Selected Themes at EASL 2013

Clinicians are eager to have safe, effective and convenient interferon-free treatment options for all HCV patients

Although clinical profiles of interferon-free regimens vary in different HCV genotypes and patient subpopulations, the perspective of treating all HCV patients with efficacious, safe and convenient all-oral therapy now seems feasible in light of abundant promising data from emerging HCV-specific direct antivirals. We believe interferon-free regimens will be the most widely used treatment option.

Emerging HCV-specific direct antivirals continue generating impressive clinical data (selected results reported below)

At EASL-2013, Gilead presented data from several sofosbuvir trials. The company acquired this nucleoside HCV polymerase inhibitor in a $11b acquisition of Pharmasset, and it keeps moving through clinical development demonstrating an excellent clinical profile. Although interferon-free sofosbuvir-based regimens generated impressive data in HCV3, other viral genotypes will require a longer duration of treatment and the addition of another direct antiviral into the regimen (the company is working on an IFN-free combination containing sofosbuvir and ledipasvir, which has already demonstrated excellent efficacy in HCV1 patients).

Abbott's IFN-free combination regimen (ritonavir-boosted protease inhibitor ABT-450, a NS5A inhibitor ABT-267, nonnucleoside inhibitor ABT-333, and ribavirin) demonstrated strong data in HCV1 patients. However, this regimen carries a higher pill burden than its future competitor Gilead's sofosbuvir / ledipasvir combination.

J&J's protease inhibitor simeprevir demonstrated a strong clinical profile in combination with peg-IFN/ribavirin; however, the commercial potential of this agent will depend on its performance in the IFN-free setting (J&J collaborates with several companies for evaluating interferon-free regimens combining simeprevir with antivirals daclatasvir (BMS), VX-135 (Vertex), IDX-719 (Idenix), and sofosbuvir (Gilead; however, we believe the companies are unlikely to continue development of this promising regimen since Gilead is developing a combination of sofosbuvir with its own NS5A inhibitor ledipasvir).

BMS's daclatasvir is the most advanced NS5A inhibitor in development. It has a high anti-viral potency and excellent safety; however, to achieve strong clinical results in the interferon-free settings it requires co-administration of additional direct antivirals. BMS is developing daclatasvir in combination with its own asunaprevir and BMS-791325 (efficacy of regimen lags that of sofosbuvir-based therapy in HCV1) and also collaborates with other companies for studying daclatasvir in interferon-free combinations with antivirals simeprevir (J&J), VX-135 (Vertex), and sofosbuvir (Gilead).

Treating now vs waiting for emerging combinations with improved clinical profiles to launch

Data on multiple emerging HCV therapies indicate that patients without co-morbidities and with slow liver fibrosis progression will benefit from waiting for the novel therapies (especially interferon-free regimens) with improved clinical profiles (better efficacy, safety and delivery) to become available as opposed to receiving currently available treatments. Novel therapies are forecasted to launch by 2014. Data from various HCV patient subpopulations indicate currently available regimens (Incivek- and Victrelis-based) are a good option for selected patients, but due to their suboptimal safety profile these regimens should be used carefully in patients with impaired liver function. Data from postmarketing trials support twice daily dosing of telaprevir and shorter duration of treatment for selected subpopulations, but we do not expect these results to have a major impact on declining sales of the first-generation HCV protease inhibitors; clinicians are warehousing most of their HCV patients in anticipation of interferon-free therapies.

Incivek and Victrelis perform well in real-life settings except in selected subpopulations

According to multiple reports at EASL, in the real-life settings the currently available HCV protease inhibitors Vertex / J&J/ MTP's Incivek / Incivo / Telavic and Merck's Victrelis demonstrated efficacy and safety similar to those shown in clinical trials. However, data from French Early Access Program (CUPIC) revealed low SVR rate (40%) of Incivek- and Victrelis-based regimens in prior nonresponders with compensated cirrhosis (50% in prior relapsers, 35% in partial responders, and 24% in null responders). Additionally, data from a large US cohort (3,732 commercially-insured and Medicare patients) revealed low treatment rate and low treatment completion rates.
Increasing attention to specific subpopulations
Clinicians are eager to see data for emerging HCV antivirals in special subpopulations including patients with liver cirrhosis and pre- and post-transplant patients. Data in these patients are limited for the first-generation direct antivirals (Incivek, Victrelis), but increasingly companies now include such patients into their clinical trial programs (e.g., sofosbuvir Phase III program includes a significant proportion of cirrhotic patients; trials in pre- and post-transplant patients are ongoing for interferon-free regimens by Gilead and Abbott).

HCV genotype 3 difficult to treat with direct antivirals

At the times of peg-IFN/ribavirin being a gold standard of HCV treatment, HCV genotype 1 was viewed as the most challenging genotype to be treated, while HCV2 and HCV3 were considered easier to treat genotypes and were lumped together in treatment algorithms. However, HCV3 infection now emerges as the hardest-to treat with direct antivirals. Indeed, although emerging HCV therapies allow shortening duration of treatment and elimination of interferon injections for HCV2 patients, results are less optimistic for HCV3. Data indicate that clinicians will likely have to treat HCV2 and HCV3 patients with different therapies. HCV3 genotype will likely require longer treatment duration and (similar to HCV1) more complicated treatment regimens combining more than one direct antiviral agent.

HCV therapy in low-income countries

The high price of novel HCV-specific direct antivirals is expected to restrain the use of these drugs in low-income countries. Unless price negotiations allow decreasing the cost of HCV treatment significantly compared to the major markets (as happened in Egypt for pegylated interferon), we do not expect significant uptake of direct antivirals in these geographies.

Selected Data on Emerging HCV Direct Antivirals from EASL-2013 Meeting

GILEAD

1. Sofosbuvir works well in combination with ribavirin in HCV2, but not so well in HCV1 and HCV3 patients.

1a. To be used in IFN-free setting in these subpopulations sofosbuvir will need co-administration of another direct antiviral.

All-oral interferon-free sofosbuvir + ribavirin treatment regimen demonstrated a very good efficacy in HCV2 patients (treatment-naive and prior nonresponders), including those with cirrhosis. The regimen was less efficacious in patients infected with HCV3 genotype (especially those with cirrhosis). Interferon-free sofosbuvir + ribavirin therapy was efficacious in patients for whom interferon is not an option (those who discontinued peg-IFN due to adverse events or have never started peg-IFN therapy owing to contraindications). Notably, cirrhotic patients who currently have very limited treatment options achieved high cure rate. Tables below highlight sustained virologic response rate 12 weeks after treatment (SVR12) data from Phase III sofosbuvir trials.

FISSION; Phase III; N=250

HCV2, HCV3 treatment-naive

HCV 2

HCV3

overall

no cirrhosis

cirrhosis

overall

no cirrhosis

cirrhosis

sofosbuvir + ribavirin 12 weeks

97%

98%

91%

56%

61%

34%

Peg-IFN + ribavirin 24 weeks (control)

78%

--

--

63%

--

--

FUSION; Phase III; N=201
HCV2, HCV3 prior nonresponders

HCV 2

HCV3

no cirrhosis

cirrhosis

no cirrhosis

cirrhosis

sofosbuvir + ribavirin 12 weeks

96%

60%

37%

19%

sofosbuvir + ribavirin 16 weeks

100%

78%

63%

61%

POSITRON; Phase III; N=278
HCV2, HCV3; IFN not an option

HCV 2

HCV3

no cirrhosis

cirrhosis

no cirrhosis

cirrhosis

sofosbuvir + ribavirin 12 weeks

92%

94%

68%

21%

1b. Sofosbuvir performs great in HCV1 in IFN-free setting in combination with other direct antiviral agents and ribavirin.

Although sofosbuvir + ribavirin combination demonstrated a suboptimal efficacy in HCV1 patients (especially in prior null-responders to peg-IFN + ribavirin therapy), addition of another direct antiviral to the regimen improved efficacy dramatically see the table below. A combination of sofosbuvir with Gilead's own NS5A inhibitor ledipasvir is currently in development as a fixed-dose combination, which will increase convenience of the regimen via decreasing pill burden.

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