December 31, 2013

Patent battle lines drawn as sofosbuvir gains approval

NATURE REVIEWS DRUG DISCOVERY | NEWS AND ANALYSIS | PATENT WATCH

Charlotte Harrison

Nature Reviews Drug Discovery 13, 12 (2014) doi:10.1038/nrd4220
Published online 31 December 2013

nrd4220-i1

Atmotu Images/Alamy

Just days before Gilead's first-in-class hepatitis C virus (HCV) drug was approved by the US Food and Drug Administration on 6 December, the specialist antiviral company Idenix filed two lawsuits in the United States, alleging that sofosbuvir infringes on their patents. Given that the drug is poised to make estimated peak annual worldwide sales of almost US$5.3 billion, the battle for who owns the intellectual property to the drug is likely to be fierce. Indeed, Roche and Merck are also claiming they have patent rights to sofosbuvir.

Sofosbuvir (Sovaldi; also known as GS-7977) is a nucleotide analogue prodrug that inhibits the HCV RNA polymerase NS5B, which is crucial for viral replication. Importantly, the drug is part of the first oral drug regimen that will allow patients to be treated without interferon (see Nature Rev. Drug Discov. 13, 5–7; 2013). If Gilead prevails in its patent disputes, its key patents for sofosbuvir will expire in 2025 (US 7429572) and 2029.

In the first district court filing, Idenix and their collaborator the University of Cagliari are seeking to ascertain that sofobuvir infringes on patents US 6914054 and US 7608597, which claim treatment of HCV using 2-methyl nucleosides. In the second district court filing, Idenix's additional collaborators are the French National Centre for Scientific Research (CNRS) and Montpellier 2 University. Together, they allege that sofosbuvir infringes on a patent (US 7608600) that claims modified 2′ and 3′ nucleoside prodrugs for treating Flaviviridae virus infections.

In addition, the second lawsuit states that Idenix's '600 patent and a patent owned by Gilead's predecessor Pharmasset (US 8415322, which describes modified fluorinated nucleoside analogues) both try to claim the same invention. Because Idenix asserts that it was the first to file its application, it should have “priority of invention” for the overlapping claims, and so be awarded the patent at the expense of Gilead. Another dispute between Gilead and Idenix, involving their respective patent and patent applications related to 2′ methyl, 2′ fluoryl nucleotide, is before the US Patent and Trademark Office. Moreover, the two companies are also at loggerheads over related patents in Canada, Norway and Australia.

Merck (as Merck and Co. and Merck Sharp & Dohme), together with Isis Pharmaceuticals, is also waging in on the patent battle against Gilead. Last summer, Merck allegedly asked Gilead to license two patents — US 7105499 and US 8481712, which describe nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase — and their counterparts in other countries by paying Merck a 10% royalty on net sales of sofosbuvir. Gilead disagreed, and promptly filed a lawsuit, seeking to determine that it either did not infringe the '499 and '712 patents, or that the patents were invalid.

Gilead notes that Roche also claims that it is entitled to receive licence fees for sofosbuvir. Roche partnered with Pharmasset — which was purchased by Gilead for a mammoth US$11.2 billion in 2011 — to develop PSI6130, a cytidine analogue that is also an NS5B inhibitor (the development of which has now been discontinued). Roche alleges that sofosbuvir is a prodrug of PSI6130 and therefore it is entitled to an exclusive licence. Gilead contends that Roche is not entitled to such a licence because the collaboration between Roche and Pharmasset ended before Gilead bought Pharmasset.

So, the recent approval of sofosbuvir in the United States and its anticipated marketing authorization in Europe and other regions heralds a new era for the treatment of HCV, but Gilead will have to await the outcome of these ongoing patent fights, and probably appeals, before knowing whether it has to share the revenue.

Patent advisors

Daniel M. Becker: Dechert LLP, Mountain View, CA, USA.

Luke Kempton: Wragge & Co., London, UK.

Leslie Meyer-Leon: IP Legal Strategies Boston, MA, USA.

George W. Schlich: Schlich & Co., London, UK.

John A. Tessensohn: Shusaku Yamamoto, Osaka, Japan.

Philip Webber: Dehns, London, UK.

Source

December 30, 2013

Journal of Viral Hepatitis

Cost-effectiveness Analyses

L. M. Hagan, Z. Yang, M. Ehteshami, R. F. Schinazi

J Viral Hepat

Abstract and Introduction

Abstract

Interferon-based standard of care treatments (SOC) for chronic hepatitis C are unable to provide high cure rates in certain subgroups of the infected population and can cause debilitating side effects. Clinical trials evaluating all-oral, interferon-free treatments have demonstrated high rates of sustained virologic response with no resistance or major adverse events in most populations. As these drug regimens move towards FDA approval, it will be important to assess their cost-effectiveness in addition to their clinical efficacy. A decision-analytic Markov model with a lifetime, societal perspective was used to evaluate the cost-effectiveness of a generalized all-oral drug regimen compared to SOC by modelling the progression of a 50-year-old, HCV-positive cohort through disease natural history and treatment. In base case analysis, all-oral treatment dominated SOC across a range of willingness-to-pay (WTP) thresholds with an incremental cost-effectiveness ratio (ICER) of US$44 514/quality-adjusted life year (QALY). In sensitivity analyses, the model was sensitive to all-oral drug costs as well as rates of SVR and treatment uptake among noncirrhotic subjects, but robust to variations in all other parameters. All-oral treatment was most cost-effective among genotype 1 subjects but remained cost-effective for genotypes 2 and 3 at WTP thresholds ≥$80 000/QALY. Quality-adjusted life years gained per dollar spent were maximized in younger treatment cohorts. Using this model, the degree of cost-effectiveness depended on the WTP threshold and the final cost set for approved drug combinations.

Introduction

Approximately 150 million people globally and 3.3 million in the United States (US) are chronically infected with hepatitis C virus (HCV).[1] Because most cases are asymptomatic, up to 75% of HCV-positive individuals in the US are unaware of their infection, often resulting in untreated progression to advanced fibrosis, cirrhosis, hepatocellular carcinoma (HCC) and premature death.[2]

Chronic hepatitis C (CHC)-related mortality and healthcare costs are expected to rise as infected individuals in the high-prevalence 1945–1964 birth cohort, most of whom were infected 20–30 years ago, progress towards cirrhosis and liver cancer.[3–5] In response to this trend and to the demonstrated cost-effectiveness of birth cohort-based HCV screening,[6] the Centers for Disease Control and Prevention (CDC) recently recommended universal one-time screening for adults in this age group. This announcement coincided with the first National Hepatitis Testing Day in the US on 19 May 2012.[7]

As these screening initiatives yield increased CHC diagnoses, development of curative, cost-effective treatments will be paramount.[8] Treatment has evolved rapidly since the discovery of HCV in 1989, demonstrating progressive improvement in cure rates measured by sustained virologic response (SVR). The first treatment available, injected interferon monotherapy, resulted in SVR for 10% of those treated. Sustained virologic response increased to 25% with the addition of ribavirin and to 45% with the substitution of pegylated interferon.[8,9] Current standard of care (SOC) treatment for viral genotypes 2 and 3, pegylated interferon plus ribavirin (combination therapy), achieves SVR in up to 80% of noncirrhotic individuals, but in only 43% of those with cirrhosis,[10,11] Genotype 1 infections, which account for approximately 73% of CHC cases in the US, have historically been more difficult to treat and require triple therapy with the addition of a protease inhibitor (boceprevir or telaprevir),[12,13] SVR rates with triple therapy reach 72% among noncirrhotic genotype 1 individuals but are still much lower (42%) among those with cirrhosis,[14,15]

Despite rising SVR rates, current treatment with interferon and ribavirin often causes debilitating flu-like symptoms, depression, skin rashes and anaemia that can undermine treatment completion.[2] The next major advance in CHC treatment is expected to be the adoption of all-oral regimens that eliminate interferon, and possibly ribavirin, using direct-acting antiviral agents that increase SVR by preventing selection of drug resistant viruses and leveraging the lack of latent phase in HCV replication.[16]Numerous pharmaceutical companies are sprinting towards the finish line in advanced stage clinical trials testing novel all-oral, interferon-free drug combinations, some of which have achieved SVR in more than 90% of some subgroups, including null and partial responders to prior interferon-based treatment.[17]

The final cost of these drugs will be unknown until they reach the market and may ultimately exceed the cost of SOC for some genotypes. In addition, because clinical trial results are based on relatively small sample sizes of carefully chosen subjects, they may overestimate the SVR rates that will be attained among a more diverse and representative population. Therefore, while data on costs and anticipated SVR remain in flux, it will be important to consider the cost-effectiveness of emerging all-oral treatments across multiple possible scenarios.

This analysis investigated the cost-effectiveness of all-oral CHC treatment compared to SOC using a range of potential drug costs, treatment-associated quality of life estimates and rates of SVR for genotypes 1, 2 and 3-infected, treatment-naïve subjects with and without cirrhosis. Because it is not yet certain which specific drug combination(s) will receive FDA approval, our model used a generalized all-oral regimen to determine the cost threshold at which these drugs would be cost-effective compared to SOC.

Materials and Methods

Using TreeAge Pro 2012 software (TreeAge Software, Inc., Williamstown, MA, USA), we constructed a decision-analytic Markov model to simulate the progression of a 50-year-old cohort through CHC natural history and possible treatment with either SOC or an all-oral regimen. Cohort age was chosen based on CDC estimates of peak US HCV seroprevalence in the current 50–59 age group (4.3%),[18] coupled with the expected rise in CHC-related healthcare costs as infected individuals in this cohort progress to late-stage liver disease.[3–5]

Markov Model

A Markov model (Fig. 1) is a recursive decision tree that guides a cohort through a series of probabilities representing disease natural history, medical care, possible treatment and treatment outcomes. Based on the probability-driven pathways in our model (Fig. 2 and 3), subjects accrued costs and quality-adjusted life years (QALYs) at the end of each model year (stage), depending on their disease state and treatment profile. Cumulatively, these accruals were used to calculate the incremental cost-effectiveness ratio (ICER), which measures the cost per QALY gained by implementing all-oral treatment compared to SOC. Death was possible from any model stage. Subjects alive at the end of a given stage continued cycling through the model as determined by their health or treatment outcome in the preceding stage. Analysis terminated when the cohort reached its average life expectancy. Base case values for all model parameters, as well as ranges used in sensitivity analyses, can be found in Tables S1–S5.

817888-fig1

Figure 1. Simplified Markov model. As the HCV-positive cohort progresses through the model, subjects accrue medical costs and QALYs based on probabilities for disease progression and treatment outcome. Those who do not die from any cause during a given stage continue through the model for an additional year. Aggregate costs and QALYs are summed and used to calculate the ICER. HCV = hepatitis C virus; CHC = chronic hepatitis C; QALY = quality-adjusted life year; ICER = incremental cost-effectiveness ratio.

817888-fig2

Figure 2. Model schematic of CHC natural history and treatment. Model subjects progress through fibrosis stages F0–F4, decompensated cirrhosis and HCC based on annual probabilities (white circles, solid lines). Those who initiate SOC or all-oral treatment (light grey squares) either achieve SVR (black stars) or fail/discontinue and continue progressing through CHC natural history without retreatment (dark grey hexagons). Further fibrosis progression after SVR is possible for subjects in stages F3, F4 and decompensated cirrhosis (dotted lines). F3 subjects can progress directly to decompensated cirrhosis or HCC within one year, bypassing F4 (dotted lines). Subjects with decompensated cirrhosis can be treated in the all-oral treatment pathway, but not in the SOC pathway. Subjects with decompensated cirrhosis and HCC receive liver transplants according to published annual probabilities. Death is possible from any cause at any stage in the model. See Table S1 for specific progression probabilities. CHC = chronic hepatitis C; F0–F4 = Metavir fibrosis stages; Tx = treatment; SVR = sustained virologic response; HCC = hepatocellular carcinoma.

817888-fig3

Figure 3. Decision tree excerpt. A selection of the decision tree underlying the Markov model, where M represents the starting point for each annual model cycle, and individual probabilities are included under each branch. Subjects who reach terminal branches (boxes with thick borders) begin untreated progress through CHC natural history in the subsequent model year (solid black boxes). Chronic hepatitis C natural history progression probabilities are not depicted but are summarized in Table S1. Branches involved in treatment uptake and outcome are illustrated under F2 only, but this subtree was included in all fibrosis stages in the model. HCV = hepatitis C virus; SOC = standard of care treatment; CHC = chronic hepatitis C; F0–F4 = Metavir fibrosis stages; Tx = treatment.

Background Mortality Rates

Age-specific background morality rates were applied throughout the model, estimated at 2.37 times the rates for non-CHC-infected individuals,[19,20] After SVR, subjects were assigned lower mortality rates, estimated at 1.4 times non-CHC rates based on evidence that virus clearance improves overall health outcomes.[21] Subjects with advanced liver disease were assigned higher mortality rates based on published literature (Table S1).

Screening

This hypothetical cohort included only screened, laboratory confirmed HCV-positive subjects. It did not include HCV-positive individuals unaware of their infection because they would not have the opportunity to be treated with either drug regimen.

All-oral Parameter Estimates

Aside from SVR rates, which were estimated from clinical trial data, published values for parameters associated with all-oral CHC treatment were not available because these drugs are not yet approved. Estimates for specialist referral and attendance, contraindications to treatment, treatment uptake and discontinuation, and QALYs associated with all-oral treatment and SVR were derived from interviews with clinical hepatologists practicing at Emory University in Atlanta, Georgia, hereafter referenced as 'expert opinion' (Karpen S, Spivey J, Ford R, Parekh S. Personal communication). Due to the uncertainty of these estimates, most sensitivity analyses involving all-oral treatment parameters used ranges of at least ± 20%. To remain conservative, ranges often included the corresponding SOC parameter's base case (Tables S3–S5).

Fibrosis Progression

Probabilities of treatment uptake and SVR were dependent on CHC genotype and fibrosis stage, defined by METAVIR score (F0 = no fibrosis; F1 = portal fibrosis without septa; F2 = portal fibrosis with few septa; F3 = numerous septa without cirrhosis; F4 = compensated cirrhosis).[22] Initial distribution of subjects across fibrosis stages was based on a meta-analysis of 111 clinical studies including over 33 000 individuals with CHC in fibrosis stages F0–F4,[23] adjusted to include decompensated cirrhosis.[24]Subjects progressed to later fibrosis stages, HCC, liver transplant and death based on annual progression probabilities from the same meta-analysis and other published estimates (Tables S1–S2).[23,25–32] At the end of each model year in which a disease state transition occurred (e.g. progression from F0 to F1, or from F4 to decompensated cirrhosis), subjects accrued the costs and QALYs associated with the disease state in which they began the year; the following year, they accrued the costs and QALYs associated with the state to which they had transitioned.

Treatment Probabilities

Subjects had multiple opportunities to be treated. In the initial model year, a subject's probability of treatment was the product of individual probabilities for specialist referral, specialist attendance, likelihood of contraindications and acceptance of treatment that was offered, which varied by treatment pathway (Table S3; Fig. 3). Subjects eligible for treatment (i.e. with no immutable contraindications) but not treated in the initial model year transitioned to treatment in subsequent years at annual rates varying from 1–10% depending on genotype, fibrosis stage and treatment pathway. These probabilities were based on published literature for SOC and expert opinion for all-oral treatment,[28,33]

Due to lower SVR rates for genotype 1 compared to genotypes 2 and 3 with SOC treatment, combined with physicians' expectations for improved treatments in the near future, many genotype 1 individuals in clinical care with little or no fibrosis delay treatment.[28] To remain consistent with clinical practice, this model did not treat genotype 1 F0 subjects in the SOC pathway during the initial model year. However, these subjects transitioned to treatment at a higher rate in subsequent years compared to subjects in later fibrosis stages, as modelled in a recent cost-effectiveness analysis of CHC screening strategies by Coffin et al..[28] Because of high expectations for SVR with all-oral treatment, all genotype 1 subjects in the all-oral pathway were treated at the same rate in the initial model year, regardless of fibrosis stage. Subjects were assumed treatment-naïve. Those who failed or discontinued treatment were not retreated in the model.

Liver Biopsy

In the clinic, approximately 70% of genotype 1 subjects who attend a specialist visit undergo a liver biopsy to determine fibrosis stage, which helps determine whether to initiate treatment or to wait.[28] If SVR rates rise as expected with the adoption of all-oral treatment, most individuals diagnosed with CHC will likely be treated regardless of genotype or fibrosis stage, reducing the need for liver biopsy. Based on expert opinion, we assumed that only 40% of genotype 1 individuals would receive a liver biopsy once all-oral treatment becomes widespread.

Treatment of Subjects With Advanced Liver Disease

Because few individuals with decompensated cirrhosis can tolerate interferon, treatment with SOC is rare in this group,[34,35] One of the benefits of an eventual all-oral regimen is greater expected compatibility with late-stage disease, increasing treatment access for cirrhotic individuals. Therefore, this model allowed subjects with decompensated cirrhosis to be treated with all-oral therapy, but not with SOC. Estimates of treatment uptake and associated QALYs for decompensated subjects were derived from expert opinion. Treatment discontinuation rates were set at higher levels for these subjects compared to those in stages F0–F4 due to the possibility of more frequent adverse events.

Fibrosis Regression After SVR

To account for evidence of liver regeneration after viral eradication, this model allowed post-SVR fibrosis regression according to probabilities from clinical literature.[35–42] Regression rates for decompensated subjects after all-oral treatment were assumed equal to rates for those with compensated cirrhosis.

Costs and QALYs

Most costs and QALYs associated with SOC treatment and nontreatment-related CHC care were derived from two recent cost-effectiveness studies on CHC screening and treatment strategies, which provide comprehensive reviews of these parameters from a variety of published sources,[28,31]Treatment costs incorporate both the cost of the drugs themselves and the costs of medical care during treatment, including adverse events. Base case parameters were chosen as mid-range estimates (Tables S4-S5). Costs were adjusted to 2012 US dollars, and costs and QALYs were discounted 3% per year.

We used $70 000 as the base case cost for one course of all-oral treatment based on the anticipated market entry cost ($47 000) for sofosbuvir (GS-7977), one of the leading direct-acting antiviral candidates currently in advanced clinical trials,[43] combined with expectations that eventual FDA-approved all-oral regimens will include more than one drug. Due to the uncertainty of this estimate, we used a wide range of all-oral drug costs in sensitivity analyses (Figs 4,5).

817888-fig4

Figure 4. Top ten most influential parameters for cost-effectiveness. A series of one-way sensitivity analyses, generated by TreeAge Pro software, depicts the influence that individual model variables exert on the ICER. The length of a given bar indicates the magnitude of change effected by variations in a model parameter. Variables were tested over ranges listed in Tables S1–S5. ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life year; CHC = chronic hepatitis C; F0–F4 = Metavir fibrosis stages; SVR = sustained virologic response.

817888-fig5

Figure 5. Maximum all-oral drug costs at three WTP thresholds. Cost of all-oral drugs was plotted against the ICER to determine the maximum drug cost at which all-oral treatment (dashed line) can remain cost-effective compared to SOC treatment (solid line) at various WTP thresholds. Maximum costs of all-oral drugs at WTP thresholds of $50 000/QALY, $80 000/QALY and $100 000/QALY are shown in black boxes. WTP = willingness-to-pay; SOC = standard of care treatment; ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life year.

ICER and Sensitivity Analyses

To assess cost-effectiveness, we calculated the incremental cost-effectiveness ratio (ICER), which measured the average cost per QALY gained by using all-oral treatment instead of SOC. We conducted one-way sensitivity analyses to determine which model parameters had the greatest impact on the ICER and ran sub-analyses to explore differences in cost-effectiveness by viral genotype and age at treatment.

Results

Model Validation

Because no published models to date compare all-oral treatment to SOC, we validated our model indirectly by comparing a cohort sent through our SOC branch to a cohort that progressed untreated through CHC natural history. This strategy allowed us to validate our SOC pathway by comparing it to similar published models assessing cost-effectiveness of currently available therapies (SOC) vs no treatment. We then built the all-oral treatment pathway based on the validated SOC model.

Our SOC validation model yielded an average of $54 603 in medical costs and 13.4 QALYs for subjects in the treatment branch compared to $40 407 and 12.1 QALYs for untreated subjects. These numbers compare well with those reported by Salomon et al. ($22,000/19.4 QALYs treated vs $8,200/18.9 QALYs untreated).[44] The absolute numbers differ between the two models, partly due to differences in cohort age (40 year-olds in Salomon, published 10 years ago, vs. 50-year-olds in our model) and cost of treatment regimens (combination therapy for genotype 1 subjects in Salomon vs. more expensive triple therapy in our model). However, the cost and QALY differences between the treated and untreated branches in the two models are comparable. After validation, we added decompensated cirrhosis to the initial fibrosis distribution to account for the possibility of treatment for decompensated subjects in the all-oral pathway.

Base Case Results

In the base case model, all-oral treatment dominated SOC (ICER = $44 514/QALY), yielding higher costs but more QALYs for a cohort of 50-year-old subjects (SOC: $74 619/10.7 QALYs; all-oral: $93 315/11.1 QALYs).

Sensitivity Analysis

A series of one-way sensitivity analyses (Fig. 4) demonstrated that the ICER was driven primarily by all-oral drug costs and was also sensitive to rates of SVR and treatment uptake for noncirrhotic subjects. As rates of SVR and treatment uptake for all-oral therapy increased, the ICER decreased, demonstrating greater cost-effectiveness. The ICER was robust to changes in all other parameters including QALY estimates, extended treatment duration for cirrhotic subjects and nontreatment-related CHC costs.

All-oral Drug Cost and Willingness-to-Pay Threshold

Assessment of cost-effectiveness depended on the willingness-to-pay (WTP) threshold chosen, which indicates how much stakeholders are willing to pay for all-oral treatment per QALY gained compared to SOC. The maximum costs that all-oral drug regimens can reach while remaining cost-effective under different WTP scenarios are illustrated in Fig. 5. With a $50 000/QALY WTP threshold, the maximum cost-effective all-oral drug cost was $74 217 for one course of therapy; at WTP thresholds of $80 000/QALY and $100 000/QALY, all-oral treatment ceded cost-effectiveness to SOC at drug costs of $97 279 and $112 653, respectively.

Genotype

All-oral treatment dominated SOC in sub-analyses by viral genotype. It was most cost-effective for genotype 1 but remained cost-effective for genotypes 2 and 3 at WTP thresholds ~$80 000/QALY or higher (ICER = $30 881/QALY for genotype 1; $78 146/QALY for genotypes 2 and 3).

Age at Treatment

In parallel analyses comparing cohorts of 50-, 30- and 10-year-old subjects, all-oral treatment was most cost-effective among younger aged cohorts (cost/QALY = $8 384, $7 673, and $3 414, respectively).

Discussion

Using the base case parameters in this model, a generalized all-oral treatment regimen was cost-effective compared to SOC for a cohort of 50-year-old, monoinfected, cirrhotic and noncirrhotic subjects with genotype 1, 2 and 3 HCV infections. The model was robust to changes in treatment duration, nontreatment-related medical costs and QALY estimates, but sensitive to all-oral drug costs as well as rates of treatment uptake and SVR for noncirrhotic subjects. The cost ceiling for all-oral drugs was dependent on the WTP threshold and ranged from $74 217 at a $50 000/QALY WTP to $112 653 at a $100 000/QALY WTP. Depending on their budgets and priorities, diverse stakeholders may choose different WTP thresholds, which will affect the price at which these drugs can remain cost-effective compared to SOC.

The higher cost and lower SVR rates associated with SOC treatment for genotype 1 offer greater opportunity for cost reduction and QALY improvements compared to genotypes 2 and 3. As a result, all-oral treatment was most cost-effective for genotype 1 subjects. Cost per QALY gained was minimized in younger cohorts, possibly due to lower initial fibrosis levels among younger subjects and longer life expectancy after SVR.

This analysis has certain limitations. Because clinical trials investigating all-oral drugs are ongoing, most parameters involved in all-oral treatment are not yet known and were estimated from expert opinion. As additional data become available for a more generalizable population of CHC subjects, these parameters may need to be re-evaluated.

In addition, this model assumed that a 50-year-old CHC-infected cohort exhibited the same initial fibrosis distribution as the overall CHC-infected population. Because this age group falls into the high-risk 1945–1964 birth cohort likely to have been infected 20–30 years ago, this assumption may underestimate the true proportion of late-stage fibrosis and cirrhosis. A model including a higher percentage of late-stage disease may yield higher estimates of cost-effectiveness for all-oral drugs. Model costs associated with CHC treatment and care were based on direct medical costs only.

Due to the uncertainty of many parameters contributing to all-oral treatment and SVR, this model was designed to be conservative, and cost-effectiveness of all-oral treatment could be higher than we have reported for several reasons. Our model excluded certain groups that may ultimately be eligible for all-oral treatment. Specifically, although SOC treatment has demonstrated the potential to reduce reinfection following liver transplant, our model does not account for posttransplant treatment.[34]Similarly, it does not allow for treatment in those with HCC, which may be possible with all-oral drugs. Successful CHC treatment could allow some individuals with HCC to undergo cancer treatments for which they would otherwise be ineligible, potentially reducing HCC-related mortality and increasing cost-effectiveness of all-oral treatment. In addition, although clinical trial data demonstrate up to 90% SVR in some treatment-experienced subgroups, our model does not include treatment-experienced individuals, many of whom may be eligible for retreatment with all-oral drugs,[45,46] Once evidence-based estimates for treatment eligibility and outcomes are available for these groups, future models should account for late-stage treatment and retreatment with all-oral drugs to determine whether their inclusion impacts cost-effectiveness.

It is also possible that post-SVR fibrosis regression rates will be higher following treatment with all-oral drugs than our model has estimated. Even with SOC treatment, some subjects have demonstrated cirrhosis reversal after SVR, which we did not account for in our model.[47] The percentage of decompensated subjects treated with all-oral drugs may also be higher than we estimated due to tolerability of interferon-free regimens.

Finally, if advanced clinical trials confirm high expectations for SVR and tolerability of all-oral drugs, HCV screening efforts will likely intensify, and treatment uptake can be expected to increase from current low rates of 12–28%,[48,49] Uptake could increase more markedly than we have estimated, resulting in greater cost-effectiveness for all-oral regimens. Factors contributing to uptake include clinician confidence in treatment outcomes, the possibility of direct treatment by primary care physicians (possibly reducing loss to follow-up at the specialist referral stage), lower rates of discontinuation due to side effects and more widespread screening.

Universal clinical HCV screening in the general population has been demonstrated to be cost-effective under multiple scenarios,[28,50] and some researchers are investigating the feasibility and cost-effectiveness of targeted testing and treatment efforts in specific high prevalence populations such as prison inmates and high-risk birth cohorts, both to improve health and to curb further transmission.[6,17,51] Because of the increased SVR and tolerability of interferon-free regimens, all-oral treatments can be expected to reduce CHC-related morbidity and mortality beyond what is possible with current treatment options. Once these drugs become available in the clinic, it will be possible to determine whether broader treatment eligibility and greater opportunities for early treatment due to more aggressive screening efforts will have further implications for their cost-effectiveness.

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Source

 

 

A One-Tablet Cure for Hepatitis C May Be Here Sooner than You Think

Provided by The Motley Fool

By Todd Campbell | More Articles
December 30, 2013 | Comments (0)

Investors thinking the battle between hepatitis C drugmakers would calm following the FDA's approval of Gilead's (NASDAQ: GILD ) Sovaldi and Johnson & Johnson's (NYSE: JNJ ) Olysio are mistaken. Positive data for Gilead's single-tablet combination of its Sovaldi and ledipasvir reignites the race with AbbVie (NYSE: ABBV ) and Bristol-Myers (NYSE: BMY ) for a ribavirin and interferon free cure.

Moving in the right direction
Patients and doctors were likely applauding when the FDA approved Gilead's Sovaldi and J&J's Olysio in late 2013. The two treatments are ushering in a new generation of shorter, more effective treatments that rely less and less on side-affect laden drugs interferon and ribavirin.

However, both drugs still require dosing alongside those troublesome prior generation treatments -- at least for now. Sovaldi is approved for use with ribavirin, but without interferfon, in less-common genotype 2 and 3 patients. Sovaldi will need to be matched up with interferon in far more common genotype 1 cases, though. Meanwhile, Olysio will still be dosed with both those drugs for all patients.

That means that the hunt is still on to bring the first oral interferon-and-ribavirin-free treatment to market.

Quickly moving toward approval
Gilead took heat for shuttering a promising trial using Sovaldi alongside Bristol's daclatisvir in early 2013. In phase 2 trials, that combination produced a nearly 100% cure rate among patients who previously failed to respond to treatment by Vertex and J&J's Incivek or Merck's Victrelis.

Gilead's strategic decision to focus on its own in-house combination is still putting up impressive results, however, including a 96% cure rate. That success has Gilead forecasting that it may file the ribavirin- and interferon-free tablet for approval as early as the first quarter of 2014.

That puts it slightly ahead of AbbVie's three-drug interferon-free oral cocktail. AbbVie's combination therapy, which still relies on ribavirin, offered a similar 96% cure rate in phase 3 trials. The company will need to quicken the pace of its mid-year timeline if it hopes to beat Gilead in the race to file with the FDA, however.

This also gives Gilead a more attractive position to battle Bristol in overseas markets, especially if the combination proves more effective in genotype 1b, which is more common in countries like Japan. Bristol applied for approval of its daclatisvir interferon- and ribavirin-free combination in Japan during November.

Fool-worthy final thoughts
During phase 3 trials, Gilead's Sovaldi and ledipasvir combination not only cleared more cases of hepatitis C than the Sovaldi, ledipasvir, and ribavirin arm of the treatment, but did so with fewer side effects including nausea and insomnia. That positions it to win a big piece of the $20 billion market for hepatitis C treatments if it can win FDA approval. 

More data from Gilead's trials will be released in the first quarter, including information tied to the 24-week treatment course which could move the needle. Investors will also likely hear from Japan on Bristol's daclatisvir, and given Gilead's results it wouldn't be shocking to see AbbVie try to accelerate its filing as well. This suggests that investors should stay tuned because it's likely we haven't heard the last from any of these companies in their race to a more effective cure.

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Todd Campbell has no position in any stocks mentioned.  Todd owns E.B. Capital Markets, LLC. E.B. Capital's clients may or may not have positions in the companies mentioned. Todd also owns Gundalow Advisors, LLC. Gundalow's clients do not have positions in the companies mentioned. The Motley Fool recommends Gilead Sciences and Johnson & Johnson. The Motley Fool owns shares of Johnson & Johnson. Try any of our Foolish newsletter services free for 30 days. We Fools may not all hold the same opinions, but we all believe that considering a diverse range of insights makes us better investors. The Motley Fool has a disclosure policy.

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2013/12/30 22:49:49

Taipei, Dec. 30 (CNA) A new drug targeted at preventing the recurrence of liver cancer after it is treated surgically is expected to receive approval in most Asian countries by 2015, according to the company authorized to develop, produce and market the drug.

Third stage clinical trials of the drug, known as PI-88, reached their 500-patient target on Dec. 27, said Stanley Chang, chairman of Taipei-based Medigen Biotechnology Corp., and if the results meet expectations, drug approval applications will be filed sometime next year.

In Taiwan, the Food and Drug Administration has already launched a rolling review procedure for PI-88, and the company expects the new drug to obtain approval and marketing authorization by the end of 2014 at the earliest, Chang said.

According to Medigen, third-stage experimental trials on PI-88 were conducted at 25 medical centers in Taiwan, mainland China, Hong Kong and South Korea.

The Medigen chairman touted the drug in a press briefing as the world's first drug approved for post-surgical therapy for early-stage liver cancer.

The company won global commercialization rights for PI-88 from Progen Pharmaceuticals of Australia in 2010, and it has since attracted global attention, being recognized as an orphan drug in Europe and the United States, Chang said.

The new drug has also been taken seriously by authorities in Taiwan and China, and it is eligible for a cross-Taiwan Strait cooperation program for new drug research and development.

In the future, efforts will be taken to seek joint certification of the drug by Taipei and Beijing so that it can be sold throughout Greater China, where liver cancer is highly prevalent, Chang said.

In terms of PI-88's market scale, an assessment by the Academia Sinica's Institute of Biomedical Science found that the drug could generate between NT$52 billion (US$1.7 billion) and NT$73.8 billion in annual sales once it enters the global market.

(By Luo Hsiu-wen and Elizabeth Hsu)
Enditem/ls

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The 5 Most Common Infectious Diseases

Provided by The Motley Fool

By Sean Williams | More Articles
December 29, 2013 | Comments (0)

According to the World Health Organization, as of 2011 there were 12,420 different diseases and health-related ailments. In other words, you should be thanking your immune system and modern medicine before you go to sleep each and every night.

Of those numerous diseases, perhaps none is more common than infectious diseases, which are defined by WHO as "any pathogenic microorganism that can be spread directly or indirectly from one person to another."

flu-vaccine_large

Source: Daniel Paquet, Flickr.

In a given year, we are literally talking about billions of people that will contract an infectious disease. Keep in mind, of course, that this could be something as simple as the common cold, which is often nothing more than a nuisance, to something as serious as the HIV/AIDS virus, which has claimed nearly 14 million lives since the epidemic began in the 1980s. Based on WHO's statistics, the combination of AIDS, malaria, and tuberculosis is responsible for half (approximately 5 million) of all infectious-disease deaths each year.

With that in mind, today we're going to look at the five most common infectious diseases around the globe. As we go through these infectious diseases, one by one, understand that much of this data is estimated because it's difficult to get a bead on infection rates in developing countries where access to health-care can be limited. Therefore, the figures can be left up to a little interpretation based on the statistics from WHO and the Centers for Disease Control and Prevention.

In addition, we'll also look at what, if any, global pharmaceutical companies may be able to take advantage of these multi-million-person, and even billion-person, opportunities.

So, without further ado, here are the five most common infectious diseases.

Hepatitis-B
According to current statistics, hepatitis-B is the most common infectious disease in the world, affecting some 2 billion people -- that's more than one-quarter of the world's population. This disease, which is characterized by an inflammation of the liver that leads to jaundice, nausea, and fatigue, can lead to long-term complications such as cirrhosis of the liver or even liver cancer. The concern is primarily for those who carry the chronic form of the disease, which is estimated to be about 350 million people.

Perhaps one of the best known therapies here is Gilead Sciences' (NASDAQ: GILD ) Viread, which was approved in the U.S. in 2008 and blocks an enzyme that the hepatitis-B virus needs to replicate in liver cells. According to Gilead's third-quarter report, sales of the drug were up 11% through the first nine months over the previous year, and it should deliver more than $900 million in cumulative sales by the time fiscal 2013 is over. With a strong presence in AIDS therapies as well, Gilead is quickly becoming an infectious-disease juggernaut.

Another name to keep an eye on here is Dynavax Technoloogies (NASDAQ: DVAX ) . Although the FDA has been less than cooperative with Dynavax's attempts to bring Heplisav to market, implying that the company may need to run an additional trial to satisfy its safety concerns, Heplisav had demonstrated impressive efficacy in clinical trials.

Malaria
Malaria, a mosquito-borne disease that tends to affect children the most in tropical and subtropical climates, affects more than 500 million people annually and results in anywhere between 1 million and 3 million deaths. Behind hepatitis-B, it appears to be the second most-common infectious disease, and it certainly is one of the most deadly on an annual basis.

Increasing public awareness of the dangers of mosquitoes in tropical and subtropical climates has helped somewhat, but malaria cases have unfortunately been on the rise again in recent years. The most common anti-malarial medication available is an oral therapy known as Lariam, which the U.S. Army invented in the late 1980s but was licensed to Roche(NASDAQOTH: RHHBY ) , which sold it through August 2009. The drug is now sold in generic versions.

While a relatively effective first-line preventative treatment and second-line therapy following contraction of the disease, Lariam also has a laundry list of side-effects, including serious neurological and psychiatric side effects that, in July, prompted the FDA to beef up its stance concerning Lariam with a black-box warning.

Hepatitis-C
Hepatitis-C is a less common and less severe form of hepatitis, but it almost always develops into a chronic, not acute, condition, unlike hepatitis-B. Although only 3 million to 4 million new cases are reported each year, some 180 million people worldwide suffer from this chronic condition, which can lead to liver cancer or cirrhosis of the liver over time.

Advancements in the U.S. for treating hepatitis-C have been nothing short of breathtaking over the past three years. Three years ago, the standard of treatment involved pegylated interferon and a ribavirin over the course of 24 or 48 weeks. The net result was a response (not a cure, just a response) in around 50% of HCV-positive patients. With the approval of Gilead Sciences' Sovaldi earlier this month, patients with genotype 1 (the most common form of the disease) can expect a sustained virologic response, or SVR (an undetectable level of disease), after 12 weeks in more than 90% of cases.

In addition, AbbVie (NYSE: ABBV ) is also developing its own direct-acting antiviral combo drug, which has demonstrated a 12-week SVR of greater than 90% as well in the tough-to-treat genotype 1 patient subset. It's extremely rare to develop a cure for such a global disease nowadays, but we could well be on our way to one when it comes to treating hepatitis-C.

mosquito-biting_large

Source: U.S. Department of Agriculture, Wikimedia Commons.

Dengue
It's at times like these that we curse mosquitoes, because a very specific type of mosquito (Aedes aegypti) is responsible for the transmission of dengue to approximately 50 million people each year. Dengue is most common in Africa and Asia and thankfully occurs in only mild to moderate forms, which can cause high fever, severe headaches, and joint and muscle pain, but rarely leads to the death of the infected patient.

Amazingly enough, even though this infectious disease affects some 50 million people annually, there isn't a specific drug designed to treat dengue fever. The most commonly prescribed medication to reduce the symptoms associated with dengue fever is ... Tylenol. That's right, Johnson & Johnson's (NYSE: JNJ ) Tylenol, whose active ingredient is acetaminophen, works to reduce both fever and muscle pain in patients. In the most serious cases of dengue fever, IVs and blood transfusions may be needed.

Tuberculosis
As I mentioned previously, estimating new and ongoing cases for some of these diseases can be downright difficult, and perhaps none more so than tuberculosis. TB is caused by a bacteria found in the lungs that can cause chest pain and a bad cough, as well as lead to a number of other nasty side-effects. According to WHO, it's also the second-leading global killer behind AIDS as a single infectious agent.

The majority of TB-associated deaths (95%) occur in low- to middle-income countries where TB awareness and prevention simply aren't where they need to be. The good news is that TB death rates on a global basis are falling; however, there were still 8.6 million new cases of TB reported last year, and roughly one-third of the world's population carries a latent form of TB, meaning they've been infected but aren't ill and can't transmit the disease yet.

While many of today's TB treatments have long since come off patent, the FDA did approve a new drug in late 2012 named Sirturo, made by Johnson & Johnson, to treat multidrug-resistant TB. Plainly put, not all strains of TB respond to the common forms of treatment, and MDR-TB is an especially virulent killer, so Sirturo has a genuine shot at treating what is essentially the worst of the worst when it comes to TB strains. Peak sales estimates for the drug range between $300 million and $400 million.

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Fool contributor Sean Williams has no material interest in any companies mentioned in this article. You can follow him on CAPS under the screen name TMFUltraLong, track every pick he makes under the screen name TrackUltraLong, and check him out on Twitter, where he goes by the handle @TMFUltraLong.

The Motley Fool owns shares of, and recommends Johnson & Johnson. It also recommends Gilead Sciences. Try any of our Foolish newsletter services free for 30 days. We Fools don't all hold the same opinions, but we all believe that considering a diverse range of insightsmakes us better investors. The Motley Fool has a disclosure policy.

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Omar El Adl  /   December 30, 2013  /   0 Comments

Egyptian scientist Tarek Hassanein has been working on the development of one of the new drugs that promise a better future for patients suffering from Hepatitis C

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Dr Tarek Hassanein
(Photo from Chronic Liver Disease Foundation)

Millions of Egyptians suffer from genotype 4 Hepatitis C but new drugs scheduled to hit the market over the next two years have been making national headlines and giving patients hope. Daily News Egypt sat down with Dr Tarek Hassanein, an Egyptian doctor at the University of California San Diego who has contributed to the research behind one of the new drugs, to tell us what Egyptians can expect in the coming years.

“The new drugs have a 95% to 100% success rate,” said Dr Hassanein.

Dr Hassanein said that in 2004, scientists discovered more about the structure of the virus and took a new approach, “instead of stopping the virus in one step, stop it in two or three. We have been able to identify the enzymes responsible for the virus’ reproduction and target them.”

Dr Hassanein’s main contribution to the research came in the second phase of the development of the drug Sofosbuvir, when he was working with Pharmasset under Gilead Pharmaceuticals.

“They started testing on Hepatitis types 1, 4, 5, and 6. We found that the cure was 96% effective on type 4, which is most common here in Egypt. There is also another drug from Johnson and Johnson that has gotten FDA approval. Both drugs received FDA approval last December.”

One issue is that both drugs are very expensive. Gilead’s option costs $90,000 for a treatment that lasts three months and does not require injections, while Johnson and Johnson’s new drug costs a more affordable $66,000 but includes injections and needs to be taken for 6 months.

Dr Hassanein said there are many more drugs in the pipeline, “there is another drug scheduled for release in four months and the aim is to move beyond Interferon as the standard treatment by the end of 2014. Next year will see the release of three more drugs which makes a total of five different treatment options available and in 2015 two more are expected bringing the total up to seven new drugs to fight Hepatitis.  All these drugs track the virus differently and this plethora of options means more competition and less expensive drugs.”

Though many Egyptians are anxious to get their hands on the new drugs, Dr Hassanein said people must be patient, “Hepatitis C is chronic and takes 30, 40 or even 50 years before it becomes a cause of death. It is possible, with complications, for it to take only 10 to 15 years but even in these cases by then options will be available for patients.”

For those who are already at a critical stage Dr Hassanein said the new drugs may be unhelpful, “for example, patients with liver failure cannot handle Ribavirin or Interferon so these drugs will not work for them. Anyone in need of a liver transplant will likely have too much damage in their liver for the drugs to work.”

In less critical cases, however, Dr Hassanein said the drugs can reverse the damage done to the liver in five to seven years, provided that patients do not develop complications and avoid weight gain, drinking, smoking and other triggers. “Egyptian patients in particular need to stop taking medicine that has no basis in science. There are herbs advertised to ‘stimulate’ the liver that actually harm it. The rate of re-infection in Egypt is also unusually high. We need higher standards of cleanliness and sterilisation,” said Dr Hassanein.

Dr Hassanein stressed the importance of developing a system where Egypt can take part in the research and development of new drugs. He said the lack of a proper system was the main obstacle to cooperation of research and development with the government. “We were told that Egypt does not have the legal and scientific systems required to develop this drug here. This is partly why Egyptian patients were so concerned with human testing. They do not trust the system in place. In the US, patients sometimes offer to test new drugs because they know they are better protected and that the rules of the FDA are the international standard.”

Finally Dr Hassanein said that for the drug to be affordably available in Egypt, it should not be available only through the Ministry of Health for a special price but through multiple channels for everyone at the same price, “otherwise it will be too expensive, especially since the Ministry of Health cannot treat the required number each year. They have 23 centres in which they say 30,000 people receive treatment but in order to be effective they would need six times this amount.”

Affordable or not, by 2015 the global market will have at least seven new and different treatment options for patients with Hepatitis C, in all of its genotypes. And while Egyptian patients should be weary of expecting miracles, this cannot be but good news for the millions suffering in the country today.

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