By Katrina S.S.

Second of two parts

Clinical trials and the anti-dengue cocktail

But the bigger story is about the anti-dengue cocktail that is ActRx Triact, the clinical trials for which were started in 2012, as ordered by Dr. Ona. Acting Health Secretary Janette Garin stopped the clinical trials the moment she stepped in, declaring that it had “no legal basis” as it had yet to be approved by the Food and Drug Administration (FDA). At that point the Philippine Council for Health Research and Development (PCHRD) had questioned the soundness of the science behind the clinical trials. Since then the Philippine Medical Association (PMA), the Philippine Society for Microbiology and Infectious Diseases (PSMID), and members of the Philippine College of Physicians (PCP) have thrown their support behind Garin’s decision to stop the trials. These organizations question the science and ethics behind the clinical trials, and assert the dangers it poses to the public’s health. Dr. Sylvia Claudio has called the science behind the clinical trials “crap,” saying that it is “a medical horror story.”

Read on…

By G. U. Stuart, MD

I became aware of the ActRx TriAct controversy only after the the study was pulled or suspended by the powers that be. It wasn’t clear why, and it still isn’t. There was no outright allegation that the researchers tweaked data or fabricated results—that would certainly have justified killing the study. Instead, the DOH and a complicit media have been spewing out allegations, discrediting, questioning the validity of the study and the verity of its conclusions. Non-compliance and deficiency issues? Were there application issues? Conditions that were not met? Design flaws? Ethical issues? Monitoring failures? Statistical or methodological problems? Why was it pulled only after the Phase III results were released? Is it all “politics,” as some suggest?  In the absence of clear evidence of a bad study, I chose to give the ActRx TriAct cocktail the benefit of the doubt.

This is not a defense of Ona. I don’t know Ona from Adam. This is a defense of the public’s right to know, of the right of patients to access a drug that could potentially prevent deaths from a disease that claims thousands of fatalities a year.

There continues to be a dearth of supportive or explanatory documents relating to the ActRx TriAct phase III clinical trial study. My search always dead-ends at the ActRx website. Even if the complete study were available, I would not have the acumen to comb through the scientific minutiae. What is urgently needed is an independent review board to look at the study—to document its faults and justify the suspension, or to disprove the criticisms and dismiss the doubts.

The criticisms have been mostly negative—that the studies did not go through the usual preclinical trials or were dubiously sped through some clinical trial phases; that it is monotherapy treatment because it uses two artemisinin derivatives; that berberine, a plant derivative, should not be used as a third component; that berberine, for lack of scientific studies, was not approved by the FDA; that experts say the combination of the three drugs poses sides effects and that their use in clinical trials poses a “clear and present danger” to public health; that there is no legal basis for the study; and, horrors, that no other studies on ActRx TriaAct have been done or are being conducted elsewhere in the world.

THE CLINICAL TRIALS

The main components of ActRx TriAct are artemether and artesunate, drugs long ago studied and approved for use in malaria. Both have gone through the necessary preclinical studies. When repurposing or repositioning drugs—finding new uses for old drugs—the studies are usually allowed to skip some of the phases, certainly, preclinical trials that are done in animals to test for toxicity and pharmacokinetics. Possibly, too, it was fast-tracked and sped through Phase 0 and Phase 1 studies, getting to clinical trials faster.

Drug Repurposing or Repositioning: Drug repositioning is the process whereby a drug that is patented for treating a particular disease is discovered to be useful in treating a second disease, and developed further for that purpose. Simply said, it is a process of finding new use for an existing drug. As mentioned above, this is the case with artemether and artesunate—old drugs already approved for malaria, already tested in humans with known information on pharmacology, formulation and potential toxicity—now being tested as potential dengue treatment, allowing the new therapy to be ready for clinical trials early, hoping for a speedy review and integration into health care. Hopefully, this answers PCHRD’s concern of “deficiency”—that the study lacks scientific justification for use of artemether and artesunate for dengue therapy.

Cocktail Components

• Artesunate: Oral artesunate was probably chosen for ease of administration, with a longer half-life (20-45 minutes) and higher bioavailability of DHA, dihydroartemisnin, its active metabolite (>80%), half life of 0.5 to 1.5 hours—values not achieved by intramuscular and intravenous administration, and without the ease of oral administration.

• Artemether: Artemether has been available in the tablet, capsule, and injectable formulations. A study on sublingual spray formulation showed twice the bioavailability—1.7 to 2.2 times more absorption as a sublingual spray compared to oral tablet formulation. The sublingual route also bypasses the first-pass liver metabolism.

• Berberine: Berberine is an alkaloid extracted from various plants. (See below). It has been studied extensively. Its mechanisms of action are as varied as the many conditions it is used as supplement for.

Patent Pending

There is a patent pending on the ActRx TriAct cocktail, a two-day regimen, composed of artemether sublingual spray, artesunate and berberine tablets. Possibly, the combination use of artemether with artesunate, where the drugs might act in complementary or synergistic manner, together with the addition of berberine, is a way to get exclusivity—via an MoU (method of use) patent protection—for old drugs in a new formulation with a unique sublingual delivery system for artemether.

MONOTHERAPY

There is much criticism that using derivatives from the same plant constitutes monotherapy. True, both artemether and artesunate are derivatives of artemisinin, a peroxide lactone isolated from the antimalarial plant, Artemesia annua (sweet wormwood). The plant has been used in many traditional systems of medicine, for at least 2000 years in China. Artemether is a methyl ester derivative, while artesunate is a semisynthetic analogue derivative. Although both are artemisinin derivatives—artemether, sublingually; artesunate, orally—they may differ in their potencies with the peroxide mechanisms, half life and elimination time. Perhaps, the combination was based on peaks, half-life and elimination time, that give a synergistic effect, or delay or prevent resistance? This is a personal conjecture. I would like to know the ActRx Triact researchers’ rationale for the use of the combination.

BERBERINE and PLANTS

• The inclusion of berberine, a plant material, has also raised the hackles of some. But the landscape of medical therapies is rich with plant-derived pharmaceuticals. Like artemisinin, which is derived from the antimalarial plant Artemesia annua, berberine,  the third component of the Actrx Triact cocktail, is an isoquinoline alkaloid of protoberberine, which is found in many plants and has been used in many traditional medical systems for hundreds of years.

• In search of an herbal medicinal source for dengue cure, a 2011 study investigated the in-vitro anti-dengue activity of ten Thai medicinal plants; four plants viz. Rhizophora aciculate, Flagellaria india, Cladogynos orientalis, and Houttuynia cordite, showed significant effect on the dengue virus in-vitro and suggested potential sources for the development of an anti-DENV drug. Herbal Antivirals: Natural Remedies for Emerging & Resistant Viral Infections by Stephen Harrod Buhner lists 29 plants that have shown anti-dengue activity; four, maybe more, of them yield berberine.  Other reviews list berberine-bearing plants used in botanical medical practice: Goldenseal (Hydrastis canadensis), Oregon grape (Berberis aquifolium) Barberry (Berberia vulgarism) and Chinese Goldthread (Coptis chinensis), and two berberine-containing plants popular in Chinese medicine, Phellodendron chinense and Phellodendron amurese.

LACK OF SCIENTIFIC STUDIES ON BERBERINE?

“For lack of scientific studies on berberine, the Food and Drug Administration did not give it certification for sale in the Philippines.” Huh? Berberine has been much studied—over a third of the 2,800 studies on berberine listed on PubMed, were published in the last 5 years. The studies suggest a wide range of clinical applications—from cholesterol lowering, anti-inflammatory, antimicrobial, anti-diabetic effects to benefits for cardiovascular and neurodegenerative afflictions.

• Berbrine is an over-the-counter supplement, considered by some studies as a supplement with some effects comparable to pharmaceuticals. Its standard dose is 900-2000 mg a day in 3 or 4 divided doses. A recent study reported a concern for long-term use and a tendency to accumulate in the CNS with potential neurotoxicity. What dosages are used and what risks are entailed in a two-dose ActRx TriAct cocktail protocol should be answered by the ActRx TriAct researchers.

SIDE EFFECTS? CLEAR AND PRESENT DANGER TO PUBLIC HEALTH?

What side effects are the “experts” attributing to the ActRx TriAct treatment? Artemether and artesunate are two drugs extensively studied and used in the treatment of malaria. Berberine is a supplement in use for hundreds of years in many traditional systems, with a known good safety profile, especially for short-term use. “Clear and present danger ” to public health? Huh?

NO LEGAL BASIS FOR THE STUDY

The DOH says the controversial ActRx TriAct has not been registered with the FDA, and that the study which started in 2012 should not have happened in the first place. Is this true? By whose authority and edict was it allowed to continue? Why did they wait so long before terminating it? Were people threatened by the reported beneficial study results? What political power plays are at work? Does the non-registration mistake totally nullify the study?

THE RIGHT TO PIONEER RESEARCH

Criticism was also made that no other studies on ActRx TriAct have been done or is being done elsewhere in the world. Does the criticism imply that our scientists cannot or should not pursue original investigative studies? That is an insult, an affront, to the Philippine scientific research community.

The criticisms have remained unanswered. I am surprised and dismayed by the silence from Ona’s side, from the doctors who were involved with the actual clinical study, and from others somewhere out there in the medical community who must have a dissenting opinion to what seems to be one-sided multiple rants against Ona’s work.

Also, let us hear from those on the Garin side, who according to a post by Jarius Bondoc, “were pacified by Garin’s move—regulators, researchers, ethicists, and field doctors who, documents show, resist the remedy.” It would be most enlightening to hear from this august array of professionals what aspects of the study or remedy they resisted and why.

The Promise of a Vaccine Tomorrow, The Need for a Treatment Today

Dengue vaccine trials are being done. The experimental Dengue vaccine developed by Sanofi showed to be about 60% effective in the second large clinical trial, a slight improvement from the 56.5 percent reduction in the first trial. The scientific adviser to the Dengue Vaccine Initiative admits it’s not anywhere close to the 90s they hoped for. The vaccine was found to be more effective in people previously exposed to dengue. There are four serotypes, with lifelong immunity gained only for the specific infecting serotype—making the vaccine useful in endemic areas where people are often exposed more than once. Also, while providing 60-90% efficacy against dengue virus 1, 3, and 4, efficacy was lacking (42%) against DENV serotype 2 which accounts for almost 60% of all virologically confirmed dengue episodes. Also, in the first trial, the vaccine was found less effective in younger children, the population most vulnerable to the disease.  The early availability of the vaccine will also be limited. No matter these early limitations, a vaccine that may reduce the number of cases by half and hospitalizations by 80 percent represents a big advance.  Sanofi plans to apply for approvals in the first quarter of 2015, with sales in the 4th quarter in priority countries of Mexico, Brazil and Columbia, and possibly Singapore and Malaysia.

While the vaccine shows promise, there will still be a significant number of those vaccinated who will still contract dengue. Also, there will be many who will refuse vaccination, and many who will not be reached by vaccination programs. The WHO estimates that 2.5 billion people are at risk annually for dengue infections. Between 50 million and 100 million contract the disease each year; newer estimates suggest a number closer to 400 million. Thousands of deaths are still predictable.

Drug therapy is needed. For now there is none. The Actrx Triact cocktail presents as a potential anti-dengue drug therapy for that group of patients diagnosed with severe dengue where the risk of fatalities are high. And while the WHO has warned of the dangers of drug resistance in areas where both malaria and dengue are coendemic, there are 23 designated malaria-free provinces in the Philippines. They present testing grounds to evaluate the efficacy of the anti-dengue therapy: Cebu City, designated malaria free, topped the list with 3,081 cases of dengue with 12 deaths; Iloilo, also designated malaria-free, reported a 71% surge in dengue cases. Aklan, also malaria-free, has seen an increase of 75%, up 1,340 cases compared to 763 last year. The data collected from these malaria-free testing grounds can potentially lay the groundwork for more widespread testing and use of the cocktail.

The conflicts surrounding ActRx TriAct should be urgently resolved. Politics should be pushed aside. Let us hear from the experts, the field doctors, and ethicists, without masks of anonymity. I have heard that people in the know are afraid to talk. I have been forewarned, the issue is dead. That the powers that be have already decided.

I hope not. Yet that is what I sense from reading the press releases—a demolition stonewalling blackballing campaign. A rain of criticisms, charges and insinuations—everthing from A to Y. But there’s the Z question: Does the drug work?

It is too important a drug to die a political death. Either debunk it or release it back into testing and use. And until or unless the treatment benefit is utterly and completely debunked, dengue patients who are not involved in the clinical trials but are seriously ill should be allowed the ActRx TriAct cocktail treatment by access through compassionate use.

my son joel was going on 4 in 1977 when he came home from pre-school running a slight fever. lagnat-laki lang, i hoped, and started giving him tempra.  when the fever kept coming back and going up, i took him to his pediatrician who said to continue with the meds plus lots of water. but over the next day the fever was up to 39.5, and creeping closer and closer to 40; he was barely eating, and mostly throwing up the medicine and the little food i could force, beg, him to swallow.  freaking out, we brought him to Lourdes Hospital’s ER where the residents took one look at his inner arm, near the joint…pointed to tiny red dots i hadn’t noticed (or maybe they had just come out), and at once proceeded to draw blood for lab tests while also inserting an IV needle.  he struggled and cried and screamed, of course; i could only help hold him down.  H-fever, i.e, hemorrhagic fever, also known as dengue, was the diagnosis.  he needed transfusions, 3 bags of platelets.  it was nerve-wracking.  what if we didn’t bring him in when we did?

later, whenever i would hear news of sudden deaths by dengue, i’d remember, always, how swiftly the virus multiplies to a critical point and, lacking medical intervention, simply takes over and kills.  so, truly, the october 20 news report of a “breakthrough drug” vs. dengue, endorsed by dr. enrique ona, the DOH secretary, no less, was fantastic news for public health.

Ona said that “on March 15, Preferred and Proven Therapies Inc., ActRx Foundation and ActRx Operational Group, together with PITAHC and San Lazaro Hospital for Infectious Diseases medical research team, presented a report showing the remarkable success of the clinical trials conducted at San Lazaro Hospital on ActRx TriAct, a patented herbal-based combination of Artesunate, Berberine and Artemether as therapy treatment for dengue.”

alas, just eight (8) days after that october 20 public announcement, dr. ona went on leave, ostensibly over a pneumonia-vaccine controversy.  but suddenly there were also reports of dr. ona being in trouble over the anti-dengue drug.  i sent links on the subject to my brother butch for a medical opinion; a few days later he sent me this: Dengue, Drugs, Death and Politics, which i posted in my november 30 entry, in defense of dr. ona.

to our surprise, comments were largely negative, basically harping on the danger posed to public health by ona’s endorsement of a mysterious drug of unproven safety and efficacy.  since then, we have been combing the Web for additional information, looking for something from the ona camp that would debunk the allegations, point by point.  instead we kept coming up against blank walls, and even more questions than answers.

consider, for instance, this timeline: september 24, ona issued DOH order no. 2014-016 authorizing the use of ActRx TriAct in the treatment of dengue cases. however, we do not hear about this wonderful news until almost a month later, on october 20.  *bakit kaya*  and then just 8 days later, on october 28 he goes on a month-long leave; dr. janet garin is named acting DOH secretary.  november 14, garin suspends the anti-dengue drug. however, we do not hear about this “welcome”news until December 1.  *bakit kaya*  and then december 2, from right field, came news of a promising dengue vaccine, aha!  can this be WHY the demolition job on ona and ActRx TriAct?  but we could use both a vaccine AND an anti-dengue therapy treatment!

and we sure could use a critical and perspicacious media who would know to ask around and ferret out the facts vs. what seems to be black propaganda meant to stop ActRx TriAct in its tracks.  like, i’ve been waiting to read something from senator heherson alvarez’s hexilon (CEO of Preferred and Proven Therapies, Inc.) that would elaborate on the success story of this anti-dengue treatment beyond the few soundbites in a tv news report.  where are our investigative journalists when we need them?

Coming soon: IN DEFENSE OF THE ANTI-DENGUE COCKTAIL by G. U. Stuart, MD