How a cold call led to a Canadian experimental Ebola treatment

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Thomas Geisbert, one of the world's leading Ebola researchers, is often on the receiving end of pitches from what he calls "snake-oil salesmen" peddling cures for a disease that has long terrified the public, even before this year's devastating epidemic in West Africa.

So the American virologist was skeptical when he got an unsolicited call in late 2004 from Ian MacLachlan, a Canadian biochemist and co-founder of a small British Columbia drug company.

Dr. MacLachlan had heard Dr. Geisbert was experimenting with molecules called small interfering RNAs (siRNAs) to silence messengers in the Ebola virus's genetic code that tell it to replicate, but Dr. Geisbert was not having much luck saving guinea pigs with his approach.

The problem, Dr. MacLachlan told him, was his delivery system. "I listened to his pitch," Dr. Geisbert recalled, "and I said, 'Look, what have I got to lose?'"

He mailed some of his siRNA molecules to Dr. MacLachlan, who packaged them in his company's lipid nanoparticle delivery system, a minuscule droplet of fat or oil that protects the siRNA molecules as they travel through the bloodstream.

"All of a sudden," Dr. Geisbert said, "100 per cent of the guinea pigs were protected."

That out-of-the-blue phone call was the genesis of TKM-Ebola, the experimental treatment produced by Burnaby's Tekmira Pharmaceuticals Corp. that emerged this week from the shadow of another Canadian-developed Ebola therapy, ZMapp.

With supplies of ZMapp exhausted, TKM-Ebola has been given to "several" ill patients, the company revealed this week, including an American missionary doctor who was released from an Omaha hospital on Thursday.

Now Tekmira – a company that makes a range of therapies using siRNA technology, has 98 employees and a market value of $541-million – is one of at least three drug makers in talks with the international consortium that is trying to speed up delivery of experimental Ebola treatments to the front lines of the outbreak, which has killed nearly 3,000 people and is poised to infect thousands more if the latest bleak forecasts come to pass.

TKM-Ebola is part of Canada's larger contribution to the medical battle against the Ebola virus, a fight in which this country is punching well above its weight.

ZMapp was developed largely at Canada's National Microbiology Laboratory in Winnipeg, the same facility that played an instrumental role in creating a promising vaccine candidate that Ottawa has offered to the World Health Organization for use in West Africa.

Until recently, those two potential experimental tools, along with an American vaccine being developed by GlaxoSmithKline, have generally received more attention than TKM-Ebola, although Tekmira was the only company that had human safety trials of its product under way when the outbreak in Guinea was first reported to the World Health Organization in March.

"Tekmira's [drug] is one drug that has shown some promise, but like all of them, it still has a long way to go," said Daniel Bausch, a professor at the Tulane University School of Public Health and Tropical Medicine, who is advising the WHO on experimental approaches in this outbreak. "None of them have what we really want, which is full safety testing and full evidence of efficacy."

After Dr. MacLachlan's call to Dr. Geisbert, now a professor at the University of Texas Medical Branch at Galveston, TKM-Ebola was tested on rhesus macaques at the U.S. Army Medical Research Institute of Infectious Diseases biosafety level 4 containment lab in Maryland.

All four macaques challenged with lethal doses of the Ebola virus, then treated for seven days with TKM-Ebola, survived. (In another arm of the study, one of three macaques given four doses, instead of seven, died.)

The results, published in The Lancet in 2010, were encouraging enough to persuade the U.S. Department of Defence's biomedical research arm to sign a $140-million contract with Tekmira. A phase I clinical trial, designed to test the safety of the treatment in 28 healthy volunteers, began in January, and the U.S. Food and Drug Administration granted the drug fast-track approval in March.

But Tekmira announced in July that the trial had hit a road block: The FDA asked the company to halt the trial until it could provide more data to ensure the safety of the healthy volunteers, some of whom were being dosed with as much TKM-Ebola as would be given to a lethally infected patient. The hold was partly lifted in August, allowing Tekmira to offer the drug on an emergency basis to Ebola patients, but the trial itself is still on hiatus.

That background was initially all that doctors at the Nebraska Medical Center in Omaha had to rely on when they learned that Rick Sacra, a 51-year-old Massachusetts physician who had contracted Ebola while working for the missionary group SIM USA in Liberia, would be arriving at their biocontainment unit on Sept. 5.

Chris Kratochvil, the associate vice-chancellor for clinical research at the University of Nebraska Medical Center, immediately got on the phone with the FDA, the U.S. Centers for Disease Control and Prevention and Emory University Hospital in Atlanta, the facility that had successfully treated the first two American Ebola patients, both of whom recovered after receiving ZMapp and high-quality supportive care.

"What we did very early on was sign a confidentiality agreement with Tekmira which allowed us to access their data that they had available in the development of the drug and the animal studies of the medication," Dr. Kratochvil said. "That gave us an opportunity to really take a look at what was known about the medication."

After combing through that data, doctors decided to give TKM-Ebola to Dr. Sacra, who had begun to experience chills and minor fever seven days before landing in Omaha.

"When he arrived he was critically ill," said Philip Smith, medical director of the biocontainment unit at the University of Nebraska Medical Center. "He had low blood pressure, his body chemistries were out of whack and he was only semi-conscious."

Twenty days later, Dr. Sacra left the isolation unit after two blood tests 24 hours apart confirmed he was free of the Ebola virus. He marked his release with a written statement full of thank-yous and exuberant punctuation. "On behalf of my family, and SIM, thank you so much!!! You have made me feel so welcome that I am now an official lifetime [Nebraska Cornhuskers] Fan!!!! Go Big Red!"

Teasing out what role TKM-Ebola played in Dr. Sacra's recovery is virtually impossible. Along with his seven days of intravenous TKM-Ebola treatment, Dr. Sacra received plasma transfusions on days two and three of his treatment from Kent Brantly, an Ebola survivor whose type A blood matched Dr. Sacra's.

Dr. Sacra also received traditional supportive care that is simply not available to patients in Guinea, Liberia and Sierra Leone, where rickety health systems have collapsed under the epidemic's pressure.

Tekmira would not confirm which other patients have received TKM-Ebola so far, citing patient confidentiality. A French nurse infected in Liberia has been approved to receive three experimental drugs, including TKM-Ebola, but the details of her treatment have not been made public.

Right now, supplies of the treatment are "limited," according to Tekmira; a WHO report from early September put the number of available treatment courses at fewer than 30.

However, the same report said as many as 900 doses of the drug, which is manufactured synthetically, could be ready by the first quarter of next year.

The idea that TKM-Ebola could help more people is exhilarating for Dr. Geisbert, who wondered if a drug he had spent years developing would ever make it into the field.

"I wish you could save everybody," he said. "But I think the fact that you can save anyone is awesome."