Regulatory Decision Summary for Qalsody

This New Drug Submission was filed by Biogen Canada Inc to obtain market authorization for Qalsody (tofersen) for the treatment of adults with amyotrophic lateral sclerosis associated with a mutation in the superoxide dismutase 1 (SOD1) gene.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive disabling and fatal disease caused by motor neuron degeneration in the cortex, brainstem, and spinal cord. This leads to progressive weakness and death from respiratory failure within 3 to 5 years of symptom onset. When axons are degenerating, neurofilament (NfL) leaks into the cerebrospinal fluid (CSF) and blood. Lowering of NfL levels is thought to indicate slowing of neurodegeneration and may be a prognostic indicator for disease progression and provide evidence of treatment effect. ALS due to SOD1 mutations (SOD1-ALS), a genetic subset of ALS, in which accumulation of toxic SOD1 protein leads to loss of motor neurons, leading to loss of strength, function, and death, represents 1-2% of ALS cases (approximately equal to 40 persons in Canada), with many highly variable mutation types. Tofersen is an antisense oligonucleotide (ASO) designed to target the pathology of SOD1-ALS by binding to and degrading SOD1-mRNA, reducing the synthesis of toxic SOD1 protein. This leads to a reduction in neurodegeneration, measured by the biomarker NfL, which is hypothesized to stabilize or delay the progression of the disease.

Qalsody was generally well tolerated in both mice and monkeys, and resulted in a decrease in SOD1 protein levels in monkeys. Potential non-clinical findings that could prompt a reduced clinical efficacy identified in the pharmacodynamics review include that SOD1 protein levels reduction following treatment of transgenic mice with Qalsody was not as significant as the observed reduction in SOD1-mRNA levels and did not persist in time. In addition, the time between disease onset and death in transgenic mice was not prolonged by Qalsody, suggesting that while Qalsody may delay the onset of disease, it did not affect its progression once the process started.

The chemistry and manufacturing information submitted for Qalsody demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

Efficacy

The efficacy of tofersen in amyotrophic lateral sclerosis associated with a mutation in superoxide dismutase 1 SOD1-ALS was evaluated in the 28-week Phase 3 double-blind, placebo-controlled Study 101 Part C in 108 patients with ALS and a confirmed SOD1 mutation, randomized to Qalsody 100 milligrams (mg) (n = 72) or placebo (n = 36), plus standard of care. Dosing consisted of 3 loading doses of tofersen 100 mg intrathecal (IT) bolus every 2 weeks, followed by 100 mg doses IT bolus every 4 weeks. Following completion of Study 101 Part C, patients could enter Study 102, an ongoing open-label extension study to assess long-term safety of Qalsody 100 mg (n = 139). The studies were designed to evaluate crossover from Study 101 to Study 102. Data from Study 101 Part C were integrated across Studies 101 and 102 at week 52 for the intent-to-treat (ITT) population, to compare efficacy in patients randomized to Qalsody in Study 101 Part C (early-start group) with those randomized to placebo (delayed-start group) (n = 147). The efficacy evaluation was exploratory and no formal statistical testing was performed for the integrated efficacy analysis.

Study 101 Part C failed to reach significance on the primary efficacy endpoint of change from baseline to week 28 on the ALS Functional Rating Scale-Revised (ALSFRS-R) score in “fast progressors”, a modified intention to treat (mITT) subgroup defined by SOD1 mutation and pre-randomization ALSFRS-R slope. However, results showed a difference of 1.2 points favouring Qalsody (n = 39) over placebo (n = 21) (p = 0.97). Additionally, consistent trends in favour of Qalsody were observed at week 28 in reductions of cerebrospinal fluid (CSF) SOD1 protein, an indirect measure of target engagement and contributor to the neuronal degeneration in SOD1-ALS, and in plasma neurofilament (NfL). The effect of Qalsody on SOD1 protein is expected to prevent motor neuron degeneration by reducing NfL released into the CSF and blood, expected to stabilize or delay disease progression. The efficacy analyses supporting the benefit of Qalsody are based on plasma NfL levels, a surrogate endpoint which has not yet been validated for predicting clinical benefit but has been accepted as a neurodegeneration biomarker. However, the assessment of plasma NfL includes mechanistic evidence and biological plausibility of the effect of Qalsody based on its pharmacology and the pathophysiology of SOD1-ALS. The relationship between Qalsody-driven CSF SOD1 and plasma NfL reductions and delayed changes in functional decline in ALSFRS-R score also suggests slowing or stabilization of neurodegeneration. As such, NfL is considered reasonably likely to predict clinical benefit in patients with SOD1-ALS.

The effect of Qalsody on SOD1 protein is expected to prevent motor neuron degeneration by reducing NfL released into the CSF and blood, which is expected to stabilize or delay disease progression. The efficacy analyses supporting the benefit of Qalsody are based on plasma NfL levels, a surrogate endpoint which has not yet been validated for predicting clinical benefit but has been accepted as a neurodegeneration biomarker. However, the assessment of plasma NfL includes mechanistic evidence and biological plausibility of the effect of Qalsody based on its pharmacology and the pathophysiology of SOD1-ALS.

The relationship between Qalsody-driven CSF SOD1 and plasma NfL reductions and delayed changes in functional decline in ALSFRS-R score also suggests slowing or stabilization of neurodegeneration. As such, NfL is considered reasonably likely to predict clinical benefit in patients with SOD1-ALS.

After unblinding of Study 101 C results, post hoc exploratory analyses adjusting for baseline plasma NfL as a covariate, and in redefined faster-progressing subgroups were conducted for the integrated data from Study 101 and Study 102 at week 52 showed a greater treatment difference favoring earlier tofersen initiation. Treatment effect of tofersen on NfL was also most apparent in faster progressing disease defined by higher baseline NfL. Although none of the results could be analysed for statistical significance due to failure to reach significance on the primary efficacy endpoint, longer term data suggest a treatment effect of Qalsody, with numerical differences in favour of Qalsody across function, clinical outcomes, and biomarker levels.

Safety

The safety database for Qalsody includes the randomized, placebo-controlled study in 108 patients, and the integrated database of 147 patients treated with Qalsody 100 mg in either Study 101 or Study 102. In Study 101, adverse events (AEs) known to be associated with lumbar puncture procedures (headache, procedural pain, and post-lumbar puncture syndrome) occurred in most patients, and equally between arms. Common non-serious adverse drug reactions (ADRs) reported at a greater incidence than placebo (tofersen; placebo) included pain (back pain, pain in extremities) (42%; 22%), fatigue (17%; 6%), arthralgia (14%; 6%), myalgia (14%; 6%), CSF white blood cell count (WBC) increased (14%; 0%), CSF protein increased (8%; 3%), headache (8%; 0), musculoskeletal (MSK) stiffness (6%; 0), neuralgia (6%; 0), pyrexia (4%; 3%), aseptic meningitis (1%; 0), radiculitis (1%; 0), myelitis (2%; 0).

The main safety concern associated with Qalsody relates to the serious neuroinflammatory adverse drug reactions (SADRs) of myelitis (4/147), radiculitis (2/147), papilledema/increased intracranial pressure (ICP) (4/147), and chemical meningitis (2/147), for a total of 12 events in 10/147 patients. These are considered manageable with standard of care diagnostics and treatment. The symptoms were variable, resolving between 2 to 854 days after onset, with an average duration of 159 days. Apart from papilledema, neuroinflammatory ADRs are correlated with non-clinical findings, are only reported in tofersen-treated patients, all occurred with a higher-than-expected incidence, they share similar findings with IT administration of other ASOs, and all were associated with increased CSF WBC and CSF protein. Other potential class effects of ASOs include the risks of nephrotoxicity, thrombocytopenia, and coagulation abnormalities, which cannot be excluded.

Risk mitigation measures include labelling of neuroinflammatory serious ADRs and class effects under the Warnings and Precautions section of the Product Monograph (PM).

A Risk Management Plan (RMP) for Qalsody was considered to be acceptable by the Marketed Health Products Directorate (MHPD), to describe known and potential safety issues, the monitoring scheme and measures to minimize risks associated with the product.

Benefit-Harm Assessment

The clinical efficacy data are considered promising rather than substantial. The pivotal clinical trial did not adequately demonstrate the benefit of Qalsody for the treatment of SOD1-ALS given the primary endpoint did not reach statistical significance. However, the data showed a favourable trend, suggestive of a potential treatment benefit with Qalsody, which could lead to slowing of the disease.

A Notice of Compliance with Conditions-Qualifying Notice (NOC/c-QN) was issued due to a favourable benefit-risk assessment of Qalsody, with promising evidence of clinical effectiveness, despite its limitations, and an acceptable safety profile for a serious, life-threatening, and severely debilitating condition. Further evidence is needed to verify the clinical benefit and further characterize the benefit-harm-uncertainly profile of Qalsody.

The conditions issued in the NOC/c-QN included submission of a Letter of Undertaking, in which the Sponsor undertakes to carry out the confirmatory Studies 102 and 303, submission of progress reports of confirmatory trials, and post-marketing safety monitoring, including a summary of the risk-benefit profile of the drug on an annual basis. Conditions of the Qualifying Notice also included submitting a Product Monograph and final mock-up of the Patient Medication Information (PMI) as per the NOC/c Guidance.

For further details about Qalsody, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.