The Fate and Fortunes of the Lazaurus Drug, Part One
On the morning of Thursday, August 3, a high-stakes meeting unfolded among a small group of Canadian ME sufferers, a Canadian ME doctor and the top-most executives of the tiny U.S. biopharma company, Hemispherx, maker of Ampligen. The matter at hand: might Hemispherx, which holds the patent on the only drug to treat ME in the U.S. pipeline or anywhere else, find a capital-rich pharmaceutical company in Canada to help shepherd Ampligen—with the help of Canadian patients, doctors and Hemispherx’s experts—through Canada’s complex drug approval process? Were the Canadian patients, activists all, capable of delivering that partner to Hemispherx?
The setting was a small conference room at the Marriott Hotel near the Toronto International Airport, where Hemispherx executives would head shortly after the two hour meeting to board commercial jets to return to the U.S. A speakerphone sat in the middle of the table. Voices warbled in and out of hearing range for those few who were listening in. “Stop! I can’t hear!” was a common refrain.
Hemispherx CEO and president Tom Equels, a tall, fit-looking, white-haired man who flew helicopters into combat during the Vietnam war—winning a Purple Heart, two Distinguished Flying Crosses and the Bronze Star in the course of three tours—sought to impose order.
“There are very few opportunities at sixty-five to go back to my training as a pilot,” Equels (pronounced “ee-quals”) said, his manner delicate. “But I think we have to abide by the principles of a group of pilots on a mission—we need to take some care to have one person talking at a time.”
Equels’ metaphor, a war in which soldiers’ lives depend on cooperation, seemed particularly apt for this private meeting, sought by a handful of Canadian patients.
One participant was a severe ME sufferer who has lost the ability to speak and so needed to type her occasional short questions online from her bed far away. Another was a caregiver for a pediatric patient; she was connected to the first patient via computer and spoke on her behalf. A third patient, John Adams—an ME sufferer and expert in what he called Canada’s “labryinthine” process of drug approval—was on the call but physically in Mexico. His son has the rare disease PKU (Phenylketonuria) and Adams already had helped shepherd one PKU drug through the tedious Canadian drug approval process. It took five years instead of the more common seven or eight. He was attempting to do the same with a second PKU drug.
Also present was Toronto resident Scott Simpson, a self-described “mild” sufferer who experienced sudden onset ME after being diagnosed with HIV fourteen years earlier and recovering fully from AIDS on antiretrovirals. After his bout with AIDS, he remembers, “I taught myself to swim and ended up on the national triathlon team. I was the first HIV-positive person to compete at the triathlon world championship in my age group.”
Simpson was preparing for his next triathlon when he crashed suddenly in 2012. The symptoms were devastating. His doctor said to him, “You realize this has nothing to do with HIV?”
Nevertheless, five years passed before Simpson obtained an ME diagnosis and then only after presenting his doctor with the Canadian-initiated ICC definition. Simpson believes he has remained a “mild” case, even experiencing two full remissions, because he continues to take antiretrovirals. His Twitter handle is Millions Missing Canada.
Simpson had made the overture to Hemispherx for this meeting weeks earlier.
Equels was the sole Hemispherx executive who spoke during the two hour meeting, but William Mitchell, an oncologist, immunologist and pathologist at Vanderbilt University who has been Hemispherx’s director and now chairman for 29 years, and Peter Rodino III, the company’s counsel and director of federal affairs, accompanied Equels. Rodino is the son of the famous six-term U.S. Congressman from New Jersey for whom the Federal Building in Newark was named. David Strayer, the company’s chief scientific officer and before that, medical director, since 1988, was on the call.
Ian Hyams, a native of South Africa who runs an ME clinic and has a hospital appointment in West Vancouver, British Columbia and has treated ME sufferers in England, the U.S., and Canada with Ampligen, had traveled from the other side of the continent to be physically present at the Toronto meeting.
“I’m representing doctors in Canada,” Hyams said by way of introduction. “I have an appointment in a hospital where this treatment is offered and I have my own private practice in British Columbia.”
Several years ago, Hyams was invited by Dan Peterson to partner with the Incline Village doctor and even succeed him in time, but U.S. rules would have required Hyams to, in effect, complete medical school a second time in order to obtain a license to practice in Nevada. He has also worked with Paul Cheney in the latter’s Charlotte clinic. He has treated patients with Ampligen in Canada on a “named patient” one-by-one basis utilizing a program offered by Canada's FDA equivalent. The effort required from the doctor in such cases is extremely time-consuming and not always successful.
A documentary filmmaker, invited by Simpson, sat wordlessly, his camera silently recording.
As to which party had the most to gain from the two-hour conversation that ensued was an imponderable. Was it the Canadians at the table or listening from their beds whose health might be restored should Ampligen be made available to them? Or was it the American executives from Hemispherx, a drug-maker that has been teetering on the brink of insolvency for much of its existence? Earlier this year, several Hemispherx executives, including Equels, agreed to forego significant percentages of their salaries for several months until the stock price rose from what was then 19 cents. In recent months, the stock has hovered between 32-39 cents.
Equels made it clear from the start that he was in Toronto to listen, but there was one matter about which he was firm and from his manner and words it seemed to be the only non-negotiable issue on the table:
“We cannot go forward without a Canadian (biopharma) partner,” Equels said. “We’ve reached the conclusion that it’s a necessity. We have to have each of four legs of the stool—Canadian doctors, patients, a manufacturer (Hemipsherx) and a Canadian pharma component, or (Ampligen approval in Canada) won’t be successful.”
For the next two hours, Equels reiterated that message when other participants, aware that the drug approval process in Canada, even if successful, could take from five to seven years, proposed measures that were not unlike efforts that have been used in the U.S. for years. These included using the Canadian equivalents of compassionate care and “early access” programs and even conducting additional trials.
Progress toward approval of Ampligen in the U.S. has been stalled for some time given the FDA’s demand for a second, confirmatory Phase Three study, which Hemispherx completed in 2004 with two-hundred patients.
In response to a question from one participant who noted that FDA approval would go a long way toward easing approval in Canada, Equels replied, “The FDA application is basically on hold. We are trying to set up a meeting (with FDA) to go over some of the issues related to the label and work out some path forward for the confirmatory studies they’re requesting. But our issue is one of restricted resources,” Equels said. “If we had twenty million dollars, undertaking a brand new clinical trial would be a no brainer, but we don’t have twenty million dollars.”
As to options that have been utilized in the U.S., Equels added, “The problem with doing it patient by patient is the amount of time it takes for the doctor and for our company to bring one patient on board…it makes it onerous and takes away from our other efforts…The problem with compassionate care and early access,” he continued, “is that the person who gets the golden ticket gets the drug and then thousands do not. Now, that’s not what we want (in order to) make Ampligen available as early as possible. This drug is not just for the rich, Ampligen is for everyone. ME does not discriminate based on class or sex. It has the potential to affect everyone and we want to be sure that what we’re creating is a safety net for everyone.”
From the most basic perspective—restoration of their health—the Canadians had the most to gain if Ampligen should be approved in Canada. But, Equels, Mitchell, Strayer and Rodino, robust men in their 60s and 70s, had a great deal to gain in terms of their ability to sustain a company to which each had devoted a significant portion of their lives and their passion.
And, lest there be doubt, there is an abiding desire among the manufacturers of Ampligen that their flagship drug be made available to ME patients worldwide. Equels said more than once during lengthy interviews for this series that the plight of ME sufferers has “brought tears to (his) eyes.”
Given that access to Ampligen has virtually ended in the U.S. after a price hike, the company's cessation of compassionate care programs and a need to pursue arenas other than the U.S. in order to keep the company and the drug viable, some will suggest Equels’s tears are crocodilian. My impression has been that Equels is exquisitely sensitive to the plight of ME sufferers and a quick study on just how devastating the disease can be.
“The frustration (ME patients) are going through is almost unimaginable,” he commented to me. “In addition to this Alzheimer’s-like brain disorder taking place they have contemporaneous profound exhaustion—it’s like (Franz Kafka’s) Metamorphosis. It’s very frightening.”
“We have compassion for people who have this problem,” Equels told one Canadian patient during the meeting. “But we cannot act on that compassion beyond our economic means. We’re a very small R and D company, the drug is very expensive. It outstrips our means if we can’t get some reimbursement for those costs to allow us to go forward…That is resolved if we find the pharmaceutical company who wants to go forward.
“Pfizer could subsidize Ampligen for free and not break a sweat," Equels added. "In fact, Pfizer could subsidize Ampligen without touching their bottom line. Whereas it would cause us to go bankrupt.”
Both sides, the Canadian patients and Hemispherx executives, seemed to realize they might be at the start of an arduous struggle that could drag on for years. On the other hand, with insane, incredible good luck—luck that had failed to land anywhere on the globe before—that struggle might be resolved rapidly. According to Simpson, if the top Health Minister in Canada—Jane Philpott at the time of this conference call—chose to do so, she could write an executive order for the Canadian health establishment to “fast track” Ampligen for ME sufferers. It seemed a long shot, a fantasy.
But, Simpson continued, “It seems to me that if we go the traditional route of getting license approval, and get each province to sign on for reimbursement—that would be a minimum five-to-seven-year process. Better to go directly to the health minister to get fast track…Say, ‘We’ve got an epidemic,’ and get it fast tracked as with HIV.”
Simpson was proposing this strategy based on new statistics from a Canadian government public health survey. The statistics revealed a startling 37.6 percent jump in ME cases in Canada between 2014 and 2015. Though the agency had yet to make the information public, and at this writing still has not done so, Simpson and his group, Millions Missing Canada, obtained a series of emails revealing the new statistics.
A statistical jump of nearly 38 percent in just one year suggested the total number of cases in Canada had exceeded 560,000 people, resulting in an attack rate that Simpson says is the highest of any country in the world: 1.9 percent—or nearly 2 percent—of the Canadian population.
There are reasons for caution in interpreting the difference between earlier years and the 2015 data, reasons that will be addressed more fully later. However Vancouver clinician Ian Hyams suggested in a recent interview that the surge might be attributable to newly implemented changes in the wording of the survey question posed by Health Statistics interviewers.
Of course, what’s remarkable to an American ear is that Canada even asks the question from year to year.
Yet, even if the attack rate was barely unchanged from 2014’s presumed attack rate of 1.3 percent, the number still constitutes a massive health crises with one-half million Canadian sufferers urgently requiring treatment.
Another, potentially less controversial point of leverage the group could utilize to promote Ampligen's approval in Canada: the reams of data accrued from Hemispherx’s twenty-six year struggle with the American FDA. After all, just fourteen months ago Argentina’s government drug approval agency—that country’s internationally respected FDA-equivalent—approved Ampligen for severe ME sufferers in Argentina based on the identical data Hemispherx has presented to the FDA. The process took four years.
Equels brought up a third point: the July paper about the relationship between cytokines and inflammation in the Proceedings of the National Academy of Science by Stanford’s Jose Montoya and Mark Davis. In Equels’ view, this study augured positively for the development of a diagnostic test.
“We have thus far seen little interest by big pharma in this drug and this disease,” Equels said. “But, it’s not that they’re not interested in the market, because it’s obviously a huge market with big profits, which is what big pharma is all about. What isn’t clear to them is first, how to identify patients and second, how to restrict the New Drug Application to patients for Ampligen so that you have a very clear path forward with little risk.”
Should the Montoya-Davis cytokine paper result in a diagnostic test, big pharma’s first problem—how to identify patients—would be resolved.
In addition, Equels pointed out, Hemispherx now has extremely strong data to identify which patients will be optimal responders to the drug. It’s data that removes the guess-work for a large pharmaceutical administering a clinical trial. Having this data is likely to lead to the greatest chance of a good outcome with Ampligen.
By Hemispherx’s own analysis, when Ampligen is given over a period of 40 weeks--the company’s long-time standard protocol--the optimum period for Ampligen efficacy is between two and eight years. Beyond that, the recovery rate dips. In order to extract this data, Hemispherx looked at results from treadmill exercise tolerance tests, as well as cognitive function and other measures of functionality--assessing Ampligen recipients' answers to questions such as, "can you hammer a nail?" and "can you fold laundry?"
“People from zero to five years have a strong response,” Equels says. “At eight years, we start to see a statistical fall off. At ten years, it flattens out at a very low response rate.”
Perhaps ironically, Hemispherx's Ampligen responder data emerged from an effort the company made last year to respond to an FDA request. Seeking to satisfy FDA, Hemispherx performed the analysis using their Phase three study. For the record, Hemispherx limits its clinical trials to patients who experience sudden, viral-like onset.
Scientific director David Strayer presented this important responder data in a poster at last fall’s IACFS meeting. A nattily-dressed Equels, who in addition to his duties as Hemispherx president and CEO has a thriving law practice in Miami, braved the potential wrath of any patients smarting from the loss of Ampligen and positioned himself next to the poster, his expression genial, seemingly eager to meet patients and scientists alike.
Hermispherx scientists observed that the greatest efficacy occurred when Ampligen was administered during the first eight years after disease onset, but Equels clarified at the Toronto meeting that patients who were ill less than two years show great benefits from the drug and yet they are not included in the responder data. That's because a small percentage of patients recover spontaneously between zero to two years. As Equels said, "Their immune system fixes itself." Thus, Hemispherx removed anyone ill less than two years from the study so as to avoid muddying the data.
One could interpret the FDA request for responder data as a desire on the part of FDA officials to winnow the patient population that might be given access to Ampligen to a bare minimum. Hemispherx's responder data fails to take into account that long-term clinical experience with Ampligen suggests the drug can ameliorate the disease even at the twenty and thirty-year marks, though success may require considerably more infusions than the 40-week protocol. In fact, many patients with the means to do so have been on Ampligen for years. They typically feel healthy unless forced to stop Ampligen infusions for some period of time. For such patients, Ampligen is a maintenance drug. At this late date, howwever, when the fate of the company is hanging in the balance, Hemispherx needs to provide to a big-pharma partner--and to federal regulators--the most unambiguous, least equivocal data available.
Equels appears fully cognizant that the responder data reported to the FDA fails to take into account long-term sufferers who have found relief from Ampligen over lengthy periods of time.
“We now know who the Ampligen responders are and we know why,” Equels said. “We spent millions of dollars in our U.S. Phase Three study. It would be unacceptable ignorance not to evaluate the data and take advantage of that data and it’s telling us where Ampligen is effective. And—it’s like dominos," he added. "If we get approval for severe M.E., then we have a basis for approaching other aspects of using this drug in M.E.
“As to the regulators,” he continued, “we have to start with them accepting that this is a biological disorder. The naysayers who say it’s malingering, psychosomatic—it’s time for them to be silent. It’s unacceptable for them to be influencing the regulators.”
On August 8, five days after the Toronto Marriott meeting, Millions Missing Canada issued a press release about the apparent jump in cases, “Epidemic of Neuro-Immune Disease Myalgic Encephalitis—Health Canada Fails to Respond to Unreleased 2015 Data.” In 2003, according to the graph published in the press release, the attack rate in Canada was 1.3; the graph showed a slow increase to 1.4 by 2014, when cases jumped significantly. In 2015, a near 38 percent increase in cases resulted in an attack rate of 1.9. The release also announced that the organization had begun circulating a petition to be delivered to the Health Minister Philpottt. (Since then, Philpott has been succeeded by Ginette Petitpas Taylor on August 28.) The petition sought the fast-tracking of Ampligen as a therapeutic intervention for the disease on the basis of the epidemic surge of ME in Canada.
Equels was quoted: “We are pleased to work with Millions Missing Canada on this very important issue…we hope to be better able to achieve the goal of providing an effective therapy for the hundreds of thousands of people who suffer from M.E….Hemispherx and Millions Missing Canada will follow the model that Hemispherx used to obtain approval in Argentina by seeking a Canadian Pharmaceutical Partner who will file for regulatory approval in Canada.” Clearly, Equels was seeking a more traditional, less controversial route to approval--a straightforward New Drug Application as was successfully undertaken in Argentina.
Like Equels, Canadian ME specialist Hyams did not address the dramatic statistical uptick in cases but talked about Ampligen’s powerful therapeutic effects in M.E.
“I have personally witnessed…the potential for severely afflicted patients to rebuild quality of life…It is an honor for me to be involved in the process of potentially introducing this drug to Canada…”
More To Come