The Fate and Fortunes of the Lazarus drug, Part Four

Hillary Johnson

“The beneficiaries of cancer research can say ‘Thank you’ to all of the patients with ME—those patients who participated in clinical studies involving Ampligen—because we benefited from their sacrifice. Thanks to them, we now have a very well established profile of dosing—safety and dosing—which we are using in our cancer work.”

---Pawel Kalinski, tumor immunology researcher and immunotherapy expert, Roswell Cancer Institute, July 2017

 

The Significance of Ampligen’s Safety “Profile”

 

Possibly the most important consequence of Hemispherx’s grand experiment with Ampligen and ME has been the establishment of at least one inarguable fact, accepted even by the FDA in 2012: Ampligen is safe, or, as Hemispherx CEO Tom Equels prefers, “generally well tolerated.” There may be side effects in some patients—skin flushing or flu-like responses that diminish completely over time—but as ME sufferers likely would agree, compared to the global, life-destroying side effects of the disease, these modest effects are as bothersome as a fly on the lapel.

FDA acknowledgment that Ampligen is safe came during a one-day hearing in 2012. Several people who had experienced recovery on Ampligen testified before an FDA panel. The panel included the CDC’s Beth Unger and Harvard’s long-time ME specialist Anthony Komaroff. Afterward, the panel took a vote on Ampligen’s safety profile. Somewhat astonishingly, Komaroff and perhaps less astonishingly, Unger, voted “No.” Nevertheless, the safety profile passed, eight to five. Had Komaroff and Unger voted “yes,” the vote would have been a near sweep—ten to three.   

Approximately 100,000 doses of Ampligen have been delivered without toxic consequences into the bodies of approximately 1,000 human beings.  The majority of these bodies have been people suffering from M.E. As a result, Hemispherx has been able to build an impressive safety profile and dosing regimen for Ampligen over a period of many years.

“We had spent all that time with ME, we had spent tens of millions of dollars on ME, and we knew that we were the only drug in the pipeline,” Equels says.  “We also had an enormous amount of data saying it was generally well tolerated.  So, we were sitting here with this safety profile that we had spent fifteen million dollars on and decided it made sense to invest in that because that safety portfolio allows us to move forward.  It comes in large part from (the ME clinical trials) but it also consists of data coming from HIV as well as clinical oncology trials.”

“We want to take advantage of the safety data—it translates into diseases that are highly lethal such as malignancies where people may have just six months to live.  (The safety profile allows for) a repurposing for these new indications,” Equels says.

Thus, scientists around the world are now able to press forward with clinical trials of Ampligen in cancer and infectious diseases using Ampligen’s safety profile and dosing schedule, created off the backs, so to speak, primarily of people with ME.

 

What is Ampligen?

 

How can one drug treat an array of seemingly unrelated—to the layperson—diseases? The idea has been a recurring point of contention among Hemispherx critics, who bash the company for claiming its drug will cure everything from hepatitis B to cancer to AIDS to ME. Of course, as the reality of dealing with FDA and frequently litigious stock holders has sunk in, Hemispherx executives are cautious about suggesting their drug does anything.

The simple answer, again--for the layperson--is that A) Ampligen works as an immune system “modulator” to help restore a malfunctioning immune system and B) it inhibits the replication of microbes—infectious agents.

Equels likes to cite an experiment undertaken by USAMRID, the U.S. Army Medical Research Institute of Infectious Diseases at Fort Detrick, MD just outside Washington, DC. Army researchers approached Hemispherx for a supply of Ampligen during the 2014-2016 Ebola epidemic in West Africa. 

(For more on USAMRID:  http://www.faqs.org/espionage/Ul-Vo/USAMRIID-United-States-Army-Medical-Research-Institute-of-Infectious-Diseases.html) 

“They injected cohorts of rodents with the Ebola virus,” Equels says. “All of the mice died within six or seven days.  Then they injected Ebola-infected mice with Ampligen—every single one of them survived—with no symptoms. How is it that you have one-hundred rodents dead with Ebola, and one-hundred percent alive and healthy with Ampligen?” Equels continues.

“The main reason I like to mention the Ebola test,” Equels says. “is that it shows that Ampligen has a vigorous bioactivity. (ME patients) who are responding to Ampligen are responding because they have a biological disease.  That’s been our biggest problem for about twenty years. There’s a place where we just have to draw a line and say, you HAVE to respect the fact that this is a biological disorder.  Ampligen has bioactivity. The people who respond to Ampligen must have a biological disorder…These people aren’t getting out of bed and going back to work due to some Lazarus-like miracle.” 

***

A more academic look at Ampligen reveals it to be one among a group of synthetic or man-made proteins called “toll-like receptor agonists.” “TLRs” as they are shorthanded, help the innate and adaptive immune systems fight infectious and inflammatory diseases. (http://www.nature.com/scitable/topicpage/toll-like-receptors-sensors-that-detect-infection-14396559) There are at least twelve known TLRs that occur naturally in the body and there are almost as many synthetic TLRs like Ampligen. (An “agonist” is a chemical that binds to a particular receptor, which then triggers a biological response.)

Ampligen is a TLR-3, one among four TLRs that, according to the paper cited above, “bind to microbial nucleic acids, including double and single-stranded RNA from RNA viruses and DNA from most organisms.”

Researchers who have worked with Ampligen whether in earlier years or now generally find it to be the least toxic or, alternatively, the most benign TLR3.

Ampligen and Infectious Diseases

Scientist Justin Julander, a researcher with the Institute for Antiviral Research at Utah State University, has conducted research on Ampligen to evaluate its use as an anti-microbial agent off and on beginning in the early 2000s. Julander says his institute has contracts with the National Institutes of Health to screen “various compounds that have anti-viral activity.”

“We looked at Ampligen even before 2005,” Julander says. “We knew it was an interferon inducer. That's our body's natural defense against viruses. Many viruses have evolved methods to escape the host’s interferon response, like Dengue. It’s an arms race.” 

Alternatively, Julander notes, animals with a deficient immune response pathway, “(have) a greater sensitivity to viral infection. If we knock out interferon sensors, they’ll be particularly susceptible.

“The idea behind Ampligen is that it boosts (interferon),” he continues.  “Exogenous (man-made) interferon makes you feel pretty lousy.  But there are other ways to induce interferon, and we’ve identified Ampligen as an agent that can do this—it gives you the benefit of interferon…without toxicity…Ampligen,” Julander adds, “was one of those test agents that we found to be active in inducing the interferon response against a wide range of viruses.”

Those viruses included Sars, Zika and West Nile Virus as well as bioterrorism viruses created by USAMRID in the 1950s, such as the Dr. Strangelove-like aerosolizing of Western Equine Encephalitis and Venezuelan Equine Encephalitis.  Having created such monstrous infections, the U.S. government is now apparently seeking to find cures for them.

“Those modified, weaponized viruses exist—it’s true,” Julander says, “and that provides some level of anxiety. Aerosol transmission is kind of the scariest form. If there’s an intentional release of these weaponized viruses, we want to be prepared.”

For his part, Equels notes, “It seems like the government interest in Ebola dropped off with the drop in Ebola…We saw the same thing with SARS. There was a major breakthrough done at Utah and using Ampligen with other antivirals, but then the Sars problem in China resolved itself after eight to ten-thousand deaths and the investigation also stopped.  If you don’t have government support it’s almost impossible to go forward,” Equels says, adding, “More importantly, the ability to actually do any test requires support because you have to be at a bio-level safety 4 environment—we’re sort of at the mercy of NIH or DOD (Department of Defense) as to how we move forth with these highly lethal viruses.”

***

Asked if Ampligen should be considered an anti-viral or an immune stimulator, Utah State’s Julander says, “Both.”

“If you stimulate your body’s interferon pathways,” he continues, “you’ll have many different lines of anti-viral activity…the double-stranded RNA that makes up Ampligen results in all these downstream effects that have implications in various disease manifestations, including viral infections.”

Julander seems to provide the rationale for the USAMRID mice experiments with Ebola infection and Ampligen, though during the conversation, he was unaware of the USAMRID experiments.

“During an outbreak when you know a virus is causing a high level of infections, you might take a prophylactic dose that could prevent infection with the virus, but there haven’t been any clinical trials in that area (with humans). It’s easy to do in an animal model, but in a clinical setting, it’s harder to justify.”

In other words, how do you divide an African town during an Ebola outbreak and give half the citizens Ampligen and the other half placebo?

Julander and his team are not currently working with Ampligen.

“It was a little bit difficult to obtain the drug,” he says. “We were still potentially able to get Ampligen, but it was difficult, so we’ve gone in other directions.”

Julander is asked, Are scientists in contemporary times prone to think about infection last and look to environment and genes first?”

“In some ways, yes,” he says. “You don’t want to put your reputation on the line. You can get bogged down by politics.”

 

Ampligen and MS

 

In September 2015, Hemispherx reported the publication of a journal article by a group of Italian scientists from the Italian Ministry of Health and related agencies. Its authors described why Ampligen was a candidate for treatment of multiple sclerosis. “A Toll-like Receptor 3 – Agonist as Promising Candidate in Multiple Sclerosis Treatment,” published in the Journal of Clinical and Cellular Immunology, delved into how Ampligen worked and why it was likely to be helpful in multiple sclerosis and probably other diseases, including and in particular, ME.

As Equels said recently, “We know exactly how Ampligen works in ME because an Italian researcher figured it out.”

The 2015 Italian study is particularly relevant in light of Jose Montoya and Mark Davis’ widely reported paper describing the up-regulation of numerous pro-inflammatory cytokines in ME, each of them correlating with the severity of particular symptoms. The Italians pointed out that although numerous TLRs induce the body’s production of pro-inflammatory cytokines, contributing to central nervous system damage in MS, TLR3 is “capable of inhibiting the production of harmful cytokines, thereby potentially reducing MS severity.”

The authors examined the data regarding Ampligen therapy in ME, noting as others have done for decades the “many significant overlaps between MS and CFS,” including symptoms  like mental fatigue, cognitive dysfunction, disequilibrium, aphasia and head pain, as well as immune, inflammatory, oxidative and nitrosative pathway similarities.

Not only does Ampligen stop the inflammatory damage to the central nervous system, the Italians wrote, there was evidence that Ampligen “can manipulate the immune system as an antiviral therapy.”

***

‍Says Equels, "We believe there is some kind of continuing viral infection or retroviral infection in ME. There's been a viral interference with the immune system that allows this syndrome to go forward and Ampligen modulates the immune system in a way for some people solves the problem."

It's worth noting that due to FDA’s misconception of ME as a “fatigue” state, Hemispherx has been forced to measure improvement based primarily on treadmill data even though cognitive gains are probably the most treasured result reported by ME sufferers. Unlike many drugs, Ampligen breaches the blood-brain barrier, possibly vanquishing an ME-causing virus harbored in the brain. However it happens, encephalitic symptoms are relieved by Ampligen therapy. Self-reports have been verified by measurements of raised I.Q. levels and improved mental status exam outcomes after Ampligen therapy. 

Most ME responders insist that particular result is more important to them than any recovered strength. As a survivor of the Incline Village, NV epidemic told me more than thirty years ago, "Of all the things I miss the most, I miss my mind." Perhaps mental status parameters should have been FDA's end points.

Another mystery: going by Social Media accounts alone, a small but unknown number of ME patients feel better on protease inhibitors, which were developed to inhibit HIV replication.  Stanford’s Jose Montoya suggests anti-retroviral drugs have immune-modulating properties and hypothesizes that good results in ME may derive from immune modulation rather than retrovirus-killing activity. In the absence of clinical trials, which NIH repeatedly insists are “years away,” individual experimentation with sympathetic doctors will be the rule.

 

Ampligen and Cancer

 

Tremendous excitement currently attends cancer research into therapies that harness the patient’s immune system to fight cancer and its metastasis. Immune “adjuvant” therapies are being studied for their usefulness when traditional therapies fail and  in conjunction with traditional therapies.

Oncology experts have been experimenting with TLRs--including TLR3s and more specifically, Ampligen--as immune modulatory therapy for cancer for years. A 2011 article in the journal Cancer describes the then-burgeoning interest in TLRs, including Ampligen, as potential anti-cancer drugs and discusses their mode of action. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2922045/)

At the Roswell Cancer Institute in Buffalo, NY, a distinguished tumor immunology researcher and immunotherapy expert, Pawel Kalinski, is heading up clinical trials using Ampligen in colon cancer, ovarian cancer and peritoneal mesothelioma. Kalinski is also looking forward to starting trials in breast and prostate cancer and melanoma using Ampligen. The scientist and his colleagues are testing Ampligen alone and in combination with small doses of alpha interferon and Celebrex, a non-steroidal anti-inflammatory that used to treat conditions like rheumatoid arthritis.

Kalinski has been doing research on Ampligen and cancer in collaboration with Hemispherx’s since 2013. His interest lies in what he describes as the “complicated microenvironment” of tumors.

“Our target is not cancer cells themselves, which can mutate (and become resistant to treatments).”

Instead, Kalinksi’s focus has been macrophages, dendritic cells, and other players in this supportive microenvironment.

“They are highjacked by cancer--this network of cells and tissues that support cancer cells. It’s very difficult for cancer cells to survive without this support network—it’s more or less like heading to a hotel that provides them with shelter. Cancer cells by themselves are extremely fragile—if we can just take away their supports…”

In vitro, Kalinski exposed tumors to numerous TLRs in an effort to suppress the tumor support system.

“We looked at all the TLRs but realized we really liked TLR-threes” Kalinski says. “With TLR three, first we are inducing good inflammation rather than bad inflammation—second, we are selectively activating cancer tissues and sparing healthy tissues of the patient.”

Next, Kalinski discovered that TLR3s allowed him to add interferon alpha in small doses, enhancing the “good” inflammation by 100-fold and “further suppressing bad inflammation.”

After obtaining a $7.2 million grant from NIH to pursue his research, Kalinski began experimenting with specific TLR3s, including Ampligen.

“And here we were very pleasantly surprised,” Kalinksi says.  “Ampligen was giving us even better specificity—a better ratio of good inflammation to bad inflammation.  When we combined it with interferon alpha we saw a synergistic effect.  In mice, we saw this good impact on tumor tissues and we did not see toxicity.”

“Our first paper was in colon cancer,” Kalinski says, "but we’ve since published in bladder, prostate, and are working on publishing our data in ovarian cancer, breast cancer, melanoma. I do not think we have seen a single tumor that did not respond to this combination.  We’ve also seen very exciting data in head and neck cancers. I’m confident this will be applicable in most forms of cancer.”

Kalinski also describes new experiments using Ampligen to inhibit so-called “check point blockers” in cancers.

Check point blockers inhibit immune system activity against cancer and, increasingly, are being targeted with immunotherapy drugs. Kalinski notes that every major biopharma company involved in cancer research is developing its own check point blocker drugs.

His experiments in mice have proven Ampligen to be a powerful check point blocker drug with “a very high level of synergy” when combined with interferon alpha.

“(Hemispherx) is a small company,” he continues. “Using data from our studies they will be able to grow and continue providing us with our product.”

Equels and his colleagues have traveled to Kalinski's lab at the Roswell Cancer Institute in Buffalo at least twice this past summer. Their early August meeting with Canadian ME activists in August at the Toronto airport occurred the day after a rendezvous with Kalinski in Buffalo.

With no apparent sense of irony, Kalinski says, “The beneficiaries of cancer research can say ‘Thank you’ to all of the patients with ME—those patients who participated in clinical studies involving Ampligen—because we benefited from their sacrifice. Thanks to them, we now have a very well established profile of dosing—safety and dosing—which we are using in our cancer work.”

***

Last May, Hemispherx reported it had launched an Early Access Program able to accommodate fifty patients with pancreatic cancer in the Netherlands. In addition, Hemispherx planned to “commence similar therapeutic cancer programs in other major European countries that allow for early access with full governmental compensation.” In other words, governments in Europe, not ailing patients, would reimburse Hemispherx for the costs of the drug in cancer trials.

Pancreatic cancer is the fastest rising cancer, soon to surpass the incidence of breast cancer, in Europe and one of the leading causes of cancer deaths in Europe. There is so far only one established epidemiological linkage: being carried in the womb of a mother who smokes.

Joseph Horvath, a virologist, oncologist and a Hemispherx scientist, was named Deputy Chief Medical Officer of the company. He will have oversight over the pancreatic cancer efforts in Europe. 

Tom Equels was quoted in a company press release announcing the new program: “We are repurposing Ampligen as a broadly indicated immune-oncology agent. By repurposing the experimental drug from a sole focus on ME/CFS, we take full advantage of a fully developed safety profile that emerged from the approximately 100,000 doses utilized in prior clinical studies showing that Ampligen was generally well tolerated. No other TLR agonist comes into the cancer space with such a strong and positive safety profile.  Our belief in Ampligen’s potential as a therapy in oncology is based not only on its direct antitumor cell activity, but also on its immuno-modulatory activities, which may be important in providing a favorable tumor micro-environment for therapy.” 

 

 

Bonus Content: Tom Equels, Polymath?

If one were seeking an executive with the temperament, drive and capacity for strategic thinking to deliver results to Hemispherx stockholders, Equels might seem heaven sent…

 

Equels’ official involvement with Hemispherx began in 2008, when he became the company’s Secretary, a post he held until 2016. But he has held other titles at the company over the years. He was chief financial officer from 2013 to early 2016. In August 2015, he was named president. In February 2016, Equels was elevated to CEO of Hemispherx when the company’s board fired Ampligen co-inventor and long-time CEO William Carter. Carter has since retired. Perhaps not surprisingly given his relatively litigious past, Carter is suing Hemispherx.

For some years prior to his association with Hemispherx, the 65-year-old Equels has maintained a high-powered law practice in Florida. He is a litigator and the lead partner in his eponymous law firm based in Coral Gables, Florida near Miami. He lists as a reference on his resume the Archbishop Thomas Wenski of the Archdiocese of Miami. In 1995, he was awarded the Dr. Martin Luther King Jr. Community Service Award by Miami’s Southern Christian Leadership Conference. 

His numerous international clients have included the Chinese National Petroleum Corp. and Panama. He’s obtained judgements worth hundreds of millions of dollars against bad guys, including a $44 million judgement against Manuel Noriega for public money Noriega misappropriated from the Republic of Panama.

Notably, according to his resume, “On numerous occasions, Mr. Equels has been the court appointed receiver to turnaround distressed companies.”

For the last three years, his wife, attorney Laura Equels, has been president of the Equels Law Firm. During that time, Equels has turned his full attention to Hemispherx, frequently working 15 and 16 hour days and on weekends.

“I would be in a cardiac ward if I was trying to do both,” Equels says.

One thing Equels hasn’t given up is his horse farm in north central Florida, where he breeds race horses and show horses.

Equels’ father was in the Navy and for the first three years of his life, he lived near the naval station in Key West.  For most of his childhood, he lived in semi-rural western Pennsylvania near Pittsburgh. His parents kept horses.  After his freshman year in high school, the family returned to Florida when Equels’ father began work at the Kennedy Space Center.

At nineteen, in 1972, Equels served one 12-month tour of duty in Vietnam, undertaking 300 combat missions as the pilot of a cobra attack helicopter. He left the military with two Distinguished Flying Crosses, the Bronze Star, 15 Air Medals and the Purple Heart for combat actions.

“I was a little short on common sense,” Equels says of his nineteen-year-old self.

Exposed to Agent Orange during the war, today he undergoes six-month checkups at the Veterans Administration hospital for possible side effects from the toxin.

Although a layman, Equels is a quick study who grasps the scientific issues that make Ampligen a kind of providential drug with properties that may ameliorate or cure myriad severe maladies. Combine that with his ability to conceptualize strategic solutions to complex corporate problems and it’s easy to appreciate the Hemispherx board’s decision to put Equels in charge.

“Sometimes lawyers have through their training an advantage over scientists—the one thing we can do is weigh evidence,” he says. “We’re able to detect fallacy, focus on valid logical syllogisms and reach appropriate conclusions.”

 

 End of Part Four, The Fate and Fortunes of the Lazarus Drug, Last in Series

 

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