It's always hard to know how many new therapies will make it all the way through a drug development pipeline.There are 12 combination therapies in phase II trials, 19 individual agents in phase II, and five more in phase III.
It’s always hard to know how many new therapies will make it all the way through a drug development pipeline. At the time of this writing, there are 12 combination therapies in phase II trials, 19 individual agents in phase II, and five more in phase III. The adjective being used most consistently to describe the DAAs in development is “potent.”1
Besides potency, what will new combinations need?
New combinations have to address resistance issues shown by the emergence of resistance with telaprevir and boceprevir (similar to other DAA protease inhibitors) when used as monotherapy. In addition to viral mutations triggered through treatment, most HCV patients begin treatment with pre-existing drug resistance variants with one, two, three, and even four mutations. To overcome resistance variants with four-drug resistance, a combination of more than three DAAs is probably needed.
Each agent in the combination must have the potent antiviral activity mentioned above, and should have non-overlapping resistance profiles.
To treat HCV patients safely, combination treatments should present minimal or manageable drug-drug interactions, and add minimal adverse events to drug regimens.
Finally, and ideally, all the agents should be at similar stages of development of so that the drugs can be tested in combination together.2
DAA developers are stretching to meet all four goals, and also want to be able to meet the widespread need for therapy that can cure difficult-to-treat patients. To bring successful drugs to market, developers want to be able to treat patients who have failed previous therapy or have relapsed, as well as those who did not accept SOC therapy or who were not recommended for therapy because of their conditions:
HIV and HCV co-infection
Advanced level of cirrhosis
Transplant candidates and recipients
African Americans and Latinos
Beginning in 2012 and continuing over the next few years, results of phase II and phase III studies with experimental DAA drugs and reports from clinicians will supply much more information about resistance and about efficacy in difficult-to-cure patients than we have now.
In 2012 we also expect much more information about interferon-free regimens. The most compromised patients—those with a poor prognosis—will wait if they can for DAA combination therapies without peg-IFN. Some may enter drug-drug interaction studies. All are hungry for news of IFN-free treatment success.
Two early study reports of interferon-free treatments seem to support the strategy of more-is-better when DAAs take on HCV without peg-IFN:
A small study of 21 patients with chronic hepatitis C tested the possibility that patients who had failed treatment with peg-IFN and ribavirin might be helped by a combination of 2 DAA drugs.3 In this phase II study from Bristol-Myers Squibb, 11 patients received daclatasvir (a NS5A replication inhibitor) and asunaprevir (an NS3 protease inhibitor) as combination therapy without peg-IFN and ribavirin; while 10 patients received the two DAA drugs with peg-IFN and ribavirin.
This trial proved, for the first time, that some patients could be cured by DAA drugs alone, without using IFN. Four of the 11 patients treated with DAAs alone had SVR at 12 weeks and 24 weeks after treatment. Two of the four were genotype 1a, and two had genotype 1b. Six had viral breakthrough during treatment. Resistance mutations to both antivirals were found in all cases. All patients treated with the combination of two DAAs plus SOC had SVR at 12 weeks post-treatment; nine retained the SVR at 24 weeks post-treatment.
In early 2012, Gilead Sciences released preliminary data for an interferon-free treatment using a nucleotide analogue polymerase inhibitor (known as GS-7977) plus ribavirin. The study was small with a very brief treatment period. For 12 weeks, 10 genotype 1 patients, who had failed to respond to SOC therapy, received the two-drug oral treatment. After an early SVR, eight of the responders relapsed within a month of completing the 12-week treatment period.
Can we afford to treat everyone who needs therapy?
In 2011, we learned that the pipeline is likely to become pricey. Standard of care treatment with peg-IFN costs close to $25,000 for a year, and ribavirin costs about $12,000 per course of therapy. Boceprevir adds $22,000 for 24 weeks or $48,000 for 24 to 48 weeks of therapy. Using telaprevir for 12 weeks costs $49,000. Insurance paid for most treatments, after patients and prescribers met pre-authorization requirements. The drug manufacturers offered subsidy programs for those who didn’t have insurance and qualified for help.
Can we afford not to treat?
However, questions of pipeline costs takes us back to the “viral time bomb” warning from the World Health Organization. Estimates in the United States are specific and clear about which population cohorts are most likely to have asymptomatic HCV now, and thus are most likely to develop cirrhosis, end-stage liver disease, or liver cancer.4 To meet the challenge, the Centers for Disease Control and Prevention (CDC) has proposed that primary care practices conduct HCV birth-cohort screening of everyone born between 1945 and 1965.5
The CDC funded a cost-effectiveness analysis of such an approach, which found that compared to current practices, birth-cohort screening would identify an additional 808,580 cases of chronic hepatitis C at a screening cost of $2874 per case. If the treatment that followed is the SOC (peg-IFN and ribavirin), screening would result in an incremental cost-effectiveness ratio of $15,700 per QALY (quality-adjusted life-years) gained. If judged by generally acceptable cost-effectiveness standards, this ratio is a very good result for both the health system and the patient.5 Payers and clinicians probably expect it to improve over time as sustained treatment efficacy improves with new therapies.6
Questions of cost for HCV therapy also must be considered in the context of its ability to cure. Unlike HIV and hepatitis B patients, those with HCV do not have to take medications for their lifetimes. The clinical advantage of being cured of a serious chronic disease is clear for the patient and for the health system. Moreover, every effectively treated patient diminishes the infectious pool and the risks of secondary transmission.
1. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
2. Sharma P, Lok AS. Gastroenterology. 2011;141:1963-1967.
3. Lok AS, et al. N Engl J Med. 2012;366:216-224.
4. Mitchell AE, et al. Hepatology 2010;51:729-723.
5. Rein DB, et al. Ann Intern Med. 2012;156:263-270.
6. Alter HJ and Liang TJ. Ann Intern Med. 2012;156:317-318