Table of Contents
Special thanks to Juliana Chan and Polly Clayden
Dedicated to Luis Mendão: brilliant activist and delightful human being.
In May of 2011, a long-awaited improvement in the standard of care for hepatitis C virus (HCV) became reality: the US Food and Drug Administration (FDA) approved the first direct-acting antivirals (DAAs), Merck's boceprevir (Victrelis) and Vertex's telaprevir (Incivek). But excitement about these new drugs has already been overshadowed by a triple-whammy: the first proof-of-concept that hepatitis C can be cured without peginterferon (PEG-IFN) and ribavirin (RBV); reports of better drugs on the horizon; and challenges in clinical care, including the complexity and cost of new HCV regimens, a critical shortage of specialists to administer HCV treatment, and lack of infrastructure for treatment delivery.
In April 2011, groundbreaking results from a 21-person pilot study were announced: after only 24 weeks of treatment with two oral DAAs, a protease inhibitor and an NS5a inhibitor from Bristol-Myers Squibb, four of ten people were cured. Quad therapy (with peginterferon and ribavirin added) was even more effective, curing nine of ten people.1 For now, the success of HCV treatment rests largely upon response to peginterferon. Hopefully, peginterferon will become a therapeutic relic as the standard of care for HCV continues to evolve. The next batch of DAAs may cure more people in less time than triple therapy with peginterferon, ribavirin, and boceprevir or telaprevir. Trials are exploring DAA combinations without peginterferon; some are using it only when DAAs do not fully suppress HCV. Although ribavirin plays an essential role at present, there may be equally effective and more tolerable replacements in the future.
"The availability of DAA therapy will forever change the landscape of HCV, in that we will be able to cure patients of disease who we were unable to cure in the past. Unfortunately, this medical breakthrough will be coupled with resource scarcity. ... The influx of patients requesting HCV therapy will present a significant problem. ... On average, a health care provider can reasonably initiate therapy on only three patients each week before exceeding their work capacity ... we anticipate at least 500 requests for evaluation for HCV therapy within the first few weeks of DAA availability, [so] current staffing will be unable to meet the demands of all patients with HCV."
-- Andrew Aronsohn and Donald Jensen,"Distributive Justice and the Arrival of Direct-Acting Antivirals: Who Should Be First in Line?"
The current challenge -- to fully realize the benefits of boceprevir and telaprevir by avoiding drug resistance and treatment failure -- is immediately ahead of us. In the United States, there are not enough specialists to meet current demand for HCV treatment. Many have "warehoused" patients in anticipation of better treatment, and are not seeing any new patients. At the same time, patient management is becoming more complex, involving response-guided therapy and drug-specific treatment algorithms. We are not prepared for the anticipated surge in HCV treatment uptake triggered by more effective treatment.
"... And, please, let me talk about money. In Spain, we received the news about the price of boceprevir and telaprevir in the US with incredulity. We are indignant, and we do not understand how pharmaceutical companies can justify these outrageous prices. Western society has given the private sector the opportunity to research and develop treatment, but this doesn't entitle you to charge disproportionate prices. At a time when cuts are causing the closure of entire hospital units, emergency rooms and a variety of medical services in this country, how do you expect us to be able to advocate for your new drugs?"
-- Xavi Franquet, European Community Advisory Board and Grupo de Trabajo sobre Tratamientos del VIH, Sitges IV Meeting, June 2011
Most of the 130 to 170 million people who are living with chronic hepatitis C will not be cured, because HCV treatment is too expensive. Many high-burden countries cannot afford to offer hepatitis C testing, let alone treatment. Although efforts to produce generic peginterferon are underway, access to HCV treatment remains limited or nonexistent.
In the United States, 48 weeks of peginterferon and ribavirin costs more than $30,000. Boceprevir-and telaprevir-based regimens halved treatment duration for 44% (boceprevir) to 58% (telaprevir) of study participants.2-4 But any possible savings on peginterferon and ribavirin are offset by the cost of HCV protease inhibitors (see Table 1. Cost of HCV Treatment with a Protease Inhibitor in the United States).
Unfortunately, the boom in drug development has not been accompanied by innovative and affordable diagnostics for HCV, and point-of-care viral load testing for monitoring response to treatment. There is no single test for acute-stage HCV, and diagnosis of chronic hepatitis C remains an expensive two-step process. In many parts of the world, people do not have access to HCV testing. Even when HCV RNA testing is accessible, the process can be overly cumbersome, since people have to return for a second testing visit without being given a diagnosis. Research to streamline HCV diagnostics with a single inexpensive test should proceed in tandem with drug development.
|Table 1. Cost of HCV Treatment With a Protease Inhibitor in the United States|
(Does not include: HCV RNA testing and other labs, medical visits, and additional medications for side effects)
|Drug, Duration, Price Range||Early Response||Slow Response||Responder/Relapser||Partial and Null Responders*||People With Cirrhosis|
Total duration: 28-48 weeks $45,227 to $80,675 (with PegIntron)
|24 weeks of boceprevir $26,400 (+PEG/RBV for 28 weeks at $18,827)||32 weeks of boceprevir $35,200 (+PEG/RBV for 48 weeks at $32,275)||32 weeks of boceprevir $35,200 (+ PEG/RBV for 36-48 weeks at $24,206-$32,275)||32 weeks of boceprevir $35,200 (+ PEG/RBV for 36-48 weeks at $24,206-$32,275)||44 weeks of boceprevir $48,400 (+PEG/RBV for 48 weeks at $32,275)|
Total duration: 24-48 weeks $65,322 to $81,445 (with Pegasys)
|12 weeks of telaprevir $49,200 (+ PEG/RBV for 24 weeks at $16,122)||12 weeks of telaprevir $49,200 (+ PEG/RBV for 48 weeks at $32,245)||12 weeks of telaprevir $49,200 (+ PEG/RBV for 24-48 weeks at $16,122-$32,245)||12 weeks of telaprevir $49,200 (+PEG/RBV for 48 weeks at $32,245)||12 weeks of telaprevir $49,200 (+PEG/RBV for 48 weeks at $32,245)|
* Boceprevir labeling suggests that people with <0.5 log10 drop in HCV RNA at week 4 are likely to be null responders; they were not included in the phase III trial for treatment-experienced people.
Public and private payers are sure to balk at the cost of DAAs, and are likely to impose restrictive treatment eligibility criteria and other barriers, such as prior authorization and top-tier pricing, making access difficult. It is unfortunate that payers are the strongest recourse for price controls.
HCV clinical trials are going to become even more complex, with the advent of triple therapy (peginterferon and ribavirin plus boceprevir or telaprevir). Different dosing schedules will make it difficult to assess efficacy of a single drug and to compare regimens. Boceprevir and telaprevir need to be taken every eight hours, while most second-generation DAAs are once-a-day drugs. Blinded trials will require twice-daily placebo with once-daily drugs. People who are taking a once-daily drug plus placebo may skip their only dose of active drug, placing them at higher risk for treatment failure and drug resistance, since adherence is known to worsen with more frequent dosing requirements. The advantages of a once-daily drug may be obscured by placebo.
HCV clinical trials must incorporate drug- and patient-specific considerations. Treatment algorithms and stopping rules differ for each drug and according to the population it is studied in. Host and viral factors, such as IL28B genotype, stage of liver disease, race/ethnicity, age, HCV subtype (1a versus 1b), and prior response to HCV treatment must also be taken into account. Designing clinical trials and interpreting their results will become more and more of a challenge.
Cure rates with telaprevir- and boceprevir-based regimens are high, making it more difficult for other DAAs to demonstrate superiority. Non-inferiority trials will be needed for the next generation of drugs. These agents are likely to offer other advantages, such as shortened treatment duration, simpler regimens, and more convenient and tolerable drugs. Hopefully regulators and sponsors will consider non-traditional endpoints, such as treatment duration and discontinuations for adverse events, and type, incidence and severity of side effects, along with efficacy. Tolerability and convenience are also extremely important to people who will be taking these drugs.
Interpreting data from complex clinical trials and translating them directly into clinical practice is difficult, particularly in the absence of a standing, multidisciplinary treatment guidelines panel, an approach that has optimized HIV treatment outcomes and facilitated reimbursement by public and private payers. Simplicity should become a major focus of HCV drug development.
Merck and Vertex chose not to conduct early access trials in people with urgent need, who were ineligible for their clinical trials. Early access trials could have saved lives, and allowed physicians to gather information about if and how HCV protease inhibitors could be used in patients who need them most. It is likely that boceprevir and telaprevir will be used in desperate patients, regardless of the lack of information about their safety and efficacy. It is time for the pharmaceutical industry to work with regulators, physicians, and activists to launch early access trials.
Unfortunately, boceprevir and telaprevir are not going to be able to get the job done for people with poor prognostic factors, urgent need, and peginterferon intolerance. Prior null responders with cirrhosis did not reap much benefit; adding telaprevir to peginterferon and ribavirin increased the cure rate from 10% to only 14%, and there are limited data on boceprevir in this population.5
Safety and efficacy of boceprevir and telaprevir are not yet known in HIV/HCV coinfected people (although pilot studies are ongoing, and larger ones planned). No studies have been initiated in children, the elderly, people with renal insufficiency, or liver transplant candidates and recipients (although there have been no pharmacokinetic studies of boceprevir and telaprevir is not recommended for people with hepatic impairment).
Despite low enrollment of African Americans in registration trials for boceprevir and telaprevir, it is clear that adding one of these drugs significantly increased rates of sustained virological response (SVR; meaning no hepatitis C can be detected six months after treatment completion; regarded as a cure) over PEG-IFN/RBV (see Table 2. Translating Trial Results into Clinical Practice: Boceprevir and Telaprevir in Treatment-Naive Persons). But there are lingering questions about the optimal duration of boceprevir-based therapy in African Americans, since the SVR among African Americans was 11% lower for response-guided therapy versus 48 weeks of treatment.3
Unfortunately, data on SVR among Latinos/Latinas are scarce. Latinos and Latinas comprised less than 10% of treatment-naive study participants in telaprevir phase III trials Nonetheless, telaprevir did boost SVR among treatment naive Latinos/Latinas; SVR rates ranged from to 70% to 94%, a significant improvement over peginterferon and ribavirin.2,4 Merck did not provide any data on boceprevir in Latinos and Latinas.
HCV protease inhibitors share metabolic pathways with medications that are commonly used by people with hepatitis C. Drug-drug interactions can lead to drug resistance and HCV treatment failure when levels of an HCV protease inhibitor are too low, or worsen side effects when they are too high. In turn, HCV protease inhibitors may decrease levels of other drugs to sub-therapeutic levels, or increase them to toxic levels.
Interactions between antiretroviral agents and DAAs complicate HIV treatment; a single drug or entire regimen may need to be switched before initiating hepatitis C treatment. This is tricky, because HIV/HCV coinfected people have limited options for treating their HIV while on HCV treatment; in the ongoing telaprevir coinfection trial, participants could either use an efavirenz-based regimen (with a higher dose of telaprevir) or a boosted atazanavir-based regimen (other HIV protease inhibitors cannot be used with telaprevir, due to significant drug-drug interactions).6 Unfortunately, data on boceprevir drug-drug interactions are limited to efavirenz (which lowers boceprevir levels) and tenofovir.7
Since hepatitis C is highly prevalent among current and former injection drug users, drug-drug interaction studies with DAAs and opioid substitution therapy (OST) must be a priority. If DAAs are used in people on OST without this information, a range of consequences may occur, including HCV drug resistance and treatment failure, drug overdose, or withdrawal symptoms. So far, it has been established that telaprevir reduces methadone levels; although dose adjustment may not be needed, clinical monitoring is recommended. A drug-drug interaction study of telaprevir and buprenorphine is underway. Unfortunately, there are no drug-drug interaction data on methadone and buprenorphine for boceprevir, save the warning in the label, which reads "Plasma concentrations of methadone or buprenorphine may increase or decrease when coadministered with VICTRELIS [boceprevir's brand name]. However, the combination has not been studied. Clinical monitoring is recommended as the dose of methadone or burenorphine may need to be altered during concomitant treatment with VICTRELIS."
|Are You Experienced?|
The FDA has categorized treatment-experienced people into three groups:
Responder-Relapser: HCV RNA undetectable at end of treatment with peginterferon and ribavirin, but HCV RNA detectable within 24 weeks of treatment follow-up.
Partial Responder: greater than or equal to 2 log10 (99%) reduction in HCV RNA at week 12, but not achieving HCV RNA undetectable at end of treatment with peg-interferon and ribavirin.
Null Responder: less than 2 log10 (99%) reduction in HCV RNA at week 12 of treatment with peginterferon and ribavirin.
People who could not tolerate treatment or do not know their prior response are not included; nor are people who experienced viral breakthrough during treatment.
There are dozens of HCV clinical trials underway, but most are for treatment-naive participants. Of the nine phase II/III HCV protease inhibitor trials, six are open to treatment-experienced participants (some may be limited to responder-relapsers and partial responders). Current phase II polymerase and NS5a inhibitor trials offer few options: treatment-experienced participants are eligible for only one of three NS5a inhibitor trials, one of two nucleoside/nucleotide polymerase inhibitor trials, and one of seven non-nucleoside polymerase inhibitor trials.
At present, an estimated 750,000 people in the United States (and thousands more in Western Europe) have been unsuccessfully treated for hepatitis C. Treatmentexperienced patients are likely to be first in line for treatment with new HCV drugs; financial experts project that by 2013 they will comprise at least two-thirds of the market share for DAAs. The population of treatment-experienced people is large, and will continue to grow once the first generation of hepatitis C protease inhibitors have been widely used. More trials exploring DAA combinations and treatment strategies are needed for treatment-experienced people.
Multi-DAA/quad therapy trials will help to clarify the best approach based on HCV subtype, treatment history and other factors. Abbott, Boehringer Ingelheim, Bristol Myers Squibb (BMS), Genentech, Gilead, Merck, Pharmasset, and Vertex have opened in-house combination trials.
A single company may not have all of the most exciting drugs, so cross-company clinical collaborations are needed to optimize HCV treatment. BMS and Pharmasset, who have very exciting DAA candidates, launched the first cross company clinical collaboration; in May of 2011, they announced a peginterferon-sparing trial combining BMS's NS5a inhibitors with one of Pharmasset's nucleotide polymerase inhibitors (PSI-7977), with or without ribavirin.
In July 2011, Pharmasset announced another clinical collaboration with Tibotec/Medivir, pairing PSI-7977 (its nucleotide analog) with TMC435 (a protease inhibitor), with and without ribavirin in a phase II trial of prior null responders with HCV genotype 1. The trial will be launched in the third or fourth quarter of 2011. These joint ventures are crucial for identifying best-in-class regimens and optimizing HCV treatment.
Improvements in HCV treatment (such as response-guided therapy and drug- and patient specific treatment algorithms) bring a new level of complexity to clinical care, making it unappealing to inexperienced providers. During FDA approval hearings for boceprevir and telaprevir, an antiviral advisory committee member remarked that the amount of knowledge required to treat HCV approaches the complexity-if not the wisdom-of a Talmudic scholar. Complexity brings consequences, such as greater potential for errors in prescribing and administering treatment, higher dropout rates from poorly managed side effects, and increased risk for drug resistance and treatment failure.
Clinicians and their patients will have a choice between boceprevir and telaprevirbased treatment. Although they are in the same class, these drugs are used differently. Boceprevir requires a four-week "lead-in" with peginterferon and ribavirin to lower ontreatment failure and relapse rates; telaprevir is initiated along with peginterferon and ribavirin. With each drug, there may be a peginterferon and ribavirin "tail" after triple therapy, lasting 12 to 36 weeks.
Telaprevir offers treatment-naive patients a less complex treatment algorithm, higher cure rates, and a better chance to shorten treatment than boceprevir, but tolerability may be an issue. More than half of the participants in all phase III trials were afflicted with rash (versus 32% for PEG/RBV alone). Although most cases were mild-to-moderate, 1% suffered severe rash, and a subset of these cases (<1%) experienced Stevens Johnson Syndrome (SJS, a rare, life-threatening reaction to a medication or infection) or Drug-Related Eruption with Systemic Symptoms (DRESS, another severe drug reaction).
Boceprevir worsens the hemotologic side effects of peginterferon and ribavirin, especially anemia. During phase III trials, more than 40% of participants in the boceprevir arms were treated with epoetin alfa, a red blood growth cell factor.3,8 Red blood cell growth factors carry a warning about increased mortality, serious cardiovascular and thromboembolic events, stroke and risk of tumor progression or recurrence in cancer patients. They are also expensive, adding at least $500 per week to the cost of HCV treatment. Anemia can also be managed by reducing the dose of ribavirin, but this strategy may reduce treatment efficacy; an ongoing trial of boceprevir-based treatment is comparing ribavirin dose reduction to epoetin alfa use.
|Table 2. Translating Trial Results Into Clinical Practice: Boceprevir and Telaprevir in Treatment-Naive Persons
||Characteristic||Boceprevir||Telaprevir||Lead-in||Yes; 4 weeks of PEG/RBV||No||Dosing||750 mg, every 7-9 hours, with food (meal or light snack); 12 pills/day||800 mg, every 7-9 hours with food (not-low fat); 6 pills/day.||Treatment duration||28-48 weeks||24-48 weeks||Eligible for 24-28 weeks of treatment||44%||58-60%||Adverse events||Anemia, neutropenia, thrombocytopenia, dysgeusia, dry mouth, vomiting and diarrhea||Mild to severe rash, itching, anemia, ano-rectal itching and burning, hemorrhoids, elevated bilirubin and uric acid, gout, thrombocytopenia and gastrointestinal events||Discontinuation for adverse events||14%||10-19%||SVR, overall||63-66%||72-79%||Relapse rate||9%||9%||SVR, African Americans||42-53% (~14% of participants)||65% (range: 50-94%) (~10% of participants)||SVR, Latinos/Latinas||Data not provided||79% (range: 70-94%) (~10% of participants)||SVR, bridging fibrosis or cirrhosis||41-52% (~11% of participants)||53-88% (~8% of study participants)||SVR, people on methadone maintenance||No data||33% (only 11 patients in phase III trials)||SVR, HIV/HCV coinfected people||Ongoing pilot studies; data are not yet available. Drug-drug interactions with HIV protease inhibitors and non-nucleosides; coadministration not recommended (except efavirenz)||Ongoing pilot study; data are not yet available. Cannot be used with boosted darunavir, fosamprenavir, and lopinavir; tenofovir levels are increased; monitoring recommended.||Use in hepatic and renal impairment||No dose adjustment required for mild, moderate and severe hepatic impairment; no data in decompensated cirrhosis; no dose adjustment required for renal impairment||Should not be used in people with moderate to serious hepatic impairment, since drug exposure is reduced; exposure increased in renal impairment; analysis of single-dose study underway to see if dose adjustment or multiple dose study is required||Drug-drug interactions||An extensive list is available in the prescribing information (accessed May 14, 2011)||An extensive list is available in the prescribing information (accessed May 25, 2011)||Early access trials||None||None|
Jacobson IM, McHutchison JG, Dusheiko G, et al; ADVANCE Study Team. Telaprevir in combination with peginterferon alfa-2a and ribavirin in genotype 1 HCV treatment naive patients: final results of phase III ADVANCE study. [abstract LB-2] 61st Annual Meeting of the American Association for the Study of Liver Diseases. Boston, Massachusetts. October 29-November 2, 2010. Poordad F, McCone J Jr, Bacon BR, et al; SPRINT-2 Investigators. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011 Mar 31;364(13):1195-206.
Sherman KE, Flamm SL, Afdhal NH, et al; ILLUMINATE Study Team. Telaprevir in combination with peginterferon alfa-2a and ribavirin for 24 or 48 weeks in treatment-naive genotype 1 HCV patients who achieved an extended rapid viral response; final results of phase III ILLUMINATE study. (Abstract LB-1) 61st Annual Meeting of the American Association for the Study of Liver Diseases. Boston, Massachusetts. October 29 - November 2, 2010.
Source: Prescribing information for boceprevir. (Accessed May 25, 2011.)
Source: Prescribing information for telaprevir. (Accessed May 25, 2011.)
|Table 3. Translating Trial Results Into Clinical Practice: Boceprevir and Telaprevir in Treatment-Experienced Persons
||Parameter||Boceprevir||Telaprevir||SVR, responder-relapsers||70-75%||83-88%||SVR, partial responders||40-52%||54-59%||SVR, null responders||Not studied||29-33%||SVR, cirrhosi|| F3 and F4 combined:|
partial responders: 30-46%
null responders: not studied
partial responders: 56%
null responders: 39%
partial responders: 34%
null responders: 14%
|Treatment duration recommended in labeling||For responder-relapsers and partialresponders: 36-48 weeks|
For people with compensated cirrhosis and prior null responders, 48 weeks of treatment are recommended
|For responder-relapsers; 24-48 weeks|
For people with compensated cirrhosis and partial/null responders: 48 weeks
|Discontinuation for treatment failure||20%||~37%||Discontinuation for AEs||10%||5-13% during telaprevir dosing|
Prescribing information for boceprevir and telaprevir. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2011/202258lbl.pdf and www.accessdata.fda.gov/drugsatfda_docs/label/2011/201917lbl.pdf (accessed May 25, 2011).
Bacon BR, Gordon SC, Lawitz E, et al; HCV RESPOND-2 Investigators. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011 Mar 31;364(13):1207-17.
Zeuzem S, Andreone P, Pol S, et al. REALIZE trial final results: telaprevir-based regimen for genotype 1 hepatitis C virus infection in patients with prior null response, partial response, or relapse to peginterferon/ribavirin (Opening and General Session 1) 46th Meeting of the European Association for the Study of the Liver. Berlin, Germany. March 30-April 3, 2011.
Source: Prescribing information for boceprevir.. (Accessed May 25, 2011.)
* Telaprevir labeling notes that a high proportion of null responders, especially those with cirrhosis, did not achieve SVR and developed drug resistance.
Source: Prescribing information for telaprevir. (Accessed May 25, 2011.)
Boceprevir and telaprevir have the market to themselves for the next couple of years, but the next generation of HCV protease inhibitors is already nipping at their heels. These drugs offer advantages such as more convenient dosing, activity against other genotypes, and/or against protease resistant virus. Many are being studied in combination with other DAAs, with and without peginterferon, and with or without ribavirin.
Side effects include anemia, neutropenia, thrombocytopenia, photosensitivity, itching, rash, hemorrhoids, dysgeusia, headache, elevated alanine amino transferase (ALT) and bilirubin, jaundice, elevated uric acid and gout, dizziness, nausea, vomiting, and diarrhea.
|Table 4. HCV Protease Inhibitors in Development
||Agent/Sponsor||Phase and Population||Comments||ABT 450/r|
|Phase II, HCV genotype 1, treatment-naive (PEG-IFN-free studies limited to people with the IL-28B CC genotype)||Once daily; ritonavir boosted; with PEG-IFN/RBV, and combination with ABT-333 (non-nucleoside polymerase inhibitor) plus ribavirin (not open as of May 2011)|
With ABT-072 (non-nucleoside polymerase inhibitor) plus ribavirin
|ACH-2684||Phase I; healthy volunteers followed by HCV genotypes 1 and 3, treatment-naive||Once daily; pan-genotypic activity||ACH-0141625|
|Phase II, HCV genotype 1, treatment-naive||Once daily dosing; studied with PEG-IFN/RBV||BI 201335|
|Phase III, HCV genotype 1, treatment-naive, and treatment-naive/treatment-experienced (combination study)||Once daily; with PEG-IFN/RBV for 12-48 weeks (treatment-naive)|
With PEG-IFN/RBV for 24-48 weeks (treatment-experienced; not open as of 12 August 2011)
With BI 207127 (non-nucleoside polymerase inhibitor) with or without ribavirin (treatment-naive)
|BMS 650032||Phase II, HCV genotype 1 and 4, treatment naive; genotype 1, treatment experienced||Twice daily; with BMS 914143 (peginterferon lambda) with ribavirin; with or without BMS 790052 (NS5a inhibitor) 16-48 weeks (treatment-naive)|
With PEG-IFN/RBV for 24-48 weeks (treatment-naive, genotypes 1 and 4)
With BMS 790052 (NS5a inhibitor), with or without ribavirin, and quad (PEG-IFN/RBV) prior null responders: HCV genotype 1b only in dual DAA arm
|Phase II; HCV genotype 1, null responders||Twice daily; with PEG-IFN/RBV||Danoprevir|
(formerly ITMN-181 /RG 7227)
|Phase I/II, HCV genotype 1, treatment-naive and treatment-experienced||Twice daily; ritonavir boosted; with RG7128 (nucleotide polymerase inhibitor), with or without ribavrin (treatment-naive)|
With PEG-IFNRBV in naive and experienced
With ribavrin, with or without RG7128 (nucleotide polymerase inhibitor), with or without PEG-IFN (partial and null responders)
|Phase II; HCV genotype 1, treatment-naive||Twice daily; with tegobuvir (non-nucleoside polymerase inhibitor), with or without PEG-IFN/RBV||GS 9451|
|Phase II; HCV genotype 1, treatment-naive||Once daily; with PEG-IFN/RBV, with and without tegobuvir (non-nucleoside polymerase inhibitor)|
With GS 5885 (NS5a inhibitor), tegobuvir (non-nucleoside polymerase inhibitor), and ribavirin
With PEG-IFN/RBV, with and without GS 5585 (NS5a inhibitor), IL 28B CC genotype only; 6-24 weeks of treatment. Not open as of 24 August 2011
Glaxo Smith Kline
|Phase I; HCV genotype 1, treatment-naive||With and without ritonavir boosting||MK-6335|
|Phase I, HCV genotypes 1 and 3, treatment-naive and treatment-experienced||Not open as of May 2011||MK-5172|
|Phase I, HCV genotypes 1 and 3; phase II, genotype 1, treatment-naive||Once daily; may be active against resistant virus and across genotypes|
Phase II study will be the first HCV treatment trial with an HCV protease inhibitor (boceprevir) in the control arm
|Phase II in HCV genotype 1, ongoing in treatment-experienced||Twice daily; study completed in treatment-naive; SVR rates were numerically higher than PEG-IFN/RBV + placebo, but the difference was not significant; additional trial in treatment-naive withdrawn|
Although NS5a inhibitors are very potent, these drugs have a low resistance barrier, especially in HCV genotype 1a. Nonetheless, HCV has already been cured with an NS5a inhibitor combined with a protease inhibitor. This drug class is expected to become an important part of DAA regimens, since NS5a inhibitors may have pan-genotypic activity. So far, little is known about the side effect profile of NS5a inhibitors, since they have mainly been studied with peginterferon, ribavirin, and other DAAs; headache was reported in early studies.
|Table 5. NS5a Inhibitors in Development
||Agent/Sponsor||Phase and Population||Comments||ABT-267|
|Phase II, HCV genotype 1, treatment-naive||Once daily dosing; not open as of May 2011||ACH 2928|
|Phase I expected in mid-2011||Pan-genotypic activity||BMS 790052|
Bristol Myers Squibb
|Phase II/III HCV genotype 1, treatment-naive and treatment-experienced; HCV genotypes 2 and 3, treatment-naive; In African Americans and Latinos/Latinas with HCV genotype 1, treatment-naive||With BMS 914143 (peginterferon lambda) and ribavirin, with or without BMS 650032 (protease inhibitor) 16-48 weeks|
With PSI-7977, with or without ribavirin (genotypes 1, 2, and 3, treatment-naive)
With PEG-IFN/RBV (African Americans, Latinos/Latinas, and partial and null responders)
Bristol Myers Squibb
|Phase II||Study withdrawn prior to enrollment||GS 5585|
|Phase II; HCV genotype 1, treatment-naive||Once daily; with GS 9451 (HCV protease inhibitor), tegobuvir (non-nucleoside polymerase inihibtor) and ribavirin|
With PEG-IFN/RBV, with or without GS 9451 (protease inhibitor); IL 28B CC genotype only; 6-24 weeks of treatment. Not open as of 12 August 2011
|Phase Ib, HCV genotype 1, treatment-naive||Once daily dosing (completed)|
The hepatitis C virus offers more than one binding site for non-nucleoside polymerase inhibitors, so it may be possible to combine drugs from this class with one another, and with DAAs from other classes. Unfortunately, non-nucleoside polymerase inhibitors are active only against HCV genotype 1, and have a low resistance barrier. Side effects include headache, abdominal pain, nausea, fatigue, rash, and elevated bilirubin.
|Table 6. Non-nucleoside Polymerase Inhibitors in Development
||Agent/Sponsor||Phase and Population||Comments||ABT 072|
|Phase II; HCV genotype 1, treatment-naive; PEG-IFN free studies limited to people with IL28B CC genotype only||Once daily; with PEG-IFN/RBV and with ABT-450/r (protease inhibitor) plus ribavirin||ABT 033|
|Phase II; HCV genotype 1, treatment-naive; PEG-IFN free studies limited to people with IL28B CC genotype only||Twice daily; with PEG-IFN/RBV and in combination with ABT-450/r (protease inhibitor), plus ribavirin||Setrobuvir|
|Phase II; HCV genotype 1, treatment-naive and treatment-experienced||Twice daily; 28-48 weeks; with PEG-IFN/RBV||BI 207127|
|Phase I; HCV genotype 1, treatment-naive||Twice or thrice-daily dosing; with BI 201335 (protease inhibitor), with or without ribavirin||BMS 791323|
Bristol Myers Squibb
|Phase II: HCV genotype 1, treatment naive||Twice daily; with PEG-IFN/RBV||Filibuvir (PF-868554)|
|Phase II, HCV genotype 1, treatment-naive||Twice daily; with PEG-IFN/RBV, 24-48 weeks||Tegobuvir (GS 9190)|
|Phase II, HCV genotype 1, treatment-naive||Twice-daily; with PEG-IFN/RBV|
With PEG-IFN/RBV and GS 9451 (HCV protease inhibitor)
With GS 9451 (HCV protease inhibitor), GS 5885 (NS5a inhibitor), and ribavirin
|Phase I, healthy volunteers and HCV genotype 1, treatment-naive||TMC 649128|
Medivir AB/Tibotec Pharmaceuticals
|Phase Ia; healthy volunteers||VCH 222|
|Phase I/II HCV genotype 1, treatment-naive||With PEG-IFN/RBV|
With telaprevir (HCV protease inhibitor) and PEG/RBV (dual therapy arm discontinued)
Although several candidates never made it out of phase II due to toxicity, the current nucleoside and nucleotide polymerase inhibitor candidates hold great promise. Early results from trials of Pharmasset's PSI-7797 have generated hope that nucleotides may become the next backbone of HCV treatment -- or the treatment itself.
Simplicity is king; nucleoside and nucleotide polymerase inhibitors may bypass current complexities of HCV treatment, such as IL28-B genotype, baseline viral load, race, HIV status, and HCV genotype. These drugs are not magic bullets, but nucleosides and nucleotides offer the potential to dramatically simplify and shorten HCV treatment, along with other desirable elements: a high resistance barrier, once-daily dosing, good tolerability, and pan-genotypic activity. Side effects include dizziness, fatigue, headache, and fever.
|Table 7. Nucleoside and Nucleotide Polymerase Inhibitors in Development
||Agent/Sponsor||Phase and Population||Comments||Nucleotide Polymerase Inhibitors||GS 6620|
|Phase I, HCV genotypes 1, 2, and 3; treatment naive||IDX 184|
|Phase I/II; male healthy volunteers||Originally studied with IDX 320, a protease inhibitor that has been discontinued due to liver toxicity; remains on partial clinical hold. Food effect being studied; phase IIb trial in combination with PEG-IFN/RBV open||INX-189|
|Phase I in HCV genotype 1, treatment-naive has been completed||Once-daily dosing; FDA has fast-tracked development; Phase II expected in Q2/Q3 of 2011||PSI-938||Phase I, HCV genotype 1, treatment-naive||Once daily, studied in combination with PSI 7797; Phase II combination trials, with and without ribavirin, are expected in mid-2011||PSI 7797||Phase I/II; HCV genotype 1, treatment-naive; followed by HCV genotypes 4,5,6; also being studied in HCV genotypes 2 and 3, treatment-naive||Once-daily; with PEG-IFN/RBV for 12-24 weeks|
With PEG-IFN/RBV for 12 weeks in HCV genotypes 2 and 3, with ribavirin, with or without peginterferon, and as montherapy for 12 weeks; with PEG-IFN/RBV for 8-12 weeks
With PSI 938 for up to 14 days; longer trial expected in mid-2011
With BMS 790052 (NS5a inhibitor), with or without ribavirin
|Nucleoside Polymerase Inhibitors||Mericitabine (RG7128)|
|Phase II, HCV genotype 1 (naive and experienced) and genotype 4, (treatment-naive)||With PEG-IFN/RBV (naive)|
With ritonavir-boosted danoprevir (protease inhibitor), with or without ribavrin (naive)
With ritonavir-boosted danoprevir and ribavirin, with or without PEG-IFN (experienced)
|Phase I; healthy volunteers||TMC 649128|
Medivir AB/Tibotec Pharmaceuticals
|Phase Ia; healthy volunteers|
Resistance to host-targeting agents (HTAs) is less likely to occur than DAA resistance, making these drugs an attractive addition to HCV treatment. There are different types of HTAs. Entry inhibitors work by blocking viral entry into host cells. Cyclophilin inhibitors work by binding to cellular proteins that regulate the immune system; some drugs in this class are immunosuppressants. Both Debio 025 and SCY-635 bind to host cell proteins that may facilitate HCV replication without immunosuppressive activity. Cyclophilin inhibitors may have pan-genotypic activity. Unfortunately, resistance to these drugs has been characterized. Side effects include muscle weakness, low platelets, headache, nausea and elevated bilirubin, which was reversible upon discontinuation.
|Table 8. Host Targeting Agents in Development
||Agent/Sponsor||Phase and Population||Comments||Alispovir (DEBIO 025)|
|Phase II/III; HCV genotype 1, treatment-naive|
Also genotypes 3 and 3
|Loading dose twice daily for 7 days, followed by once daily dosing||ITX 5061|
|Phase Ib; HCV genotype 1, treatment-naive and liver transplant recipients||Once daily||SCY-635|
|Phase II; HCV genotype 1, treatment-naive, IL28B C/T or TT only||Twice daily|
If DAA combination therapy doesn't pan out for everyone, new types and formulations of interferon will come in handy. These may be more convenient, or more tolerable. For example, peg lambda interferon was more effective at 12 weeks than peginterferon alfa 2a, as well as more tolerable. Flulike symptoms, anemia, neutropenia and thrombocytopenia were significantly lower among people who got peg lambda than peginterferon alfa, although the incidence of depression was similar. Transient elevations in direct bilirubin, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were reported in the highest-dose peg lambda arm, but resolved when the dose was lowered or discontinued.9
Generic peginterferon could make HCV treatment accessible to millions of people who need it. There is at least one generic peginterferon (y-shaped peginterferon alfa 2a) in development, which hopefully will make HCV treatment accessible to the millions who need it and are unable to afford Merck's Peg Intron or Roche's Pegasys. In any case, patents in the United States and Europe will be expiring in 2016 (PegIntron) and 2017 (Pegasys).
|Table 9. Novel Interferons in Development
||Agent/Sponsor||Phase and Population||Comments||BMS 914143 (Peg Lambda interferon)|
Bristol Myers Squibb
|Phase II; HCV genotypes 1, 2, 3, and 4, treatment-naive||Once weekly subcutaneous, fixed-dose injection; with ribavirin|
With ribavirin and BMS 790052 (NS5a inhibitor) and/or BMS 650032 (protease inhibitor) for 16-48 weeks
|Locteron Interferon alfa 2b, Controlled Release Formula (CR2B)|
OctoPlus; Biolex Therapeutics
| Phase IIb in HCV genotype 1, treatment-naive has been completed; Phase III has not been announced as of May 2011||Biweekly subcutaneous injection; with ribavirin Lower incidence of depression and flulike symptoms reported in lower-dose Locteron arms, but more severe adverse events than peginterferon alfa 2b||Y-shaped peg interferon alfa 2a|
Biogeneric Pharma and Xiamen Amoytop Biotech Co
|Phase I/III, no HCV genotype specified, treatment-naive||Generic product; subcutaneous, fixed-dose injection, once weekly versus once every ten days, versus biweekly, with ribavirin|
Exploration of additional ways to stimulate the immune response against HCV continues, with a variety of different approaches, including monoclonal antibodies, therapeutic vaccines, and TLR-7 agonists.
|Table 10. Immunomodulators in Development
||Agent/Sponsor||Phase and Population||Comments||CHRON-vac C|
ChronTech Pharma AB and Inovio
|Phase II, HCV genotype 1, treatment- naive||Therapeutic vaccine; unique delivery system. Administered once per month, for two months, followed by peginterferon and ribavirin||GI5005|
|Phase II, HCV genotype 1, treatment- naive and partial responders (null responders excluded)||Therapeutic vaccine, administered subcutaneously; multiple dosing schedule. Studied as both lead-in to peginterferon and ribavirin and as salvage therapy Expanded to include 40 people with the IL28B TT genotype||GS9260|
|Phase I; healthy volunteers||TLR-7 agonist; oral drug|
HCV treatment trials for HIV/HCV-coinfected people are underway, after years of pressure from activists, clinicians, and regulatory agencies. The first two trials, of boceprevir and telaprevir, were slow to enroll because coinfected people did not want to wind up receiving pegylated interferon and ribavirin with placebo (in the control arm). Regulatory guidance has changed since the first boceprevir and telaprevir trials. Regulators have now stipulated that a control arm is not necessary, as SVR with standard of care has been well-documented, and is suboptimal. A single-arm, 300-person study is sufficient for gaining an indication in coinfection.
Unfortunately, drug-drug interactions have limited the options for antiretroviral therapy coadministration with HCV protease inhibitors to date. Hopefully, dual and multiple DAA studies, with and without ribavirin and with and without peginterferon, will be launched as soon as there are data from HCV monoinfection trials and drug-drug interaction studies to support them.
|Table 11. Trials in HIV/HCV-Coinfected People
||Agent/Sponsor||Phase and Population||Comments||BI 201335 (HCV protease inhibitor)|
|Phase III; HIV-1 /HCV genotype 1, treatment-naive and relapsers|
|With PEG-IFN/RBV comparing 12 weeks of triple therapy followed by 36 weeks of PEG-IFN/RBV versus 24 weeks of triple therapy followed by 24 weeks of PEG-IFN/RBV|
First large, phase III study of a direct-acting antiviral to include coinfected treatment-naive and treatment-experienced persons
Not open as of 24 August 2011
|Boceprevir (HCV protease inhibitor)|
Treatment-experienced trial co-sponsored by French National Agency for Research on AIDS and Viral Hepatitis Rennes University Hospital Schering Plough
|Phase II; HIV-1/HCV genotype 1, treatment-naive|
Phase II; HIV-1/HCV genotype 1, treatment-experienced
|With PEG-IFN/RBV; placebo-controlled study; fully enrolled (opened in 2009)|
With PEG-IFN/RBV; opened in April 2011 (France only)
Romark Laboratories (sponsored by National Institutes of Health)
|Phase I/II; HIV-1/HCV genotype 1, treatment-experienced|
|With PEG-IFN/RBV; opened in 2010||Telaprevir (HCV protease inhibitor)|
(Treatment-experienced trial co-sponsored by French National Agency for Research on AIDS and Viral Hepatitis)
|Phase II; HIV-1/HCV genotype 1, treatment-naive|
Phase II: HIV-1/HCV genotype 1, treatment-experienced (null responders with cirrhosis excluded)
|With PEG-IFN/RBV; placebo-controlled study; fully enrolled (opened in 2009)|
With PEG-IFN/RBV; opened in April 2011 (France only)
Other approaches to HCV treatment are being studied: Santaris Pharma's injectable microRNA inhibitor, SPC3649 is entering phase II; it is being studied in treatment-naive people with HCV genotype 1.
Silymarin, the active ingredient in milk thistle, is being studied in acute viral hepatitis, as monotherapy and with peginterferon and ribavirin in treatment-experienced people.
Investments in research and drug development have paid off for hepatitis C. We need a parallel investment in health care, to fully realize the benefits of therapeutic advances. HCV drug development is moving forward rapidly, but the capacity and resources to treat people with HCV have stalled. Millions of people are without access to HCV treatment; high drug prices and the global fiscal crisis make attainment of universal access a challenge. Access to drugs is not all that is required. HCV care and treatment must be offered with linkage to mental health care, case management services, peer support, addiction treatment, and harm reduction services.
Unfortunately, boceprevir and telaprevir were approved in the absence of treatment guidelines (aside from their prescribing information). Clinicians need information about how best to use these new drugs. Otherwise, therapeutic chaos may ensue, leading to treatment failure and drug resistance.
Our biggest challenge is not curing hepatitis C, it is getting health care systems ready for the people who will be using them, as we prepare people to deal with these fragmented systems. Hepatitis C is prevalent among poor, marginalized people. Many of them struggle with addiction, psychiatric disorders and medical comorbidities as well as socioeconomic challenges such as homelessness, unemployment, poverty and incarceration. Multidisciplinary HCV care and treatment, including peer support and education programs, is effective, and these delivery systems need to be expanded. Developing and marketing new drugs will not cure people; good health care will.