| |
Hepatitis C Drug (BMS nucleotide) Halted After Patient Death
|
| |
| |
http://blogs.nature.com 24 Aug 2012 | 21:02 BST | Posted by Kat Lougheed
Bristol-Myers Squibb has halted development of a potential hepatitis C drug after nine participants in a clinical trial of the therapy were hospitalised and one died (see press release).
Hepatitis C (HCV) is a chronic viral infection spread via blood and occasionally other bodily fluids. In a large proportion of cases, patients develop chronic liver disease which can remain symptomless for decades. Cirrhosis and cancer occur in a number of cases, leading to a 1-5% death rate. The US Centres for Disease Control estimates that there are approximately 3.2 million people in the United States living with chronic HCV infection, making a new and improved HCV drug a potentially very profitable investment.
Bristol-Myers Squibb (BMS) acquired the rights to the drug BMS-986094 (formerly known as INX-189) when it bought Inhibitex of Alpharetta, Georgia for US$2.5 billion in January (see 'Pharma giants buy up hepatitis C hopefuls'). The drug works by inhibiting a polymerase enzyme called NS5B, which is essential for viral replication. It was being tested in a phase II clinical trial until 1 August, when BMS announced that they had voluntarily suspended the research (see press release). It has since been revealed that this was due to suspected heart and kidney toxicity effects, although the company cautioned that a causal link between the drug and adverse effects has not been proven. Two trial participants remain in hospital (reported in The New York Times). Abandoning the drug amounts to writing off about $1.8 billion of what BMS paid for Inhibitex. After the news of the safety crisis broke, shares in BMS fell, reducing its market value by billions (see Fierce Biotech).
This is a major blow for BMS, which had been hoping to capitalise on the multi-billion-dollar market for a new HCV treatment. The company is just one of the competitors in a hot field that has seen some big acquisitions in recent years. In February, Gilead Science bought out Pharmasset for $11 billion to take control of their hepatitis drug candidate (see Nature Biotechnology's news story - subscription required). In the same month, Enanta Pharmaceuticals secured a hepatitis C drug-development deal with Novartis, with a $34 million upfront payment and another $440 million if the drug reaches required goals, plus a double-digit percentage of worldwide sales (see Xconomy). Roche also bought Anadys Pharmaceuticals for $230 million in October 2011, after eyeing a hepatitis C drug in its pipeline (see Nature). These acquisitions had led to the share prices of other HCV drug developers to rise in anticipation of a buyout (see Investor Place)
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 see below this refers to when used with neuroleptic drug pimozide) 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). Shares in Idenix tumbled after the news was released (see Fierce Biotech and Business Week). 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. But both are being reviewed by the FDA as a result of the BMS trial (see Business Week).
Incivek (telaprevir) product labeling revised
The Incivek (telaprevir) product labeling was recently revised to include the following changes:
1. Update the clinical comment for neuroleptic drug pimozide in Section 4 Contraindications to state: "Potential for serious and/or life-threatening adverse reactions such as cardiac arrhythmias"
2. Update Section 5 Warnings and Precautions subsection 5.4 Anemia to state: "Hemoglobin should be monitored prior to and at least at weeks 2, 4, 8 and 12 during INCIVEK combination treatment and as clinically appropriate."
3. Update Section 5 Warnings and Precautions subsection 5.6 Laboratory Tests to state the following: Use of a sensitive real-time RT-PCR assay for monitoring HCV-RNA levels during treatment is recommended. The assay should have a lower limit of HCV-RNA quantification equal to or less than 25 IU per mL and a limit of HCV-RNA detection of approximately 10-15 IU per mL.
4. Update Section 7 Drug Interactions to remove desipramine from Table 5: Established and Other Potentially Significant Interactions. Also added to Section 7 was a statement that no dose adjustment is needed for Incivek when given with either raltegravir or buprenorphine. The corresponding results from the drug-drug interaction trial with raltegravir and buprenorphine are included in Section 12 Pharmacokinetics.
5. Update Section 14 Clinical Studies to include revisions to the definition of sustained virologic response (SVR) and to correct the SVR rates for African American and Cirrhotic subpopulations as follows:
SVR was defined as HCV RNA less than 25 IU per mL at last observation within the SVR visit window (i.e., weeks 32-78 for patients assigned to 24 weeks of treatment and weeks 56-78 for patients assigned to 48 weeks of treatment).
Trial 108 (ADVANCE)
· Twenty-six subjects were Black/African Americans. The overall SVR among Black/African American subjects was 62% (16/26). Among these subjects, 35% (9/26) were assigned to 24 weeks of treatment and of those 89% (8/9)achieved SVR.
· Twenty-one subjects had cirrhosis at baseline and the overall SVR in these subjects was 71% (15/21). Among subjects with cirrhosis, 43% (9/21)were assigned to 24 weeks of treatment and of those 78% (7/9)achieved SVR.
Trial 111 (ILLUMINATE)
· Sixty-one (11%) of subjects had cirrhosis at baseline. Among subjects with cirrhosis, 30 (49%) achieved an eRVR: 18 were randomized to T12/PR24 and 12 to T12/PR48. The SVR rates were 61% (11/18) for the T12/PR24 group and 92% (11/12) for the T12/PR48 group.
· Blacks/African Americans comprised 14% (73/540) of trial subjects. Thirty-four (47%) Black/African American subjects achieved an eRVR and were randomized to T12/PR24 or T12/PR48. The respective SVR rates were 88% (15/17) and 88% (15/17), compared to 92% (244/266) for Caucasians among randomized subjects.
Trial C216
· Twenty-six percent (139/530) of INCIVEK-treated subjects had cirrhosis at baseline. SVR rates among cirrhotic subjects who received INCIVEK combination treatment compared to Pbo/PR48 were: 84% (48/57) compared to 7% (1/15) for prior relapsers, 34% (11/32) compared to 20% (1/5) for prior partial responders, and 14% (7/50) compared to 10% (1/10) for prior null responders.
Four percent (19/530) of treatment experienced subjects who received INCIVEK combination treatment were Black/African Americans; the SVR rate for these subjects was 63% (12/19) compared to 66% (328/498) for Caucasians.
|
|
| |
| |
|
|
|
