Tafenoquine – Milestone In Journey Towards Malaria Elimination

[First in a two-part series, written with support from MMV.]

Tafenoquine, the first new drug to be developed in over 60 years to treat relapsing malaria, has in fact been around since the late 1970s, when researchers with the US Walter Reed Army Institute of Research first took note of its antimalarial properties. But the drug’s potential to cure relapsing malaria caused by the Plasmodium vivax parasite, the less deadly but most widespread malaria species, has only been recently been recognised.

Administering test for P vivax malaria in Brazil (MMV/Vivian Zanata)

Tafenoquine (TQ) can kill dormant P vivax parasites with a one-day dose, according to clinical trial results first published on 17 January. Untreated, these parasites hide for years, or even decades, in a person’s liver, causing repeated, debilitating malaria attacks.

This should make TQ, developed jointly by Medicines for Malaria Venture (MMV) and UK pharmaceutical company GlaxoSmithKline (GSK), a drug of significant interest to health policymakers working towards malaria elimination in parts of South-East Asia, Eastern Mediterranean, Africa and Latin America where the P vivax species is endemic.

Indeed, malaria elimination may soon become a more attainable goal thanks partly to TQ, which was approved just last year for use by both United States and Australian drug regulatory agencies.

While the P. falciparum form of malaria is responsible for the majority of malaria deaths worldwide, P vivax actually has the biggest geographic reach, putting more than a third of the world’s population at risk, noted WHO in a 2015 report [pdf].

P vivax “predominates in countries that are prime candidates for elimination,” stated the WHO report, accounting for some more than 70% of cases in countries with fewer than 5000 cases of malaria a year.

P vivax is also responsible for almost half of the malaria cases outside of Africa, with about 7.5 million clinical infections annually, according to the World Malaria Report 2018 [pdf].

“In the 1990s it became clear that there were not enough convenient tools for treatment of P vivax malaria, as the standard treatment (with primaquine) is 14 days long,” Wiweka Kaszubska, MMV’s vice president and head of product development, told Health Policy Watch. The interview was one of several with MMV officials describing the story of the drug’s development and implications for malaria control policies going forward.

The length of treatment with primaquine was a key obstacle to its use, she observed. Most P vivax victims typically are poor and living in rural areas far from health facilities. They found it hard to finish a two-week drug course – particularly after their initial symptoms had already disappeared.

Fast forward nearly two decades to 2008. As inroads were finally being made to reduce mortality from the more deadly P falciparum malaria, MMV and GSK entered into a partnership to explore TQ as a potential treatment for relapsing P vivax malaria.

“As there had been a strong decrease [of P falciparum] in some countries, proportionately P vivax became more important,” noted Elodie Jambert, MMV associate director of access and product management.

People with parasites hidden in their livers also act as a kind of “human reservoir” perpetuating the disease. In order to push ahead aggressively with malaria elimination, it became even more important to treat that population, she observed.

But clinical trial research into a treatment for relapsing P vivax malaria faces special challenges because the target is a dormant parasite, often present only at low levels in the liver. Patients thus had to be followed up for a much longer period to evaluate the drug’s anti-relapse efficacy.

“When you study a drug for the treatment of an acute malaria attack, typically, the protocols call for follow-up, up of 28-42 days, noted Isabelle Borghini-Fuhrer, MMV senior director of product development. “In this case we followed up for six months with patients coming back regularly for check-ups, which makes the study much more expensive and complicated to do,” she said.

P vivax malaria is the most widespread form of malaria disease, with victims extending from South-East Asia to North Africa and Latin America (MMV/Damien Schumann)

After almost ten years of studies to advance the drug to conclusive Phase III trials, the payoff came in the summer of 2018, when the United States Food and Drug Administration (FDA) granted regulatory approval of the treatment, followed by Australia in September.

Publication of the trial results 17 January represents another milestone. MMV can now focus on  the challenge of incorporating TQ treatment into global policy guidelines as well as national standards of practice.

Jambert outlined the first two steps required as follows:

  • Registration of TQ in countries where it is most needed;
  • Revision of WHO treatment guidelines to recommend TQ under appropriate conditions – this is required for most countries to include the treatment in their national guidelines.,

As for costs, GSK has committed to providing the drug at a cost equivalent to that of primaquine, when TQ is purchased through the Global Fund for AIDS, Tuberculosis and Malaria Jambert noted. The Fund provides critical malaria treatments to malaria endemic countries at negotiated prices.

In terms of national drug registration, GSK as the holder of marketing authorization has started the process in Brazil, Colombia and India, with plans to submit soon in other endemic countries, including Peru, Ethiopia, Laos, Vietnam, Myanmar, Thailand and Cambodia, she added. Some countries also require a national health technology assessment, considering at a local level the potential public health impact and cost-effectiveness of the new treatment as compared to the current standard of primaquine care.

As for the WHO global guidelines process, a new series of “feasibility studies” are now being planned in key countries. These studies will test the appropriateness of using the one-day treatment in front-line, primary health care facilities. The feasibility studies will also explore procedures for assigning patients to treatment with a one-day course of TQ or the 14-day course of primaquine. Notably, TQ cannot be administered if patients have particularly low levels of a specific enzyme known as G6PD, as this can lead to acute anaemia. Primaquine can, however, be used in many (although not all) of these patients. So every patient who is administered the new drug needs to be tested for their enzyme levels, using new point-of-care G6PD diagnostics, which have been developed in parallel to the new drug.

“Both TQ and primaquine have a G6PD liability,” noted Jambert. “But the threshold in order to be able to provide TQ is 70% of G6PD enzymatic activity, whereas primaquine can be given to patients who have a G6PD activity above 30%…. If, in fact, they have a lower threshold, then they cannot receive either one … the WHO recommendation is to provide primaquine once a week for 8 weeks under close medical supervisions, but this is rarely followed as it is so difficult to implement.”

This, in turn, highlights the challenges still faced in the journey towards P vivax malaria elimination; neither TQ nor primaquine can provide a complete response to all P vivax malaria victims who harbour the dormant parasite.

“There remains a gap in treatment for those with low levels of the G6PD enzyme,” concluded Jambert, “which points to the importance of continued research in still other forms of drug treatment so that no one is left behind.”


Image Credits: MMV/Vivian Zanata, MMV/Damien Schumann.