The Fight Against TB

Robert Smith, President of the Eli Lilly and Company Foundation, and Dr. Gail Cassell, Vice President for Scientific Affairs and Distinguished Research Scholar in Infectious Diseases at Eli Lilly, explain the magnitude of the health crisis caused by tuberculosis and the critical global collaboration needed to help halt the spread of the disease in regions of the developing world.

Ask any American what diseases they fear the most and rarely will you hear tuberculosis. While the Andrew Speaker incident this past summer – involving the TB-infected Atlanta lawyer who boarded an international flight – momentarily brought TB back out of the shadows in the States, many Americans tend to view TB as a long-ago defeated disease. In reality, TB has grown even more deadly.

Today TB steals approximately 1.6 million of the world’s population each year and is second only to AIDS as the deadliest infectious disease. Because TB is spread through the air, it takes no more than a cough to become infected. According to the World Health Organization (WHO), one third of the entire human population is currently infected with the germs that cause TB and someone becomes newly infected every second.

The crux of the problem is that the majority of TB cases occur in resource-limited countries of the developing world that aren’t equipped to deal with the disease. Poor healthcare infrastructures and a lack of resources in developing nations where TB is predominant have resulted in patients not fully adhering to the complex treatment regime, which in turn, has bred more dangerous and less treatable forms of the disease.

Strains of multi-drug resistant TB (MDR-TB) – a form resistant to at least two of the most powerful anti-TB drugs – have been detected in more than 100 countries and 450,000 new cases of MDR-TB are reported each year. Even scarier, an extremely virulent new form of the disease resistant to both first-line and second-line anti-TB drugs, extensively drug-resistant TB (XDR-TB), has been detected in 37 countries, including the US.

While TB may be perceived today as a quiet and distant threat to the US, poorly resourced countries like Russia, South Africa and India are battling the atrocious assault of the disease on a daily basis. The magnitude of the challenge of TB, brought on by its contagious nature and prevalence in developing nations, has created a complex and urgent health crisis that can only be confronted by global alliances among health, academic and government organizations alike.

Complex disease, complex solution
The looming complexity of the TB epidemic exists on multiple levels, beginning with the nature of the disease itself. As a bacterial disease that most commonly attacks the lungs, TB bacilli may or may not cause symptoms. In fact, it’s common for people to be infected with dormant TB germs and never become sick. Only five to 10 percent of HIV-negative people infected with TB bacilli become sick or infectious in their lifetime.

For those that are diagnosed, the majority of TB cases are treatable, though treatment isn’t simple. Due to the complexity of the organism behind TB, the treatment regime requires a unique combination of four to six antibiotics taken over a minimum of six to nine months. “You need the best scientific expertise in order to overcome the technical challenges that you have with the organism that causes tuberculosis,” Cassell admits. “The bacterium that causes tuberculosis has a doubling time that can be days to weeks and most of the time it requires growth inside cells, like macrophages. In addition it has a very complex cell wall, therefore there are unique scientific challenges in developing antibiotics for TB.”

While developing new antibiotics to beat TB may be challenging, it’s never been more necessary. As incomplete and improper use of TB antibiotics has spawned stronger, drug-resistant strains, the 40-year-old treatment regime is wearing thin against the emergence of MDR-TB and XDR-TB.

Existing antibiotics can still work for MDR-TB, which is resistant to at least two of the most powerful first-line anti-TB drugs, though treatment is more difficult and expensive. With MDR-TB, the treatment length is extended and second-line drugs need to be taken over a one to two-year period. The grave danger arises when the second-line drug treatment is disrupted or not administered properly, and strains of XDR-TB develop. First identified in the spring of 2006, XDR-TB is resistant to three or more of the six classes of second-line drugs, leaving XDR-TB patients virtually untreatable with the existing treatment available.

The threat of XDR-TB is particularly harrowing in populations where HIV is highly prevalent. Already a deadly combination, TB and AIDS accelerate the progress of each other so much that approximately 90 percent of HIV patients without proper treatment die within months of contracting TB according to the WHO. Because of the weakened immune system caused by HIV, HIV-positive individuals are up to 50 times more likely to develop TB in a given year than HIV-negative people.

For patients co-infected with XDR-TB and HIV, there’s little hope. In one extreme case, an outbreak of XDR-TB in a HIV-positive region in South Africa resulted in 52 of 53 patients dying within an average of 25 days after being diagnosed. Patients co-infected with XDR-TB and HIV face alarmingly high mortality rates and survival rates no longer than six weeks after diagnosis.

Extremely grim outlooks from some in the medical field suggest that XDR-TB could potentially undo all the progress that’s been made with HIV. XDR has already been detected in all regions of the world; however, if the disease gained a strong foothold in AIDS-stricken Africa, it could result in an out-of-control pandemic.

The severity of the situation at hand sets the stage for the urgent necessity of discovering new anti-TB drugs – to be specific, four new drugs in new classes of drugs nonetheless. Aside from the huge challenge this presents for pharma, it’s in markets that aren’t necessarily going to provide a return on investment, so the efforts must be largely philanthropic in nature.

“Developing a single drug for any disease is a huge challenge,” Cassell says. “If you couple the low optimism for getting a return on your investment for development of a TB drug with the fact that we now not only need one new drug but a minimum of four new drugs and new classes of drugs because of the resistance issues; that becomes an almost insurmountable challenge for any single company.”

Dealing with poor healthcare infrastructures
Discovering an arsenal of new anti-TB drugs is only part of the equation for defeating TB. Because MDR-TB is prevalent in countries with poor TB infrastructures – approximately two-thirds of MDR cases worldwide are in China, India and the Russian Federation – hurdles exist around the very basic elements of disease control, including supply and demand and sufficient healthcare resources.

Major deficiencies in healthcare infrastructures that are magnifying the TB challenge include: lack of infection control practices, poor diagnostic capabilities, limited lab capacity, inadequate healthcare resources, improper surveillance and more. Thus treating an advanced, contagious disease like MDR-TB, which has already developed drug resistance and is spread through aerosol transmission, is nearly impossible in such settings.

One of the largest holes in such infrastructures is the ability to accurately predict supply and demand. “Demand forecasting is acknowledged as a huge problem in resource poor countries because there isn’t the health infrastructure to track drug supply and patient need,” Cassell says. “It’s becoming more and more apparent that this is a major weak link in the supply chain.”

Part of the problem with balancing supply and demand is the need for improved diagnostics. Only a small fraction of infected TB individuals are actually diagnosed. Plus, current diagnosis practices largely rely on a sputum smear examination, an inefficient process that’s been in use for 125 years. Because many are diagnosed in the late stage of TB infection, it also increases the need for quick access to quality lab services.

Another major hurdle is providing adequate healthcare workers to properly monitor and administer treatment so as to prevent future super-resistant strains of the disease. The high-risk setting of working with a highly contagious bacterial disease complicates the treatment program and securing devoted healthcare workers. Thus, improved infection control practices are another critical component needed to contain the disease and prevent transmission in healthcare facilities between both workers and patients.

Aggressive global collaborative efforts are therefore necessary to overcome the litany of infrastructure weaknesses and strengthen overall TB programs. “The bottom line is no single government, non-governmental organization or individual pharmaceutical company has the resources or the expertise quite honestly to deal with the magnitude of the challenges that we’re facing with TB,” Cassell acknowledges. “Because it is a contagious disease spread by aerosol, it has to be a multi-government, multi-country effort to basically bring this epidemic under control. So international partnerships are essential, not just important, if we are going to make a dent in this disease.”

Eli Lilly and others
The rise of MDR-TB and XDR-TB among ill-equipped infrastructures calls for organizations worldwide to collectively pool their resources in order to help stop the spread of drug-resistant TB. One pharmaceutical company has stepped up to the challenge unlike any other.

Eli Lilly has spearheaded the TB movement in pharma, having already committed approximately $135 million to key partnerships and initiatives specifically designed to fight TB. Lilly is also responsible for developing two of the key drugs part of the anti-TB treatment regime. Those two drugs, capreomycin and cycloserine, date back to the 1950s and 60s, and served as the catalysts for Lilly’s widespread involvement with TB today. “Capreomycin and cycloserine are decades-old drugs, long off patent and are not part of our therapeutic areas of focus,” Smith says. “However, these drugs are going to be increasingly important in treating this growing health threat; therefore, we wanted to play a role in creating a sustainable supply of the medicines.”

The Lilly MDR-TB Partnership, dedicated to the prevention, diagnosis and treatment of MDR-TB, began in 2003 and was originally funded with a $120 million contribution over an eight-year time period. Today the award-winning partnership consists of an international alliance of 14 public and private organizations. “Key elements of the partnership include: increasing the supply of drugs in a sustainable fashion by transferring our manufacturing technology to other companies; improving disease diagnosis, treatment, and surveillance; and investing in the training of healthcare professionals,” Smith says.

At the centerpiece of Lilly’s efforts around TB is the transfer of technology. With two of the key anti-TB drugs developed under Lilly’s watch, and the likelihood that there will be even greater demand in the future, Lilly aims to share its expertise with other companies. Therefore, Lilly is heavily involved in transferring its technology to other manufacturing companies in areas where the disease is most prevalent in order to build a sustainable supply of the drugs. Lilly’s manufacturing partners include: Aspen Pharmacare in South Africa, Hisun Pharmaceutical in China, Shasun Chemicals and Drugs in India, and SIA International in Russia.

“The transfer of technology has represented a massive commitment on the part of Lilly,” Smith says. “These are complicated products to manufacture, so we’re not just mailing the instructions. We’re making financial payments to help build capacity and capability, and, very importantly, several dedicated Lilly employees have donated their time to help ensure the success of the transfer.”

In addition, this summer Lilly announced an ambitious public-private partnership, the Lilly Not-for-Profit Partnership for TB Early Phase Drug Discovery, focused on early-phase discovery research of new medicines to treat TB. The partnership represents a significant step towards discovering new and improved treatments for TB. “I am optimistic because I believe by having a not-for-profit, we will be able to capitalize on the best scientific expertise and drug discovery expertise in the industry, and the best scientific expertise of the academic community,” Cassell says.

The not-for-profit drug research organization will be based in Seattle, Washington and will seek to leverage expertise and resources from leading nation-wide TB and infectious drug researchers and organizations, eventually looking to secure up to 25 full-time drug researchers on-site. Lilly will fund the leasing of the space, equip the facility with machinery and biological tools, and will open its library of more than 500,000 Lilly compounds to researchers. In addition, Lilly’s own chemistry advisory committee will offer expertise and help to steer research efforts.

The partnership aims to integrate medicinal chemistry expertise with academic expertise, with the hopes that marrying the sectors will help to make a serious dent in the disease, particularly in the early phase compounds. “To overcome the technical and financial challenges, you need the best of the public sector and the private sector in order to conquer this organism,” Cassell remarks. “Essentially this is one reason that Lilly announced a not-for-profit public-private partnership for developing early-phase compounds that would be effective against TB. What seems to be a critical need right now are early phase compounds in the TB pipeline, so we elected to focus our efforts on early phase drug discovery and the development of clinical candidates.”

Lilly’s generous and ambitious philanthropic efforts should serve as a model for the rest of the industry to follow, not only for TB but for other prominent diseases of the developing world such as AIDS and Malaria that call for widespread efforts to help raise the standard of healthcare in poorly resourced nations. “The bottom line is that companies need to look at the assets they have – not just the products but the human resources and capabilities – and how they can best be deployed to help meet the needs of those suffering from disease,” Smith admits. “In addition to successfully bringing new medicines to market, the industry should continue its leadership in corporate responsibility efforts. By doing so, the industry can play a valuable role in helping the global health community solve problems.”

United against MDR-TB
Eli Lilly isn’t alone in the fight against TB, 14 unique public and private organizations have joined forces as part of Lilly’s MDR-TB partnership. We’ve highlighted five of the partners’ key contributions:

1. Aspen Pharmacare in South Africa is producing cycloserine in a brand new facility with a capacity of four billion capsules per year. Aspen is working with the WHO to begin supply to countries approved by the Green Light Committee, and has also begun construction of a facility to produce vials of capreomycin by early 2008.
2. International Council of Nurses (ICN) has launched a global TB/MDR-TB project to equip nurses around the world with the knowledge and tools for detection, treatment, and management of the disease. ICN has developed “TB Guidelines for Nurses in the Care and Control of Tuberculosis and Multi-Drug-resistant Tuberculosis,” and has established a web-based "Global TB/MDR-TB Resource Centre” for the 13 million nurses working worldwide.
3. International Federation of Red Cross and Red Crescent Societies (IFRC) implements TB-patient-support programs aimed at the most vulnerable. The programs include public awareness and anti-stigma campaigns, community outreach, psychological support and food supplements, and are currently implemented in Kazakhstan, Romania, and Uzbekistan.
4. Harvard Medical School and Partners In Health (PIH) have established a Center of Excellence for MDR-TB treatment and training in Tomsk, Russia. Several hundred doctors, nurses, and healthcare workers from Russia and the former Soviet Union have already been trained how to prevent, detect, and treat the illness.
5. TB Alert & TB Survival Project is a U.K.-based charity, focused on patient advocacy and creating public awareness of TB, that has joined forces with Paul Thorn, an HIV-positive MDR-TB survivor, to launch www.tbsurvivalproject.org, an advocacy website designed to engage MDR-TB and TB patients worldwide.