After Patient's Death, Study Shows HCV Drug Cardiotoxic in 14 of 34 Treated Patients

September 24, 2014

DURHAM, NC – The development of BMS-986094 (Bristol-Myers Squibb), a nucleotide-polymerase inhibitor for the treatment of chronic hepatitis C (HCV) infection, was terminated back in August 2012, but a new retrospective review analyzing adverse events provides an in-depth look at the cardiotoxicity associated with the investigational agent.

The findings may have profound implications for other drugs in late-stage testing or others approved for use. Investigators say understanding the mechanisms of cardiac dysfunction and its relevance to other agents will require more study.

Development of BMS-986094 was stopped after a 25-year-old male treated with 200-mg dose experienced rapidly progressive heart failure and died. The patient had been hospitalized with shortness of breath and was found to have a left ventricular ejection fraction (LVEF) <10%.

Now, as part of a retrospective review of the phase 2 study that included the index death, researchers report that 14 of 34 patients treated with BMS-986094 had some evidence of cardiac dysfunction.

The review was published online September 24, 2014 in Hepatology.

In total, six patients had severe LV dysfunction (LVEF <30%) and eight had moderate LV dysfunction (LVEF 30%-50%) in one or more evaluations in the six months following drug discontinuation.

"These are blockbuster drugs that all the pharmaceutical companies are trying to develop," lead investigator Dr Tariq Ahmad (Duke University Medical Center, Durham, NC) told heartwire . "If it weren't for the index case, it is possible that we might not have picked up on the cardiotoxicity."

BMS-986094 is a direct-acting antiviral (DAA) agent and some drugs in this class have received breakthrough-therapy status by the US Food and Drug Administration (FDA). Sofosbuvir (Solvadi, Gilead), which grabbed headlines for its $1000-per-pill price tag, is also a nucleotide-polymerase inhibitor. Given the massive potential in HCV therapeutics, Bristol-Myers Squibb paid $2.5 billion to buy Inhibitex, the company that began development on the drug that was to become BMS-986094.

Following the death of the 25-year-old patient, the FDA requested an official analysis of all patients who had been treated with BMS-986094. The company reached out to the Duke Clinical Research Institute to help with a clinical analysis of all exposed patients. Ahmad praised Bristol-Myers Squibb because it surrendered all clinical data it had on treated patients, "which is something that's unprecedented for a pharmaceutical company, because it's a major development area for them."

Exposure to BMS-986094

Of the 20 patients who received 200 mg of BMS-986094, four had severe systolic dysfunction and seven had moderate dysfunction. For the nine patients who received the 100-mg dose, two developed severe systolic dysfunction and one had moderate impairment. No patients treated with the 50-mg dose developed systolic dysfunction. Patients with cardiac dysfunction were treated with the drug longer, but drug duration in this early-stage trial ranged only from one to six weeks.

"There were quite a few people who developed [reduced systolic function] once we started looking for it," said Ahmad. "A lot of these patients didn't have any symptoms. When we did an ultrasound of their heart, they had fairly profound cardiac dysfunction, but when we looked at some of the other things we think about with heart failure, like troponin or [brain natriuretic peptide] BNP levels, they weren't too abnormal."

The researchers also analyzed the ECGs of patients with evidence of LV dysfunction and identified three main abnormalities: ST depressions, T-wave inversions, or loss of T-wave amplitude.

"The ECGs showed some abnormalities, but these are things you'd pick up after the fact," said Ahmad. "If you showed me an ECG with some T-wave or ST changes, I might not make that much of it, but in hindsight, when we looked at these people with very low ejection fractions, they did have some abnormalities. But it was nothing that would jump out [at you]."

BMS-986094 also had an adverse impact on the kidney, with most of the patients having increases in serum creatinine levels regardless of the degree of systolic dysfunction. The patient who died developed acute renal failure, while another required temporary hemodialysis. The serum creatinine levels of all patients improved once the drug was stopped.

Adverse Signs Diminished When Drug Stopped

Overall, four of the six patients with severe LV systolic dysfunction had improved LVEFs after drug discontinuation, as did six of the eight individuals with moderate dysfunction. Of the 14 patients with impaired cardiac function, the last available measurement of LVEF in seven individuals was >50%.

The researchers included Dr Jeffrey Saffitz (Beth Israel Deaconess Medical Center, Boston, MA), a world expert in cardiac pathology, and he analyzed the explanted heart of the patient who died. There was an elongation and thinning of the ventricular cells, but limited necrosis and an insufficient amount of myocarditis to have caused ventricular dysfunction. As of now, nobody knows why BMS-986094 caused heart failure.

To heartwire , Ahmad said their review also showed that patients who appear to be most at risk for developing systolic dysfunction were individuals with cardiovascular disease risk factors, such as hypertension or diabetes. These are the type of patients who are excluded from clinical trials and who would be at risk when the drugs get used in the general population of HCV patients. Also, HCV trials are smaller than cardiology studies, so it's possible the adverse cardiac effects of other nucleotide-polymerase inhibitors might simply be undetected at this point, said Ahmad.

Ahmad said the findings are important, particularly for their inability to use traditional methods to gauge myocardial dysfunction, other than an ultrasound, because of how widespread the incidence of HCV is and how many patients could potentially be treated with these drugs. "If it hadn't been for the unfortunate case of that gentleman dying, some of these patients might be walking around with ejection fractions of 20%, and nobody would know it," he said.

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