In the late 1990’s, Dr. Hostetler was approached by program officials from the Antiviral Branch of the National Institute on Allergy and Infectious Diseases for help in improving an antiviral drug called cidofovir.
Cidofovir had been sold by Gilead Biosciences as an intravenously administered antiviral drug as Vistide® and was approved to treat cytomegalovirus infections of the eye, called CMV retinitis.
The
majority of the population is already infected with CMV but it only becomes a problem when the immune system is suppressed, such as in HIV/AIDS or with the immunosuppression regimen used for a hematopoietic bone marrow transplant.
But cidofovir has activity against all five families of double-stranded DNA virus that cause human disease and death –
including smallpox variola virus, herpesviruses, polyomaviruses, and adenovirus, the one currently afflicting young Joshua Hardy. (and now ebola)
As part of our nation’s biodefense program, cidofovir emerged as one of the best drugs to use in the event of a terrorist attack with the now-eradicated smallpox, or variola virus (smallpox).
But a drug that would need to be stockpiled and then quickly distributed requires some special characteristics. It should be active when taken
orally as a pill or capsule, have few side effects, be stable under long storage conditions, and have effectiveness even in people who might have faulty immune systems.
Among the problems with cidofovir is that 1) it couldn’t be given by mouth and had to be injected continuously to be effective and 2) it could damage the kidneys if not given under careful medical supervision and the use of other drugs. But it was the best choice we had at the time because it worked against many types of viruses that could be used as bioterrorism agents.
Hostetler says that NIAID officials were aware of his previous work on making antiviral nucleoside drugs more orally bioavailable to the body. If he was willing to use some of his chemical know-how to make cidofovir a better agent against smallpox, they were willing to give his laboratory (ONLY) $100,000 to try.
(not the hundreds of millions given to Teckmira, and the zMapp people)
What’s the difference between cidofovir and CMX001?
Dr. Hostetler is a medical doctor – a clinical endocrinologist by training – but was fortunate to have in his lab a “card-carrying” synthetic chemist named Jim Beadle. With Jim and others in the group, the Hostetler team put different lengths of fatty acids, or lipids, onto cidofovir. The idea was that the special nature of the lipid would be recognized by the intestine and other cells as normal, thereby tagging the drug for absorption into the bloodstream.
The very first cidofovir relative that they made was CMX001 – the lipid attached to it resembled a natural one called lysophosphatidylcholine, or LPC. This makes CMX001 what’s called a prodrug of cidofovir: After sneaking into cells, the lipid would be clipped off and liberate cidofovir to stop viruses form reproducing in other cells.
Well, the approach worked – the lipid attachment had two immediate benefits. First, it increased the antiviral effect by 40 to 400 times that of cidofovir. Second, oral CMX001 was taken up into the bloodstream of animals – and later, humans –
more than 50 times better than cidofovir.
But didn’t that just make CMX001 even more toxic than cidofovir to the kidney or our other cells?
Hostetler noted that another advantage of adding this lipid was that it neutralized a chemical charge on the cidofovir molecule that caused the drug to concentrate in the kidney via a pump that we normally use to rid ourselves of certain acidic substances. Since CMX001 wasn’t used by this pump, it
didn’t seem to concentrate in the kidney like cidofovir does. That’s a good thing.
But researchers don’t fully understand why getting more of the drug into all of our cells doesn’t cause other problems for CMX001. The cidofovir that’s liberated from CMX001 gets activated by the cell to a form that can inhibit DNA synthesis. One might think that would attack any rapidly growing cell in the body, such as bone marrow cells. But earlier studies suggest that cidofovir is eight to 600 times better at inhibiting viral DNA polymerases – the enzymes that replicate the virus’s DNA – than the DNA polymerases of our human cells.
So that’s one of the major reasons that CMX001 is still being investigated for its safety profile in FDA-required clinical studies. And that’s where people should still look cautiously at CMX001 in that it may not be “a miracle cure” for every patient.
Columbia University virologist, Dr. Vincent Racaniello addressed these concerns in an email message today saying, “The original drug [cidofovir] is toxic because it inhibits cell DNA synthesis; since the modified compound more effectively gets into cells, it should be more toxic. However I understand it might have a better safety profile which would not be my initial prediction.”
Hostetler also didn’t have a complete answer, although he noted that the lab and David Evans at Edmonton looked at how the drug gets incorporated into the virus’s DNA versus human DNA. Perhaps the viral DNA damage cannot be repaired as easily as the human DNA damage. We do know that cidofovir (in its activated, diphosphate form) does inhibit CMV’s viral DNA polymerase about eight times more effectively than human DNA polymerase alpha. I’m certain that researchers will have to come back to this question.
What did Dr. Hostetler do with CMX001 next?
Hostetler said that his institution, the University of California at San Diego, sponsored their patent application and attempted to outlicense the compound to 30 or so companies without success. Dr. Hostetler established Chimerix to continue developing this drug and other lipid-antiviral drug therapies.
Dr. Hostetler also credits Dr. Earl Kern, a now retired professor from the University of Alabama at Birmingham, for doing many of the first animal experiments with this and other related compounds. Dr. Kern was supported by NIAID to run their Collaborative Antiviral Drug Testing Program.
Kern’s lab also discovered the antiviral activity of CMX001 against adenovirus.
Other major collaborators were Dr. Mark Buller at the Saint Louis University Health Sciences Center and Dr. John Huggins at
USAMRIID.
While CMX001 has been Chimerix’s baby up through this day, Chimerix granted a worldwide license to Merck for CMX157, the anti-HIV drug tenofovir conjugated to the same lipid used on CMX001.
So why isn’t CMX001 already approved by the FDA?
Well, so far, it’s only been fully tested up to a Phase 2 trial for safety and effectiveness in patients with CMV infections. The results of that study were published in the New England Journal of Medicine in September, 2013.
And across all clinical work with the drug, just
over 900 people have ever received it.
In the NEJM study, 230 bone marrow transplant patients were randomized to a placebo group or one of five different CMX001 dose groups. The drug significantly reduced CMV events at one of the dose levels and prevented the virus from making its DNA at several of the dose levels. The dose-limiting toxicity was diarrhea that was believed due to gastrointestinal graft-versus-host-disease and could be managed by reducing the dose.
But – here’s where drug regulators and drug company investigators worry most – these patients are already seriously ill. Eight percent of the patients in the placebo group did not survive (5 of 59). And in all but one of the CMX001 groups, eight to 13 percent of the patients did not survive despite the positive outcomes in many of the others.
Subsequent studies by Chimerix have been reported at clinical research meetings but not yet published. A February 28, 2014 press release describes their presentations on trials of CMX001 in pediatric and adult immunocompromised patients with asymptomatic adenovirus infections and another on overall safety in pediatric populations.
The work from the New England Journal of Medicine paper has now fueled a 40-center, Phase 3 trial, called SUPPRESS, in which prevention of CMV infections in 450 hematopoietic cell transplant patients will be studied. The company states, “Data from SUPPRESS are anticipated in mid-2015 and, if positive, may support Accelerated Approval of brincidofovir for the prevention of CMV infection.”
So, what’s the harm of making CMX001 available to Joshua Hardy?
We know less about its effectiveness against adenovirus than CMV. But the trial Chimerix is now doing is to assess precisely that: It’s an open-label study of 20 patients with adenoviral infection. No placebo group. We will certainly learn more about treating adenovirus because of the determination of the Hardy family and the cooperation of the FDA with Chimerix.
As a parent of a child slightly older than Josh, my stomach churns to even think about the possibilities with such a seriously ill boy.
* * *
But will the outcome of his specific case influence how the public views this drug and, ultimately, regulatory review committees deciding on its approval for larger populations?
In a presentation Chimerix officials made at a JP Morgan conference in January, they noted that the initial market for brincidofovir would be for patients with either hematopoietic cell transplants or solid organ transplants. In the US, that’s a total of
50,000 people per year, plus
another 55,000 patients in the European Union.
On one hand, you could argue that the company wants to be careful with CMX001 to make sure it gets to that market. More altruistically, one could also fear that a high-profile treatment failure with CMX001 might compromise the ultimate accessibility of the drug to these 105,000 future patients, annually.
But I’m thinking that the stakes riding on CMX001 are even greater.
Remember long back to the beginning of this piece: The original reason that
CMX001 was developed was as a potential bioterrorism agent that could be stockpiled and widely-distributed in the event of a worst case scenario.
While some might not think about the gravity of such a scenario today, put yourself back in the mindset immediately following the 2001 U.S. terrorist attacks.
If you’re of the scientific mind that CMX001 might be essential for national security, public perception of its safety and efficacy might transcend that of any of the most gripping and heart-wrenching personal stories.
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