Instant Report

Date: 09-Jan-2021

Australian TGA Accepts GSK, MMV’s Filing For Single Dose Tafenoquine In Paediatric Populations With Plasmodium Vivax Malaria

GSK and Medicines for Malaria Venture (MMV) announced that the Australian Therapeutic Goods Administration (TGA) accepted the submission of a Category 1 application to extend the indication of single-dose Kozenis (tafenoquine) to paediatric populations for the radical cure (prevention of relapse) of Plasmodium vivax (P. vivax) malaria.

The application includes data for a new, 50 mg tablet that can be dispersed in water and which was developed to facilitate use in children, who are disproportionately affected by the disease.

The submission is supported by a phase 2b clinical study (TEACH) that evaluated dosages of tafenoquine based on weight for children between the age of 6 months and weighing at least 5 kg, up to 15 years.

Kozenis is a single-dose treatment for the radical cure (prevention of relapse) of P. vivax and was approved for people aged 16 years and older by the TGA in 2018. It should be used with a course of chloroquine to treat the active blood stage infection.

The current standard of care for prevention of P. vivax relapse requires a 14-day course of treatment and at present there is no age-specific paediatric formulation.

P. vivax malaria is estimated to cause around 6.4 million clinical infections every year, and children are four times as likely as adults to be affected. The clinical features of P. vivax malaria include fever, chills, vomiting, malaise, headache and muscle pain, and in some cases, can lead to severe malaria and death. The prevalence of P. vivax peaks in children aged 2-6 years old.

Further regulatory submissions for a paediatric indication for tafenoquine are planned in malaria-endemic countries.

Tafenoquine Exposure Assessment in CHildren (TEACH) was an open-label, non-comparative, multi-centre phase 2b study to assess the pharmacokinetics (PK), safety, and efficacy of single-dose tafenoquine in the treatment of paediatric subjects with P. vivax malaria.

The primary objective was to evaluate the PK of tafenoquine in children and adolescents aged =2 years to <16 years with P. vivax in order to identify appropriate doses that achieve a similar exposure to that of the tafenoquine adult dose of 300 mg. Secondary objectives were to assess the safety of tafenoquine when administered to paediatric subjects with P. vivax malaria; to assess the clinical and parasitological efficacy of tafenoquine as a radical cure for paediatric subjects with P. vivax malaria when co-administered with chloroquine. Another secondary objective was to assess the PK of tafenoquine in infants aged =6 months to <2 years (weighing =5kg) with P. vivax (if data permitted).

In all, 60 paediatric subjects were recruited (median age 10 years [range 2 – 15 years]) and dosed at three sites in Vietnam and one in Colombia. All subjects received a single dose of tafenoquine and a course of chloroquine administered per local or national treatment guidelines to treat the acute blood stage of the illness. All subjects were screened for glucose-6-phosphate dehydrogenase (G6PD) deficiency prior to receiving tafenoquine and excluded from the study if they had <70% of the normal G6PD enzyme activity levels.

There were no unexpected safety findings. The overall percentage of subjects reporting adverse events was similar to previous studies in adults and adolescents 16 years and older [37/60 (62%)], with the highest-frequency adverse event being vomiting in 12 (20%) subjects. No drug-related, serious adverse events were reported. The relapse-free efficacy rate of 95 per cent at four months was in line with studies of tafenoquine in adults and older adolescents.

P. vivax malaria has a significant public health and economic impact, primarily in South-Asia, South-East Asia, Latin America and the horn of Africa.

The Plasmodium parasite is a complex organism with a lifecycle spanning both humans and mosquitoes. After an infected mosquito bite, the P. vivax parasite infects the blood and causes an acute malaria episode. It also has the ability to lie dormant in the liver (in a form known as hypnozoite), from where it periodically reactivates to cause relapses of P. vivax malaria. Hence, a single P. vivax infection can give rise to multiple episodes of malaria, in the absence of a new mosquito bite. These relapses can occur weeks, months or even years after the initial infection. The dormant liver forms of the parasite cannot be treated with most antimalarial treatments active against the blood-stage parasite.

The use of a medicine that targets the dormant liver forms of the P. vivax parasite, co-administered with currently available blood stage antimalarials such as chloroquine is known as radical cure.

Tafenoquine developed by GSK and MMV was first approved by the US Food and Drug Administration for the radical cure of P. vivax malaria in July 2018 for use in adults and adolescents =16 years old who are receiving appropriate antimalarial therapy for acute P. vivax infection. It was subsequently approved by regulators in Australia, Brazil and Thailand.

Regulatory applications are being progressed in other malaria-endemic countries. All approvals were based on efficacy and safety data from a comprehensive global clinical development programme for P. vivax radical cure, conducted in nine malaria-endemic countries, which supported an overall positive benefit–risk profile for the use of the product.

Tafenoquine needs to be co-administered with chloroquine to treat both the blood and liver stages of acute P. vivax malaria infections (known as radical cure). Before taking tafenoquine or primaquine, patients must be tested for deficiency of a specific enzyme known as glucose-6-phosphate dehydrogenase (G6PD), which helps protect red blood cells. Patients with a G6PD enzyme deficiency could have severe adverse reactions, like haemolytic anemia, during treatment with radical cure drugs and only those with >70% G6PD enzyme activity should receive tafenoquine.

Medicines for Malaria Venture (MMV) is a leading product development partnership (PDP) in the field of antimalarial drug research and development. Its mission is to reduce the burden of malaria in disease-endemic countries by discovering, developing and facilitating delivery of new, effective and affordable antimalarial drugs.

Date: 11-Jan-2021

Australian TGA Accepts GSK, MMVs Filing For Single Dose Tafenoquine In Paediatric Populations With Plasmodium Vivax Malaria

GSK and Medicines for Malaria Venture (MMV) announced that the Australian Therapeutic Goods Administration (TGA) accepted the submission of a Category 1 application to extend the indication of single-dose Kozenis (tafenoquine) to paediatric populations for the radical cure (prevention of relapse) of Plasmodium vivax (P. vivax) malaria.

The application includes data for a new, 50 mg tablet that can be dispersed in water and which was developed to facilitate use in children, who are disproportionately affected by the disease.

The submission is supported by a phase 2b clinical study (TEACH) that evaluated dosages of tafenoquine based on weight for children between the age of 6 months and weighing at least 5 kg, up to 15 years.

Kozenis is a single-dose treatment for the radical cure (prevention of relapse) of P. vivax and was approved for people aged 16 years and older by the TGA in 2018. It should be used with a course of chloroquine to treat the active blood stage infection.

The current standard of care for prevention of P. vivax relapse requires a 14-day course of treatment and at present there is no age-specific paediatric formulation.

P. vivax malaria is estimated to cause around 6.4 million clinical infections every year, and children are four times as likely as adults to be affected. The clinical features of P. vivax malaria include fever, chills, vomiting, malaise, headache and muscle pain, and in some cases, can lead to severe malaria and death. The prevalence of P. vivax peaks in children aged 2-6 years old.

Further regulatory submissions for a paediatric indication for tafenoquine are planned in malaria-endemic countries.

Tafenoquine Exposure Assessment in CHildren (TEACH) was an open-label, non-comparative, multi-centre phase 2b study to assess the pharmacokinetics (PK), safety, and efficacy of single-dose tafenoquine in the treatment of paediatric subjects with P. vivax malaria.

The primary objective was to evaluate the PK of tafenoquine in children and adolescents aged =2 years to <16 years with P. vivax in order to identify appropriate doses that achieve a similar exposure to that of the tafenoquine adult dose of 300 mg. Secondary objectives were to assess the safety of tafenoquine when administered to paediatric subjects with P. vivax malaria; to assess the clinical and parasitological efficacy of tafenoquine as a radical cure for paediatric subjects with P. vivax malaria when co-administered with chloroquine. Another secondary objective was to assess the PK of tafenoquine in infants aged =6 months to <2 years (weighing =5kg) with P. vivax (if data permitted).

In all, 60 paediatric subjects were recruited (median age 10 years [range 2 – 15 years]) and dosed at three sites in Vietnam and one in Colombia. All subjects received a single dose of tafenoquine and a course of chloroquine administered per local or national treatment guidelines to treat the acute blood stage of the illness. All subjects were screened for glucose-6-phosphate dehydrogenase (G6PD) deficiency prior to receiving tafenoquine and excluded from the study if they had <70% of the normal G6PD enzyme activity levels.

There were no unexpected safety findings. The overall percentage of subjects reporting adverse events was similar to previous studies in adults and adolescents 16 years and older [37/60 (62%)], with the highest-frequency adverse event being vomiting in 12 (20%) subjects. No drug-related, serious adverse events were reported. The relapse-free efficacy rate of 95 per cent at four months was in line with studies of tafenoquine in adults and older adolescents.

P. vivax malaria has a significant public health and economic impact, primarily in South-Asia, South-East Asia, Latin America and the horn of Africa.

The Plasmodium parasite is a complex organism with a lifecycle spanning both humans and mosquitoes. After an infected mosquito bite, the P. vivax parasite infects the blood and causes an acute malaria episode. It also has the ability to lie dormant in the liver (in a form known as hypnozoite), from where it periodically reactivates to cause relapses of P. vivax malaria. Hence, a single P. vivax infection can give rise to multiple episodes of malaria, in the absence of a new mosquito bite. These relapses can occur weeks, months or even years after the initial infection. The dormant liver forms of the parasite cannot be treated with most antimalarial treatments active against the blood-stage parasite.

The use of a medicine that targets the dormant liver forms of the P. vivax parasite, co-administered with currently available blood stage antimalarials such as chloroquine is known as radical cure.

Tafenoquine developed by GSK and MMV was first approved by the US Food and Drug Administration for the radical cure of P. vivax malaria in July 2018 for use in adults and adolescents =16 years old who are receiving appropriate antimalarial therapy for acute P. vivax infection. It was subsequently approved by regulators in Australia, Brazil and Thailand.

Regulatory applications are being progressed in other malaria-endemic countries. All approvals were based on efficacy and safety data from a comprehensive global clinical development programme for P. vivax radical cure, conducted in nine malaria-endemic countries, which supported an overall positive benefit–risk profile for the use of the product.

Tafenoquine needs to be co-administered with chloroquine to treat both the blood and liver stages of acute P. vivax malaria infections (known as radical cure). Before taking tafenoquine or primaquine, patients must be tested for deficiency of a specific enzyme known as glucose-6-phosphate dehydrogenase (G6PD), which helps protect red blood cells. Patients with a G6PD enzyme deficiency could have severe adverse reactions, like haemolytic anemia, during treatment with radical cure drugs and only those with >70% G6PD enzyme activity should receive tafenoquine.

Medicines for Malaria Venture (MMV) is a leading product development partnership (PDP) in the field of antimalarial drug research and development. Its mission is to reduce the burden of malaria in disease-endemic countries by discovering, developing and facilitating delivery of new, effective and affordable antimalarial drugs.