CLINICAL TRIALS PROFILE FOR DACLATASVIR DIHYDROCHLORIDE

505(b)(2) Clinical Trials for Daclatasvir Dihydrochloride

This table shows clinical trials for potential 505(b)(2) applications. See the next table for all clinical trials

Trial Type	Trial ID	Title	Status	Sponsor	Phase	Start Date	Summary
New Combination	NCT02292966 ↗	Impact of HCV Treatment on Neurocognitive Functions and Brain Metabolism	Withdrawn	Bristol-Myers Squibb	Phase 4	2015-07-01	The purpose of this study is to examine whether neurocognitive impairments experienced by patients with chronic hepatitis C virus (HCV) infection can be reversed by treating HCV, with a new combination of direct acting antiviral drugs (daclatasvir (DCV), asunaprevir (ASV) and beclabuvir (BCV)). The study will assess the effect of HCV on the central nervous system (CNS) by assessing neurocognitive function and brain injury prior to treatment, and comparing it to the end of treatment, and 4, 12 and 24 weeks after treatment.
New Combination	NCT02292966 ↗	Impact of HCV Treatment on Neurocognitive Functions and Brain Metabolism	Withdrawn	Kirby Institute	Phase 4	2015-07-01	The purpose of this study is to examine whether neurocognitive impairments experienced by patients with chronic hepatitis C virus (HCV) infection can be reversed by treating HCV, with a new combination of direct acting antiviral drugs (daclatasvir (DCV), asunaprevir (ASV) and beclabuvir (BCV)). The study will assess the effect of HCV on the central nervous system (CNS) by assessing neurocognitive function and brain injury prior to treatment, and comparing it to the end of treatment, and 4, 12 and 24 weeks after treatment.
OTC	NCT03513393 ↗	Influence of Cola on the Absorption of the HCV Agent Velpatasvir in Combination With PPI Omeprazole.	Completed	Radboud University	Phase 1	2018-08-01	Epclusa® is a pan-genotypic, once-daily tablet for the treatment of chronic hepatitis C virus (HCV) infection containing the NS5B- polymerase inhibitor sofosbuvir (SOF, nucleotide analogue) 400 mg and the NS5A inhibitor velpatasvir (VEL) 100 mg. Velpatasvir has pH dependent absorption. At higher pH the solubility of velpatasvir decreases. It has been shown that in subjects treated with proton pump inhibitors (PPIs) such as omeprazole, the absorption of velpatasvir is reduced by 26-56%, depending on the dose of omeprazole, concomitant food intake, and timing/sequence of velpatasvir vs. omeprazole intake. As a result, concomitant intake of PPIs with velpatasvir is not recommended. For a number of reasons, the prohibition of PPI use with velpatasvir is a clinically relevant problem. First, PPI use is highly frequent in the HCV-infected subject population with prevalences reported up to 40%. Second, PPIs are available as over-the-counter medications and thus can be used by subjects without informing their physician. Third, although HCV therapy is generally well tolerated, gastro-intestinal symptoms such as abdominal pain and nausea are frequently reported, which my lead to PPI use. One solution of this problem could be the use of other acid-reducing agents such as H2-receptor antagonists or antacids. In general, they have a less pronounced effect on intragastric pH, and are considered less effective than PPIs by many patients and physicians. A second solution would be the choice of another HCV agent or combination that is not dependent on low gastric pH for its absorption such as daclatasvir. Daclatasvir, however, is not a pan-genotypic HCV agent and may be less effective against GT 2 and 3 infections than velpatasvir. Second, not all subjects have access to daclatasvir, depending on health insurance company or region where they live. A third solution, and the focus of this COPA study, is to add a glass of the acidic beverage cola at the time of velpatasvir administration in subjects concurrently treated with PPIs. This intervention has been shown to be effective for a number of drugs from other therapeutic classes who all have in common a reduced solubility (and thus reduced absorption) at higher intragastric pH, namely erlotinib, itraconazole, ketoconazole. The advantages of this approach are: (1) only a temporary decrease in gastric pH at the time of cola intake; the rest of the day the PPI will have its therapeutic effect (2) cola is available worldwide (3) the administration of cola can be done irrespective to the timing of PPI use.

All Clinical Trials for Daclatasvir Dihydrochloride

Trial ID	Title	Status	Sponsor	Phase	Start Date	Summary
NCT00546715 ↗	A Single Ascending Dose Study of Daclatasvir (BMS-790052) in Hepatitis C Virus Infected Subjects	Completed	Bristol-Myers Squibb	Phase 1/Phase 2	2007-11-01	The primary purpose of this study is to evaluate the safety profile and tolerability of single oral doses of daclatasvir in subjects with chronic hepatitis C infection
NCT00663208 ↗	A Multiple Ascending Dose Study of Daclatasvir (BMS-790052) in Hepatitis C Virus Genotype 1 Infected Subjects	Completed	Bristol-Myers Squibb	Phase 2	2008-05-01	The primary purpose of this study is to assess the change in Hepatitis C Virus RNA during dosing with daclatasvir and during the follow-up period in subjects with chronic hepatitis C infection
NCT00874770 ↗	Safety and Efficacy of Daclatasvir (BMS-790052) Plus Standard of Care (Pegylated-interferon Alpha and Ribavirin)	Completed	Bristol-Myers Squibb	Phase 2	2009-06-01	The purpose of this study is to identify 1 or more doses of daclatasvir, which when used in combination with pegylated interferon alpha and ribavirin, are safe and demonstrate sufficient anti-hepatitis C virus activity.
NCT01016912 ↗	Safety and Efficacy of Daclatasvir (BMS-790052) Plus Standard of Care (Pegylated-interferon Alpha-2b and Ribavirin) in Japanese Patients	Completed	Bristol-Myers Squibb	Phase 2	2009-12-01	The purpose of this study is to identify at least 1 dose of daclatasvir that is safe, well tolerated, and efficacious when combined with peginterferon-alfa and ribavirin for the treatment of hepatitis C virus genotype 1 in chronically infected patients who are treatment-naïve and nonresponsive to the standard of care
NCT01017575 ↗	Safety and Efficacy of Daclatasvir (BMS-790052) Plus Standard of Care in Japanese Patients (Pegylated-interferon Alpha-2a and Ribavirin)	Completed	Bristol-Myers Squibb	Phase 2	2009-12-01	The purpose of this study is to identify at least 1 dose of Daclatasvir, that when combined with peginterferon-alfa (PegIFNα) and ribavirin (RBV) for the treatment of chronically infected HCV genotype 1 treatment-naïve and non-responder to standard of care subjects is safe, well tolerated, and efficacious

Clinical Trial Conditions for Daclatasvir Dihydrochloride

Condition Name

Condition Name for Daclatasvir Dihydrochloride
Intervention	Trials
Hepatitis C	50
Hepatitis C, Chronic	16
Chronic Hepatitis c	15
Hepatitis C Virus	10

Condition MeSH

Condition MeSH for Daclatasvir Dihydrochloride
Intervention	Trials
Hepatitis C	109
Hepatitis	79
Hepatitis A	56
Hepatitis C, Chronic	50

Clinical Trial Locations for Daclatasvir Dihydrochloride

Trials by Country

Trials by Country for Daclatasvir Dihydrochloride
Location	Trials
United States	348
Japan	98
Australia	61
Canada	60
United Kingdom	31

Trials by US State

Trials by US State for Daclatasvir Dihydrochloride
Location	Trials
Texas	31
California	30
Florida	24
Maryland	23
Pennsylvania	18

Clinical Trial Progress for Daclatasvir Dihydrochloride

Clinical Trial Phase

Clinical Trial Phase for Daclatasvir Dihydrochloride
Clinical Trial Phase	Trials
Phase 4	11
Phase 3	34
Phase 2/Phase 3	8

Clinical Trial Status

Clinical Trial Status for Daclatasvir Dihydrochloride
Clinical Trial Phase	Trials
Completed	88
Unknown status	14
Withdrawn	10

Clinical Trial Sponsors for Daclatasvir Dihydrochloride

Sponsor Name

Sponsor Name for Daclatasvir Dihydrochloride
Sponsor	Trials
Bristol-Myers Squibb	61
Tehran University of Medical Sciences	4
Tanta University	4

Sponsor Type

Sponsor Type for Daclatasvir Dihydrochloride
Sponsor	Trials
Other	162
Industry	83
NIH	5

Daclatasvir Dihydrochloride: Clinical Trials, Market Analysis, and Projections

Introduction

Daclatasvir dihydrochloride, marketed as Daklinza, is a groundbreaking direct-acting antiviral (DAA) agent developed by Bristol-Myers Squibb. It targets the non-structural protein 5A (NS5A) of the hepatitis C virus (HCV), playing a crucial role in the viral life cycle. Here, we delve into the clinical trials, market analysis, and future projections for this significant drug.

Clinical Trials Overview

Trial Design and Participants

The FDA approval of Daklinza was primarily based on evidence from a clinical trial involving 152 patients with HCV genotype 3 infection. This open-label trial included both treatment-naïve and previously treated patients, some of whom had cirrhosis. Patients received Daklinza in combination with sofosbuvir once daily for 12 weeks, followed by a 24-week post-treatment monitoring period. The primary endpoint was the Sustained Virologic Response (SVR) at post-treatment week 12, defined as HCV RNA below 25 IU per mL[1].

Efficacy and Safety

The trial demonstrated high efficacy, with SVR rates indicating a significant cure rate for patients with HCV genotype 3. The combination of Daklinza and sofosbuvir showed robust antiviral activity and a favorable safety profile. Similar efficacy was observed in other trials, including those conducted in China, where Daklinza was approved in combination with Sunvepra (asunaprevir) for genotype 1b, achieving a 91-99% cure rate[4].

Global Clinical Trials

Daklinza has been tested in various combination regimens, including with pegylated interferon and ribavirin, as well as with other DAAs like sofosbuvir and asunaprevir. These trials have been conducted globally, with approvals in over 60 countries across different regions, highlighting its broad genotypic coverage and effectiveness[5].

Market Analysis

Market Approval and Penetration

Daklinza has received regulatory approvals in multiple countries, including the United States, China, Japan, and numerous countries in Europe, Latin America, and the Asia-Pacific region. Its approval in China marked the country's first all-oral treatment regimen for HCV genotype 1b, a significant milestone given the high prevalence of HCV in China[4].

Competitive Landscape

The HCV treatment market has seen a paradigm shift with the introduction of DAAs. Daklinza, along with other DAAs like sofosbuvir and asunaprevir, has revolutionized the treatment landscape by offering highly effective, all-oral regimens that replace traditional interferon-based therapies. The market competition is intense, but Daklinza's broad genotypic coverage and synergistic effects in combination therapies have established it as a key player[5].

Pricing and Access

The pricing of Daklinza varies by region, with efforts to ensure access in low- and middle-income countries. Bristol-Myers Squibb has entered into sub-license agreements to allow the production and sale of generic daclatasvir in over 100 countries, aiming to increase global access to this life-saving medication[5].

Market Projections

Growing Demand

The demand for effective HCV treatments is expected to grow, driven by the increasing awareness and diagnosis of HCV infections. The global HCV market is projected to expand as more countries implement screening programs and treatment access improves.

Expanding Indications

Daklinza's indications are likely to expand as ongoing and future clinical trials explore its efficacy in combination with other antiviral agents for different HCV genotypes and patient populations. This could further solidify its position in the market.

Generic Competition

While patent protections are in place, the eventual introduction of generic versions of daclatasvir could impact market dynamics. However, Bristol-Myers Squibb's strategic licensing agreements and ongoing research into new formulations and combinations are expected to maintain Daklinza's market relevance[5].

Key Benefits and Differentiators

Broad Genotypic Coverage

Daklinza's ability to treat multiple HCV genotypes, including genotypes 1-6, makes it a versatile treatment option. This broad coverage is a significant differentiator in the market[3].

High Efficacy Rates

Clinical trials have consistently shown high SVR rates, indicating a high cure rate for patients treated with Daklinza in combination with other antiviral agents[1][4].

Favorable Safety Profile

The safety profile of Daklinza, particularly when used in combination with sofosbuvir, has been favorable, with minimal adverse effects reported in clinical trials[1].

Challenges and Future Directions

Patent Landscape

The patent situation for daclatasvir is complex, with multiple patents covering different aspects of the drug. While these patents protect the drug from generic competition in many regions, they also present challenges for access in countries where these patents are enforced[5].

Resistance and Mutations

The emergence of resistance-associated variants (RAVs) in the NS5A protein is a concern. Screening for these mutations can help identify patients most likely to benefit from NS5A-containing regimens[4].

Ongoing Research

Continued research into new combination therapies and formulations will be crucial. For instance, studies exploring the use of Daklinza with other DAAs or in different patient populations could expand its therapeutic utility.

Key Takeaways

• Clinical Efficacy: Daklinza has demonstrated high efficacy in treating HCV genotypes 1-6, particularly when combined with sofosbuvir or asunaprevir.
• Global Approvals: Approved in over 60 countries, Daklinza has a strong global presence.
• Market Competition: Despite intense competition, Daklinza's broad genotypic coverage and synergistic effects in combination therapies maintain its market position.
• Access Initiatives: Sub-license agreements aim to increase access to generic daclatasvir in low- and middle-income countries.
• Future Directions: Ongoing research into new combinations and formulations will be key to expanding its therapeutic utility.

FAQs

What is Daklinza used for?

Daklinza is used in combination with other medicinal products for the treatment of chronic hepatitis C virus (HCV) infection in adults with compensated liver disease, including those with cirrhosis[3].

How is Daklinza administered?

Daklinza is administered orally, once daily, and may be taken with or without food. It must be used in combination with other antiviral agents as specified in the prescribing information[3].

What are the common side effects of Daklinza?

While generally well-tolerated, common side effects can include fatigue, headache, and nausea. Serious side effects are rare but can include liver enzyme elevations and other adverse reactions[1].

Is Daklinza effective for all HCV genotypes?

Daklinza has shown efficacy across multiple HCV genotypes (1-6) when used in combination with other antiviral agents like sofosbuvir and asunaprevir[3][4].

Are there generic versions of Daklinza available?

Generic versions of daclatasvir are available in some regions through sub-license agreements, but patent protections still apply in many countries[5].

Sources

1. FDA: Drug Trials Snapshots: DAKLINZA - FDA
2. TGA: Extract from the Clinical Evaluation Report for Daclatasvir / Daklinza
3. TGA: Australian public assessment for Daclatasvir / Dihydrochloride
4. Bristol-Myers Squibb: China FDA Approves Country's First All-Oral Regimen for Chronic Hepatitis C
5. WHO: DACLATASVIR - World Health Organization (WHO)