Bristol-Myers Squibb Foundation Reaches New Heights to Help Lower Viral Hepatitis Burden in China
April 28, 2017
Families celebrate the Torch Festival in Liangshan Yi Autononmous Prefecture. In China alone, the Bristol-Myers Squibb Foundation has invested more than $9 million, and its partners have been active in 28 provinces and cities, reaching more than 8 million people.
The Liangshan Yi autonomous prefecture in southern Sichuan Province is a vast area of mountainous terrain where poverty is as common as the cliffs. Many villages in Liangshan Yi are perched among those cliffs, with some places reachable only via climbs up vines of trees and steep ladders made of ropes.
In early March, representatives from the Bristol-Myers Squibb Foundation and the Chinese Foundation for Hepatitis Prevention and Control (CFHPC) made their way to Liangshan Yi to launch, along with local officials, the Liangshan Yi HIV/HCV co-infection Prevention and Management Program. Through seminars, training and field visits, the program will help bring more effective HIV/HCV co-infection prevention and control to the region. Reaching a destination as remote as Liangshan Yi is the latest milestone in a journey undertaken by the Bristol-Myers Squibb Foundation in a country where as many as 10 million people are infected with the hepatitis C virus and millions more are at risk for contracting it.
The path to a new era in viral hepatitis treatment in China began more than 15 years ago for Bristol-Myers Squibb. During this span, the Bristol-Myers Squibb Foundation's Delivering Hope™ initiative has supported projects in China and India that provide intervention in hepatitis B and hepatitis C virus infection and provide resources for better disease management. In China alone, the foundation has invested more than $9 million, and its partners have been active in 28 provinces and cities, reaching more than 8 million people at high risk of hepatitis infection with information on how to minimize their risk of contracting the diseases and the importance of treatment.
Because the stigma associated with a blood-borne disease like HCV infection can be significant, some people with HCV in China have difficulty finding work and are often ostracized within their own families.
CFHPC, the Bristol-Myers Squibb Foundation's longest standing partner in China, is now leading a three-year initiative to establish a Hepatitis Center of Excellence in coordination with four other Bristol-Myers Squibb Foundation partners – Wu Jieping Medical Foundation, Shanghai Charity Foundation, Inno Community Development Organisation and Shanghai Xintu Center for Community Health Promotion. Each organization is leveraging its own expertise and resources to train health care providers, provide patient support and conduct intervention programs for high-risk populations in places like Liangshan Yi, as well as thousands of oil field workers in Karamay, migrant workers in Guangzhou and individuals at risk in Beijing. In Shanghai, the Hepatitis Center of Excellence has created a support program to aid hundreds of people with chronic hepatitis.
Because the stigma associated with a blood-borne disease like HCV infection can be significant, some people with HCV in China have difficulty finding work and are often ostracized within their own families. To bridge this gap, the Hepatitis Center of Excellence also is supporting the development of online resources, including the Peking University Education Foundation's Virtual Community for Hepatitis C Management. The University is building a platform that will allow doctors to monitor patients' treatment, communicate with patients, and access the latest research and scientific developments in the field and view case studies. To date, more than 20,000 patients, 221 general practice physicians, 398 liver specialists and 77 hospitals have registered.
Hepatitis C virus infection is a global pandemic, disproportionately affecting countries in Africa and East Asia.
Hepatitis C virus infection is a global pandemic, disproportionately affecting countries in Africa and East Asia. In China, it is estimated that of the 10 million people infected with the virus, between 50 to 85 percent will develop chronic hepatitis. Of those, between 20 and 30 percent may progress to liver cirrhosis that can lead to liver cancer.
Reaching those at risk isn't easy. On a sunny day in March with wind providing a cold bite, a drive upward through fog and clouds finally broke into a sunny day in Liangshan Yi. Training sessions, conducted by public-health officials who had come from all over China, made for a quick start to a multi-year effort that will include HCV training for local healthcare professionals, public awareness education, HCV screening among high risk groups and HCV treatment support. Liangshan Yi now could be found on the map of places where the Bristol-Myers Squibb Foundation is delivering hope.
April 2017 Bristol-Myers Squibb
The work of the Foundation is centered on making a difference by delivering hope and addressing health disparities in communities around the world, including Asia, where the burden of viral hepatitis touches millions of individuals due to poor healthcare access, lack of educational and prevention programs and prevalent social stigmas, among other factors. Through ongoing collaboration with government, academia and the public sector, the Foundation builds programs that support innovative and comprehensive public health responses while working to improve health outcomes for populations around the world.
The Foundation has focused support efforts in four key areas:
⋅ Creating awareness of viral hepatitis and addressing existing social stigmas;
⋅ Prevention, especially among those communities at highest risk;
⋅ Disease education for lay and professional health care workers;
⋅ Operational research to develop data and inform projects focused on sharing, adapting and applying successful lessons to future efforts.
⋅ Wu Jieping Medical Foundation, for a multi-center, nationwide study of the status of HCV treatment in China among liver disease specialists and patients. The study, which includes a two-pronged survey of 5,600 patients across geographic regions and a focus on the socio-economic status of special populations such as patients coinfected with HIV, tuberculosis or HBV, and patients with cirrhosis or kidney damage, is designed to inform policy around enhancement of standard care, insurance, and disease education and intervention.
⋅ China Foundation for Hepatitis Prevention and Control (CFHPC), the Foundation's longest standing partner in China, collaborated in the training of more than 130,000 healthcare practitioners on HCV prevention, diagnosis and treatment in Shaanxi province; the implementation of a patient empowerment program in conjunction with hospitals across six provinces; and coordinating with partners to build a Center of Excellence to help scale up community-based HCV intervention programs and leverage existing resources across wider education and prevention projects.
⋅ Shanghai Charity Foundation & Shanghai Nursing Association, for training over 10,000 migrant workers serving as nursing aides and other local healthcare workers to promote HBV awareness and prevention among high-risk groups in Shanghai.
⋅ Inno Community Development Organization, for awareness programs and 10 community-based HCV Intervention Centers for the migrant population in Guangdong Province.
⋅ Peking University Education Foundation, for the development of an online community for hepatitis patients that empowers self-management and facilitates physician monitoring of the disease, communication with patients and access the latest scientific research and case studies. To date, almost 20,000 patients, 180 general practice physicians, nearly 400 liver specialists and over 70 hospitals have registered.
⋅ Hepatitis B Foundation, for disease education and management programs to improve self-management and encourage adherence among rural patients, coupled with training for rural doctors on HBV diagnosis, prevention, care and support.
Daklinza® (daclatasvir)/Sunvepra® (asunaprevir) Hepatitis C Treatment Regimen
About Daklinza and Sunvepra
The Daklinza and Sunvepra regimen is an all-oral, interferon- and ribavirin-free combination of two direct-acting antiviral drugs (DAAs) approved in China for the treatment of genotype (GT) 1b chronic hepatitis C virus (HCV):
⋅ -Daklinza (daclatasvir, an NS5A replication complex inhibitor) 60 mg tablet once daily
⋅ -Sunvepra (asunaprevir, an NS3 protease inhibitor) 100 mg caplet twice daily
Daklinza is also approved in China for combination use with other agents, including sofosbuvir, for adult patients with HCV genotypes 1-6 infection.
Daklinza (daclatasvir) is an NS5A replication complex inhibitor that is used as a foundational drug for multiple DAA-based combination regimens for the treatment of HCV. Daklinza was the first of this class of drugs, which target the NS5A protein by directly disrupting its normal function. The NS5A protein plays essential roles in the HCV viral life cycle, including viral RNA replication and virion (viral particle) assembly. Daklinza-based treatment regimens are approved for use in more than 60 countries, and approximately 500,000 HCV patients around the world have been treated with daclatasvir-based regimens.
Sunvepra (asunaprevir) is an NS3 protease inhibitor, an agent that binds to the NS3 protein of the HCV virus to block its activity. The NS3/4A protease is required to form new viral particles.
With its recent approval in China, the Daklinza and Sunvepra regimen has now been approved in more than 15 countries around the world, including throughout Asia, where HCV GT 1b is prevalent.
First Proven in Japan
First approved in Japan in 2014, the Daklinza and Sunvepra regimen marked the first all-oral, interferon- and ribavirin-free treatment regimen for HCV genotype 1b patients there, including those with compensated cirrhosis. Cirrhosis, or scarring of the liver, can occur in patients with HCV who are not treated.
Since its launch in September of 2014, approximately 50,000 hepatitis C patients in Japan have been treated with Daklinza and Sunvepra. In clinical trials, cure rates (defined as sustained virologic response 12 weeks after the end of treatment, or SVR12) reached upwards of 95-98% after excluding those with baseline NS5A resistance-associated variants (RAVs). HCV NS5A RAVs exist naturally (albeit in low prevalence vs. wildtype) and can emerge after virologic response failure. Screening for the presence of specific NS5A mutations can help physicians determine the most suitable patients for treatment by identifying those most likely to achieve cure with an NS5A-containing regimen.
Daklinza and Sunvepra also demonstrated high cure rates (greater than 90%) in elderly Japanese patients, and its pharmacokinetic profile is compatible with patients with renal impairment.
Daklinza and Sunvepra Phase 3 Clinical Trial Data in Chinese Patients
The 036 Clinical Trial
In 2015, Bristol-Myers Squibb completed the first-ever all-oral, interferon- and ribavirin-free HCV regimen Phase 3 trial to include a Chinese patient population. The trial is published in the Journal of Gastroenterology and Hepatology.
In the multi-center Asian study, interferon-ineligible and -intolerant patients with genotype 1b infection received Daklinza 60 mg tablets once-daily plus Sunvepra 100 mg soft capsules twice-daily for 24 weeks. Of the 159 patients enrolled, 127 were from mainland China. The primary endpoint was SVR at post-treatment Week 24 (SVR24). The combination achieved impressive cure rates:
⋅ -In the overall population, 91% (145/159) of genotype 1b patients who had been previously interferon-ineligible or interferon-intolerant achieved SVR (or cure) at post-treatment week 24.
⋅ -The cure rate was higher, at 99%, in patients without baseline NS5A RAVs (L31M or Y93H; n=137/139)
As detailed in the published Phase 3 trial, one death (0.6%), five on-treatment serious adverse events (3%), and three grade 4 laboratory abnormalities (2%) occurred on-treatment; none were considered related to study drugs. Two patients (1%) discontinued due to adverse events (AEs). The most common grade 1–4 on-treatment AEs (>5% of patients) were platelet count decrease (14, 9%), upper respiratory tract infection (13, 8%), ALT increase (a diagnostic indication of liver disease or damage) (11, 7%), neutrophil count decrease (11, 7%), monocyte (large white blood cell) count decrease (10, 6%), white blood cell count decrease (10, 6%), thrombocytopenia (decrease in the number of platelets in the blood) (10, 6%), and pruritus (itchiness) (9, 6%); most were mild or moderate in intensity. Treatment was generally well-tolerated regardless of cirrhosis status.
Prevalence of baseline NS5A RAVs was 12% (19/159) overall, and 8% in mainland China patients (10/127).
Data from other studies conducted outside of China investigating Daklinza in combination with sofosbuvir were also considered as part of the approval.
The 114 Clinical Trial
In a multi-center study, treatment-naive patients with genotype 1b infection received Daklinza 60 mg tablets once-daily plus Sunvepra 100 mg soft capsule twice-daily for 24 weeks. Of the total 206 patients, 161 were from mainland China. Patients were randomized 3:1 into two treatment arms: an immediate Daklinza and Sunvepra treatment group (n=155) or a placebo-deferred Daklinza and Sunvepra treatment group (n=52). The primary endpoint was SVR at post-treatment Week 12 (SVR12) in the immediate treatment arm, for comparison with the historical SVR rate achieved with pegIFN/RBV (70%).
The SVR12 rate was 92% in treatment-naive patients with HCV genotype 1b infection in the immediate treatment arm. Baseline NS5A-L31 or Y93H polymorphisms were present in 11% (17/154) of these patients. The SVR12 rate was 96% (132/137) in patients without these baseline polymorphisms; 89% (17/19) with cirrhosis, 97% (115/118) without cirrhosis.
Discontinuations due to AEs were infrequent (1%). The most common AEs (any grade, ≥5%) in the overall population were ALT increase, upper respiratory tract infection, hypertension, AST elevation, INR elevation, blood bilirubin elevation, and fatigue.
Chinese HCV Guidelines: Daklinza and Sunvepra Recommendations
The Chinese Society of Hepatology and Society of Infectious Diseases published an updated "Guideline for Prevention and Treatment of Hepatitis C" in late 2015, taking into account the next generation of DAAs not then approved in China, and providing recommendations for treatment by genotype. Designed to assist physicians in the diagnosis, treatment and prevention of HCV, the guidelines cite the pivotal Phase 3 China study data to recommend the use of Daklinza and Sunvepra:
In genotype 1b patients both with and without cirrhosis, Daklinza and Sunvepra is recommended for a treatment duration of 24 weeks.
In addition, Daklinza in combination with sofosbuvir is the only all-oral pan-genotypic regimen recommended in the guideline.
HCV in China
HCV represents a significant public health burden in China and is now the fourth most commonly reported infectious disease countrywide.
⋅ -An estimated 10 million Chinese people are currently living with HCV
⋅ -Genotype 1b, one of seven major genotypes of the virus, is the most common, representing 56.8% of the total infected population in China
Until now, standard treatment options in China have included interferon- and ribavirin-containing regimens which have left some patient groups with unmet needs. There is a significant portion of the population, including the elderly, who are ineligible for or intolerant to these regimens.