Changes in tafenoquine CYP 2D6-mediated clearance could potentially exacerbate any parent molecule-mediated toxicity despite drastically reducing its liver-stage efficacy mediated through CYP 2D6 metabolism.
Colonel Bryan Smith and colleagues, Differential Cytochrome P450 2D Metabolism Alters Tafenoquine Pharmacokinetics, 2015
The tafenoquine-CYP 2D interaction is also problematic due to the likelihood of CYP 2D6-mediated drug-drug interactions in humans with other antimalarial drugs and commonly prescribed medications.
RECENTLY retired U.S. Army Colonel (Dr) Bryan Smith is among a group of military doctors and scientists from the Walter Reed Army Institute of Research (WRAIR) and the U.S. Army Medical Materiel Development Activity (USAMMDA) who raised serious concerns about the safety and efficacy of tafenoquine, in a series of papers published in scientific journals from 2013 to 2015.
The papers began to be published four years after scientists at WRAIR discovered – in laboratory studies uncovered through FOIA requests by retired U.S. Army Dr Remington Nevin – that tafenoquine “is the only antimalarial more neurotoxic than mefloquine.” Tafenoquine is from a class of 8-aminoquinoline antimalarials which were originally discovered to have been neurotoxic during a WWII-era drug discovery program, on par with the Manhattan project in terms of scientific scale, which found more than 85 of these drugs caused lasting or permanent brain damage in primates subjected to pre-clinical safety testing. For safety reasons, these highly dangerous drugs were then excluded from the clinical testing program which ultimately led to the introduction of primaquine, the standard P. vivax malaria treatment drug for the past six decades.
The papers by Colonel Smith and his colleagues examine the role of the Cytochrome P450 2D6 (CYP2D6) enzyme in metabolizing the 8-aminoquinoline drug primaquine and it’s newer analogue tafenoquine. The studies were undertaken as part of the late-stage tafenoquine drug development process, almost 15 years after tafenoquine was tested on 1,540 Australian peacekeeping troops in a series of notorious drug trials in Bougainville (Papua New Guinea) and East Timor.
CYP2D6 is known to metabolize a quarter of all clinically used drugs and plays a key role in drug safety, efficacy and drug-drug interactions. For people with reduced CYP2D6 function, representing up to one third of some populations, certain drugs can be ineffective and/or dangerous. Additionally, many drugs can inhibit CYP2D6 function, resulting in dangerous drug-drug interactions. One such drug is chloroquine, another quinoline antimalarial which has commonly been co-administered with primaquine in the treatment of P. vivax malaria.
The papers cast serious doubts about the safety, efficacy and hence the commercial value of tafenoquine. In January 2018, researchers from GlaxoSmithKline (GSK) and Oxford University published the results of a large-scale clinical trial comparing tafenoquine to primaquine in the treatment of P. vivax malaria, which found both drugs failed to treat the serious disease in more than a quarter of patients.
The U.S. FDA and Australian Therapeutic Goods Administration had approved tafenoquine several months earlier. Australian neurotoxicologist Professor Jane Quinn and retired Australian Army Major Stuart McCarthy, responded to the GSK/Oxford study in the New England Journal of Medicine, raising further serious doubts about tafenoquine:
Although the participants in the trial by Llanos-Cuentas et al. were not all screened for CYP2D6 status, Baird et al. recently estimated that 38.8% of the population living at risk of P. vivax infection are unable to receive safe and effective primaquine therapy because of glucose-6-phosphate dehydrogenase (G6PD) deficiency and reduced CYP2D6 function. We therefore recommend that CYP2D6 allelotype screening be included in future clinical studies of tafenoquine to address unresolved safety and efficacy concerns before this drug is widely used for P. vivax eradication or prophylaxis in travelers worldwide.
The 8-aminoquinoline/CYP2D6 papers were published while Colonel Smith was the product manager for tafenoquine at USAMMDA, the U.S. Army agency responsible for medical product commercialization and approval. During this period, Colonel Smith oversaw the contractual work of Australian expatriate Dr Geoffrey Dow, a former U.S. Army employee who in 2010 founded his own company, 60 Degrees Pharmaceuticals (60P), then in 2014 was awarded the U.S. Army license for tafenoquine as part of an $18+ million contract to register the drug in the U.S. and Australia. The following year, 2015, Dr Dow stated that his motivation in seeking FDA approval for tafenoquine was to obtain a “priority review voucher” valued at up to $350 million.
According to Colonel Smith’s written testimony to a 2018 Australian Senate Inquiry, he retired from the Army at the end of 2015 then immediately began employment with the pharmaceutical consulting firm Clinical Network Services (CNS). Since that time, he has also been employed as the 60P chief medical officer.
Since January 2016 I have been employed full-time as the Principal Medical Consultant for Clinical Network Services. Within this role I am contracted to also operate as the Chief Medical Officer for 60 Degrees Pharmaceuticals. Other than my salary as an active duty officer in the U.S. Army, my current Army retirement pay, and my current salary as Principal Medical Consultant for Clinical Network Services (CNS), I have received no other compensation of any kind for the work I have performed for USAMMDA, CNS, or 60 Degrees Pharmaceuticals.
Colonel Bryan Smith (retired), testimony to Australian Senate inquiry, 2018
After Colonel Smith had commenced his lucrative post-Army career at CNS/60P, three of his former U.S. Army colleagues co-authored a 2016 “current state of the art” paper on CYP2D6 primaquine metabolism with findings that have since been confirmed in a breakthrough study published in a July 2019 edition of Nature Communications, one of the world’s most prestigious scientific journals. The 2016 Marcsisin, Reichard & Pybus paper also made some highly significant conclusions for the commercial viability of tafenoquine (emphasis added):
In addition to addressing the questions raised above, there is a need for the development of liver stage/radical curative antimalarial drugs that do not require metabolism by polymorphic CYP enzymes. Currently, there are no drug candidates in the drug development pipeline that are radical curative that do not seem to require hepatic metabolism. The only other 8-aminoquineoline that is close to fielding and under late stage development for radical cure is tafenoquine. Tafenoquine is a single dose radical curative agent that is a promising alternative to primaquine, however, tafenoquine might also require hepatic metabolism for efficacy as indicated by pre-clinical testing in animal models. … there is a need for the discovery and development of new safer antimalarial agents that treat relapsing strains of malaria and do not require CYP 2D6 metabolism for activity.
This is the first in a series of posts about the dealings of Colonel Smith, Dr Dow, 60 Degrees Pharmaceuticals and their associates. Although Smith and his associates have denied any wrongdoing, in subsequent posts we will dig deeper into this aspect of a story that bears all the hallmarks of yet another pharmaceutical industry corruption racket.
The Tafenoquine Dossier 