WHO Essential Medicines List Application DACLATASVIR

1. Summary statement of the proposal for inclusion, change or deletion This submission proposes daclatasvir as a new inclusion on the WHO EML. Daclatasvir (DCV) is a newly- approved direct acting antiviral (DAA) medicine for treatment of hepatitis C (HCV), a disease that affects approximately 170 million people globally, causing half a million deaths each year. Used in combination with other HCV medicines, DCV has pan-genotypic potential, results in high cure rates and is well-tolerated. The introduction of DAA-based HCV therapy has helped enable new 2014 WHO guidelines on the treatment of HCV disease and has also enabled greater interest on the part of national government and international actors to support programming to treat HCV.

In order to facilitate the move to providing diagnosis, care and treatment for HCV globally, it will be critical that key DAAs are made available to populations in need. The most important DAAs are those that have high efficacy (including in special populations such as people living with HIV), safety, are pan-genotypic, and have low risk for drug-drug interactions with common medicines, such as antiretroviral drugs. Daclatasvir meets these criteria. Inclusion of DCV on the WHO Essential Medicines List will help provide a signal to manufacturers, generic producers, country programmes and international donors that this DAA will be a key medicine to help treat HCV.

2. Name of the focal point in WHO submitting or supporting the application (where relevant) Philippa Easterbrook

3. Name of the organization(s) consulted and/or supporting the application

MSF/Médecins Sans Frontières - Access Campaign Rue de Lausanne 78 P.O Box 116 1211 Geneva, Switzerland Contact: Jennifer Cohn, Medical Coordinator ([email protected])

4. International Nonproprietary Name (INN, generic name) of the medicine Daclatasvir (as dihydrochloride)

5. Formulation proposed for inclusion; including adult and paediatric (if appropriate) Daclatasvir (as dihydrochloride), Daklinza®, manufactured by Bristol Myers Squibb--BMS 30mg as oral administration (tablet), for adults. Each film-coated tablet contains daclatasvir dihydrochloride equivalent to 30 mg daclatasvir and contains 58 mg of lactose (as anhydrous).

Daclatasvir (as dihydrochloride), Daklinza®, manufactured by Bristol Myers Squibb--BMS 60mg as oral administration (tablet), for adults. Each film-coated tablet contains daclatasvir dihydrochloride equivalent to 60 mg daclatasvir and contains 116mg of lactose (as anhydrous).

6. International availability - sources, of possible manufacturers and trade names Daclatasvir 30 mg tablet, as dihydrochloride (Trade name: Daklinza®; Manufacturer: Bristol Myers Squibb-- BMS), EMA approved on August 22nd 2014.

Daclatasvir 60 mg tablet, as dihydrochloride (Trade name: Daklinza®; Manufacturer: Bristol Myers Squibb-- BMS), EMA approved on August 22nd 2014.

7. Whether listing is requested as an individual medicine or as an example of a therapeutic group The request for inclusion is for the single medicine Daclatasvir, both the 30mg and 60mg strengths. 1

8. Information supporting the public health relevance (epidemiological information on disease burden, assessment of current use, target population)

Epidemiology and burden of disease Chronic Hepatitis C virus (HCV) infection is a major pandemic, affecting almost 170 million individuals worldwide and killing about 500,000 people each year (Kanda, Yokosuka, & Omata, 2013). The majority of these people live in resource-poor settings where there is currently little or no provision for diagnosis or treatment and low- and middle-income countries (L&MICs) alone account for over half of the HCV-related mortality (The Economist, 2012; Center of Disease Analysis). The prevalence rate of the disease varies depending on the global regions; regions with high prevalence rate (over 3.5%) include Central Asia covering Mongolia, China, South-East Asia, and North Africa. Regions with low prevalence rate (below 1.5%) include Asia covering South Korea and Japan, North America including the United States (US), and South America. (KASL clinical practice guidelines: Management of Hepatitis C, 2014). Studies estimate that between 3 and 4 million new patients are infected with HCV every year and that the disease burden will continue to grow (UNITAID Secretariat, 2013).

In L&MICs, the transmission of HCV is mainly nosocomial - via contaminated blood transfusions or unsafe injection practices (Prati, 2006). Estimates suggest that up to 40% of all HCV infections worldwide are the result of unsafe medical practices (Papatheodoridis & Hatzakis, 2012). Other routes of transmission include sexual transmission, usually involving men who have sex with men (MSM), and transmission among intravenous drug users (IVDUs) (UNITAID Secretariat, 2013). In some countries, HCV prevalances among IVDU’s reaches 90% (Papatheodoridis, 2012). Mother-to-child transmission has also been reported. The risk of perinatal HCV transmission was higher in female infants, HIV-positive mothers, and mothers with high blood HCV RNA levels. For example, among mothers who were positive for HCV-RNA there was a transmission rate of 4.3% versus 1.7% among all anti-HCV positive mothers (KASL, 2014).

Six different HCV genotypes exist. This is significant as the different genotypes have different responses to HCV treatment, both for pegylated-interferon based treatment and direct acting antiviral (DAA) treatment. Globally genotype 1 is most common (42%), followed by genotype 3 (26%) and 2 (17%) (Razavi, 2013). Genotype 1a is most common in Northern Europe, North America and parts of Latin America while genotype 1b is most common in Central and Far East Asia and Central, East and Southern Europe. Genotype 3 is most common in South Asia and genotype 4 is most common in the Middle East, Egypt, and Central Africa. Genotype 5 is common in South Africa and genotype 6 is common in Hong Kong, Macau, and Vietnam (KASL, 2014).

HCV/HIV co-infection

2 Between 4-5 million people with human immunodeficiency virus (HIV) and HCV are estimated to be co- infected, representing 16% of people living with HIV globally (UNITAID Secretariat, 2013). Common modes of transmission for HIV and HCV may lead to a high prevalence of co-infection in key populations such as IVDUs and MSM populations. In sub-populations like these, rates of co-infection can exceed 60% (Solomon et al., 2008). Co-infection of HIV and HCV have negative and reciprocal clinical implications for patients. HIV accelerates the progression of HCV. Those with co-infection progress to significant liver disease and cirrhosis much more quickly and more often than those only infected with HCV alone, with nearly 80% developing liver damage (Deng, 2009; Limketkai et al., 2012; Lo Re et al., 2012; Hadigan & Kottilil, 2011). Despite patients taking anti-retroviral therapy (ART), patients with HIV-HCV co-infection remain at significantly increased risk of overall mortality as compared to their HIV mono-infected peers (Anderson, Guest & Rimland, 2004). Further, co-infection with HCV in the era of ART is associated with worse HIV-related outcomes including weaker immune recovery with ART (lower mean CD4 counts), more rapid progression to AIDS, higher levels of HIV virus in the blood, poorer virological control on highly active antiretroviral therapy (HAART) (11% loss of ART efficacy in co-infected patients), and more common neurocognitive deficits (Greub et al., 2000; Pulido, van Delft & Moecklinghoff, 2012; Vivithanaporn et al., 2012).

Chronic HCV infection is independently associated with a 50% increase in mortality among patients with a diagnosis of AIDS (Branch et al., 2012). Even in the era of ART, HCV represents a substantial cause of morbidity and mortality for people living with HIV/AIDS (PLWHA). In a multicentre cohort study of PLWHA in high-income countries, liver disease was considered the number one cause of non-AIDS related mortality, causing 14-18% of all deaths (Weber et al., 2006). This is not very far behind AIDS-related mortality in overall mortality for PLWHA. Another cohort showed that by 2005, HCV-associated liver- related mortality accounted for nearly 17% of deaths among PLWHA (Rotman & Liang, 2009; Vivithanaporn et al., 2012).

HCV-related mortality is undoubtedly set to increase in light of the high prevalence of HCV/HIV co- infection now documented in some countries and the increased morbidity and mortality in these patients (Rotman & Liang, 2009; The Economist, 2012). Further, while safer injection practices may help to decrease HCV transmission in the future, given the natural history of HCV, morbidity and mortality related to HCV is likely to increase over the coming decades unless treatment becomes more widely available. Several models using data from high-income countries have shown that rates of HCV-related morbidity and mortality continue to rise several decades after HCV incidence has peaked (Deuffic-Burban et al., 2007).

Thus, the burden of HCV in co-infected individuals will become more pronounced, both due to the natural history of the disease, and due to its increasing importance as other AIDS-related causes of death decrease with increasing ART use. In order to maximise the benefits from increased ART use globally, interventions

3 designed to address the growing burden of HCV in PLWHA must be rapidly rolled out. Without such interventions, many lives saved by ART will soon be lost to HCV.

Current use Due to a range of factors, use of daclatasvir is extremely limited currently. Daclatasvir is a new direct acting antiviral (DAA) for HCV and was approved by the European Medicines Agency on 22 August, 2014 (European Medicines Agency Press Office, 2013). Thus, its use has been limited, although patients have been treated both as part of clinical trials and through a compassionate use programme. 798 patients have received daclatasvir as part of clinical trials, including compassionate use as of 16 October 2014, and an unknown but small number as part of market use (Bristol-Meyers Squibb Pharmaceutical Limited, 2014).

Target Population The WHO 2014 HCV guidelines recommend HCV screening for all individuals who are part of a population with high background HCV seroprevalence or who have a history of HCV risk exposure or behavior. This includes people living with HIV, people who have received medical or dental procedures in settings where infection control practices are sub-standard as well as people who inject drugs or use drugs internasally. These guidelines also provide a strong recommendation that all patients with chronic HCV be assessed for potential HCV treatment (World Health Organization, 2014). According to WHO guidelines, all patients who are chronically infected with hepatitis C should be assessed for hepatitis C therapy, including HIV-HCV co-infected patients, people who use injected drugs and those with compensated cirrhosis. This recommendation includes treatment with DAAs such as daclatasvir. The European Association for the Study of the Liver (EASL) recommends treatment for all patients with moderate or severe liver fibrosis (METAVIR F2 or higher) and states that for patients with no or mild fibrosis, the decision to treat can be individualized.

9. Treatment details (dosage regimen, duration; reference to existing WHO and other clinical guidelinces; need for special diagnostics, treatment or monitoring facilitites and skills)

Daclatasvir is an oral NS5A inhibitor that is licensed by the European Medicines Association for the treatment of hepatitis C infection, in combination with other drugs active against HCV. The main goal of hepatitis C treatment is to cure HCV infection (as defined by those who achieve a sustained virological response (SVR) at 12 or 24 weeks post-treatment) and to prevent complications or mortality from liver cirrhosis and Hepatocellular Carcinoma (HCC) (Bruno et al., 2007). The current WHO HCV treamtent guidelines do not include daclatasvir as they were released before the approval of daclatasvir. However, these guidelines do include recommendations for the available DAAs, including sofosbuvir and simeprevir, which were on the market at the time of guideline publication and these closely reflect other expert guidelines such as the EASL and American Association for the Study of the Liver (AASLD) HCV treatment guidelines. The next update of the WHO guidelines is expected to include recommendations for use of

4 daclatasvir in treating patients with HCV (personal communication with Stefan Wiktor, team leader of the WHO’s Global Hepatitis Program, and Philippa Easterbrook, senior scientist at the WHO’s HIV department).

EASL guidelines support the use of daclatasvir for treatment of HCV (European Association for the Study of the Liver, 2014): • Genotype 1: Daily daclatasvir (60 mg) plus daily sofosbuvir (400 mg) for 12 weeks for treatment naïve patients or 24 weeks for treatment-experienced patients. • Genotype 1b: Daily daclatasvir (60 mg) plus weekly pegylated IFN-α plus daily weight-based ribavirin (1000 or 1200 mg in patients <75 kg or ≥75 kg, respectively) for 24 weeks. For patients who achieve an HCV RNA level <25 IU/ml at week 4 and undetectable at week 10, daclatasvir may be discontinued after week 12 and the patient treated with PEG-RBV for weeks 12-24. • Genotype 2: Daily daclatasvir (60 mg) plus daily sofosbuvir (400 mg) for 12 weeks • Genotype 3: Daily daclatasvir (60 mg) plus daily sofosbuvir (400 mg) for 12 weeks for treatment naïve patients or 24 weeks for treatment-experienced patients. • Genotype 4: Daily daclatasvir (60 mg) plus weekly pegylated IFN-α plus daily weight-based ribavirin (1000 or 1200 mg in patients <75 kg or ≥75 kg, respectively) for 24 weeks. For patients who achieve an HCV RNA level <25 IU/ml at week 4 and undetectable at week 10, daclatasvir may be discontinued after week 12 and the patient treated with PEG-RBV for weeks 12-24. • Genotype 4: Daily daclatasvir (60 mg) plus daily sofosbuvir (400 mg) for 12 weeks for treatment naïve patients or 24 weeks for treatment-experienced patients.

Contraindications to use of daclatasvir will include pregnancy, hypersensitivity to daclatasvir or hemodialysis (EASL, 2014; BMS, 2014). No data exist on the effect of daclatasvir on pregnancy, but daclatasvir has been associated with teratogenic and embryotoxic effects in animals (BMS, 2014). Women should use contraception during use and for 5 weeks thereafter. No dosage adjustments are needed for renal impairment (except dialysis), nor for moderate or severel liver impairment (BMS, 2014). Daclatasvir is metabolized via the cytochrome P450 3A4. Thus it is recommended that with concomitant administration of strong inducers cytochrome P450 3A4 to increase the daclatasvir dose to 90mg or consider change therapy. It is recommended that with the concomitant use of strong inhibitors of cytochrome P450 3A4 to reduce the daclatasvir dose to 30 mg. Daclatasvir can be taken with or without meals (BMS, 2014).

Hepatitis C diagnosis includes an initial HCV serologic test, a virologic confirmation test and a HCV genotype. Liver staging by liver biopsy, liver ultrasound elastography or through use of indirect seromarkers (e.g. APRI, based on AST, ALT and platelets) is recommended to determine the degree of liver fibrosis. Baseline labs and monitoring will depend on whether daclatasvir is used in pegylated interferon-free regimen or not. When used with pegylated interferon, monitoring will include full blood count, creatinine, Alt

5 measured at baseline, weeks 1, 2, 4, 8, 12 (and 24 if the regimen continues to 24 weeks) and TSH at baseline, week 12 and 24. For regimens that do not include interferon, thyroid function (by measuring TSH) will not be needed. Daclatasvir does not require the need for special diagnostics such as pre-treatment resistance testing.

10. Summary of comparative effectivness in a variety of clinical settings:

A systematic review was performed using Pubmed, Medline and Embase databases with the search term daclatasvir, BMS-790052 or Daklinza either as in the title or as a keyword. Additionally, abstracts of the 2013 and 2014 AASLD and EASL conferences and the journals Hepatology and Journal of Hepatology were searched with the same searchterms. 31 titles were identified of which 15 clinical trials with efficacy outcomes were included. Overall, the quality of the included studies was high (see GRADE table of phase 2b and 3 studies) and efficacy, as defined by SVR12 or 24, with daclatasvir-containing (both interferon-sparing and interferon-free) regimens is excellent, with large numbers of patients with GT 1 studied and smaller numbers of patients with GT2, 3 and 4 included. Overall, 79.2% (476 of 601) of patients in daclatasvir trials and eligible to be included in a long-term follow up assesemnt achieved SVR12. This follow up study of all trials including daclatasvir-containing regimens has also revealed that HCV cure is durable, with 99% (471 of 476) of patients who achieve SVR12 maintaining SVR at the most recent follow-up assessment (Reddy, 2014).

In vitro studies demonstrated potent pan-genotypic activity (gentoypes 1-6) (Fridell et al., 2011; Wang et al., 2012; Wang et al., 2013). Initial phase 2a blinded parallel-group studies performed in 48 patients with genotype 1 looked at escalating doses of daclatasvir plus PEG-RBV to find an appropriate dose according to achieving undetectable HCV viral load 12 weeks after starting treatment. In this study, five of 12 patients (42%, 80% CI 22–64%) who received 3 mg daclatasvir, ten of 12 (83%, 61–96%) who received 10 mg daclatasvir, ten of 12 (83%, 61-96%) who received 60 mg daclatasvir, and one of 12 (8%, 1–29%) who received placebo achieved SVR24 (Pol et al., 2012). Thus, a dosage of 60mg by mouth daily was taken forward for further clinical trials. These trials have examined daclatasvir’s efficacy in genotype 1a, 1b , 2, 3 and 4.

Genotype 1 Several phase 2a studies looked at daclatasvir (60mg once daily) with either the nonstructural protein 3 protease inhibitor, asunaprevir (initially 600 mg twice-daily, then subsequently reduced to 200 mg twice- daily) or with PEG-RBV. Lok et al. looked at 21 patients with genotype 1 who had previously failed to achieve ≥2 log decline in HCV RNA after ≥12 weeks of treatment with PEG-RBV and treated them either with daclatasvir and asunaprevir (group A) or daclatasvir, asunaprevir and PEG-RBV (group B) for 24 weeks. Group A and B had, respectively, a median age of 54 years and 56 years, 82% male and 40% male,

6 82% caucasian and 70% caucasian and 91% and 90% CT or TT IL28B genotypes (associated with unfavorable outcomes for PEG-RBV treatment). In the daclatasvir and asunaprevir group, 2 of 9 patients with genotype 1a and 2 of 2 with genotype 1b achieved cure as defined by SVR12. In the daclatasvir, asunaprevir and PEG-RBV group, 10 of 10 achieved SVR 12 and 9 of 10 achieved SVR 24 (sustained virologic response at 24 weeks after the end of therapy) (Lok et al., 2012). Thus, it was determined that the dual-DAA all oral daclatasvir and asunaprevir combination would only be tested in genotype 1b. Larger phase 2b trials have also looked at daclatasvir and PEG-RBV. COMMAND-1 studied 24 weeks of daclatsvir 20mg or 60mg daily and PEG-RBV in patients with either genotype 1 or 4. In the 20mg and 60mg groups, respectively patients had median age of 50 and 51, 67% and 65% were male, 9% and 13% Black 72% and 77% genotype 1a and 63% and 65% IL28B CT or TT genotypes. SVR12 for the 20mg, 60mg and PEG-RBV groups, respectively were 59%, 58% and 38% for GT1a and 78%, 87% and 31% for GT1b (Hezode et al., 2012). COMMAND-2 evaluated 24 weeks of 20mg or 60mg of daclatasvir and PEG-RBV for 419 patients with genotype 1 and prior null or partial response to PEG-RBV. Significantly, 17.4% had cirrhosis; 92.6% had either IL28B CT or TT genotypes. After 12 weeks of treatment, HCV viral load undetectable was reached in 30% (DCV 20 mg) and 34% (DCV 60 mg) among null responders and 44% (DCV 20 mg), 57% (DCV 60 mg), among partial responders (Ratziu et al., 2012).

In another open-label phase 2a study, Chayama et al studied 10 Japanese patients with chronic HCV genotype 1b infection and previous null response (<2 log10 reduction in HCV RNA after 12 weeks) to Peg- IFN and RBV treatment. The subjects’ mean age was 62 years, 40% were male and only 2 patients had the IL28B CC genotype, which is associated with better treatment outcomes for PEG-RBV therapy. In this study, patients received daclatasvir and asunaprevir treatment for 24 weeks. Nine of the ten patients completed the 24 weeks of treatment and 9 of 9 achieved SVR12. One patient discontinued treatment after 2 weeks secondary to grade 4 bilirubin elevation. This patient also acheved SVR12 (Chayama et al., 2012). In a similar open-label, phase IIa study by Suzuki et al., the researchers treated Japanese patients with chronic

HCV genotype 1b infection, including 21 null responders (<2 log10 HCV RNA reduction after 12 weeks of peginterferon/ribavirin) and 22 patients intolerant to peginterferon/ribavirin therapy. Null responders and intolerant subjects had, respectively, a median age of 61 and 68, 38% and 27% male, 85% and 27% IL28B CT genotype. Both groups received daclatasvir and asunaprevir for 24 weeks. The primary efficacy endpoint was SVR 12 weeks post-treatment. Overall, 76.7% of patients achieved SVR12 and SVR24, including 90.5% of null responders and 63.6% of ineligible/intolerant patients (Suzuki et al., 2013). Daclatasvir and asunaprevir have also been studied in combination with either ribavirin or PEG-RBV. Lok (2014) studied 101 previous null responders in 4 groups: 38 genotype 1b patients treated with asunaprevir (200 mg) twice- (DUAL A1) or once-daily (DUAL A2); 36 genotype 1a and 5 genotype 1b patients treated with asunaprevir twice- (QUAD B1) or once-daily (QUAD B2) plus PegIFN/RBV; and 18 genotype 1a and 4 genotype 1b patients treated with asunaprevir twice-daily plus ribavirin (TRIPLE B3). The primary endpoint was SVR12. SVR12 rates were 78% for DUAL A1, 65% for DUAL A2, 95% for QUAD B1, 95% for QUAD B2 and

7 23% for TRIPLE B3. In the TRIPLE B3 arm, only 1/18 patients with genotype 1a achieved SVR, compared with 4/4 patients with genotype b1. This confirmed that the combination asunaprevir and daclatasvir with or without ribavirin has high efficacy for genotype 1b, but not 1a (Lok et al., 2014).

A phase 3 study also performed in Japan included 135 PEG-intolerant patients and 87 who had previously failed treatment with PEG-RBV with HCV genotype 1b and treated these patients with daclatasvir 60mg once daily and asunaprevir 10mg twice daily for 24 weeks. The primary endpoint was defined as SVR24. Significantly, this trial included cirrhotic patients. Subject characteristics of PEG-intolerant and previous treatment failures were, respectively, 64 years and 60 years, 28% and 44% male, 30% and 81% IL28B CT or TT. SVR24 was achieved by 87.4% of PEG-intolerant patients and 80.5% of previous treatment failures (null and partial responders); rates were similar in cirrhotics (90.9%) and non-cirrhotics (84.0%), and in patients with IL28B CC (84.5%) or non-CC (84.8%) genotypes (Kumada et al., 2014). Another phase 3 study evaluated daclatasvir and asunaprevir for 24 weeks in a variety of patients, including treatment naïve patients, those with partial or null response to PEG-RBV, PEG-intolerant patients and those with cirrhosis. SVR12 rates were similar across all groups and did not significantly differ between non- cirrhotic (85%; n = 437) and cirrhotic (84%; n = 206) patients (Manns et al., 2014). Another phase 3 trial in Japan compared the combination of daclatasvir 60mg once daily and asunaprevir 100mg twice daily for 24 weeks (n=119) or telaprevir and PEG-RBV for 12 weeks plus an additional 12 weeks of PEG-RBV (n=111) in treatment naïve GT1b patients. An additional arm assessed daclatasvir and asunaprevir for 24 weeks for prior non-responders to PEG-RBV. SVR 12 was achieved in 89% of treatment-naive patients receiving daclatasvir+asunaprevir vs. 62% of patients receiving telaprevir+PEG-RBV. No differences were observed in SVR12 based on age, IL28B genotype, HCV viral load or fibrotest score. In patients who relapsed on previous PEG-RBV therapy, 96% achieved SVR12 (Chayama et al., 2014).

Adding another oral DAA, BMS-791325 (a non-nucleoside NS5B inhibitor), to daclatasvir and asunaprevir has also lead to high rates of cure in genotype 1. A phase 2a study evaluated this triple-DAA regimen (daclatasvir 60mg daily, asunaprevir 200mg twice daily and BMS-791325 at either 75mg or 150mg twice daily) without ribavirin for 12 or 24 weeks in 66 treatment-naïve patients. Subjects had a median age of 50 years, 39% were male, 18% were African American, 74% had HCV genotype 1a and 70% had IL28B CT or TT genotypes. Based on a modified intention to treat analysis, 92% achieved SVR12, with similar results regardless of duration of treatment (12 vs. 24 weeks), between patients with HCV genotype 1a or 1b and regardless of IL28B genotype (Everson et al., 2014a). A study expansion then included an additional 46 previous null responders to PEG-RBV, including 10% cirrhotic patients, in either the 12 or 24 week groups. In a modified intention to treat analysis, SVR12 was achieved in 91% of the 12 week group and 92% of the 24 week group, including 100% of the cirrhotic patients (Everson et al., 2014b).

Other studies have evaluated the all-oral DAA combination of daclatasvir and sofosbuvir (SOF). Sulkowski et al. treated HCV genotypes 1, 2 and 3 with daclatasvir 60mg once daily plus sofosbuvir (a NS5B

8 polymerase inhibitor) at a dose of 400 mg orally once daily, with or without ribavirin, for 12 or 24 weeks, with previously treated subjects all receiving 24 weeks of therapy. Subjects included those who were previously untreated and those who had virologic failure with treatment with PEG-RBV plus either the protease inhibitor telaprevir or boceprevir. Median age of these experimental group ranged from 54-59, 47%- 64% were male and 5%-17% were Black. Among patients with genotype 1 infection, 98% of 126 previously untreated patients and 98% of 41 patients who failed treatment with HCV protease inhibitors achieved SVR12. Success rates were not significantly affected by use of ribavirin or not for either the treatment-naïve or the previously treated groups nor by the duration of therapy (12 or 24 weeks) (Sulkowski et al., 2014).

One study has evaluated 23 patients with genotype 1 treated with 12 weeks of the combination of daclatasvir and VX135 (100mg or 200 mg daily), a uridine nucleotide analog HCV NS5B inhibitor. Median age of subjects was 52 years, 52% were male, 100% were White, 78% had HCV genotype 1a and 61% had IL28B CT or TT genotypes. In the intention to treat analysis, 73% and 83% of those treated with daclatasvir+VX135 100mg and daclatasvir+VX135 200mg, respectively achieved sustained virological response at 4 weeks post-treatment (Gane et al., 2014).

Non-Genotype 1

151 treatment-naïve patients with genotype 2 or 3 were treated either with Daclatasvir and PEG-RBV for 12 or 16 weeks or standard 24 weeks of PEG-RBV. Twenty-two percent of GT3 and 1.4% of GT2 patients were cirrhotic. A modified intention to treat analysis demonstrated SVR12 of 88%, 83% and 71% in the 16 week, 12 week and control arms, respectively, for GT2 and 78%, 69% and 52%, respectively, for GT3. Relapse was higher for GT3 cirrhotics in the 12, but not 16 week arms (Dore et al., 2014).

Sulkowski (2014) also evaluated treatment-naïve patients with HCV genotype 2 or 3 treated with daclatasvir and sofosbuvir with or without ribavirin for 24 weeks. Overall, 92% of 26 patients with genotype 2 infection and 89% of 18 patients with genotype 3 infection achieved SVR12 (Sulkowski et al., 2014). Asselah’s study showed similar results with 100% of patients treated with 12 weeks of daclatasvir+sofosbuvir, 88% of patients treated with 7-day lead-in of sofosbuvir and then 12 weeks of daclatasvir+sofosbuvir and 86% of patients treated with 12 weeks of sofosbuvir+daclatsvir+RBV achieving SVR12 (Asselah, 2014).

The ALLY-3 study evaluated the effect of 12 weeks of daclatasvir 60mg+sofosbuvir 400mg daily for the treatment of genotype 3 disease in 101 treatment-naïve and 51 treatment-experienced subjects. The population characteristics of the treatment-naïve and –experienced subjects were, respectively: male 57% and 63%; white 91% and 88%; cirrhosis 19% and 25%. SVR12 in this study was 90% and 86% for the treatment-naïve and –experienced patients, respectively (Nelson et al., 2014).

Thirty genotype 4 patients were treated with either 20mg or 60mg of daclatasvir and PEG-RBV in the COMMAND-1 study. In the 20mg, 60mg and PEG-RBV groups respectively SVR12 was achieved in 67%, 100% and 50% of patients (Hezode et al., 2012). The COMMAND-4 study enrolled only patients with GT4

9 and randomized patients to either daclatasvir+PEG-RBV (n=82) or placebo+PEG-RBV (n=42) for 24 weeks. Median age was 49 years, 77% were white, 19% were black/African-American, 4% were Hispanic or Latino, 10% percent had compensated cirrhosis, and 75% of patients had IL-28B CT or TT genotypes. SVR12 was achieved in 82% vs 42% of patients on daclatasvir+PEG-RBV vs placebo+PEG-RBV (BMS, 2014).

Special populations Several of the above clinical trials have included subjects with advanced fibrosis or cirrhosis. A pooled anlaysis of these studies revealed that the efficacy of all-oral daclatasvir-containing regimens did not vary by fibrosis stage. In phase 3 studies of daclatasvir+asunaprevir, SVR12 was achieved by 84-91% of cirrhotic patients (N=228) and by 84-85% of non-cirrhotic patients (N=637). Studies of the combination of sofosbuvir+daclatasvir ± RBV, SVR on or after posttreatment Week 12 was achieved by 100% of patients with advanced fibrosis (F3/F4–F4; N=32) and by 98% of patients with F0-F3 (N=179) (Jensen et al., 2014). Several studies are either recently completed or on-going to evaluate the efficacy of daclatasvir in HIV-HCV co-infection, including NCT01866930, a phase 3 study to evaluate daclatasvir+PEG-RBV in HIV/HCV co- infected patients with GT 1, 2, 3 or 4; NCT02124044, a phase 2 study to assess safety and efficacy of daclatasvir+asunepravir in HIV/HCV co-infected patients with GT1b; NCT01471574, a phase 3 study to evaluate daclatasvir+PEG-RBV in HIV/HCV co-infected patients with GT 1; NCT02032888, a phase 3 study to evaluate daclatasvir+sofosbuvir in HIV/HCV co-infected patients with GT 1, 2, 3, 4, 5, 6; and NCT01725542, a phase 2 study to evaluate the safety and efficacy of daclatasvir+asunaprevir+PEG-RBV in HIV/HCV co-infected patients with HCV genotype 1 or 4 and prior null response to PEG-RBV.

At this point, no data on patients <18 years old are available.

Based on the above review of the literature, there is high-quality evidence supporting daclatasvir’s use in the treatment of hepatitis C. Please see the summary and GRADE tables.

Preferred combinations Although daclatasvir has shown a favorable efficacy profile with a number of different combinations, including interferon-sparing (PEG-RBV+DCV), DCV+asunaprevir, DCV+asunaprevir+ BMS-791325 and DCV+SOF+/-RBV, we suggest the consideration of DCV+SOF as a potential preferred combination. Ideal HCV combinations will have high efficacy, an acceptable safety profile, have pan-genotypic potential and will be all-oral. DCV+SOF appears to meet all these criteria based on the available data. Furhter, BMS has chosen to discontinue further development of asunaprevir.

11. Summary of comparative evidence on safety: Preclinical data for toxicology revealed that dogs experienced bone marrow hypocellularity at 9-fold above the clinical AUC exposure (although these results have not been repeated in humans). Daclatasvir has not been shown to be mutagenic at 8- or 4-fold above the clinical AUC exposure in mice or rats and exhibited no

10 in vitro mutagenesis. No effects on fertility in female rats were observed up to 18-fold the clinical AUC exposure. However, daclatasvir is embryotoxic and teratogenic at or above 4-fold (rat) and 16-fold (rabbit) the clinical AUC exposure (BMS, 2014). Based on 8 additional clinical trials with data from 798 patients with HCV treated with daclatasvir 60mg once daily in interferon-sparing regimens or interferon free regimens (e.g. sofosbuvir-daclatasvir), daclatasvir has been shown to be safe and tolerable (BMS, 2014).

A series of Phase I studies to test the safety and antiviral properties of daclatasvir demonstrate its safety. A phase 1 randomized, double-blinded, placebo-controlled, single-ascending dose study in which daclatasvir was administered alone at six dose levels to healthy subjects over a range of 1 to 200 mg showed that up to 200mg, daclatasvir was considered safe and no clinically relevant side effects were detected (Herbst & Reddy, 2013). A second Phase I study investigated daclatasvir administered as an oral solution to Genotype 1 patients at 1, 10 or 100 mg doses. Daclatasvir up to 100 mg was considered safe and well-tolerated. Up to this dosage, no deaths, serious adverse events or cessation of therapy due to side effects or clinically relevant adverse events were encountered. The most frequent AE was headache (Herbst, 2013). Phase 2 and three trials investigated safety of treatment combinations including daclatasvir.

For patients on PEG-RBV, the safety profile of daclatasvir+PEG-RBV was similar to that of PEG-RBV alone, thus most of the AEs likely arose from PEG-RBV. In patients on DCV+PEG-RBV (n=587), the most frequently reported adverse reactions were fatigue, headache, pruritus, insomnia, influenza-like illness, dry skin, nausea, decreased appetite, alopecia, rash, asthenia, irritability, myalgia, anaemia, pyrexia, cough, dyspnoea, neutropenia, diarrhoea and arthralgia. The most frequently reported adverse reactions of at least Grade 3 severity (frequency of 1% or greater) were neutropenia, anaemia and lymphopenia (BMS, 2014). For example, in one phase 3 study of DCV 20mg or 30mg +PEG-RBV vs PEG-RBV, rates of SAES were 5.9% (12/203), 5.0% (10/199), and 17.6% (3/17), respectively. Further, grade 3-4 laboratory abnormalities did not significantly differ across the treatment groups (Ratziu et al., 2012). Adverse events in the COMMAND-1 study are also consistent with the above findings, with only dry skin, influenza like illness and nausea being >10% more common in the DCV+PEG-RBV versus the PEG-RBV group (Hezode et al., 2012). Smaller phase 2 studies are also consistent with these larger studies (Pol et al., 2012).

For the combination of daclatasvir+sofosbuvir (n=211), the most frequently reported adverse events (AEs) were fatigue, headache and nausea. Low phosporous and high glucose were the most common grade 3 or 4 laboratory abnormalities. Hemoglobin did not significantly decrease in patients not also receiving ribavirin (Sulkowski et al., 2014).

For the combination of DCV+ASV, there were low overall numbers of AEs. In a phase 3 study of this combination, serious AEs occurred in 6% and AEs leading to discontinuation (reversible elevated ALT/AST most common) in 2%, with no deaths. Only 2% of subjects experienced grade 3/4 laboratory abnormalities,

11 including low incidences of ALT elevations (Manns et al., 2014). Another study which compared DCV+ASV to telapravir+PEG-RBV, reported discontinuations due to AEs in 5% and 20%, respectively without any deaths. In the DCV+ASV arm, no reports of anemia (<10 g/dL) or rash-related events occurred, while in the telapravir+P/R arme 48% experienced anemia (<10 g/dL) and 14% reported rash. Grade 3/4 ALT lab abnormalities were more frequent with DCV+ASV than with telapravir+P/R (13% vs 3%). Five of 119 DCV+ASV patients discontinued due to ALT elevations (Chayama et al., 2014). Kumada reports 13 patients (5.9%) experienced serious AEs in this phase 3 study of DCV+ASV, with 11 treatment discontinuations, 10 of which were due to grade 3-4 liver enzyme abnormalities. No patient died or experienced hepatic decompensation. Overall the most common AEs in this study were nasopharyngitis, increased ALT and AST, headache, diarrhea, and pyrexia (Kumada et al., 2014). Other smaller phase 2 studies are consistent with these findings (Suzuki et al., 2013; Chayama et al., 2012; Lok et al., 2014).

In all-oral DCV-containing regimens, AEs are similar between patients with cirrhosis (n=229) and without cirrhosis (n=689) (Jensen et al., 2024).

Translation of clinical data to practice Although there is yet to be experience with the safety and effectiveness of this drug in real-life, non-trial settings in patients living in low- and middle-income countries, we believe the magnitude of the effect size and consistency of safety and efficacy data across various patient groups and genotypes makes a very good case for daclatasvir’s importance as a key drug to treat HCV.

12. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group (range of costs of the proposed medicine; resource use and comparative cost-effectiveness presented as range of cost per routine outcome):

Daclatasvir is currently only produced by the originator company, BMS. While BMS has not yet announced specific pricing for low- and middle-income countries, they have announced they will be following a tiered pricing system for L&MICs. Further, they will be providing a voluntary license for generic production which covers 90 L&MICs (“HCV Developing World Strategy”). While generic production is still 2-3 years off, the entry of generic competition will significantly decrease prices. A study by Hill et al. (2014) predicted that the manufacturing costs in US dollars for 12-week courses of HCV DAAs were $21–$63 for ribavirin, $10–$30 for daclatasvir and $68–$136 for sofosbuvir. As ribavirin is already available as a generic (at prices procured by MSF $157 for a 12 week course of quality assured generic ribavirin), Gilead has announced a 90-country voluntary licesense for the generic production of sofosbuvir, DCV-containing cominbations using these drugs will also likely be affordable. Thus, for example a 12-week combination of DCV+SOF could cost $78-$166. Importantly, these low prices (see Figure 3) could make widespread access to HCV treatment in low- and middle-income countries a realistic goal.

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Figure 3. Table 5 and Table 6 illustrate the predicted minimum costs of hepatitis C virus direct-acting antivirals and the Potential regimen costs, respectively.

13. Summary of regulatory status of the medicine (in various countries)

Approved by the European Medicines Agency, August 22 2014. The indication is for treatment of HCV genotypes 1, 2, 3 and 4 in combination with other HCV medicines.

Approved by the Japanese Ministry of Health, Labor and Welfare, July 7 2014 as the combination daclatasvir and asunaprevir. The indication is for chronic hepatitis C genotype 1, or chronic hepatitis C genotype 1 with compensated cirrhosis: (1) patients who are ineligible or intolerant to interferon-based therapy, and (2) patients who have failed to respond to interferon-based therapy.

Submitted to USFDA, April 7, 2014

14. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia,

United States Pharmacopoeia, European Pharmacopeia)

Not yet included in these pharmacopoeias.

15. Proposed new text that could be included in a revised WHO Model Formulary

Treatment of Hepatitis C

Daclatasvir 30 mg tablet, as dihydrochloride*

Daclatasvir 60 mg tablet, as dihydrochloride*

*To be used in adults with other HCV medicines

13 References

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