The Good News
Today Vertex's drug Telaprevir Received FDA Priority Review" both in U.S. and Canada. On Jan 6th Mercks Boceprevir received FDA Priority Review and EMA Accelerated Assessment.
Telaprevir and boceprevir have been deemed the new generation of drugs both of which appear to be able to improve sustained response while shortening duration of therapy.
The Confusion
The headlines on these two drugs have been misleading and confusing for anyone newly diagnosed. With tag lines reading; "New Hepatitis C Drugs Telaprevir, and Boceprevir can boost cure rates as high as 75 percent with only 24 weeks of treatment". Okay, maybe I embellished a bit, but you get the gist of what I am trying to convey. If I were new to the world of hepatitis C my assumption would be I had a 75 percent chance at a cure. I may even assume treatment duration would be at 24 weeks. However, there are many factors to consider when figuring in these cure rates. Boceprevir and telaprevir will improve the chance for achieving a cure, but a 75 percent cure rate will not be seen in all people treating HCV. The cure rate for these drugs differ and hinge on genotype, treatment naïve patients, relapsers, partial responders, null responders, amount of liver damage/host factors, race and age. The lingo used by physicians or technicians can be difficult to remember; below is a clear definition of these terms. In this blog entry I hope to establish a better understanding in relation to achieving SVR/cure when treating with telaprevir or boceprevir.
Learning The Buzz Words
Cure-Among patients the word "Cure" has had its share of controversy. The definition deemed a cure by researchers/scientist or physicians is defined as having no detectable levels of the virus for more than six months after stopping treatment. *Follow-up studies have shown no trace of the virus in the blood or liver for over 10 years.
SOC - Standard of care therapy for hepatitis C is a FDA approved regime consisting of pegylated interferon and ribavirin.
When treating with standard of care alone the chance for SVR is approximately 40 to 50 percent for people with genotype 1, and 80 percent or more with genotypes 2 and 3.
SVR- sustained viral response; A negative viral load test six months after the completion of therapy is predictive of sustained virologic response. In contrast, failure to achieve a 100-fold reduction in viral load by week 12 of therapy has a strong negative predictive value for sustained virologic response and suggests that treatment is likely ineffective.
What Is A 100-fold reduction in viral load ?
Changes in viral load are sometimes expressed in terms of logs: a 1-log change means a 10-fold increase or decrease; a 2-log change is a 100-fold increase or decrease.
What Is A 2 Log Drop?
Example: 2 log drop = 15,000,000 IU/Ml to 150,000 IU/mL; a viral load that starts at 15,000,000 IU/mL and does not decrease to 150,000 IU/mL or lower.
Genotype
Genotype refers to the genetic make-up of an organism or a virus. Six genotypes (numbered 1–6) and more than 50 subtypes (identified by lowercase letters, e.g., 1a and 1b) have been identified. Genotype 1 is the most common genotype seen in the U.S. and the most difficult to threat. HCV genotype is the strongest predictor of responses to IFN-based therapy. HCV is an RNA virus related to the flavivirus family. RNA viruses are genetically less stable than DNA viruses and are prone to mutate during replication. It’s a common misconception that hepatitis C is just one virus, but in reality (as a result of mutation over hundreds of years), it’s a group of very closely related strains. They are similar enough to be called HCV, but based on genetic differences, they can be classified into distinct groups called genotypes.
Host Factors
The presence of bridging fibrosis and cirrhosis has been reported as one of the most unfavorable predictors for IFN-based therapy. Several studies have demonstrated that SVR rates are lower in patients with coexistent insulin resistance and/or hepatic steatosis or steatohepatitis. Racial differences in response to efficacy of IFN exist and have been one of the host factors. clinical Trials with IFN-ribavirin combination therapy demonstrated that SVRs were highest among Asians (61%), followed by Whites (39%), Hispanics (23%), and African-Americans (14%) . Hispanics and African-Americans were less likely to respond to PegIFN-α-ribavirin compared to Whites .
( host factors are discussed below in the trial results for telaprevir/boceprevir)
Familiar Treatment Terms
Response guided treatment- Or viral load monitoring during treatment is intended to enable the physician to determine the duration of combination therapy based on a patients viral response. *Note Boceprevir protocol below
Naïve- No prior treatment/first time treating HCV.
Relapsers- People whose viral load drops to an undetectable level with treatment but rises again after treatment ends.
Partial responders- People who have at least a 2 log10 (100-times) drop in viral load, but do not reach undetectable levels in the blood by week 24.
Null responders- People who failed to reduce their viral load by at least 2 log10 (100 times) after 12 weeks of prior treatment, which is the currently recommended Food and Drug Administration (FDA) definition for clinical trials of investigational hepatitis C treatments.
Terms Used In Response guided treatment
(RVR)-Rapid Viral Response; Is an undetectable viral load four weeks into treatment. In SOC if you have an RVR your chance of cure is better than 78% and 92% and your doctor may recommend that you shorten your treatment.
(cEVR) Complete early viral response- Is an undetectable viral load 12 weeks into treatment. If you have a complete EVR you have a good chance of being cured .
(pEVR) Partial early viral response - A drop in viral load of at least 2-log (e.g. from 600,000 IU/mL down to 6,000 IU/mL) at 12 weeks of treatment, but still detectable virus in your blood. In people with genotype 1 the chance of viral clearance is low and treatment is generally stopped.
(non-EVR) Non-response- No significant drop in viral load in the first 12 weeks of treatment.
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Telaprevir: Treatment In Genotype 1 *Naïve
In the Phase III ADVANCE trial
What is the ADVANCE Trial?
In ADVANCE investigators compared two telaprevir-based regimens with standard therapy in 1,088 treatment-naive patients with chronic genotype 1.
What Patients Were Treated For Only 24 Weeks ? Patients Who Achieved RVR.
Patients who achieved extended, rapid virologic response (RVR) – defined as undetectable viral load (HCV RNA) at treatment weeks 4 and 12 – were treated with standard therapy for an additional 16 and 12 weeks, for a total of 24 weeks.
Significantly improved SVRs were also observed in difficult-to-treat subgroups; Among black patients, the [SVR] rates were 58% and 62% in the 8- and 12-week treatment arms, and 25% in the control arm*which is SOC, and in cirrhotic patients the respective rates were 53%, 62%, and 33%.
What where the results?
Cure Rate=75%
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Telaprevir: Treatment In Genotype 1 *Failed to respond to prior therapy
In the Phase III REALIZE trial
What is the REALIZE trial?
REALIZE is a pivotal Phase 3 clinical trial of telaprevir in combination with peginterferon alfa-2a (PEG) and ribavirin (RBV) in 662 people with genotype 1 chronic hepatitis C who "failed" to achieve sustained virological response (SVR or viral cure) with prior pegylated interferon-based therapy. The trial evaluated the safety, efficacy and tolerability.
Who Was Enrolled In The Trial And What Were The Results ?
Patients in the study were enrolled based on their response to prior treatment:
Out Of 662 Enrolled In The Study 53% were prior relapsers or 354 relapsers
What were the results ?
Cure Rate= 86%
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Out Of 662 Enrolled In The Study
19% were prior partial responders or 124 partial responders
What were the results ?
Cure Rate=57%
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Out Of 662 Enrolled In The Study
28 percent were prior null responders or 184 null responders
What where the results ?
Cure Rate=31%
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Tell Me More About The Host Factors
In this study, 26% of patients overall had cirrhosis and 89% of patients overall had a high viral load (HCV RNA More Then 800,000 IU/mL) when entering the study.
Specifically in the null responder population, there were an even greater number of people with cirrhosis (33%) and high viral load (95%). Approximately 50% of patients were genotype 1a and 50% were genotype 1b.
Boceprevir Treatment In Genotype 1 *Naïve
HCV SPRINT-2, examined patients with hepatitis C with genotype one who had not yet been treated with the standard treatment.
The treatment protocol consisted of a 4 week lead-in phase of PegIntron plus ribavirin (without boceprevir), followed by the triple combination of boceprevir, PegIntron and ribavirin. Duration and continuation of treatment was guided by the type of on-treatment response to the medications.*
By using a lead-in strategy it can aid physicians in identifying the patients response to interferon before adding boceprevir. This also will provide an early indication of the likelihood of treatment success. An additional advantage of response-guided therapy is it can enable physicians to be flexible in managing their patients’ therapy by adapting treatment duration to individual patient response.
What Were The Results ?
The SVR Rates according to the different treatment arms are listed below:
a. If HCV RNA (viral load) negative at week 8 through week 24, triple therapy was continued for a total treatment duration of 28 weeks;
Cure Rate = 63%
a. If HCV RNA positive at week 8 but undetectable at week 24, boceprevir was stopped at week 28 and PegIntron/ribavirin combination therapy (without boceprevir) was continued for a total treatment duration of 48 weeks;
Cure Rate = 66%
a. The control arm was *standard of care – PegIntron plus ribavirin only—with a treatment duration of 48 weeks;
Cure Rate= 38%.
African Americans/Blacks—Treatment Response
There were also 159 African American/Black patients in the study—African Americans/Blacks comprised 15% of the patient population in this trial.
The SVR rates by different treatment arms are listed below:
a. If HCV RNA negative at week 8 through week 24, triple therapy was continued for a total treatment duration of 28 weeks: Cure Rate= 42%
a. If HCV RNA positive at week 8 but undetectable at week 24, boceprevir was stopped at week 28 andPegIntron/ribavirin combo therapy without boceprevir) was continued for a total treatment duration of 48weeks; Cure Rate= 53%
a. The control arm was *standard of care – PegIntron plus ribavirin only—with a treatment duration of 48weeks; Cure Rate= 23%.
*If the virus was detected in any patients;(HCV RNA positive ) at week 24 all treatment was stopped.
Boceprevir Treatment In Genotype 1 “treatment-failure”
The RESPOND 2 study included 403 HCV genotype 1“treatment-failure” patients. The patients were comprised of null responders, nonresponders and relapsers. In all study arms, previous relapsers and previous null responders fared better than prior nonresponders. The study included a 4 week lead-in phase of PegIntron plus ribavirin(without boceprevir), followed by the triple combinationof boceprevir, PegIntron and ribavirin and treatment duration was based on type of on-treatment response.
What Were The Results ?
The SVR rates and duration of treatment periods for all patients are listed below;
a. If HCV RNA negative at week 8 and at week 12 the total treatment duration was 36 weeks; Cure Rate= 59%
a. IF HCV RNA positive at week 8, but undetectable atweek 12, boceprevir was stopped at week 36 and the combination of PegIntron/ribavirin was continued for a total treatment duration of 48 weeks;
Cure Rate= 66%
a. Control arm was *standard of care – combination of PegIntron plus ribavirin only—for a total treatment durationof 48 weeks;
Cure Rate= 21%
*If any patients were HCV RNA positive at week 12 all treatment was stopped
It is important to know that the treatment duration in the boceprevir containing arms were 28, 36 or 48 weeks depending on the type of on-treatment response.
The Side Effects
Telaprevir
Telaprevir ILLUMINATE trial
There were more adverse event–related treatment discontinuations in the longer-treatment group (12.5% vs. 0.6%), suggesting a benefit to the shorter-duration therapy
Telaprevir ADVANCE trial
Rates of treatment discontinuation due to adverse events, such as rash and anemia, were 8% and 7% in the 8- and 12-week in telaprevir groups compared to SOC, which was at 4% .
Formally known as Protease Inhibition of Viral Evaluation 3 (PROVE3).
Quote from John McHutchison, MD:"The benefit of adding telaprevir, however, was offset somewhat by significant side effects. About half of those receiving telaprevir developed a rash, and 5 percent of those who did so had to stop therapy because the rash was severe. Patients who received telaprevir-based therapy were also more likely to discontinue therapy (50 of 339, or 15 percent) than were patients who received standard therapy (5 of 114, or 4 percent). "While it is true that patients receiving all three drugs were more likely to experience side effects, especially rash and anemia, the benefit of the regimen can be substantial," said McHutchison. "Adding telaprevir to standard treatment for hepatitis C is very helpful to large numbers of patients who originally failed to fully respond to previous treatment."
Drug Rash with Eosinophilia and Systemic Symptoms due to Telaprevir.
Dermatology. 2010; 221(4):303-5. Epub 2010 Aug 25.
Summary
We report a case of drug rash with eosinophilia and systemic symptoms (DRESS) due to telaprevir (VX-950), a specific inhibitor of the hepatitis C virus (HCV) serine protease. A 57-year-old woman with chronic hepatitis C was included in a phase 2 rollover study of VX-950. She received VX-950 in combination with pegylated interferon alfa-2a and ribavirin. Six weeks later, she developed a generalized pruritic maculopapular exanthema with malaise, fever, dyspnoea and lymph node swelling. She had an eosinophilia (up to 2.7 x 109 cells/l), large activated lymphocytes and increased concentrations of aminotransferases. Histological examination of a cutaneous biopsy was consistent with a drug rash reaction. The HCV treatment was stopped, and she was treated with topical and oral steroids. Cutaneous and systemic symptoms disappeared within 1 month. Telaprevir was considered the culprit drug. We report to our knowledge the first case of DRESS syndrome due to telaprevir. The safety data of telaprevir is derived mainly from the PROVE1, PROVE2 and PROVE3 studies. They showed a high frequency of cutaneous side effects reported under the imprecise terms of pruritus and rash, leading to an increased rate of treatment discontinuation. Telaprevir, due to its efficacy, is probably on the way to obtaining regulatory approval in the near future. It is therefore important to be aware of the high incidence of cutaneous side effects and better describe them. Our observation suggests that potentially severe hypersensitivity reactions may belong to the spectrum of rashes induced by this drug.
Affiliation
Department of Dermatology, University Hospital of Nice, Nice, France.
Journal Details
Name: Dermatology (Basel, Switzerland)ISSN: 1421-9832
Source
The Bottom Line:
Safety and Tolerability Information for ADVANCE, ILLUMINATE and REALIZE
The safety and tolerability results of telaprevir-based combination regimens were consistent across the Phase 3 studies. The most common adverse events (AEs) were rash, fatigue, pruritis, headache, nausea, anemia, insomnia, diarrhea, flu-like symptoms and pyrexia with the majority being mild or moderate in severity. Rash and anemia occurred more frequently in the telaprevir treatment arms compared to the control arms.Rash was primarily characterized as eczema-like, manageable and resolved upon stopping telaprevir. More than 90% of rash was mild to moderate and was primarily managed with the use of topical corticosteroids and antihistamines. Anemia was primarily managed by reducing the dose of ribavirin. Erythropoiesis-stimulating agents (ESAs) were used in only 1% of people in the Phase 2 and Phase 3 studies. Discontinuation of all drugs due to either rash or anemia during the telaprevir/placebo treatment phase was 1% to 3% in the telaprevir treatment arms.
Boceprevir
SPRINT-2 trial-"Treatment appeared to be associated with two side effects compared with placebo -- anemia and a distorted sense of taste, or disgeusia. Overall, patients on treatment had greater use of erythropoietin "Note (rescue drugs)" to treat anemia compared with controls (43% for short- and full-course, versus 24% of those on placebo). More boceprevir patients also had to reduce their treatment dose due to anemia (20% and 21% versus 13%).Other adverse events included nausea, headache, and fatigue, at similar rates across all three groups".
RESPOND-2 trial -- genotype 1 patients who'd failed prior therapy; Anemia also appeared to be problematic for the treatment groups in the 403-patient study.
Unfortunately according to previous clinical studies the two new drugs did not seem to lessen side effects of HCV treatment, they are however likely to improve efficacy. Which is really the bottom line, improved SVR rates with shorter treatment duration. The best combo we have had thus far !
Additional Information:
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Updated; As reported On Feb 25 2011
Scripps Health ;IL28B Genetic Testing to Hepatitis C Patients Now Available
Hepatitis C:New direct-acting antivirals' combination/2011
(IL28B) Genotype Test Likeihood Of Achieving SVR
Information On Both The RESPOND 2 , HCV SPRINT-2, from HCV Advocate Fact Sheets.
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