Regulatory Decision Summary for Amivas-Artesunate

This New Drug Submission (NDS) - New Active Substance (NAS) was filed by Amivas Ireland Pharmaceuticals Inc. to obtain market authorization, pursuant to section C.08.004 of the Food and Drugs Regulations, of artesunate (Amivas-Artesunate) for the following indication:

Amivas-Artesunate is indicated for the initial treatment of severe malaria in adult and pediatric patients.

The recommended dosing regimen for Amivas-Artesunate is 2.4 mg/kg intravenously (IV) every 12 hours administered over 60 minutes by infusion for a total of 3 doses in the initial twenty four hours (every 12 hours) and then if needed once daily in subsequent days of treatment. The total duration of treatment is at the discretion of the treating healthcare professional.

The NDS for artesunate was filed and accepted for review under Health Canada’s Priority Review Policy. The Canadian regulatory decision of the review of Amivas-Artesunate was based on a critical assessment of the data package submitted to Health Canada. The primary sources of evidence that supported the efficacy and safety of Amivas-Artesunate were two phase 3 randomized controlled trials in patients with severe malaria: one in an Asian, mostly adult population, and another in an African pediatric population. The foreign review completed by the United States Food and Drug Administration (FDA) was used as an additional reference.

Malaria is a mosquito-borne disease caused by Plasmodium protozoa. Plasmodium (P.) falciparum is the most prevalent and pathogenic malaria parasite, most commonly associated with severe illness and death. According to the World Health Organization World Malaria Report 2024, there were 263 million cases of malaria in 2023. Malaria is endemic in more than 90 countries, but not in Canada or in the United States.

Canada sees about 100 cases of severe malaria per year, typically in people who recently travelled from areas with endemic malaria. Severe malaria typically is caused by Plasmodium parasitemia - virtually always P. falciparum - and meets at least one of 9 clinical criteria: 1) coma measured by Glascow or Blantyre coma scale, 2) circulatory shock, 3) abnormal blood bicarbonate, 4) abnormal hematocrit in the presence of P. falciparum parasitemia, 5) visible jaundice and P. falciparum parasitemia, 6) abnormal blood urea nitrogen, 7) asexual P. falciparum parasitemia, 8) abnormal plasma glucose or 9) respiratory distress.

Artesunate and its active metabolite, dihydroartesunate (DHA), contain an endoperoxide bridge which increases oxidative stress and inhibits protein and nucleic acid synthesis, which is associated with decreased P. falciparum growth and survival.

The primary sources of evidence to support the efficacy and safety of artesunate for the treatment of patients with severe malaria were two pivotal, multicenter, open-label Phase 3 trials: the Southeast Asian Quinine and Artesunate Malaria Trial (SEAQUAMAT) and the African Quinine and Artesunate Malaria Trial (AQUAMAT), which were conducted in patients with severe malaria (based on clinician’s impression at randomization and subsequently confirmed post-randomization). In SEAQUAMAT, approximately 7% of patients were less than 15 years of age and the mean age was 28 years. In AQUAMAT, all the patients were less than 15 years of age and the mean age was 2.9 years in the quinine treatment arm (range 1.7-4.3) and 2.8 in the artesunate arm (range 1.6-4.2 years of age). Sample sizes were 1,461 in SEAQUAMAT and 5,425 in AQUAMAT. The trials randomized patients 1:1 to artesunate or to quinine, which was the contemporary standard of care for severe malaria when SEAQUAMAT and AQUAMAT were conducted (2003-2005 and 2005-2010, respectively). The artesunate dose was 2.4 mg/kg given on admission to hospital (0 hours), at 12 hours, at 24 hours, and then once daily until oral medication could be taken reliably. In both studies, the primary endpoint was all-cause in-hospital mortality in the intent-to-treat population (until discharge or up to one week).

SEAQUAMAT was stopped early for benefit with approximately two thirds of the planned enrolled patients. In the intent-to-treat population, there was a mortality of 14.7% (107/730) in the artesunate group compared to 22.4% (164/731) in the quinine group (site-adjusted odds ratio (OR) 0.60 (95% confidence interval (CI): 0.45, 0.78; p = 0.0002). Mortality in patients with confirmed severe malaria was 19.8% (101/509) with artesunate versus 28.1.% (152/541) in the quinine treatment arm: a site-adjusted OR 0.64 (95% CI: 0.48, 0.87; p = 0.0031).

In AQUAMAT, the mortality in the artesunate arm in the intent-to-treat population was 8.5% (230/2712) versus 10.9% (297/2713) with quinine: OR 0.75 (95% CI: 0.63-0.90; p = 0.0022). Mortality in AQUAMAT patients with confirmed severe malaria was 9.9% (226/2280) with artesunate versus 12.4% (291/2338) with quinine: OR 0.77 (95% CI: 0.64, 0.93; p = 0.0055).

In SEAQUAMAT, the most commonly reported treatment-emergent adverse events (TEAEs > 2% incidence and greater than the incidence in the quinine treatment arm) in the artesunate arm compared to the quinine treatment arm were dialysis (8.2% vs. 6.6%) and blackwater fever (6.7% vs. 4.5%). The most commonly reported treatment-emergent adverse events in AQUAMAT (TEAEs > 2% incidence and greater than the incidence in the quinine treatment arm) were acute anemia (5.7% vs. 4.6%), coma (5.1% vs. 3.5%), convulsions (10.1% vs. 8.3%) and hypoglycemia (2.8% vs. 1.8%). In SEAQUAMAT, the overall incidence of any persistent neurological sequelae at discharge was 1% (24/706) in the artesunate arm and 0.3% (23/737) in the quinine arm at discharge from the study. In AQUAMAT, in assessed (cerebral malaria) survivors at 28 days, the overall incidence of any persistent neurological sequelae was 2.4 % in the artesunate arm and 2.3% in the quinine treatment arm. CDC-060, the single arm, open-label, retrospective data abstraction trial in U.S. patients receiving artesunate, reported TEAES of anemia (65%), transaminase elevations (27%), AST elevations (22%) and hyperbilirubinemia (14%). Post-market adverse reactions included post-artesunate hemolytic anemia (PADH) as well as pancreatitis and immune hemolytic anemia. PADH is defined as a 10 percent decrease in hemoglobin from baseline up to one month after receiving treatment with intravenous artesunate. Cases of post treatment hemolytic anemia severe enough to require transfusion have been reported. The Product Monograph Warnings & Precautions contains a recommendation to monitor for post artesunate delayed hemolysis.

The dosing and administration section of the Product Monograph contains a recommendation that, after stopping artesunate, all patients should receive a complete treatment course of an appropriate oral combination antimalarial regimen. Also, the Product Monograph contains a recommendation that for patients with severe malaria due to Plasmodium vivax or Plasmodium ovale, artesunate should be administered with an antimalarial agent that is active against the hypnozoite liver stage forms of Plasmodium such as 8-aminoquinolone drug. The results of the comparative bioavailability study support the proposed administration of artesunate powder to be taken with or without food and without any dietary restriction. A dedicated QTc study was not performed in this new drug submission and the artesunate Product Monograph (PM) was labelled accordingly.

Limitations of the submission will be addressed by post market Phase IV commitments requested by the Food and Drug Administration (FDA). This includes a single arm, descriptive, international study collecting data for exposure to IV artesunate in pregnancy to assess risks of pregnancy and maternal complications and adverse effects on the fetus, neonate and infant. In this study of at least 7 years’ duration, infant outcomes will be assessed throughout the first year of life. A multiple-dose, safety, tolerability, and pharmacokinetics study in pediatric patients with severe malaria from 0-12 months of age receiving 2.4 mg/kg artesunate for injection is also under way. A Risk Management Plan (RMP) for artesunate was submitted to Health Canada. The RMP is designed to describe known and potential safety issues, to present the monitoring plan and when needed, to describe measures that will be put in place to minimize risks associated with the product. The RMP was reviewed by the Marketed Health Products Directorate (MHPD).

The evidence derived from the two Phase 3 pivotal studies demonstrated substantially reduced mortality with artesunate versus quinine in the treatment of adult and pediatric patients with severe malaria. On the basis of the information reviewed from the pivotal Phase 3 studies, artesunate presented an acceptable and manageable safety profile in consideration of the intended population. Overall, the benefit-harm-uncertainty profile was favorable for artesunate for the recommended indication when used under the conditions of use as stated in the Product Monograph. Therefore, a Notice of Compliance (NOC) was recommended.

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