Summary of Cancellation for Sabizabulin (*Sabizabulin Capsule)

This New Drug Submission (NDS) was filed as an NDS with flexibilities for designated COVID-19 drug (NDS-CV). The purpose of this NDS-CV was to seek a market authorization for sabizabulin in the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in hospitalized patients with moderate to severe COVID-19 infection who are at high risk for acute respiratory distress syndrome (ARDS).

The proposed indication for sabizabulin was based primarily on the efficacy and safety data from a single pivotal Phase 3 trial (Study 902). Study 902 was an international, multicenter, randomized, double-blind, placebo-controlled, parallel group study of 60 days duration that evaluated the efficacy and safety of sabizabulin in hospitalized adult patients with COVID-19 infection described as being at high risk for acute respiratory distress syndrome (ARDS). Eligible participants were aged 18 years of age or older with World Health Organization (WHO) ordinal scale category 6 (mechanical ventilation); category 5 (non-invasive ventilation or high-flow oxygen), or category 4 (oxygen by mask or nasal prongs). Patients included those with asthma, chronic lung disease, diabetes, hypertension, severe obesity (Body Mass Index [BMI] ≥40), 65 years of age or older, primarily residing in a nursing home or long-term care facility or immunocompromised. 204 patients were randomized 2:1, 134 received sabizabulin 9 mg oral capsules by mouth or via nasogastric (NG) tube daily for up to 21 days and 70 patients received placebo.

A Notice of Deficiency (NOD) was issued on April 14, 2023. The sponsor asked for a 3-year extension to respond to the NOD which was denied due to the length of the requested extension. On June 8, 2023, the sponsor opted to withdraw the submission from review. Voluntary withdrawal of a submission does not disqualify a sponsor from refiling the application at a later date based on new evidence.

Study 902 met its primary endpoint of Day 60 all-cause mortality (78.4% of the sabizabulin arm remained alive compared to 58.6% of the placebo arm [risk difference: 19.0%, 95% confidence internal (CI): 5.8%, 32.2%], odds ratio: 2.77, 95% CI [1.37, 5.58]).

Despite meeting the primary endpoint there were several concerns that generated uncertainty regarding the data provided. It is notable that the mortality rate in the placebo group was significantly higher than that reported in current literature, with an overall mortality rate of 38.6% in the placebo group and specifically, 56.5% in the placebo group in North America. Reasons for this finding may be multifactorial. The number of patients included in Study 902 was small, particularly when compared to other studies in hospitalized patients with COVID-19. Notably, 6.7% of the sabizabulin arm had received >14 days of standard of care medications for COVID-19 prior to randomization compared to 0% of the placebo arm. Similarly, 4.5% of the sabizabulin arm had been admitted to the hospital for >14 days prior to randomization compared to 0% of the placebo arm, and the mean time from hospital admission to randomization was numerically higher in the sabizabulin compared to the placebo arm. Time from admission to randomization varied amongst the groups with 4.2 days in sabizabulin and 3.8 days in placebo. It is unclear what the trajectory of the clinical course was at inclusion into the study, and if patients who had been receiving standard of care medication(s) and had been in hospital longer were improving already compared to those who were randomized into the study shortly after admission to hospital (as in the placebo group).

Further, there were concerns surrounding the appearance of powder form sabizabulin versus powder/water administration for nasogastric tube administration. The placebo and sabizabulin differed in appearance, leading to the concern of unblinding events which may have introduced potential performance bias or impact on goals of care.

Importantly, although most patients did receive corticosteroids (80.6% in the sabizabulin arm, 77.1% in the placebo arm), very few patients received other recommended standard of care medications: remdesivir, tocilizumab or baricitinib. It is unclear how this impacted mortality results; however, this may be responsible for the greater than expected mortality rates in the placebo arm when compared to reported mortality rates in the literature. As a result, the role and efficacy of sabizabulin in Canada in patients receiving standard of care medications as suggested was uncertain.  

Most patients in Study 902 completed fewer than 10 days of study drug treatment, and disposition data suggest that 81.3% of the sabizabulin arm discontinued treatment prior to Day 21, with a median time to discontinuation of study medication of 9.1 days. There was uncertainty based on the proposed mechanism of action and available clinical data from prior studies regarding the minimum duration of treatment that would be expected to provide an efficacy benefit.  

Assessment of subgroups found that although a numeric reduction in mortality was observed, significance was not reached in several pre-specified groups including female patients, vaccinated patients (vaccinated patients was defined as having at least one dose of vaccine: 83.3% of Canadians have received 1 dose with 80.5% had their primary series) and geographical location (e.g., North America or Europe). The study was not powered to show statistical significance in each of these subgroups. Further, standard of care medications, and likely intensive care unit (ICU) care, was different amongst these countries raising the concern that sabizabulin may be of limited use in these circumstances.

The sponsor’s mechanism of action rationale for sabizabulin in COVID-19 relies on indirect anti-viral activity and the assumption of downstream anti-inflammatory actions and the potential efficacy of sabizabulin in COVID-19 was unclear.

Safety data for sabizabulin was comprised of data from 130 patients exposed to sabizabulin in Study 902 with additional supportive data from 19 patients receiving sabizabulin in the Phase 2 study, V0211901. In review of Study 902, treatment emergent adverse events (TEAEs) considered related to study drug were reported in 21 (10.6%) patients overall, including 13 (10.0%) patients in the sabizabulin 9 mg group and 8 (11.6%) patients in the placebo group. The most common TEAEs considered related to study drug were increased transaminases (2.3% patients), dyspepsia (1.5% patients), and diarrhoea (1.5% patients). Most TEAEs were Grade 1 or 2. The adverse events (AEs) data suggest a potential safety signal for urinary tract infections with the use of sabizabulin compared to placebo.

Overall, the small sample size and short follow-up of Study 902 limit its ability to allow for detection of rare events with any certainty, particularly significant adverse events (SAE) of interest. 

In summary, no significant or unmanageable safety signals were identified; however, despite this, significant uncertainty exists regarding the overall safety profile of sabizabulin as a small sample size has limitations in terms of adequately characterizing the safety profile, especially when considering rare events. Furthermore, the safety profile was limited by short treatment duration which was 9.1 days and a total safety follow-up duration of 60 days. It is acknowledged that clinical care of hospitalized patients with COVID-19 is characterized by short-term treatment and monitoring throughout inpatient hospitalized acute care.

Overall, despite reaching its primary efficacy endpoint of Day-60 all-cause mortality, significant uncertainty remained regarding the appropriate population for use, the appropriate duration of treatment to achieve efficacy and significant uncertainty regarding the substantiality of the efficacy data presented, particularly considering the small patient population studied. Additionally, there was limited safety data to adequately characterize the safety profile of sabizabulin. Taken together, the overall benefit-risk-uncertainty profile of sabizabulin for the proposed indication could not be established based on the current data provided. Health Canada acknowledges the importance and clinical relevance of a reduction in Day 60 all-cause mortality; however, it was concluded that a larger confirmatory study would be required to support the requested indication. 

There is no expected impact for patients in clinical trials. Sabizabulin is not being accessed under the SAP.