Viral hepatitis Breaking new ground

As we mark Hepatitis Awareness Month this May, the Bristol-Myers Squibb Foundation’s Delivering Hope initiative which supports community- based models to increase awareness, prevention and care, could be a ray of hope for India’s viral hepatitis population. Viveka Roychowdhury reviews the Foundation’s major projects in India

World wide spread of hepatitis B virus (HBV) infection
(Source: Bristol Myers Squibb)

“Your voice, your choice, your life.” That’s a catchy slogan, applicable to just about anything. But the setting is surreal. We are sitting in a restaurant called Tandoor, in Taiwan, and Phangisile Manciya has to compete with loud ‘Bollywood Nite’ music to be heard as she explains what the Bristol-Myers Squibb Foundation is all about. And this slogan, one of the many pithy one liners Manciya peppers her conversation with, sums it up well: the BMS Foundation believes in making the patient’s voice count, by making them aware that their choices can impact their lives.

As the BMS Foundation’s Director of Corporate Philanthropy, Manciya is passionate about what she hopes to achieve. The Foundation was set up by the New York-based biopharmaceutical major in 2002, with the stated mission ‘to reduce health disparities around the world—and in so doing, to deliver hope to those in need.’

The BMS Foundation’s modus operandi is to partner with civil society, government and non profit groups, helping to ‘bridge gaps in healthcare’. The programmes initiated by it focus on four disease areas: HIV/AIDS in Africa, viral hepatitis in Asia, mental illness and diabetes in the US, and cancer in Central and Eastern Europe.

Manciya was in Taiwan to participate in the annual conference of the Asia Pacific Association for the Study of the Liver (APASL) which was held this February. While the BMS break out sessions focused on the company’s viral hepatitis pipeline and the results with its investigational molecules, Manciya and John Damonti, President, BMS Foundation highlighted the fact that controlling viral hepatitis would need more than next generation treatments.

The statistics are worrying. According to figures from various reports like the Global Alert and Response of the World Health Organization (WHO), chronic hepatitis B and C is estimated to affect over 500 million people worldwide. The Asia Pacific region is home to an estimated 56 per cent of the total hepatitis C population. Similarly, 70 per cent of 350 million people living with chronic hepatitis B live either in Asia Pacific or Oceania.

For perspective, the latest global figures for HIV infection stand at 33 million but HIV/AIDS is perceived as a more serious health threat and consequently receives more attention and funding than viral hepatitis.

In India, it is estimated that about three-four per cent of the country’s population is infected by the hepatitis B virus (HBV). Of this, chronic hepatitis B (CHB) constitutes more than 50 per cent of the cases. The situation is compounded by the fact that the disease remains asymptomatic for a long time, and many cases go undetected and remain undiagnosed until too late. Ethnicity too plays spoilsport, with Asian patients predisposed to common co-morbidities like diabetes, hypertension, osteoporosis, low BMI, low bone mineral density and lactose intolerance.

Treatment of viral hepatitis is long term, dependent on patient characteristics like ethnicity and habits like smoking. To make matters worse, HBV mutates and this leads to resistance, requiring a shift to more potent medication. Most developing nations remain resource challenged, in terms of access to healthcare and medication.

And that’s where BMS Foundation, under its Delivering Hope programme, literally offers a ray of hope. In the decade since its formation, Delivering Hope has invested in and initiated 38 programme grants across Asia, totalling more than $9.7 million, specifically 16 grants in mainland China, three in Taiwan, 15 in India and four in Japan. At February’s APASL meet, the Foundation announced three new grants, totalling about $8 million, to organisations in China and India, to improve prevention, diagnosis and care of HBV and HCV infected patients.

A ray of hope

In India since 2006, the Foundation’s activities in India under the Delivering Hope initiative span the National Liver Foundation and Federation of Bombay Blood Banks, the Hepatitis Foundation of Tripura,  the Hope Initiative, Liver Foundation in West Bengal and the Christian Medical College and Christian Mission Hospitals among several others across the country. The central theme remains the same: increasing awareness, prevention and education for HBV and HCV.

Each intervention addresses a specific category of patients affected by viral hepatitis. For instance, BMS Foundation’s grant to the National Liver Foundation and Federation of Bombay Blood Banks is being used to develop a demonstration project to counsel blood donors in Mumbai who test positive for HBV or HCV, and will create counselling protocols and a referral system, to provide care for infected donors.

The Hepatitis Foundation of Tripura (HFT) first launched a HBV awareness and immunisation programme in 2002, but it was only in 2007, when the BMS Foundation stepped in with a grant that the HFT was able to structure their community outreach and mobilisation campaigns among local healthcare providers and community health volunteers in a more organised fashion. 

The Hope Initiative on the other hand, targets school children, their families and local healthcare providers in approximately 1,000 urban and rural schools in Uttar Pradesh while the Liver Foundation in West Bengal, recipient of one of the grants announced this February, targets lay community health workers in rural areas, already part of the anganwadi system, and trains them to add HBV education and awareness to existing programmes. Here too, the project will reach out to offer HVB counselling services to blood donors who test positive for HBV and aim to create a HBV registry to help track and counsel them. 

The BMS Foundation will also support the use of video conferencing to train healthcare workers and expand awareness about HBV, linking Vellore’s Christian Medical College with 15 other mission hospitals across India to reach out to schools, colleges and hospitals surrounding these 15 mission hospitals. 

Source: Delivering Hope: Community-based models for hepatitis awareness, prevention and care in Asia.

Second time lucky?
On the corporate front, BMS India is set to touch the Rs 1000 crore mark in India in the next three years, according to Dr Ajaykumar Sharma, Practice Head – Pharma, Healthcare Practice, Frost & Sullivan, South Asia & Middle East.

BMS’ first innings in India kicked off way back in the ’50s, in partnership with the Sarabhai group. It was one of the MNCs to exit the country in the mid ’80s, disappointed with India’s product patent regime.

But two decades down the line, BMS could no longer keep India out of its emerging markets strategy. Sharma comments that BMS seems to have read the market pretty well this time, launching key products year on year with the right set of strategic partnerships.

BMS India seems more committed to the Indian market this time around, with the company’s website stating that clinical trials for hepatitis C and Alzheimer’s disease are planned in the country. But will the policy paralysis on drug pricing rules and rulings like the grant of India’s first compulsory license to Natco Pharma weaken their resolve?

170 million people worldwide chronically infected with hepatitis C virus (HCV)
(Source: Bristol Myers Squibb)

A quiver full of partnerships
Not likely, says Sharma, reasoning that such regulations can only have a temporary setback. Spelling out the opportunity, he says, “The long term strategy for all MNC’s is to invest heavily in India based on the sheer volumes which India has to offer with a support of the growing middle class population.”

Globally, he sees BMS positioning itself as the next biopharma leader, by focusing on two key aspects globally as well as in India. Firstly, it has built up a strong pipeline of novel products and secondly, it put in place the right set of partnerships.

For example, BMS has partnered with competing MNCs (AstraZeneca on the diabetes front and Pfizer for cardiovasculars) on the marketing front.

On the manufacturing front, in 2006, BMS transferred intellectual property and technical know-how to two generic companies, Africa’s Aspen and the Pune-based Emcure for one of its anti retroviral products, atazanavir.

And on the R&D side, BMS has partnered with Biocon, resulting in the BMS Biocon R&D Centre in Bangalore, leveraging the country’s scientific talent pool to build its R&D presence in the Asia region. It also partners with Accenture for pharmacovigilance activities.

Hand in hand with these strategic partnerships, the BMS Foundation, as its a corporate philanthropy arm, forges partnerships aimed at taking it closer to the end beneficiary: the patient. (See box: A ray of hope)

Sharma observes that BMS India has always given priority to the patient servicing model and physician training rather than getting into unnecessary price cuts as has been the practice. Both Perfalgan and Ixempera have hardly seen any price manipulation during the last three years since their launch.

Defusing the “viral time bomb”
And there is no doubt that we need all the help we can get to deal with the  silent spread of viral hepatitis infection. Lack of awareness and apathy of policy makers has meant that we are only just realising the extent and spread of the  infection.

Even though Hepatitis Awareness Month was first established by the US Center of Disease Control and Prevention in 2001, it was not until almost a decade later, in May 2010, that the World Health Assembly ratified a resolution on viral hepatitis (WHA63 R18), which for the first time recognised the full scale of the challenge and finally put viral hepatitis on the global healthcare agenda, alongside HIV/AIDS, TB and malaria.

With health agencies like the WHO referring to the rise in viral hepatitis as a ‘viral time bomb’ and issuing a Global Hepatitis Strategy (See report: ‘CEVHAP hosts agenda-setting meet on hepatitis policy’, Express Pharma, March 16-31, 2012), the disease  is finally getting the attention it deserves, both from healthcare authorities as well as the pharmaceutical industry.

While most of the hepatitis infected population is in underdeveloped or developing countries, liver diseases are detected quite late (typically, only after 70 per cent of the liver is damaged), thanks to the acute scarcity of resources faced by countries where viral hepatitis is endemic. This explains why the market share of these countries in the global hepatitis market is currently relatively lower than expected. The large patient population, long- term treatment, and significant unmet need spell good growth opportunities for pharma companies.

In the pipeline
Indeed, new treatments for HBV and HCV infection, which together account for 80 per cent of global primary liver cancer cases, have become acquisition targets in the recent past as pharma companies try to build up their viral hepatitis portfolio.

For example, in January this year, BMS bought out Inhibitex, impressed enough to cough up a substantial (163 per cent) premium to its share price, thanks to later’s hepatitis C drug INX-189. BMS’ own pipeline of hepatitis medication has the advantage of offering an oral regimen and INX-189 is thought to be a good addition to this portfolio. Gilead Sciences had already acquired another company researching a new hepatitis C treatment, Pharmasset, this time at a 90 per cent premium.

But this increased focus also means increased competition. Analyst reports  point out that the viral hepatitis market now has a number of big players like Roche, Merck, GSK, Gilead and Vertex, most of them with experimental molecules neck-to-neck in clinical research and trials.

Globally, BMS seems to be one of the front runners in terms of a promising pipeline. Not only did it bag the “Most Innovative Pipeline’ tag in January 2011 (R&D Directions magazine), but what is more of interest to patients and clinicians, is that “real world” data with “real patients” is holding up to scrutiny and helping to shape further treatment.

‘Real world’ data
Speaking on the sidelines of the BMS breakout sessions at APASL, Paul Slade, Executive Director, Virology Medical, BMS drew attention to recent ‘real world’ data on approved HBV products (Baraclude (entecavir)) as well as the HCV pipeline.

Slade’s reference was to data gathered on Baraclude, over the past seven- eight years post approval, which support its continued long-term use, according to company officials and lead investigators on these studies. At its launch Baraclude’s major USP was that as a pill, it improved patient compliance and no doubt this was a major factor  for support from the medical community. This is borne out by sales figure on the company’s website. Baraclude notched up global revenues of $1.2 billion in 2011, and was BMS’ fifth largest selling product, after Plavix ($7.1 billion), Abilify ($2.8 billion), Reyata ($1.6 billion) and the Sustiva franchise ($1.5 billion).

Expanding on Slade’s comments, Prof Harry Janssen, of the Erasmus MC University Hospital, Rotterdam, The Netherlands explained that “real world” data comprising patient use from the time of Baraclude’s launch in 2006, is “exciting” because trial data is based on chosen subjects who meet inclusion/exclusion criteria. Moreover, experimental studies done prior to approval are carried out under controlled conditions where as in real life clinical situations, doctors would receive patients at all stages of liver damage. Janssens gave details of three follow up trials (one based out of China, one with an Italy cohort and the third, the VIRGIL surveillance study, conducted in 10 large European centres).

The main goals of HBV treatment is to suppress the virus to undetectable levels, reduce cirrhosis, and improve survival rates. Based on the data from these three trials in real-world settings, Janssens concluded that long-term entecavir mono therapy was safe and effective in that it provided high rates of virologic suppression. Secondly, the probability of achieving virologic response to entecavir did not seem to be influenced by severity of liver disease. According to Janssens, these results showed for the first time that virologic response to entecavir was associated with a lower probability of disease progression. For HBV patients, this association holds out some chance that long term treatment with entecavir could not just prevent/arrest the development of more severe complications, but could also possibly reverse disease progression. This conclusion, of course depends on future results staying in line with current trends. So while there is still no cure for HBV, except for vaccination, which again is effective only for individuals with no prior exposre to the virus, drugs like Baraclude at least make it treatable.

Patient characteristics that must be considered: Ethnicity
(Source: Bristol Myers Squibb)

HCV pipeline
In contract to HVB, HCV is considered ‘curable’ once the amount of virus (viral load) in the blood is reduced to an undetectable level using antiviral medicines. Slade also shared insights on BMS’ HCV pipeline, consisting Daclatasvir, Asunaprevir, INX-189, BMS-791325 and lambda combination therapy. These compounds have different mechanisms of action and span biologics as well as small molecule antivirals. The company’s investigational molecule for HCV, peginterferon-lambda-1a, has the potential to score over existing alpha interferon therapy because it offers more specific action, as there are fewer lambda receptors in the body, offering the possibility of a more targeted delivery of interferon therapy.

This theory seems to be supported by ongoing trials. At The International Liver Congress in Barcelona this April, BMS presented results from the phase IIb EMERGE clinical trial, where the investigational compound, a combination of peg interferon lambda-1a and ribavirin, showed viral suppression comparable with alpha interferon, but with fewer flu-like and musculoskeletal symptoms.

According to Slade, BMS’s commitment was to expand therapeutic options across the continuum of liver disease, beyond HVB and HCV to include hepatocellular carcinoma (HCC). Thus BMS’ research goal is to address chronic liver disease progression through multiple targets. He spoke about Brivanib, an investigational oral medicine in phase III development for the treatment of HCC.

Dr Pei-JerChen, Professor at the Graduate Institute of Clinical Medicine and Department of Internal Medicine in the College of Medicine, and Hepatitis Research Centerof NTU Hospital, Taiwan National University in Taipei shared some observations of HCC management patterns based on an interim analysis of the Asia-Pacific cohort of the Global HCC BRIDGE Study. As the first multiregional (North America, Europe, and Asia-Pacific), large-scale, observational study to document real-world HCC patient experience from diagnosis to death, it is hoped that the HCC BRIDGE study will help shape better treatment patterns and result in better treatment outcomes in the future.

Making hepatitis B history. This was the title of a presentation at APASL and it reflects the determination of the pharma industry to beat back viral hepatitis. BMS’ strategy of investing in its R&D programmes as well as in BMS Foundation’s patient outreach programmes, reflects the reality that viral hepatitis, like most chronic conditions, has to be confronted on multiple fronts. Both in the lab, researching better treatments and in the real world, to ensure that these treatments reach as many patients as possible.

(The author attended the annual 2012 conference of APASL at the invitation of BMS)

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