GSK and MMV Seek Pediatric Approval for Kozenis (Tafenoquine) to Radically Cure Plasmodium vivax Malaria in Children Aged 6 Months to 15 Years

January 12, 2021 /BioValleyBIOON/ --GlaxoSmithKline(GSK) and the non-profit organization Medicines for Malaria Venture (MMV) recently announced that the Australian Therapeutic Goods Administration (TGA) has accepted their Class 1 application to expand the indication of single-dose Kozenis (tafenoquine) to the pediatric population for the radical cure (prevention of relapse) of Plasmodium vivax malaria. Previously, the drug was approved by the TGA in 2018 for use in individuals aged ≥16 years. When treating active infection, the drug should be administered alongside a course of chloroquine.

This pediatric application includes clinical data for a new 50 mg tablet that can be dispersed in water, specifically developed to facilitate use in children, a population disproportionately affected by malaria. Children are at high risk of Plasmodium vivax infection, which is why the development of a pediatric formulation of tafenoquine is critical. Clinical data show that,In pediatric patients aged 6 months to 15 years, the radical cure efficacy rate of single-dose tafenoquine is as high as 95%.

In July 2018, single-dose tafenoquine (U.S. brand name: Krintafel) was the first to receive U.S.FDAApproved for use in patients aged ≥16 years who are receiving appropriate antimalarial therapy for acute Plasmodium vivax (P. vivax) infection, to achieve radical cure (prevention of relapse) of malaria caused by Plasmodium vivax (P. vivax). This approval enablesKrintafel Becomes the First New Drug for Treating Plasmodium vivax Malaria in Over 60 YearsSubsequently, single-dose tafenoquine also received approval from regulatory authorities in Australia, Brazil, and Thailand, with regulatory applications and reviews in other malaria-endemic countries progressing.

Currently, the standard of care for preventing relapse of Plasmodium vivax malaria requires a 7- or 14-day treatment course, and there are no age-specific pediatric formulations available. This pediatric application is supported by data from a Phase 2b clinical study (TEACH). The study investigated a new 50 mg dispersible tablet, developed to facilitate administration in children, and also utilized the approved 150 mg tablet.

TEACH is an open-label, non-comparative, multicenter Phase 2b study designed to evaluate the pharmacokinetics (PK), safety, and efficacy of a single dose of tafenoquine in pediatric patients with Plasmodium vivax malaria. The study was conducted in children and adolescents aged 6 months to 15 years, weighing at least 10 kg, with P. vivax malaria. All patients received a single dose of tafenoquine and a course of chloroquine for the treatment of acute blood-stage infection, in accordance with local or national treatment guidelines.

In the study, patients received different doses of tafenoquine based on body weight: patients weighing 10–20 kg received a 100 mg dispersible tablet; those weighing 20–35 kg received a 200 mg dispersible tablet; and those weighing >35 kg received 300 mg (two 150 mg tablets). Although no patients were enrolled in the lowest weight group (≥6 months to <2 years of age, with body weight ≥5 kg to ≤10 kg), pharmacokinetic (PK) modeling data from the TEACH study indicated that children in this weight range should receive a 50 mg dose of tafenoquine.

A total of 60 patients were enrolled in this study, and the results showed that during the 4-month follow-up period,95% of patients with Plasmodium malariae did not experience relapse.The recurrence-free efficacy rate was consistent with that observed in studies of tafenoquine in adult and adolescent patients (≥16 years of age). In the study, apart from vomiting following early administration, the safety profile was consistent with previous clinical studies, and no drug-related serious adverse events were reported.

Plasmodium vivax Malaria (Vivax Malaria) has a significant impact on public health and the economy, primarily in South Asia, Southeast Asia, Latin America, and the Horn of Africa. It is estimated to cause approximately 7.5 million clinical infections annually. The clinical features of Plasmodium vivax infection include fever, chills, vomiting, malaise, headache, and myalgia; in some cases, it can lead to severe malaria and death. The prevalence of Plasmodium vivax peaks in children aged 2–6 years. Furthermore, children are four times more likely to be affected than adults.

Plasmodium parasites are complex organisms whose life cycle spans both humans and mosquitoes. Following the bite of an infected mosquito, Plasmodium vivax infects the bloodstream and triggers acute malarial episodes. P. vivax can also remain dormant in the liver as hypnozoites, which periodically reactivate, leading to relapses of P. vivax malaria. Consequently, a single P. vivax infection can cause multiple malarial episodes without any new mosquito bites. These relapses may occur weeks, months, or even years after the initial infection. The dormant liver-stage parasites cannot be treated with most antimalarial drugs that target the blood-stage parasites.

The use of a drug targeting the liver hypnozoites of *Plasmodium vivax* in combination with currently available blood-stage antimalarial agents (such as chloroquine) is referred to as radical cure. Until recently, the 8-aminoquinoline primaquine was the only approved drug for targeting the hepatic dormant stage to prevent relapse. However, the 14-day primaquine regimen is often associated with poor adherence, leading to reduced efficacy.

Tafenoquine was first synthesized in 1978 by scientists at the Walter Reed Army Institute of Research (WRAIR) in the United States. It is an 8-aminoquinoline derivative with activity against the lifecycle of Plasmodium vivax, including its dormant forms in the liver.

GSK and MMV established a strategic partnership as early as 2008, and after a decade of arduous efforts, the single-dose tafenoquine Krintafel (tafenoquine) was first approved by the U.S. in July 2018FDA, for adults and adolescents aged ≥16 years. Subsequently, the drug received regulatory approval in Australia, Brazil, and Thailand. Regulatory reviews are ongoing in other malaria-endemic countries. All approvals were based on efficacy and safety data from the global integrated clinical development program for the radical cure of Plasmodium vivax malaria, which was conducted in nine malaria-endemic countries and supported the overall positive benefit-risk profile of Krintafel.

Tafenoquine needs to be used in combination with chloroquine to treat the blood and liver stages of acute Plasmodium vivax infection (known as radical cure therapy). Before administering tafenoquine or primaquine, patients must be tested for glucose-6-phosphate dehydrogenase (G6PD) deficiency, as this enzyme helps protect red blood cells. Patients with G6PD enzyme deficiency may experience severe complications during radical cure treatment.Adverse Reactions, such as hemolyticAnemia, only patients with G6PD enzyme activity >70% should receive tafenoquine treatment. (Bioon.com)

Original Source: GSK, MMV filing for Kozenis (tafenoquine) in paediatric populations with Plasmodium vivax malaria accepted by Australian Therapeutic Goods Administration