Leaked emails reveal how the U.S. Army’s tafenoquine project manager stonewalled a crucial follow-up safety study on Australian Army drug trial subjects, 18 months before landing a post-Army job with the drug manufacturer

Since taking over as the product manager for our lead antimalarial drugs we’ve continued to work closely together on tafenoquine’s development program, with key attention being paid to how best to adequately and accurately address and potential central nervous system (CNS) toxicity liabilities that it may have.

Colonel Bryan Smith, “Colonel Jennifer Caci USASOC request,” USAMMDA leaked email, February 10, 2014

LAST week we revealed how a recently retired U.S. Army Colonel – Dr Bryan Smith – raised serious concerns about the safety and efficacy of tafenoquine in a series of papers published in scientific journals from 2013 to 2015, before landing the Washington DC-based company 60 Degrees Pharmaceuticals an exclusive $18+ million government contract for the drug’s continued development.

Today we continue the story by revealing a series of leaked emails from Colonel Smith and his current boss Dr Geoff Dow – the CEO of 60 Degrees Pharmaceuticals – showing how Smith stonewalled a crucial follow-up safety study on injured Australian Army drug trial subjects, presumably to facilitate the drug’s FDA approval.

Tafenoquine is from a class of 8-aminoquinoline antimalarials which were 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. Eight years after tafenoquine had been tested on 1,540 Australian soldiers deployed on peacekeeping operations in Bougainville and East Timor, laboratory studies at the Walter Reed Army Institute of Research (WRAIR) found that tafenoquine “is the only antimalarial more neurotoxic than mefloquine.”

One senior Australian soldier who was subjected to the trials said to a 2018 government inquiry that “the fraud and corruption involved in these drug trials is huge.” In one of more than 100 written submissions to the inquiry, the daughter of another soldier subjected to the same trial wrote:

I will never get my father back … He was mistreated and used as a guinea pig along with many other people who served our country.

In 2014, Colonel Smith was the product manager for tafenoquine at the U.S. Army Medical Materiel Development Activity (USAMMDA) in Fort Derrick MD. USAMMDA is the organization which commercializes medical products developed by the Army, ensuring they are safe and effective prior to regulatory approval by the Food and Drug Administration (FDA).

A series of emails obtained from a source at USAMMDA now show that Colonel Smith was approached by military colleagues concerned about tafenoquine’s safety, to approve a follow-up study on a group of the Australian soldiers subjected to the notorious Australian Army drug trials at the turn of the century. The report of “Study 033”, which involved 492 tafenoquine subjects and 162 mefloquine subjects, published in 2010 almost a decade after the trial, had found:

In total, 64 (13.0%) tafenoquine subjects and 23 (14.2%) mefloquine subjects reported neuropsychiatric adverse events, the most common being vertigo, dizziness and various sleep disorders.

On February 10, 2014, Colonel Smith emailed retired U.S. Navy Commander Bill Manofsky, seeking his advice on how best to approach the continued development of tafenoquine “in a much more open, transparent and thorough way than was done during mefloquine’s development.”

In the same email, Colonel Smith wrote:

Weve also had a number of recent interactions with mutual colleagues in the Special Operations community, including with Colonel [Jennifer] Caci as we product developers continually attempt to support their medical and materiel needs.

Several months earlier, in September 2013, Colonel Caci – a senior medical officer at U.S. Army Special Operations Command (USASOC) – had drafted the order banning mefloquine from use in that command and establishing dedicated follow up care for those affected by the drug’s neurotoxic effects. This followed the FDA’s 2013 “black box” warning, which stated mefloquine can cause “lasting or permanent” neurological damage.

Three days before Colonel Smith’s email to Commander Manofsky, Dr Geoff Dow had also emailed Commander Manofsky and Colonel Caci regarding concerns over the drug’s safety. In his email of February 7, 2014, Dr Dow wrote in part:

None of us engaged on tafenoquine wish to repeat the mistakes of the past or to move a drug forward that harms soldiers.

As CEO of 60 Degrees Pharmaceuticals (60P), a company he established in 2010 after having worked as a U.S. Army employee at WRAIR, in 2014 he was engaged by USAMMDA as a contractor for the development of tafenoquine. According to information removed from the company’s website in 2018, 60P has received more than $18 million from the U.S. Army for the continued development of this drug.

These funds included payments for the work undertaken by Dr Dow as part of the 2014 Cooperative Research and Development Agreement (CRADA) between 60P and USAMMDA, which awarded 60P an exclusive license for the drug on the proviso that the company work with USAMMDA to have the drug approved by the FDA and the Australian Therapeutic Goods Administration (TGA).

For additional background, having obtained this license and funding from the U.S. Army, in 2015 Dr Dow stated in an interview with CEO-CFO Magazine that his motivation in seeking tafenoquine’s registration with the FDA was to obtain a “priority review voucher” valued at up to $350 million dollars:

Those vouchers can be sold to another company that allows fast track review at the FDA of an unrelated therapeutic. They are freely salable on the open market. The most recent sale was for three hundred and fifty million by United Therapeutics to Abbvie. Three out of four of our products are eligible for the PRV and it is a financial incentive independent of your actual development program or the therapeutic you are moving forward. Therefore, that definitely has interest for individual investors, but also big pharma who have an interest in molecules that happen to be in your portfolio.

Going back to his email of February 7, 2014, Dr Dow explained that he and Colonel Smith had previously worked together on quinoline drug development at WRAIR. During the mid 2000s, Dr Dow had in fact conducted some of the key studies on which proved that mefloquine is neurotoxic. Dow’s email went on to state to Commander Manofsky that Colonel Smith and Colonel Caci “will be reaching out to you” to discuss “the patient safety and product development risks associated with” tafenoquine. Mentioning the results of the 2009 WRAIR study which found tafenoquine to be “the only antimalarial drug more neurotoxic than mefloquine”, Dow continued:

Scientifically, it would be a mistake to over-interpret [the WRAIR results] and to rush to judgement on a solution that may not achieve the solution we are all trying to seek.

With up to $350 million at stake for Dr Dow’s investors, what’s debatable is whether the “solution” he was trying to seek was, or is, indeed the same “solution” in the interests of those whose health might be placed at risk by this dangerous drug, when safer alternatives were, and are, already available on the market.

During the months that followed those two February 2014 emails from Dr Dow and Colonel Smith, what we can also reveal is that Commander Manofsky and Colonel Caci had arranged for a follow-up study on the Australian tafenoquine subjects to be undertaken by U.S. Navy Captain (Dr) Michael Hoffer, a specialist vestibular physician. The proposed study was to examine any long term damage to the vestibular system among the 1,540 subjects, including the 492 tafenoquine subjects of Study 033, which later provided the basis for Dr Dow’s application to the FDA via this 2017 “integrated safety analysis.”

On August 15, Commander Manofsky wrote:

Just wanting to see if you connected with Dr Hoffer at Balboa regarding possible vestibular analysis of the tafenoquine test subjects in East Timor.

Three days later, the reply from Colonel Smith was, “We obviously won’t be getting anything off the ground,” based on the pretext Captain Hoffer was on leave.

Over the coming weeks, we will continue to reveal and analyse key documents from the Tafenoquine Dossier such as these, including the 2014 60P-USAMMDA CRADA. We will also reveal similar parallel efforts by Australian tafenoquine veterans being stonewalled by their government officials after repeatedly requesting similar follow up studies. What is becoming clear is that these efforts were repeatedly thwarted, with up to $350 million at stake for the pharmaceutical industry and their cronies in key government appointments, as they facilitated the approval of a dangerous drug by the FDA and the TGA.

Editors note: We have approached the current USAMMDA commander, Colonel Gina G. Adam, for comment on the emails and welcome any future response.

“I will never get my father back”: How the neurotoxic U.S. Army antimalarial drug tafenoquine destroyed the lives of countless Australian service families

It’s not fair on them, to grow up and have a parent have to go through this. I’ve destroyed not just my life. Everyone around me really. All for the sake of some trial drug I was made to take.

Mr Aaron King, Australian Army “Study 033” tafenoquine trial subject

THIS post highlights the devastating impact that tafenoquine has had on hundreds of the families of soldiers who where subjected to the notorious Australian Army Malaria Institute (AMI) drug trials in Bougainville and East Timor at the turn of the century.

Aaron King was one of 492 tafenoquine subjects in the AMI Study 033, involving a total of 654 soldiers from the 1st Battalion, the Royal Australian Regiment (1 RAR) while deployed on peacekeeping duties in East Timor in 2000-2001. Prior to the deployment, the soldiers were given “loading doses” of 600 mg tafenoquine, then 200 mg weekly for the rest of their seven month deployment. Despite the experiences of Aaron and many of his fellow soldiers, the trial report eventually published in 2010 did not include a single severe neuropsychiatric event report. For this and other reasons, the published report is believed to be fraudulent.

This was one of a series of tafenoquine drug trials undertaken by the Australian Defence Forces as part of a commercial agreement with the pharmaceutical industry which a former Director of the U.S. Walter Reed Army Institute of Research (WRAIR) conceded was “naive” and “desperate.” Tafenoquine is a product of the same WRAIR antimalarial drug discovery program as mefloquine. Both drugs are known to be neurotoxic. Despite the concerns of hundreds of the drug trial subjects like Aaron, the U.S. Army Medical Materiel Development Activity (USAMMDA) continued to commercialize the drug, in a contract with 60 Degrees Pharmaceuticals worth $18+ million, until in 2018 it was granted regulatory approval as Arakoda® in the U.S. and Kodatef® in Australia.

During last year’s Australian Senate Inquiry into the AMI drug trials, more than 100 written submissions were made by the participants or their families, while dozens testified in person at hearings held across the country. Below is the full written submission from Aaron’s daughter, Ms Angela King. Mrs Raelene King’s written submission is here and a transcript of her oral testimony is here. Included below is a video she made while preparing her written submission.

My name is Angela King,

I am writing to you about my Father Aaron King who was given Tafenoquine.

As a young girl growing up I had a great life. I loved going to the park and kicking the soccer ball with my dad. My dad was always there to read me stories before bed, help me with my homework and on certain nights we would have a game of Yahtzee.

I remember my dad joining the army, it had always been his dream and he used to talk it about with so much pride. I remember him loving his job, he wasn’t home much but when he was he always had time for me.

Things changed when he came back from East Timor in 2001. My dad left to go overseas to fight for our country and never came back.

What did come back was the shell of him, but he wasn’t inside, he wasn’t my dad. 

It wasn’t until 2017 that I leant he was given a drug called Tafenoquine and after reading about it, everything that was happening with my dad made sense. This wasn’t PTSD, this was poison.

I might have only been 6, but I remember like it was yesterday. My father turned to alcohol to cope, he was rarely home and this affected me deeply.

He was constantly in and out of hospital and rehabilitation centres, and still is to this day. I was lucky to have such a strong mother, but I grew up a lot faster then what I should have, having to help my mum with my younger siblings while dad wasn’t around.

I was put into counseling at the young age of 10. I was depressed, and had bad anxiety as I was constantly walking on eggshells waiting for the bomb to blow. 
I left home at the age of 15. I struggled concentrating in school as I was always worrying about what was going on at home and always had the fear of getting a call to say my dad had taken his life.

I could never understand why my dad was the way he was. I researched a lot about PTSD over the years. I knew everything about it, but with my dad deteriorating I knew there was more to it.

After dad having more hospital admissions I was still struggling to cope and turned to drugs. Still to this day i struggle with my own mental issues as a result of the way he is. 17 years later there has been minimal improvement with his mental state. I have read up a lot about the drug he was given, and read many stories that others have shared, and I know deep in my heart the drug Tafenoquine is to blame for making him like this.

I will never get my father back that I knew as a young girl, and every girl needs their father.

He was mistreated and used as a guinea pig along with many other people who served out country.

Is this your way of saying thank you for keeping our country safe?

By leaving them like this without any help or explanation?

Yours Sincerely,

Angela King

Over the coming weeks, we will continue to post more testimonies like these, highlighting not only the personal impact of tafenoquine on the affected service personnel and their families, but the systematic fraud, abuse and corruption which paved the way for this drug to be approved by drug regulatory agencies including the FDA and the Australian TGA.

Senior U.S. Army medical officer who previously raised doubts about the safety and efficacy of tafenoquine retires, gets job with drug manufacturer after landing them an $18+ million government contract

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.

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.

Colonel Bryan Smith and colleagues, Differential Cytochrome P450 2D Metabolism Alters Tafenoquine Pharmacokinetics, 2015

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.

The devastating impact of the Australian Army tafenoquine drug trials

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.

USAMMDA promotional video including the tafenoquine U.S. FDA approval celebration in 2018

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.

Australian Army poisons one of its officers with tafenoquine then continues to use him in their recruiting ad campaign

With the deployments to East Timor and Bougainville, over 3,000 Australian soldiers were subjected to these quinoline drugs, as part of a trial through the military. We’ve assessed through the Department of Veterans’ Affairs own statistics that about 1,000 of the people who were subjected to these drugs have been diagnosed with severe mental health disorders like post-traumatic stress disorder.

Retired Australian Army Captain Andrew George, Sky News Australia, June 6, 2018

ANDREW George was one of the 1,540 Australian Defense Force (ADF) personnel given tafenoquine during the Army Malaria Institute’s notorious quinoline drug trials which involved more than 4,000 troops in Bougainville (Papua New Guinea), East Timor and Australia from 1999 to 2002. The ADF has since admitted that it did not subject tafenoquine to appropriate neurotoxicity testing on primates either before or after these clinical trials. In 2009, scientists from the U.S. Walter Reed Army Institute of Research, which developed both tafenoquine and mefloquine, conducted laboratory studies which found “tafenoquine is the only antimalarial more neurotoxic than mefloquine.”

Like many of the other tafenoquine trial subjects, Andrew was subsequently discharged from the ADF and continues to experience severe, chronic ill-health consistent with quinoline poisoning, against a wall of denials from senior ADF officials including the Surgeon-General, Air Vice Marshal Tracy Smart. Through all this, the ADF continued to feature Andrew in their Army Reserve – Challenge Yourself recruiting campaign on billboards, brochures and television.

Tafenoquine was granted regulatory approval by the U.S. Food and Drug Administration and the Australian Therapeutic Goods Administration in 2018. The FDA approval entitled GlaxoSmithKline to a “priority review voucher” which can be sold on the open market for hundreds of millions of dollars, even if a single tablet of the drug is never sold.

“Andrew George, a former infantry soldier and public relations officer with the Army Reserve, was treated with tafenoquine in Sydney and claims it left him with damaging side effects.

“Mr George, who features in promotional material for the reserves, said he was given the drug after being diagnosed with malaria but does not recall giving informed consent after a detailed explanation of the drug.

“He is one of many veterans seeking answers about the drugs with many believing it complicated their diagnosis and management of post-traumatic stress-disorder.”

Source: Henry Belot, “Therapeutic Goods Administration warned military doctors before using experimental drug on soldierssoldies,” Sydney Morning Herald, April 29, 2016

Senior Australian Army doctor accused of culpability over the deaths of tafenoquine and mefloquine drug trial subjects

Australian Army Major Stuart McCarthy in 2015

Vice Admiral Griggs cannot wash his hands of this, try as he might. The ADF caused it, to our eternal shame. The AMI and the authors of those drug trial reports—among them the ADF’s director of military medicine, Colonel Leonard Brennan—bear direct responsibility for those deaths and the legacy of widespread chronic illness among coalition troops. 

Major Stuart McCarthy, testimony to Australian Senate inquiry, 2015

IN Bougainville and Timor, army medical officers also prescribed a drug known as tafenoquine to 1512 troops, even though it had not — and still has not — been approved for use by Australian authorities.

A series of allegations have now been made about the ethics of these trials and the impact they may have had on the mental health of the participants.

One serving army officer who took mefloquine, Major Stuart McCarthy, alleges the trials were “manifestly unethical” because officers compelled soldiers to take the drug without properly warning of the risks.

He’s supported by a US expert who believes the ADF trials were “deeply unethical”.

McCarthy alleges one commanding officer of troops headed for Timor told his men they would not be deployed unless they took part in the trial, which McCarthy says amounts to compulsion.

In evidence to a Senate committee last week, McCarthy named the ADF’s director of military medicine, Colonel Leonard Brennan, as having “direct responsibility” for the chronic illness and death of Australian and allied troops. Brennan is mentioned in academic journals as having been part of the “study team” that tested tafenoquine and he has co-authored articles about the testing of both drugs on soldiers.

Source: Paul Cleary, “Drug trial a test of ethics,” The Australian, September 11, 2015