Sunday, August 26, 2012

Hepatitis C And Clinical Trials

Good evening folks,

As most of you know, on Thursday Bristol-Myers Squibb announced they were discontinuing a mid-stage study of the experimental nucleotide polymerase inhibitor BMS-986094 for the treatment of hepatitis C.

On August 1, 2012 the company initially suspended the phase II trial due to a patient who experienced heart failure which now has resulted in death. There have been nine patients hospitalized and two remained hospitalized. As of yet, Bristol-Myers has not established a definitive relation between BMS-986094 and heart and kidney toxicity.

The press release is available here.

Friday - August 24, 2012, Janet Schaefer Vella, a nurse from Texas sued Bristol-Myers and Alamo Medical Research allegedly over heart problems after taking part in the hepatitis C BMS-986094 clinical trial in early July. A week into the trial she underwent a diagnostic test which indicated possible heart problems, now Ms. Vella is need of a heart transplant, read the complete article written by John MacCormack online here.

Recently IDX184 which is another experimental nucleotide polymerase inhibitor from Idenix Pharmaceuticals, was put on partial hold because of the potential for heart damage.

On Aug 27 Idenix placed IDX19368 on clinical hold, also a nucleotide polymerase inhibitor - (no patients have been exposed to IDX19368). The FDA informed Idenix of concerns related to serious heart issues seen in Bristol-Myers nucleotide polymerase inhibitor BMS-986094.

The FDA verbally informed Idenix that it placed IDX19368 on clinical hold due to concerns related to the serious cardiac-related adverse events reported for HCV patients treated with BMS-986094, a nucleotide polymerase inhibitor previously under development by Bristol-Myers Squibb Company.
To date, no patients have been exposed to IDX19368.
"Based on our discussions with the FDA, we understand the clinical hold is a precautionary decision made by the FDA in light of the adverse events seen with BMS-986094," said Ron Renaud, President and CEO.
"Both IDX184 and IDX19368 fall into the same broader class of NS5B inhibitors, and share the same active metabolite as BMS-986094. However, there are many attributes of our compounds, particularly the prodrug approach, that we believe favorably differentiate the toxicity profiles from that of BMS-986094. We recently learned that Bristol-Myers Squibb has agreed to share relevant information on BMS-986094 with us and hope this helps us to resolve this issue quickly."

The Loss Of A Patient

Great sadness has been expressed throughout the HCV community for the recent loss and hospitalized patients who participated in the BMS-986094 clinical trial. I offer my sincere condolences to the family and concern for all the patients involved.

Hepatitis C And Clinical Trials

When diagnosed with a serious chronic illness what ensues is a life met with uncertainty, riddled with mental and emotional challenges. Stressful medical decisions must be made as day-to-day life continues.

Battling this virus isn't for the weak, clinical trials use powerful medications, involving a bit of courage to administer, and a leap of blind faith to use.

This unfortunate death is a shocking reminder of the rare, but potential risk to all patients who volunteer to test new hepatitis C agents.
Entering into a clinical trial is like walking into a dimly lit room, small milestones bring a glimmer of light, but the room remains dark until the final results are in. 

We saw new and additional side effects with protease inhibitors telaprevir and boceprevir, we now have nucleotide polymerase inhibitors and obviously new serious concerns. Until we fully understand how or why this death happened, apprehension and concern remains for all the patients who took part in the BMS-986094 clinical trial.

The Doctor And Patient

Over the last 50 years the role between a doctor and patient has changed, now patients make the final decision regarding medical care or treatment. This has become an overwhelming process, especially for people living with a chronic and serious disease. In a 2010 study, at the University of Chicago, researchers found that two out of three patients would rather their doctor make those final decisions, although, only 14% of patients were assertive enough to speak up when they disagreed with the doctors recommendation.

Have you ever felt intimated by a doctor? Have you found yourself too polite or too scared to disagree with a new test or treatment advice?  Even when symptoms are present, explaining them becomes awkward, who wants to complain? For instance, how many times have you made an appointment because you're feeling pretty bad, although, when the doctor enters the room asking how you are, you quickly reply with - I'm fine thank you.

 Speak Up

For people participating in a clinical trial strong communication about any side effects is essential. Gone are those days of feeling intimated, bets are all off when you enter into a clinical trial. By speaking up early, the risk for serious side effects are lowered, plus an early assessment will help to ensure your safety.

If you are considering a clinical trial check out this guide from HCV Advocate first -
Guide to Understanding Clinical Trials and Medical Research in Hepatitis C

The Good News

With the help of  sites like HCV Advocate, and NATAP, patients are now treatment savvy, the day of the naive patient is slowly changing.

 Bristol-Myers and Idenix

With the enormous success of past and current hepatitis C clinical trials a false sense of security may have fallen upon the HCV community. Never did anyone anticipate a death, or toxicity issues as serious as those alleged with BMS-986094 or IDX184.

A few days ago Nature published an article reporting on the recent BMS trial. The excerpt below offers a quick look at a few HCV drugs.

For many years, the only available treatment for HCV was a combination of interferon-α and ribavirin. The interferon acted to boost the patient’s immune system, while ribavirin inhibited virus replication. A modified version of interferon-α, pegylated-interferon-α, which remains in patients’ bodies for longer, was introduced in 2001. But the treatment had severe side effects, including anaemia, severe depression and flu-like symptoms, and was not effective in all patients.
Last year, two new drugs, boceprevir and telaprevir were approved by the US Food and Drug Administration (FDA). Both of these drugs target HCV’s NS3-4A protease, which the virus needs to generate functional proteins. Both drugs, however, do have side-effects. Because they are taken in combination with interferon-α and ribavirin to prevent the emergence of resistance, the side effects of the original treatment regimen are still a problem.
Telaprevir was recently relabelled to take into account its potential for causing cardiac arrhythmias (FDA update) while boceprevir has been found to interact with HIV protease inhibitors, so co-administration is not recommended (FDA update).
Pharmaceutical companies are trying to find new drugs that are more effective and have fewer side effects. In addition to protease inhibitors, other potential drugs (including BMS-986094) act on the NS5B RNA polymerase enzyme, preventing amplification of viral RNA. 
Another class of drugs aim to stop viruses penetrating the host’s cells (see ‘New drug targets raise hopes for hepatitis C cure’).
Idenix Pharmaceuticals had a drug in trial that acted in a similar way as BMS-986094. That trial has now been put on partial hold by the FDA as a result of the BMS trial failure (see press release).  There may still be hope for other NS5B inhibitors in the pipeline, as not all of them share the same mechanism of action as BMS-986094. Gilead has an NS5B inhibitor in phase 3 trials, and Vertex is working on a similar drug.

The Pipeline

Additional information on new hepatitis C drugs can be found in a recent article written by Tracy Swan and Karyn Kaplan. The article was included in the "2012 Pipeline Report" by TAG.  The report includes the following topics: HCV drug resistance, DAA drug-drug interactions, nucleosides and nucleotide polymerase inhibitors, HCV protease inhibitors, and the next generation of drugs.

The report: Hepatitis C Drug Development Goes from Pony Ride to Rocket Launch

NATAP has just added these updates-
New HCV Drugs: non nucleoside polymerase inhibitors 
HCV Update Selected Highlights: key new HCV drugs, timelines & recent news developments 

Another quick resource for information is: The Hepatitis C New Drug Pipeline

Fortunately for me, my trial experience ended with a cure.  May your own experience be carefully researched, just as successful, and extremely safe.

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