GSK’s Krintafel (Tafenoquine) Demonstrates 95% Efficacy in Single-Dose Radical Cure of Plasmodium vivax Malaria in Children Aged 6 Months to 15 Years

November 21, 2020 /BioValleyBIOON/ --GlaxoSmithKline(GSK) and the non-profit organization Medicines for Malaria Venture (MMV) recently announced positive data from the TEACH study on single-dose Krintafel (tafenoquine) for radical cure (prevention of relapse) of Plasmodium vivax malaria in children and adolescents at the American Society of Tropical Medicine and Hygiene (ASTMH) 2020 Virtual Annual Meeting.

In July 2018, Krintafel was approved by the U.S. FDA for radical cure (prevention of relapse) of malaria caused by *Plasmodium vivax* (*P. vivax*) in patients aged 16 years and older who are receiving appropriate antimalarial therapy for acute *P. vivax* infection.This approval makes Krintafel the first new drug in over 60 years for the treatment of Plasmodium vivax malaria.Notably, upon approval of Krintafel,FDAGSK was also awarded a Priority Review Voucher (PRV) for neglected tropical diseases in recognition of its outstanding contributions to the research and development of medicines for neglected tropical diseases (NTDs).

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. Tafenoquine (Krintafel) has been approved for individuals aged ≥16 years. The TEACH study investigated a new 50-mg dispersible tablet, developed to facilitate administration in children, and also utilized the approved 150-mg tablet.

The TEACH study is an open-label, non-comparative, multicenter Phase 2b trial designed to evaluate the pharmacokinetics (PK), safety, and efficacy of a single dose of tafenoquine in pediatric patients with Plasmodium vivax malaria. The study enrolled children and adolescents aged 6 months to 15 years and weighing at least 10 kg with P. vivax malaria. All patients received a single dose of tafenoquine plus 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 100 mg dispersible tablets; those weighing 20–35 kg received 200 mg dispersible tablets; and those weighing >35 kg received 300 mg (two 150-mg tablets). Although no patients were enrolled in the lowest weight group (aged ≥6 months to <2 years, 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:During the 4-month follow-up period, 95% of patients experienced no recurrence of Plasmodium malariae.The relapse-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.

Data from the TEACH study will support regulatory submissions in Australia and malaria-endemic countries.GlaxoSmithKlinePauline Williams, Head of Global Health R&D, stated: “The results announced today represent an encouraging step forward in the prevention and treatment of Plasmodium vivax malaria in children, providing evidence to support the pediatric formulation of tafenoquine. Non-adherence to the current standard of care can lead to relapses of Plasmodium vivax malaria from its dormant stage, causing severe suffering among affected young populations and sustaining malaria transmission, thereby undermining malaria elimination efforts. These data underscore GSK’s commitment to combating infectious diseases, particularly those affecting children, as well as our dedication to discovering and developing interventions for malaria control.”

David Reddy, CEO of MMV, stated: “Children are at high risk of Plasmodium vivax infection, which is why developing a pediatric formulation of tafenoquine is critical. At MMV, our goal is to provide treatments for the most vulnerable populations, and we are proud to collaborate with GlaxoSmithKline to address this unmet need by preventing relapse in children as young as six months of age through a single-dose regimen.”

Plasmodium vivax Malaria (Vivax Malaria) exerts 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 manifestations of Plasmodium vivax infection include fever, chills, vomiting, malaise, headache, and myalgia; in some cases, it can progress to severe malaria and death. The prevalence of Plasmodium vivax peaks among 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 a bite from 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 even in the absence of 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 hepatic hypnozoites of Plasmodium vivax, in combination with currently available blood-stage antimalarial drugs (such as chloroquine), is referred to as radical cure therapy. Until recently, the 8-aminoquinoline primaquine was the only approved drug targeting the liver dormant stage to prevent relapse. However, the 14-day treatment regimen of primaquine 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 life cycle 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 product Krintafel (tafenoquine) was first approved by the U.S. in July 2018FDA, for use in 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 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 must be administered in combination with chloroquine to treat the blood and liver stages of acute Plasmodium vivax infection (known as radical cure therapy). Prior to 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 deficiency may experience severeAdverse Reactions, such as hemolyticAnemia, only patients with G6PD enzyme activity >70% should receive tafenoquine treatment.(Bioon.com)

Original Source: GSK and MMV Present Positive Data on Treatment for Plasmodium vivax Malaria in Children from 6 Months up to 15 Years of Age