Pf looks at how the pharmaceutical industry is working with WHO to transform the developing world by defeating neglected diseases such as sleeping sickness and river blindness.

In January 2012, the World Health Organisation (WHO) launched a roadmap to defeat 10 key neglected tropical diseases, with support from 13 major pharmaceutical companies. The campaign targets diseases that are widespread only in the developing world and form major barriers to the economic development of the affected countries. The companies pledged to work in partnership with WHO, governments and health and finance organisations to strengthen their drug donation programmes, support drug distribution and implementation, and increase R&D in this disease area.  

Trojan horses
Most neglected tropical diseases (NTDs) are carried by parasites (such as tsetse flies) or are parasites (such as flatworms), which makes them difficult to treat as parasites are well adapted to the biology of the host. The parasite often acts as a ‘Trojan horse’ introducing disease into the human body. While preventative measures such as sanitation are important for controlling infection, only effective drug treatment can strike at the lethal team of parasite and micro-organism. The challenge is not only to develop effective drugs, bu to ensure they reach the populations affected by the disease.

In the ‘London Declaration on Neglected Tropical Diseases’, WHO and 13 drug companies committed to these objectives for 2020: to eradicate guinea worm disease; make progress towards eliminating lymphatic filariasis, blinding trachoma, sleeping sickness and leprosy; and achieve control of schistosomiasis, river blindness, Chagas disease, visceral leishmaniasis, and soil-transmitted helminthes. The companies involved are Abbott, AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, Gilead, GSK, Johnson & Johnson, Merck KGaA, Merck Sharp & Dohme (MSD), Novartis, Pfizer and Sanofi.

Margaret Chan, Director General of WHO, said: “The efforts of WHO, researchers, partners, and the contributions of industry have changed the face of NTDs. These ancient diseases are now being brought to their knees with stunning speed. I am confident almost all of these diseases can be eliminated or controlled by the end of this decade.” For some of the world’s poorest nations, that means an end to a crippling burden of endemic disease.

As a Sanofi video commented, NTDs are neglected because the populations they affect are neglected. For the pharma industry, offering drug donation, training and education to defeat these diseases is an opportunity to put down roots in important future markets, as well as boosting the industry’s public image through concrete achievements. Despite the current global economic crisis, funding for neglected disease R&D has increased significantly since 2007. Corporate social responsibility is a key aspect of any global drug company’s strategy – especially for companies based in Europe
and the US, where reputation can be a difficult issue.

In May 2012, Dr Margaret Chan commented on work to fight schistosomiasis in Africa: “These Cinderella diseases, long ignored and underappreciated, are a rags-to-riches story. We can blanket this part of the world with medicines that rid every schoolchild of worms and eggs, parasites that interfere with their learning, impair cognitive development, and compromise their nutritional status.” Such achievements, which depend on the pharmaceutical industry, are of historic importance on the world stage.

River blindness
Onchocerciasis (river blindness) causes an estimated 270,000 people each year in Africa and elsewhere to lose their sight. Its biological audit trail is complex: a nematode worm enters the body through the bite of a blackfly; the worms spread through the body, carrying symbiotic bacteria; when the worms die, the bacteria trigger the human immune system, causing severe itching and damaging eye tissue. Some 37 million people are infected with river blindness.

The most successful treatment is MSD’s Mectizan (ivermectin), an oral medication that kills the parasite in its larval stage. On 11 October 2012 (World Sight Day), MSD celebrated 25 years of its programme to donate Mectizan for treatment of river blindness. Through this programme, progress has been made towards eliminating the disease in Nigeria, Uganda, Senegal, Mali and Sudan. MSD is committed to maintaining drug donations until the disease is eliminated.

The Mectizan Donation Programme has influenced the development of other initiatives to fight NDTs in two ways: its multi-sector partnership model and its use of community-directed intervention (CDI). Stakeholders working with MSD to build the programme include WHO, the World Bank, governments, NGOs and communities. The CDI strategy, whereby communities plan their own means of delivering treatment, has enabled Mectizan to be delivered to 75 million people in Africa each year.

Former US President Jimmy Carter commented: “In Africa, where it was once thought river blindness could only be controlled, strides are being made to completely eliminate the disease from a number of countries. Thanks to MSD, the commitment of endemic communities, and strong partnerships, we can now envision a world someday free of river blindness.”

A leading distributor of Mectizan in Africa is Sightsavers, an NGO committed to preventing blindness. Simon Bush, Sightsavers’ Director for NTDs, told Pf: “Sightsavers will, through its support to river blindness programmes in Africa, treat over 25 million people this year as well as playing our part in supporting a network of about one million community-directed distributors.

“We have also the proof of the elimination of transmission of the disease in Kaduna state in Nigeria, which shows that elimination of the disease can be achieved in Africa through treatment with Mectizan alone.” 
The contribution of MSD has been “vital”, Bush said: “Sightsavers would not be able to support the elimination of river blindness and blinding trachoma if it were not for the drug donation programmes. We would not have been able to go to scale.” The supply chain reaching from a major pharmaceutical company to a network of community-directed distributors, reaching through society and across the world, is expected to eliminate transmission of the disease in the targeted countries by 2021.

Blood fluke
Schistosomiasis (blood fluke) is a parasitic flatworm infestation. The larvae enter the body from fresh water sources, mature in the liver and travel through the blood vessels, laying eggs that trigger destructive immune reactions. The disease is estimated to affect 200 million people in Africa and to cause 200,000 deaths each year.

The only medicine with which all forms of schistosomiasis can be treated is Cesol (praziquantel) from Merck Serono (a division of Merck KGaA). In 2007, the company committed to donate 200 million Cesol tablets to WHO for distribution to school-age children primarily in Africa, and to support an awareness programme in schools. In January 2012, Merck Serono doubled its annual donation of tablets to 50 million, to be maintained until the disease is eliminated. It has committed to work with partners to develop a pre-school version of the drug.

Seven million children were treated with Cesol in 2012, bringing the total to 28 million. At the end of November, Merck Serono symbolically donated the 100 millionth Cesol table to WHO, and announced a new programme to distribute the medicine throughout Kenya.

The company’s CEO, Stefan Oschmann, said: “Merck Serono is committed to more effectively fighting neglected tropical diseases.” He added that partnership is the essence of the campaign: “The closer we co-ordinate the donation activities, research and development of new drugs, as well as the supply and distribution of drugs with each other, the more effectively we’ll be able to fight these diseases.”

Sleeping sickness
Trypanosomiasis (sleeping sickness) is one of the tropical world’s most feared diseases. It is spread by the bite of the tsetse fly and affects the brain, causing sleepiness, coma and death. Almost always fatal if untreated, sleeping sickness may be the real basis of the ‘zombie’ myth. But now, according to Dr Margaret Chan, “the stage is set for the elimination of sleeping sickness, a prospect that was unthinkable a decade ago”. For over ten years, Sanofi has worked with WHO to provide drugs and develop treatment protocols for the disease via the campaign ‘Human African Trypanosomiasis – Not Neglected by Sanofi’.

In 2011, Sanofi renewed its commitment to fighting sleeping sickness through a $25m donation, extending its partnership with WHO by another five years. The company donates three of the five drugs used to treat the disease. In January 2012, Sanofi announced a global partnership with Eisai and the Bill & Melinda Gates Foundation to eliminate five NTDs including sleeping sickness and lymphatic filariasis. In July, it noted that the sleeping sickness treatment programme had saved 170,000 lives and reduced the number of new cases from 30,000 in 2001 to 6,500 in 2011. By 2020, WHO has said, Africa may be clear of the disease.

Sanofi’s video from Chad illustrates the methods used to implement treatment. By funding mobile medical teams working in towns and villages, the campaign has brought daily drug therapy to people unable to travel long distances to the city hospitals. Seeing the effects of treatment within the community encourages other patients to be treated there. Sanofi is committed to providing the drugs and supporting their implementation until sleeping sickness is eliminated.

Most of the leading pharmaceutical companies are improving access to their medicines in the developing world, a new report shows.

The Access to Medicine Index identifies GSK, J&J and Sanofi as the companies doing most to make their drugs available and affordable in poorer countries.

Better pricing deals and development of drugs for neglected diseases are among the areas of company activity praised by the report, but the management of drug trials in developing companies is criticised.

GSK, which topped the Index in 2010, remains in front though its overall rating is only slightly higher. J&J and Sanofi have significantly improved their ratings.

The major Japanese firms are bottom of the league, as well as being absent from such initiatives as the WHO campaign to fight neglected tropical diseases.

In its third year, the Netherlands-based Index notes that companies are showing better internal organisation in relation to drug access issues.

Of the 20 largest pharma companies, 17 have improved access to their drugs in the developing world since 2010: they are developing more relevant drugs and doing more to facilitate patient access to them.

In particular, more companies are using tiered pricing schemes to make products more affordable for certain countries or population groups – most notably Gilead, whose HIV drugs are used worldwide.

However, the Index states that companies could do more to support generic versions of their drugs and adapt drug packaging to local needs.

It also notes that the outsourcing of clinical trials to Contract Research Organisations lacks transparency and control, with only four companies (GSK, Sanofi, Eisai and Merck & Co.) saying they enforce ethical codes.

Wim Leereveld, CEO of the Index, said: “Access to medicine is a multi-faceted challenge and the pharmaceutical industry has a critical role. While it has made strides in many areas, companies that have sector-leading practices also show us there is more the industry can contribute.”

The first proven drug for prevention of HIV infection has been recommended for FDA approval by an expert panel.

Truvada from Gilead Sciences, an oral combination therapy used since 2004 to treat HIV infection, may shortly be available as a preventative therapy.

The panel emphasised that the drug is less effective in women than in men, and must not be used in place of other preventative strategies.

Adherence was also highlighted as an issue, since Truvada is ineffective if not taken every day.

Truvada was recommended for prescription to people at high risk of HIV infection, including gay and bisexual men and heterosexual couples with one HIV-positive partner.

The medication is a combination of two anti-HIV drugs, Emtriva and Viread. Its off-label use to prevent HIV infection is already widespread.

In 2010, a three-year study by the US government found that daily doses of Trevada together with condom use reduced the risk of HIV infection by 42% in gay and bisexual men. In 2011, a similar study found that it reduced infection by 75% in heterosexual couples where one partner was HIV-positive.

The drug’s value is contested among people working to control HIV infection, due to concerns that Trevada will give people who are not compliant with the need for condom use and/or daily dosage a false sense of security.

While the cost of widespread prescription is not a factor in whether the FDA grants marketing approval for Trevada, it will clearly affect its uptake by health workers relative to other strategies.

Interferon, part of the standard treatment for hepatitis C, is a major cause of depression in patients with the disease.

A new study has linked the high rate of suicide among hepatitis C patients to side-effects of interferon, which is usually taken together with ribavarin.

These findings will increase clinicians’ interest in alternatives to interferon in the treatment of the life-threatening infectious disease.

Researchers at Loyola University, Chicago, observed: “Depression is a relatively frequent and potentially serious complication of interferon therapy for hepatitis C virus infection.”

Hepatitis C is an increasingly widespread infection worldwide, causing pain, fatigue, disability and death.

The standard treatment is a combination of ribavirin and pegylated interferon. The latter can relieve muscle and joint pain and reduce fatigue.

However, interferon affects serotonin levels and is consequently associated with depression. The study reports that between 10% and 40% of hepatitis C patients receiving interferon experience depression and may be at risk of suicide.

The study authors recommend that patients with a personal or family history of depression or suicide attempts should be carefully assessed and possibly treated for that condition before treatment with interferon begins.

There is conflicting evidence about the effectiveness of antidepressants in patients who are receiving interferon – they may help to reduce the symptoms, but do not seem reliably able to prevent the condition.

Interferon also has flu-like symptoms, and the new study will increase the pressure to develop alternative treatments such as the combination therapy involving drugs from Gilead and BMS that recently demonstrated strong clinical efficacy in a phase II trial.

Novartis is expected to overtake Pfizer and become the biggest manufacturer of prescription medicines by 2018, according to new consensus data.

Research by EvaluatePharma estimates Novartis will record sales of more than $50bn in six years’ time, with its eye care business Alcon and generic unit Sandoz driving growth.

But the outlook is not good for US-based companies with only Pfizer remaining in the top five by 2018 and Sanofi, GSK and Roche maintaining a strong presence.

Data found that despite generic competition on Diovan and Glivec and disappointment from key projects such as Gilenya and its new respiratory franchise, Novartis is expected to record annual growth between 2011 and 2018 of 1.2%.

This is in contrast with AstraZeneca whose annual sales are expected to drop from $32.4bn in 2011 to $22.1bn in 2018 representing a negative growth of 5.3%.

Gilead Sciences is expected to experience the biggest increase in annual growth of the top fifteen companies with data showing sales will rise from $8.1bn to $15.7bn at a rate of 9.9% per year.

Novo Nordisk is also forecast to enter the top 15 ranked companies for the first time due to an increasing demand for its diabetes medicines. Annual growth is expected to be 7% until 2018 with sales totalling nearly $20bn.

One of the biggest casualties, data found, will be Eli Lilly. The Indianapolis research-based company currently claims to be the 10th biggest pharmaceutical company in the world. But Lilly fails to make the top 15 companies after research found a drop in sales will see it fall to 17th place by 2018. But researchers did note that Lilly’s Alzheimer’s candidate, solanezumab, could reverse the trend if it successfully enters the lucrative market.

Lilly will be replaced in the list by German healthcare giant Bayer, which also enters the top 15 global companies for the first time, with annual sales of around $16.5bn by 2018 boosted by Xarelto.

A new drug to treat the lethal condition pulmonary arterial hypertension (PAH) has shown impressive phase III trial results for efficacy and safety.

Actelion’s macitentan has the potential to replace its current PAH treatment, Tracleer, as the company’s leading product – and even to become the standard treatment for PAH.

The trial results boost the Swiss biotech company’s prospects of being acquired by a major pharma company.

Tracleer currently accounts for 90% of Actelion’s sales, but will lose patent protection in 2015 and is facing competition from Gilead’s PAH drug Letairis.

The SERAPHIN phase III study with 742 patients – the largest ever clinical study of a PAH treatment – showed that macitentan reduced the incidence of morbidity and mortality by 45% relative to placebo over three and a half years.

In addition, the drug did not show the negative side-effects on liver function associated with Tracleer, enabling it to compete more effectively with Letairis.

PAH is a chronic, life-threatening disease in which high blood pressure in the pulmonary arteries affects both lung and heart function.

Finance analyst UBS has suggested that macitentan could not only dominate the PAH market but increase its size, with potential annual sales of up to $2.8bn.

Actelion expects to apply for EMA and FDA marketing authorisation for the product by the end of 2012.

Macitentan, a dual endothelin receptor antagonist, was created through a tailored drug discovery process. It has superior sustained receptor binding and tissue penetration properties relative to other ERAs, and its propensity for drug-drug interactions has been shown to be low.

Two senior advisors on the SERAPHIN trial highlighted the study’s importance. Lewis J. Rubin, Emeritus Professor at the University of California, San Diego, said: “With this well-designed PAH study, Actelion pursued an ambitious goal to focus on outcome benefits as the primary endpoint. The impressive results of this landmark study are setting a new standard in how to conduct studies in this devastating disease.”

Gerald Simonneau, Head of the Department of Pulmonary Disease and Intensive Care Unit at the Hospital Antoine Beclere-Clamart in France, added: “These results represent an important milestone in the history of clinical trials in PAH and show that macitentan has the potential to offer a new treatment paradigm for these patients.”

The combination of two oral drugs from Gilead Sciences and Bristol-Myers Squibb (BMS) has the potential to offer a faster cure for hepatitis C.

Gilead’s GS-7977 and BMS’s daclatasvir, taken daily for six months, cured almost all patients in a phase II clinical trial while sparing them the side-effects of interferon.

However, the lack of a partnership between the two companies could delay patient access to the drug combination.

The companies said that all 88 trial participants who took the two-drug combination had undetectable virus levels after four weeks, and 84 had undetectable virus levels four weeks after the end of the 24-week trial.

The most common side-effects of the combination were fatigue, headache and nausea; the non-ribavirin treatment group also showed low phosphorus and high cholesterol levels.

Gilead also reported two 12-week phase II trials: one where GS-7977 and ribavirin cured 22 of 25 hepatitis C patients (with undetectable virus levels a month after the trial end); and and one where GS-7977, ribavirin and interferon cured 90% of patients.

Hepatitis C is a chronic blood-borne infection than can cause life-threatening liver damage. No complete oral treatment for the infection currently exists.

In 2011, Vertex and Merck introduced oral medications that increased the cure rate from 60% to 80% – but these need to be used alongside alpha interferon, which is injected weekly for up to a year and has flu-like side-effects.

As yet Gilead and BMS have not agreed to collaborate in order to bring the new combination therapy to market.

Dr Douglas J. Manion, a Senior VP at BMS, said the company was “keen” to work with Gilead but the latter was “unwilling to engage in that collaboration.”

Norbert W. Bischofberger, Executive VP for Research and Development at Gilead, said the company wanted to wait for further clinical trial data: “We told them it’s too early to jump wildly into this collaboration.”

In particular, he noted, Gilead wanted to establish whether the combination of GS-7977 with the generic ribavarin would be as clinically effective as using daclatasvir. If so, not only would the combination be cheaper, but Gilead could increase its profits by using its own ribavarin.

Finally, Bischofberger observed that if no collaboration took place, doctors would still be able to use GS-7977 and daclatasvir together.

The price of antiviral drugs used for the treatment of HIV/AIDS is set to increase as more physicians embrace new, innovative combination medicines, a new report has found.

Researchers found that the cost of annual treatment for HIV/AIDS increased to an average of $12,829 in 2010 from $9,971 in 2002 and is set to continue to rise.

The report noted that the cost of treatment has increased steadily over the past decade after the launch of new combination therapies.

These new treatments are expensive but have demonstrated their worth through impressive efficacy, particularly in patients who have developed a resistance to standard options, and have become the treatment of choice for doctors.

As a result, revenue from the global HIV/AIDS market grew at a compound average growth rate of 10.9% from 2002 to 2010.

This year a number of key brands used in the treatment of HIV/AIDS will lose patent protection. Sustiva and Combivir will go off patent in 2012 after Epivir, Epzicom, Trizivir, Ziagen, Invirase and Lexiva lost protection in either 2010 or 2009.

Whilst generic alternatives have now been made available, it is the use of these combination medications which has seen the market continue to grow.

The market is also expanding, the report found, due to decreasing mortality and increasing treatment-seeking rates, which has encouraged further pharmaceutical innovation.

This innovation has been highlighted with the release of Gilead’s new Quad treatment and late-stage pipeline products including Edurant and Vicriviroc.

Northern Ireland-based pharma company Galen has acquired a chemotherapy agent to treat advanced HIV-related Kaposi’s Sarcoma (KS) from Gilead Sciences.

DaunoXome (daunorubicin citrate liposome injection) has been approved in the US since 1996 as a first-line cytotoxic therapy for advanced KS, a typical disease in patients with active HIV.

Galen US, a wholly-owned subsidiary of Galen Ltd, will market DaunoXome in the US.

DaunoXome has been shown to be as effective as a triple chemotherapy regimen in the treatment of KS, which affects the skin and internal organs.

Before treatment for them existed, KS lesions were considered a key indicator of HIV infection.

“HIV-associated KS is an AIDS-defining illness, which has considerable impact on patient prognosis,” commented Dr. Anil Tulpule, Associate Professor of Medicine at the Norris Cancer Center, Los Angeles, California.

“For some HIV patients with advanced or poorly controlled KS, chemotherapy may be required alongside highly active antiretroviral therapy, to effectively target the cancer. DaunoXome provides a much-needed option for physicians needing to treat advanced HIV-associated KS patients with such chemotherapy regimens.”

Mark Scrutton, President of Galen, said: “DaunoXome marks our first step into the oncology arena, and this exciting new acquisition provides us with the opportunity to offer more widely a much-needed therapy.”

Galen is seeking to expand its global reach through international strategic partnerships and drug discovery focused on cancer treatments.

Swiss biotech company Actelion has seen its share value dip following concerns over a late-stage drug trial in which 120 out of 740 participants died.

The results of the SERAPHIN phase III trial of macitentan, a drug candidate to treat pulmonary arterial hypertension (PAH), have still to be analysed.

A reported comment by Actelion’s CEO Jean-Paul Clozel that the trial results were “very unlikely” to show that the drug extended life triggered a 9% drop in the company’s share value.

Until the encrypted trial results are decoded and published in the second quarter of this year, Actelion said, the reason for the deaths will not be known and the trial cannot be declared a success or a failure.

According to company spokesman Roland Haefeli, “PAH is a deadly disease, therefore it is to be expected that people die. We did expect and observe deaths. Until the code is broken, we do not know [the cause].”

An analyst commented that there had been “a misinterpretation around CEO comments” and that “nothing negative was said”.

The SERAPHIN trial aimed to show that macitentan significantly reduced both morbidity and mortality in patients with symptomatic PAH, so patient deaths were anticipated as marking the point where the trial would end.

The trial is crucial for Actelion, which relies on macitentan to restore its profile in the PAH market following competition to its existing Tracleer drug by Gilead’s rival Letairis (ambrisentan).

Sales of Tracleer fell by 7% in 2011, and Actelion posted a net financial loss of 146m francs after a profit of 390m francs in 2010.

The company has also started a pivotal study of macitentan in patients with ischaemic digital ulcers.