Setbacks in HCV Drug Development Highlight Uncertainties in Treat or Wait Decisions
Clinical Care Options
Graham R. Foster FRCP, PhD - 10/22/2012
At the opera, the show isn’t over until the large lady begins her aria. In drug development, licensing and effective treatment of thousands of patients define a successful launch. Following recent problems with emerging drugs for HCV, I am reminded of the difficulties of turning chemicals into drugs and the importance of waiting until the development cycle is complete before claiming success.
I first sensed trouble in April 2012 when it was announced that trials of alisporivir were being suspended. Over 1800 patients had received this cyclophilin antagonist, with impressive virologic responses (Capsule Summary). A phase III trial was moving forward, and I was surprised to learn that a patient receiving alisporivir had died of pancreatitis. The US Food and Drug Administration noted a possible association of pancreatitis with alisporivir and instituted a “clinical hold.” A full evaluation of the alisporivir data set is now under way, and we wait to see whether any possible risks can be managed and whether it is safe to resume testing. Worse news followed in August when unexpected cardiac toxicity was seen with BMS-986094, a nucleotide analogue polymerase inhibitor, leading to the death of a patient and suspension of clinical trials. This nucleotide was just one of a molecular family, and concerns that cardiotoxicity may be a class effect led to studies with related drugs (such as a compound in phase IIb development, IDX184) being placed on full or partial clinical hold. The suspension of this drug family leaves only 1 nucleotide at an advanced stage of development (sofosbuvir, previously known as GS-7977), and I am now crossing my fingers and hoping that its current impressive safety record continues. The failure of drugs in late-stage clinical trials has reminded me that unexpected safety concerns are common, and despite the best efforts of companies and regulators, clinical trials remain challenging.
Safety problems are not restricted to clinical trials. Following the launch of the protease inhibitors telaprevir and boceprevir, data started to accrue in patients with advanced cirrhosis (who were excluded from the clinical trial program). Early results indicate an increase in adverse effects over that seen in clinical trials, particularly with severe anemia and multiple treatment-related deaths, most commonly due to sepsis (Capsule Summary). I certainly find in my practice that patients with advanced cirrhosis are fragile, so it is perhaps not surprising that a small proportion develop serious complications when receiving potent antiviral therapy. However, the unexpected severity of the adverse effects and the associated mortality demonstrate again that a successful phase III trial by no means guarantees the safety of a drug in more challenging patient populations.
The recent concerns with licensed and unlicensed drugs serve as a salutary reminder of the difficulties of drug development. As patients and clinicians who are awaiting the arrival of interferon-free treatment regimes, we should remember that excellent responses in small patient cohorts do not guarantee eventual success. As we wrestle with the decision of whether to treat now or wait for more effective regimens, we need to keep in mind that we still have hurdles to overcome before we can celebrate safe, effective all-oral combination therapy for HCV. In my clinic, I remind my patients that waiting for new drugs is not entirely risk free, and if a decision to wait for better drugs is made, it is important to review the decision in a few months to see if the changing drug development landscape necessitates a review of the original decision. The large lady is on the stage, but the show is not yet over.
Tell me your thoughts: Do these hiccups in drug development alter how you counsel your patients regarding future HCV therapies? Do you discuss the potential safety challenges or focus on the efficacy successes?