleus (Novartis, 2023)

4. The self complementary DNA encoding the human SMN1 gene forms a circular episome structure under the control of the strong promoter -> continuous SMN protein production (Thomsen et al., 2021)

5. SMN protein quantities increase to counteract SMA phenotype (Novartis, 2023)

• 100% of patients surpassed the 20-month age mark where traditionally only 8% survived without permanent ventilation.

• As of the May 2022 data cut, all patients were alive and free of permanent ventilation. 

• With 100% of patients maintaining motor milestones achieved at the end of START, Zolgensma was found to exhibit durability of effect up to 7.5 years post-treatment.

• 30% of patients even gained an additional motor milestone of standing with assistance. 

• Add-on SMA therapy was not needed for ⅔ of the patients.

• Aligning with results from START, 91% (20/22) of patients surpassed the 18-month age mark.

• Patients were alive and free of permanent ventilation.

^{** 1 patient withdrew from the study and another passed away due to respiratory failure unrelated STR1VE-US.}

• The range of ethnicities represented was limited.

• The rationale behind why the low-dose cohort had 3 patients and the high-dose cohort had 12 was left unaddressed.

• ⅓ of patients in START LTFU received add-on therapy. As such, gain and maintenance of motor milestones for these patients may not solely be attributed to Zolgensma.

  
  

STR1VE:

• Traditionally, Phase III compares treatment of interest with standard current drug therapy (or placebo). However, that was not the case for STR1VE.

• A larger sample size would also improve statistical significance.

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• DNA tests for individuals considering children

• Test fetus during pregnancy

• Screen newborns for genetic issues

• Treatments for genetic disorders