Regulatory Decision Summary for TPOXX

The efficacy of TPOXX for treatment of smallpox disease has not been determined in humans because adequate and well-controlled field trials have not been feasible and inducing smallpox disease in humans to study the drug’s efficacy is not ethical. Therefore, the efficacy of TPOXX for the treatment of smallpox was established based on results of adequate and well-controlled animal studies. Specifically, efficacy studies were conducted in cynomolgus macaques infected with monkeypox virus and New Zealand White rabbits infected with rabbitpox virus. The treatment with tecovirimat for 14 days at 10 mg/kg in monkeys and 40 mg/kg in rabbits resulted in statistically significant improvement in survival (the primary efficacy endpoint) relative to placebo, except when tecovirimat was given to monkeys starting at Day 6 post-challenge. It should be noted, however, that survival rates observed in the animal studies may not be predictive of survival rates in clinical practice. The recommended human dose of TPOXX (600 mg BID) is expected to provide an exposure exceeding that associated with a fully effective dose in animals. Indeed, at the recommended therapeutic dose, the mean values of C_max, AUC_24hr, and C_min were approximately 2-fold, 2-fold, and 4-fold higher, respectively in healthy adult volunteers as compared to the fully effective dose in monkeys.

TPOXX efficacy may be reduced in immunocompromised patients based on studies demonstrating reduced efficacy in immunocompromised animal models. In addition, animal studies have indicated that co-administration of TPOXX at the same time as live smallpox vaccine (vaccinia virus) may reduce the immune response to the vaccine and the clinical impact of this is unknown. This information is presented in the TPOXX Product Monograph.

Tecovirimat has a relatively low resistance barrier and certain amino acid substitutions in the target VP37 protein can confer large reductions in tecovirimat antiviral activity. The TPOXX Product Monograph recommends that the possibility of resistance to tecovirimat be considered in patients who either fail to respond to therapy or who develop recrudescence of disease after an initial period of responsiveness.

No safety data for TPOXX is available from patients with smallpox disease. However, TPOXX safety was evaluated in 359 healthy adult subjects ages 18-79 in a Phase 3 clinical trial. The most frequently reported adverse reactions were headache (12%), nausea (5%), abdominal pain (2%) and vomiting (2%). Six subjects (2%) had their treatment with TPOXX discontinued due to adverse reactions.

TPOXX has been reported to cause prolongation of the QTc interval. The TPOXX Product Monograph recommends that caution be observed if TPOXX is administered to patients who are considered to be at a high risk of the torsade de pointes arrhythmia.

Co-administration of TPOXX and repaglinide may cause mild to moderate hypoglycemia. The TPOXX Product Monograph recommends that patients be monitored for blood glucose and hypoglycemic symptoms when administering TPOXX with repaglinide.

No clinical studies in pediatric patients are available because such studies would not be ethical.  Pharmacokinetic simulation was used to derive the dosing regimens of TPOXX in pediatric patients that are predicted to be comparable to adult exposure from the recommended dose of TPOXX.

The risks and uncertainties associated with TPOXX are addressed in the TPOXX Product Monograph and Risk Management Plan. In addition, the sale of TPOXX will be restricted to federal, provincial and territorial, and municipal government(s).

In conclusion, based on the data provided, Heath Canada considers that the benefit-harm-uncertainty profile of TPOXX in the treatment of human smallpox disease in adults and pediatric patients weighing at least 13 kg is favourable under conditions of use described in the TPOXX Product Monograph at this time.