Regulatory Decision Summary for Tembexa

The purpose of this (Extraordinary Use) New Drug Submission ([EU]NDS) was to obtain a market authorization for Tembexa (brincidofovir) in the treatment of human smallpox disease caused by variola virus in adult and pediatric patients, including neonates.

The efficacy of Tembexa in the 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 Tembexa in the treatment of smallpox disease was established based on results of adequate and well‑controlled animal studies in New Zealand White rabbits and BALB/c mice infected with non-variola orthopoxviruses, which cause severe disease and mortality in the immunocompetent animals. A survival rate relative to placebo was the primary efficacy endpoint. In the rabbit study, animals were lethally challenged intradermally with 600 plaque-forming units of rabbitpox virus strain Utrecht and brincidofovir was administered orally (every 48 hours for 3 doses) at 20/5/5 mg/kg on Day 3, 4, 5, or 6 post-challenge. Clinical signs of disease were evident in some rabbits at Day 3 post-challenge but were evident in all rabbits by Day 4 post-challenge. In the mouse study, animals were lethally challenged intranasally with 200 plaque-forming units of ectromelia virus strain Moscow and brincidofovir was administered orally (every 48 hours for 3 doses) with a treatment regimen of 20/5/5 mg/kg initiated on Day 4, 5, 6, or 7 post-challenge or a treatment regimen of 10/5/5 mg/kg initiated on Day 4, 5, or 6 post-challenge. All mice had detectable viremia by Day 4 post-challenge. In both studies, treatment with brincidofovir resulted in statistically significant improvement in survival relative to placebo, except when the 10/5/5 mg/kg regimen was initiated at Day 6 post-challenge in the mousepox study; however, the survival rates observed in the animal studies may not be predictive of survival rates in clinical practice. The recommended human dose of Tembexa is associated with greater systemic exposures (AUC and C_max) of brincidofovir and greater than or equal to intracellular concentrations of cidofovir diphosphate (the active metabolite) compared with their exposure in above animal models.

The safety of Tembexa has not been studied in patients with smallpox disease and clinical safety data for brincidofovir is generally from clinical trials conducted for the prevention of cytomegalovirus (CMV). The data from a randomized, placebo-controlled Phase 3 study suggested an increased risk in mortality if brincidofovir is used for a duration longer than the recommended dosage in the treatment of human smallpox disease (i.e., once weekly dose for 2 doses). In this study, a total of 303 patients received brincidofovir twice weekly and 149 patients received matching placebo for up to 14 weeks. All-cause mortality at Week 24 was 16% in the brincidofovir group compared to 10% in the placebo group.

During the first 2 weeks of dosing with brincidofovir in Phase 2 and 3 randomized, placebo-controlled clinical trials in 392 adult patients, the most common adverse event was a composite term of diarrhea (all grade, all cause) that occurred in 40% of brincidofovir -treated patients compared with 25% of patients in the placebo control group. Treatment with brincidofovir was discontinued in 5% of patients due to diarrhea (composite term) compared with 1% in the placebo control group. Additional gastrointestinal (GI) adverse events included nausea, vomiting, and abdominal pain. Based on these data, patients should be monitored for GI adverse events including diarrhea and dehydration, and if necessary, the second and final dose of Tembexa should not be administered.

Elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin have been observed in the clinical studies with brincidofovir; there were cases of concurrent increases in ALT and bilirubin. Severe hepatobiliary adverse events including hyperbilirubinemia, acute hepatitis, hepatic steatosis, and veno-occlusive liver disease have been reported in less than 1% of patients. During the first 2 weeks of brincidofovir therapy in Phase 2 and 3 randomized, placebo-controlled clinical trials in 392 adult patients, ALT elevations >3x the upper limit of normal were reported in 7% of patients and bilirubin elevations >2x the upper limit of normal were reported in 2% of patients. These elevations in hepatic laboratory tests were generally reversible and did not require discontinuation of brincidofovir. Based on these data, hepatic laboratory testing should be performed in all patients before starting Tembexa and while receiving Tembexa, as clinically appropriate; patients who develop abnormal hepatic laboratory tests during Tembexa therapy should be monitored for the development of more severe hepatic injury; discontinuation of Tembexa should be considered if ALT levels remain persistently >10x the upper limit of normal; and the second and final dose of Tembexa on Day 8 should not be administered if ALT elevation is accompanied by clinical signs and symptoms of liver inflammation or increasing direct bilirubin, alkaline phosphatase, or International Normalized Ratio (INR).

In 23 pediatric patients aged 7 months to 17 years in a randomized, placebo‑controlled clinical trial, the adverse reactions and laboratory abnormalities observed with brincidofovir were similar to those in adults. An additional 166 pediatric subjects aged 3 months to 18 years received brincidofovir in uncontrolled studies or expanded access. Considering the potential effects of physiological immaturity on Tembexa pharmacokinetics and because safety has not been established in neonates, caution is advised for use of Tembexa in neonates and monitoring for adverse events, particularly bilirubin elevation, is recommended.

The non-clinical studies with brincidofovir identified the potential risk of carcinogenicity, male infertility and teratogenicity. Pregnancy testing in individuals of childbearing potential should be performed before initiation of Tembexa and Tembexa should not be used in pregnant individuals, in individuals who think they might be pregnant, or in women of childbearing age not using contraception during treatment with Tembexa and for at least 2 months after the last dose; alternative therapies should be used if possible in these patients. Male patients of reproductive potential with female partners of childbearing potential should be advised to use condoms during treatment with Tembexa and for at least 4 months after the last dose.

The identified risks associated with Tembexa have been communicated in the approved Product Monograph along with risk mitigation recommendations, and will continue to be monitored post market as outlined in the Risk Management Plan.

Overall, based on the efficacy and safety data submitted in this (EU)NDS, it is considered that the benefit-harm-uncertainty profile of Tembexa is positive for the treatment of human smallpox disease in adult and pediatric patients, including neonates, under the conditions of use recommended in the approved Product Monograph. However, the safety and efficacy of Tembexa have not been established for the treatment of diseases other than human smallpox disease.

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