The Fate and Fortunes of the Lazarus Drug, Part Three

Hillary Johnson

Deadly Bias

 

The Food and Drug Administration’s refusal to approve Ampligen for ME was bound to have significant, even dramatic consequences, perhaps the least surprising result being the near-bankrupting of the tiny biopharma company, Hemispherx, that manufactures Ampligen. Hemispherx worked for a generation—29 years—to provide FDA with data in hopes of persuading the agency to approve ME.

“We have probably spent more on ME—tens of millions of dollars—than the entire federal government,” says Tom Equels, Hemispherx’s chief executive officer.

Given the government’s veil of secrecy around its ME spending, including its well-documented history of writing off efforts in other diseases and infections as ME-related, verification of Equels’ suspicion would require a fleet of forensic accountants. Suffice to say, several hundred millions of dollars have been wasted or stolen and yet the government has performed no reliable epidemiology or contact tracing; has required no case reporting, identified no risk factors and made no demands that the disease be included in medical school curricula. The government can offer neither credible assurances that the blood supply is safe, nor does it offer suggestions for avoiding contracting the disease.

Hemispherx, in contrast, has over the years produced a large body of scientific studies and data sets about ME, the totality of which could be the basis for an introductory course on the disease in any major medical school and probably should be considered required reading for scientists who wish to enter the field. These include papers on the relationship between symptom severity in ME and low NK cell counts; inhibition of HHV6 in vitro by Ampligen; functional impairment in ME measured by cardiopulmonary exercise testing and more.  http://me-pedia.org/wiki/David_Strayer

Thus, Equels' comment seems credible on its face, considering not only the clinical trials Hemispherx has conducted over the last three decades but its published studies on the disease itself.      

As the years passed and the healing properties of the drug were increasingly evident to Hemispherx’s directors and scientists, their frustration had to have been enormous when faced with the FDA’s intransigence.

In a manner not dissimilar to the NIH’s grant review panels, FDA exhibited years of bias against a medical explanation for the disease and committed numerous bureaucratic and strategic missteps as a result. These included reassigning successive reviews of Hemispherx’s data to different (and inappropriate) FDA panels, few of whose members knew much if anything about ME. 

Likely, FDA decision-makers were steered in the wrong direction in the early 1990s, when Hemispherx initially sought to fast track Ampligen for ME just as FDA had done for AIDS drugs during the same era. Stephen Straus was FDA’s “scientific” advisor on Ampligen beginning in 1991. His influence no doubt impacted FDA leadership until his death in 2007 and possibly for some time after. Straus, of course, was for nearly twenty years NIH’s influential denier-in-chief. He lectured to large medical societies as late as 1994 that ME could be blamed on “poor sleep hygiene” and that brain abnormalities seen on MRI and Neurospect exams had been performed “in little shops…with no credibility.” Those “little shops” included Harvard, UC Irvine, UC San Diego and other major university medical centers. Sufferers were primarily "women with unachievable amibtions," he also wrote.

In some respects, Hemispherx’s dilemma has been akin to American women seeking the right to vote from exclusively male politicians, a Sisyphean struggle that went on for nearly a century.  

There have been significant exceptions, however. A little over a year ago, sanity reared its head in South America, for instance, when the Argentinian government approved Ampligen as a therapy for “severe” ME.    

According to Equels, the incidence of ME in Argentina is similar to that of the U.S. 

“Argentina is one of those South American countries that in many respects mirrors Eruo and American culture—which may account for incidence of the disease, or it may account for the fact that we know of the disease there.  In a rural country, we may not know---in South Sudan, who knows?  There’s no infrastructure to even get close to knowing if ME exists.”

More to the point, he adds, “If you are going to choose a place to market a drug, Argentina has one of the most highly respected (drug) regulatory bodies in that region.”

Equels is referring to Argentina’s ANMAT, its National Administration of Drugs, Food and Medical Technology.

The fact that ANMAT approved Ampligen in Argentina has been duly noted by European countries. The decision has aided Hemispherx in its efforts to facilitate cancer research trials in Europe using Ampligen. 

“We approached (the Argentinan agency),” Equels says. “They’re familiar with the disease.  We had to submit a new drug application.  Approval took four years.  But, the Argentinians understood that this was a real disease that destroys people--so why wouldn’t you consider a drug for that?  And [our] data says that one out of four people are helped by Ampligen.  It’s a no brainer.”

Nevertheless, Equels emphasizes, “It was not a simple transaction. They requested a lot of additional data.”

What’s perhaps most notable about the Argentinian decision is that the data Hemispherx presented to ANMAT was in every way the identical data it has presented over the decades to the American FDA.

Equels makes the broader point that the U.S. FDA has held far too much sway in international circles when it comes to ME.

“I’ve been engaged in international business for many, many years, and I’ve worked in different cultural contexts and policies, and (as regards the FDA) there has often been this deference to the United States.  ‘Whatever the U.S. does, we’ll do.’ We cannot accept that in Argentina, or Canada or France.  We cannot accept that people suffering from this disease in Canada, for instance, have to wait until the (U.S.) FDA does something!”

(Hemispherx’s August 2017 meeting with Canadian ME activists to strategize Ampligen approval in Canada is described in full in Part One of this series.)

“FDA,” Equels continues, “That’s certainly where the solution to this problem resides…But it wasn’t until two or three years ago that there was anything even approaching a conclusion that ME was even a real disease. Now, we’ve always thought it was a disease…There’s going to be a point in the United States when the government believes it’s a medical disease. There will be a time when the government will not tolerate psychological disease theories because they know it’s a biological disease.  I’m very confident that once they understand this disease at NIH, for instance, they’ll be able to understand the way Ampligen works.”

 

Discretionary Issues 

 

A show-stopper in already strained FDA-Hemispherx relations occurred when FDA asked Hemispherx to perform a second phase three trial with Ampligen in ME using 300 patients. Hemispherx’s first phase three trial included 194 patients and was completed in 2004.

“The efficacy in this last phase three trial with extremely broad inclusion criteria—we were getting twenty-five percent efficacy,” Equels says, his frustration evident. “In any other disease of such severity, a drug with that kind of efficacy would have been approved…What happens to the one in four people who must stay in bed because we can’t get past this misconception that ME is psychological disease?”  

Phase three trials are commonly the final step prior to a drug’s approval by FDA. Hemispherx’s phase three included patients at several sites in the U.S. Participants demonstrated improved performance on treadmill walking tests and, secondarily, improved cognitive function. 

To undertake the FDA’s request for a “do-over” however, would cost Hemispherx $20 million, Equels says.

“This is not a discretionary issue,” he adds. “If you don’t have the money, you can’t do it. We had to come up with a creative approval that costs less. We had to focus on a business plan that assures the survival of the company and the approval of Ampligen for as many applications as possible as quickly as possible. That will assure the approval of Ampligen in some form (for ME).”

Hemispherx has continued to cooperate with FDA over the years, last fall responding to an agency request to identify the ME patients most likely to be Ampligen “responders.” The results, discussed in Part Two in this series, were presented by Hemispherx at the 2016 IACFS meeting in Ft. Lauderdale. Not surprisingly, patients who are closest to onset (ill less than ten years) are more likely to have a full recovery or—short of recovery—a significantly improved quality of life.

Doctors with vast experience in providing Ampligen agree the drug can be extremely helpful to many patients who have been ill for ten, twenty, even thirty or more years, however.

North Carolina’s Charles Lapp notes, “I believe our results show that patients with a shorter duration of illness respond more quickly, but many subsets have responded even after many years of illness duration. That’s the beauty of Ampligen!”

Hemispherx executives certainly must be aware of Ampligen’s potential to change sufferers’ lives at any stage of their disease, but they are limited in their ability to lobby for the drug’s efficacy beyond any results they have presented to FDA.

Equels’ sense of urgency about getting Ampligen into ME-afflicted bodies is nearly palpable.

“There are doctors, engineers, scientists, artists, writers with (ME),” Equels says.  “Look at what’s lost if these people are lost! This is something worth fighting for. And we can’t allow ourselves to be ground out of existence so that we…can’t win this battle. We’ve got to come up with a way to win.”

 

How to Win

 

Winning, Equels realized soon after he was named CEO of Hemispherx last year, was going to require moving the company in new directions. One of those directions was cancer. Unknown to many M.E. sufferers may be the fact that Ampligen was invented as a cancer therapy.  Among other things, it’s an interferon inducer, a protein that can positively alter the immediate environment of malignant tumors and interfere with tumor growth. Indeed, researchers in the late 1960s and 1970s hoped interferon might be a “magic bullet” cure for cancer. The ability to create synthetic interferon in large quantities during this period was seen as a scientific breakthrough. Unfortunately, synthetic interferons proved too toxic in the doses required.  Ampligen’s co-inventor in the 1960s, William Carter, initially conceived of Ampligen as a cancer therapy that would work like interferon but without the toxicity. Among its many properties, Ampligen induces the body's natural production of interferon.

Later, Ampligen showed promise in inhibiting the replication of several lethal viruses, beginning with HIV in 1987.

These are heady indications for any drug, certainly, and renewed excitement about Ampligen is quietly brewing in a number of research labs around the world. Equels believes a return to studying Ampligen’s promise in infectious diseases and cancer will inevitably swing FDA’s attention back to Ampligen’s value as an ME therapy. He clearly hopes ME sufferers will make that connection, too—however counterintuitive it may seem. In truth, for many ME patients, Hemispherx’s new direction is likely to be, excuse the unworthy pun, a difficult pill to swallow given that most have waited years and even decades for help. 

“I would hope that people with ME would respect the fact that the spillover effect of recognizing the bioactivity of action of Ampligen in these other diseases will lead to an understanding of the role of Ampligen at the cellular level in the immune system,” Equels says.

“And if you understand how Ampligen works,” he adds, “then we can look at ME patients in which Ampligen is working and, as with Penicillin, we can work backwards.”

In other words, the etiology of the disease could be revealed once Ampligen’s precise mechanism(s) of action in M.E. are known, much the way a curative dose of Penicillin narrows the etiology to bacteria.

 

Same Drug, Different Diseases

 

Upon being named chairman, Equels began an intensive review of the company’s entire research portfolio.

“I was faced with a conundrum,” Equels says. “I had to come up with a plan to afford the prosperity of the company to afford what we’re doing in ME.

“There was a wide range of research done twenty and thirty years ago. As a personal project,” Equels continues, “I gathered up all that material.  There was a huge amount, and I took the time to read and understand it.”

One of the first items Equels acquainted himself with were early research efforts that employed Ampligen in the treatment of specific cancers.  

“Before we became focused on ME (in 1988),” Equels says, “there were a number of programs focused on renal cell cancer and melanoma” using Ampligen as an adjuvant therapy.  

“FDA granted orphan drug status to Ampligen in both renal cell cancer and melanoma,” Equels continues. “We had a number of stage four melanomas that went into remission.  In one case, the tumor just disappeared and at least one of those patients was alive thirty-five years later.”

The doctor treating this particular melanoma patient was Hahnemann University oncologist David Strayer, Hemispherx’s long-time scientific director and then colleague of Carter’s, who was also an oncology specialist at Hahnemann. Strayer was the first Hemispherx scientist to administer Ampligen to ME patient Nancy Kaiser in Dan Peterson’s Nevada clinic in 1988, the experiment that launched Hemispherx’s optimistic commitment to seeing their premiere drug approved in ME.

A second, dramatically successful Ampligen application occurred in AIDS in 1987. The logic seemed correct:  Ampligen’s presumed success in particular cancers was thought to be its ability to modulate the immune system, in the case of cancer, providing the body with tools to vanquish malignant cells. AIDS was seen as nothing if not an immune system disease. Plus, at the time, the primary treatment for HIV was the highly toxic AZT which helped keep HIV in check but was causing additional disease in AIDS patients.

Ten AIDS patients enrolled in a pilot study were treated with Ampligen for 18 weeks at a dose that was one-half the current ME dose. The results were spectacular, particularly since Ampligen was benign compared to AZT. The results also suggested that in addition to other properties, Ampligen was a powerful antimicrobial that inhibited HIV.  Lancet published the study, which concluded, “…[I]n the short term, Ampligen seems to have the dual ability to restore immunological function and to control HIV replication.” (italics added) http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(87)90543-5/fulltext 

Not surprisingly, the Lancet study generated tremendous excitement throughout the AIDS patient community. Biopharma company DuPont, too, wanted to get in on the ground floor of this potential wonder drug. DuPont contracted with Hemispherx to conduct a trial of Ampligen in 300 AIDS sufferers.

Philadelphia journalist Mindy Kitei chronicled those years in her page-turner for Philadelphia magazine in 1994, headlined “The AIDS Drug No One Can Have.” Kitei recounted how the company’s decision to focus its energies on ME in 1988 came only after the ill-fated DuPont AIDS trial.

DuPont invested $30 million in the trial but Ampligen exhibited none of the promise it had shown the pilot study. Carter and other Hemispherx scientists, Kitei wrote, “…pored over the data, trying to determine what had gone wrong.” They discovered that Dupont had dispensed the drug in plastic bags rather than the glass bottles from which Hemispherx dispensed the drug. The Hemispherx scientists determined that the plastic, Kitei wrote, “…unraveled the RNA strands in the fragile compound, rendering it ineffective.” According to Kitei, other scientists who studied the problem supported Hemispherx on this claim, but DuPont executives were unmoved.   

Ampligen’s potential as an AIDS therapy went unexplored as DuPont’s relationship with Hemispherx devolved into a series of lawsuits and ill will, according to Kitei. Nevertheless, for those who can intellectually bifurcate the Lancet data from the follow-up disaster of the DuPont study—never published—the original AIDS pilot study still stands as a reminder of Ampligen’s potential to tamp lethal infectious agents without toxic side effects and speaks to its powerful anti-viral properties.

The profound disappointment among AIDS organizations over the loss of Ampligen as a potential therapy when the DuPont trial blew up is described in this New York Times story from 1988.http://www.nytimes.com/1988/10/14/us/poor-results-bring-end-to-anti-aids-drug-study.html

More to Come....

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