Vertex’s telaprevir, Schering Plough’s boceprevir, and Human Genome Sciences’ Zalbin

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Vertex’s telaprevir, Schering Plough’s boceprevir, and Human Genome Sciences’ Zalbin

In Case You Missed It :

Three drugs are in phase III development in the U.S. -

Oct 9 2009

Dr. Jules Dienstag spoke for in

Thought’s expert discussion series on Tuesday, where he highlighted the limitations of current hepatitis C virus (HCV) treatments.

Two developmental drugs in phase III - Vertex’s(VRTX) telaprevir and Schering Plough’s (SGP)boceprevir – are likely to increase efficacy and acceptability of treatment.

Telaprevir appears more efficacious than boceprevir, as it clears virus in less time and with fewer adversities.

Dr. Dienstag believes that adding telaprevir will become standard of care nearly immediately after FDA approval, and that it will be used to treat the typical HCV population as well as as

Contact in Thought for details on our probability of approval models for telaprevir and boceprevir, and on our revenue models for seven marketed and developmental HCV agents.

Vertex’s telaprevir, ScheringPlough’s boceprevir, and Human Genome Sciences’ Zalbin.Dr. Dienstag believes that the two that will be used most by the medical community are telaprevir and boceprevir,as they increase “cure rates†and potentially shorten treatment regimes.Telaprevir and boceprevir are each used in conjunction with the current treatment of interferon plus ribavirin. Although these new drugs do not lessen side effectsof HCV treatment, they are likely to improve efficacy.Telaprevir may indirectly improve over all treatment-related adversity by shortening the duration of interferon treatment, leading to better patient adherence to the treatment regimen.According to Dr. Dienstag, the current treatment shave a “cure rate†of about 45% to

50%, but the upcoming treatments, including telaprevir and boceprevir, increase the cure rate to at least 65%.By “cure rate,†it is meant that the viral load becomes undetectable in blood tests, but that the virus could return at some point in the future.Telaprevir vs. BoceprevirEfficacy and SafetyPhase II trials suggest that telaprevir, interferon, plus ribavirin makes a six-month treatment duration possible, while boceprevir’s addition typically yields a one-year treatment duration.Some early boceprevir responders may be able to stop treatment after six months.The most impressive aspect of telaprevir, accordingto Dr. Dienstag, is its efficacy.Telaprevir quickly reduces the level of HCV virus to undetectable.It will drop the level of virus in >80% of patients in thefirst 4 weeks.The downside to telaprevir is a rash that occurs at a median of eight weeks into treatment

(telaprevir is used with interferons and ribavirin for 12 weeks and then only interferons and Telaprevir may ribavirin are used for the remainingthree months).This rash was considered improve over all to be severe in 7% of patients in the phase II study. The rash is red, raised, treatment-itchy, and quite uncomfortable.It is typically treated with corticosteroid adversity by creams.Shortening the duration of Boceprevir’s phase II trial showed a 55%response rate at 6 months and a 65% interferon rate at one year (a full treatment).Boceprevir’s one-year efficacy was similar to telaprevir’s six month response rate.Both drugs demonstrating response rates better than the current standard of care, which yields 40% to 45%.About 50% of boceprevir recipients experience anemia.Dr. Dienstag expects telaprevir to be preferred over boceprevir as a first-line agent because of efficacy, adversity, and

duration oftreatment advantages, becoming a new standard of care shortly after its approval.ZalbinZalbin is a long-acting interferon alpha in phase III trials for the treatment of HCV.Dr. Dienstag does not see Zalbin having a significant impact on HCV treatment. Zalbin has to date shown non-inferiorityto currently available interferons, but concerning adversity and toxicity profiles. Adversities include shortness of breath, cough, and pulmonary complications.Changing Treatment ParadigmsOnce approved, telaprevir is likely to change current treatment paradigms from two drugs to triple drug therapy, but it may also shorten treatment time to six months from at least a year.Some have speculated that telaprevir could be usedas a monotherapy. Dr. Dienstag does not see telaprevir monotherapy as a possibility because thehepatitis C virus replicates very quickly, making more than one antiviral

necessary.He does thinkthat there is a possibility that telaprevir with only ribavirin could be a viable treatment. Dual therapy without interferon could be more tolerable than traditional triple drug therapy, leading to anincrease in the percent of people treated as well as adherence to treatment.In Australia, Intermune’s phase II protease inhibitor, ITMN-191, and Pharmasset’s nucleoside polymerase, R7128, were used as dual therapy for two weeks without interferons, suggesting that significant viral load reduction is possible even without interferon injections.Shorter duration of therapy with a telaprevir background is also possible. Dr.Dienstag predicts that three months of triple drug therapy using telaprevir +peginterferon + ribavirin would be efficacious, but that six months will be better.Impact on the HCV MarketWith an estimated 4.7 million infected people in the United States, we believe that only around 1.5

million know they are infected, and only around 25% of the diagnosed seek treatment. With shortened therapy, thepercent treated is likely to increase.The over all percent treated increases from 8% today to 12% by 2018 in our model. The potential to use new therapies without interferons, which cause sideeffects like flu like symptoms and fatigue, could increase treatment rates even more.Telaprevir has additional upside due to potential use in infected people who have not responded to current therapies. Nearly half of patients do not respond to the current therapy. This large population could be immediate adopters of the triple drug therapy.Dr. Dienstag believes that 40% of non-responderscan effectively be treated with telaprevir. At the American Association for the Study of Liver Diseases(AASLD) meeting October 30 to November 4, an abstract titled,“PROVE3 Final Results and 1-Year Durability of SVR with

Telaprevir-Based Regimen in Hepatitis C Genotype 1-Infected Patients with PriorNon-response,Viral Breakthrough or Relapse to Peginterferon-Alfa-2a/b and Ribavirin Therapy†by McHutchison et al shows that viral response rates in patients receiving telaprevir + peginterferon +ribavirin were significantly higher than with patients receiving peginterferon + ribavirin for 48weeks.The trial showed that patients who failed prior peginterferon + ribavirin therapy can successfully be treated with a telaprevir-based regimen and maintain viral response one year after the end of treatment.Similarly, boceprevir in prior non-respondersshowed good results in the abstracts for the liver meeting.An abstract titled,“Clonal analysis of mutations selected in the HCV NS3 protease domainof genotype 1 non-responders sequentially treatedwith boceprevir (SCH503034) and/or pegylatedinterferon alfa-2b (PEG-IFN α-2b),†by

Vermehrenshowed that non-responders who were subsequently treated with boceprevir + peginterferon + ribavirin showed a consistent viral decline.HCV PipelineTwo classes of HCV drugs are being developed: protease inhibitors, such as telaprevir and boceprevir, and non-nucleoside polymerase inhibitors.Of the protease inhibitors, Dr. Dienstagbelieves that Boehringer Ingelheim’s BI 201335 is most interesting. It is in phase II in Europe.Phase I showed no patients discontinuing monotherapy, indicating that it is well tolerated. The drug was administered as monotherapy for two weeks followed by peginterferon + ribavirin for two more weeks.The trial showed a strong and rapid antiviral response compared to placebo.The liver meeting abstracts show that BI 201335 with peginterferon +ribavirin demonstrated rapid, potent antiviralactivity with virologic responses at weeks 4 and 12 in the

abstract titled,“Early antiviral activity andsafety of BI 201335 combined with peginterferonalfa-2a and ribavirin in treatment-naïve patientswith chronic genotype 1 HCV infection,†by SulkowskiITMN-191 is InterMune and Roche’s orally available protease inhibitor. It is in phase II trials in the U.S.Like the other protease inhibitors, it is typicallyused with peginterferon and ribavirin.Early studies show that this combination is generally safe and well tolerated.An abstract from the liver meeting showed that among 40 patients receiving ITMN-191 monotherapy, 14 patients experienced virologicrebound. This study indicates the possibility of getting a strong response using only monotherapy.TMC-435 was called out by Dr. Dienstag. It is a protease inhibitor being developed by Tibotec (a subsidiary of & ) as an oral treatment to be used in combination with peginterferon

and ribavirin. In April, Tibotecr eleased positive efficacy and tolerability data after 28 days of triple therapy. No data are expected at the liver meeting.ANA 598 is a phase II drug being studied by Anadys Pharmaceuticals.This small molecule, non-nucleoside, polymerase inhibitor is being studied asa monotherapy. It has been shown to be welltolerated. No data are expected AASLD.Vertex is in phase I with its oral small-molecule,non-nucleoside inhibitor called VCH 222. Dr. Dienstag found this drug interesting, as it could beused as a single therapy.In March, Vertex announced that in patients receiving 750mg twice daily demonstrated the most significant viral load reductions for polymerase inhibitors seen to dateafter only three days of single therapy.Results were consistent from patient to patient. IDX 184 is a once-daily oral nucleotide polymerase inhibitor being developed

Pharmaceuticals.Early studies have shown a significant reduction in viral load after only days of therapy. Dr. Dienstag finds this to also be an interesting drug candidate.

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