The TB Armamentarium

Tuberculosis (TB) kills one person every two minutes in India and 750 people every day, says Dr Madhukar Pai, Associate Professor, McGill University, Dept of Epidemiology and Biostatistics. India has the world’s highest burden of tuberculosis, and accounts for nearly one-fifth of the new TB cases that occur in the world every year. According to Shakti Chakraborty, Group President – India Region Formulation and CIS, Lupin, “TB is a very serious disease in a developing country like India. It is estimated that annually around 330,000 Indians die due to the TB.”

WHO’s Global Tuberculosis Report 2012 indicates that India has the most number of TB patients. In India, the prevalence is 3.1 million at best and 4.3 million at worst. Even in prevalence rate (per one lakh population a year), India is 249 (number in thousands) at best and 346 at high. Presently, there are a number of Indian and multi-national companies producing drugs for the anti-tubercular portfolio. Lupin, Macleods Pharma, Cadila, Strides Arcolab, Svizera, Sandoz and Wockhardt are few companies that have impressive anti-TB drug portfolios. Amongst MNCs—Pfizer, Novartis, Sanofi and Abbott have been manufacturing, marketing and researching anti-TB drugs. In India, especially anti-infectives have remained a major therapeutic category of focus for companies.

Drugs availability

“TB is clearly indicating that the demand for drugs would be largely confined to economies where price control is deliberate and the scope for profits is much more limited.” Hitesh Gajaria, Partner, KPMG India

WHO states TB as a major public health problem in India. Each year nearly two million people in India develop TB, of which around 0.87 million are infectious cases. This in turn has led to an increase in the production and marketing of TB drugs in India. Hitesh Gajaria, Partner KPMG India reveals the TB generic drugs availability in the Indian market, “R-Cinex ((Isoniazid / Rifampin – manufactured by Lupin) and Forecox (Ethambutol + Isoniazid Ethambutol – manufactured by Macleods) are the two of the most widely prescribed anti-TB drugs. Together, they capture close to 15 per cent of the market share in India. AKT-4, Combutol, Akurit -4, Pyzina are other majorly prescribed drugs for TB. Together these four brands capture ~20 per cent of the market sales of anti-TB drugs and are all manufactured by Lupin.”

Chakraborty reiterates this and says, “There are numerous domestic and some international pharma firms manufacturing or marketing drugs in the country as well as globally. Lupin has been the trail blazer and still remains the undisputed global heavy weight in the anti-TB drugs space. Leave alone India, where we have close to 50 per cent market share (IMS Health). We are global leaders in drugs like Rifampicin where we have close to 80 per cent global market share.”

Treating TB

“We are now looking at expanding our offerings in the Anti-TB range to include APIs in the MDR TB category.” Shakti Chakraborty Group President – India Region Formulation & CIS, Lupin

Drug resistance in TB is a serious problem compromising both the treatment and control programmes. Poor usage of the available anti TB drugs has led to progressive drug resistance-multi drug resistance (MDR), extensively drug-resistance (XDR) and even total drug resistance (TDR). While drug sensitive TB is completely curable, MDR-TB is difficult to treat, XDR and TDR are often fatal. Non availability of new drugs to treat drug resistant cases further complicates the problem. The emergence of mycobacteria which are resistant to drugs used to treat TB has become a significant public health problem world over creating an obstacle to effective TB control. Its presence has been known virtually from the time anti-TB drugs were introduced for the treatment of TB but drug resistant TB is being encountered more frequently now in most countries including India. There have been a number of reports on drug resistance TB in India, but most studies were undertaken using non-standardised methodologies with bias and small samples usually from tertiary level care facilities. Treatment of TB usually involves taking several antibiotic drugs for at least six months and sometimes for as long as 12 months. Four of the biggest high-burden countries —India, Indonesia, Pakistan, and Philippines – have a large private sector pharmaceuticals presence, capable of producing enough TB drugs to treat all incident TB patients with a full TB drug regimen.

Some Bilogical drugs in development for MDR TB

MDR-TB treatment

According to the WHO, Eastern Europe is in the midst of a MDR-TB disaster with 30 per cent of incident cases resistant to major therapies. Globally, five per cent of TB cases in developing countries are MDR compared to two per cent in developed countries. This is indicative of the fact that there is an urgent need to get the situation under control. The scale of the MDR-TB epidemic is massive, with 310,000 new cases reported in 2011. Globally, however, only 19 per cent of people thought to be infected are receiving treatment.

Types of treatments

The drugs that are used for the treatment of drug resistant TB are grouped according to how effective they are, how much experience there is of their use and the drug class. All the “first line” anti TB drugs are in Group 1, apart from streptomcycin which is classified with the other injectable agents in Group 2.

Group 1: First Line Oral Agents

• pyrazinamide
• ethambutol
• rifabutin

Group 2: Injectable Agents

• kanamycin
• amikacin
• capreomycin
• streptomycin

“New patients are presumed to have drug susceptible TB (i.e. TB which is not drug resistant) unless there is a high level of isoniazid resistance in new patients.” Udayasree Ovaldas Asso. Research Manager, Cognizant Technology Solutions

Udayasree Ovaldas—Associate Research Manager, Cognizant Technology Solutions suggests, “The first line drugs are those drugs that generally have the greatest bactericidal activity when used for TB treatment. New patients are those who have no history of prior TB treatment, or they have received less than one month of anti TB drugs. New patients are presumed to have drug susceptible TB (i.e. TB which is not drug resistant) unless there is a high level of isoniazid resistance in new patients, or the patient has developed active TB disease after known contact with a patient documented to have rug resistant TB.”

She continues, “It is recommended that patients take the TB drugs every day for the six months, although taking them three times a week is possible in some circumstances. It is essential that all the recommended drugs are taken. If only one or two drugs are taken, then the treatment probably won’t work, because the TB bacteria that a patient has develops resistance to the drugs. Not only is the patient then still ill, but to be cured they then have to take drugs for the treatment of drug resistant TB, and these drugs are more expensive and have more side effects.”

New milestone in MDR TB treatment

“Anti-TB drug does not generate enough sales for pharma companies to consider it a worthwhile return on investment.” Kambhampati Vally Maya Research Manager, Cognizant Technology Solutions

Kambhampati Vally Maya, Research Manager, Cognizant Technology Solutions informs, “A new class of drug specifically for the treatment of TB had not been developed for almost four decades after discovery of rifampicin. One important reason is that a novel anti-TB drug does not generate enough sales for pharma companies to consider it a worthwhile return on investment.” However, after more than four decades, recently Johnson & Johnson (J&J) received US FDA approval for Sirturo, a MDR-TB drug which became a lead for success. Sirturo has been approved under the FDA’s accelerated approval programme for orphan drugs. While the FDA generally requires a lengthy three-stage testing process before any approval, Sirturo was given an approval after just two periods of study- the second phase is still ongoing. Inspite of a few untoward incidences that were observed, the FDA permitted its entry with a caution. The FDA warned that the drug carries risks of potentially dangerous heart problems and should be prescribed carefully by doctors. Gajaria feels that on an overall balance the FDA judged the benefits of accelerated approval process to outweigh the negative side effects, especially when the medical fraternity has been put to notice of the possible negative side effects – necessitating due care in the prescription process. He highlights, “Sirturo is active against drug-resistant forms of the disease. In addition to Sirturo, another new drug that is active against MDR-TB called Delamanid, developed by Otsuka, is undergoing registration by the European Medicines Agency and is expected to be approved for use in 2013. It is likely that many more drugs will hit the market if the approval process is relatively relaxed in light of the prevalent emergency.”

In order to maintain the quality and provide better drugs, United States Pharmacopeial Convention (USP) a scientific nonprofit organisation that sets standards for the identity, strength, quality, and purity of medicines, food ingredients, and dietary supplements manufactured, distributed and consumed worldwide works with the following 12 medications, which treat MDR-TB or extensively drug-resistant TB (XDR-TB). They are as follows:

• Amikacin, 500 mg/2 ml solution for injection ampule or vial; 1 g powder for injection amp or vial*
• Capreomycin, 1 g powder for injection, vial*
• Cycloserine, 250 mg capsule
• Ethionamide, 250 mg tablet/capsule
• Kanamycin, 500 mg or 1 g powder for injection, vial*
• Levofloxacin, 250 mg tablet/capsule; 500 mg or 750 mg tablet
• Moxifloxacin, 400 mg tablet/capsule
• Ofloxacin, 200 mg or 400 mg tablet/capsule
• Para-Aminosalicylic Acid (PAS), 4 g granules, sachets
• Para-Aminosalicylic Acid (PAS) Sodium, 100 g granules, jar; 4 g or 9.2 g granules, sachets; powder for oral solution, sachets
• Prothionamide, 250 mg tablet/capsule

“Recently, it was reported that 40 per cent of TB cases in Belarus were MDR-TB—a shocking number.” Patrick Lukulay Vice President, Global Health Impact Programs and Director, PQM Programme, US Pharmacopeial Convention

“The Promoting the Quality of Medicines (PQM) programme, a US government-funded programme implemented by the US Pharmacopeial Convention (USP), offers a free technical assistance to assist Indian manufacturers (and those worldwide) in achieving WHO pre-qualification. WHO pre-qualified medicines are comprehensively evaluated for quality, safety and efficacy. Those that meet WHO’s standards are added to its list of pre-qualified medicinal products, which is a vital tool that today is widely used by United Nations agencies as well as a range of groups involved in purchasing medicines in bulk. More information on this assistance is available at http://www.usp.org /around-world/pqm-uspusaid/increasing-supply-qa-medicines,” shares Patrick Lukulay, Vice President, Global Health Impact Programmes and Director, PQM Programme, US Pharmacopeial Convention.

“Countries around the world are grappling with TB, but the Newly Independent States appear to be most in need at this point. MDR-TB is spreading fast in this part of the world, and is some ways is an epicenter for MDR-TB. Recently, it was reported that 40 per cent of TB cases in Belarus were MDR-TB—a shocking number,” informs Lukulay.

Sirturo- risks involved

Sirturo (bedaquiline) is designed specifically for treating MDR TB. Bedaquiline inhibits the enzyme that Mycobacterium tuberculosis needs to replicate and spread throughout the human body. However, because the drug also carries some significant risks, doctors should make sure they use it appropriately and only in patients who don’t have other treatment options. Despite nine patients receiving Sirturo in a clinical trial dying compared to two on placebo, the FDA approved Sirturo under its accelerated approval programme. J&J (Janssen Therapeutics), Sirturo’s makers, is continuing additional studies to confirm its efficacy and safety.

Chakraborty stresses, “There are many factors that must be taken into consideration for this. There is a fairly complicated process for procuring new drugs that are still being tested. Over the past four decades, the TB bacteria have also evolved. In fact, even J&J’s Sirturo drug was approved by the FDA under its accelerated approval programme — clearing innovative drugs based on promising preliminary results.”

Maya, Research Manager, Cognizant Technology Solutions reminds, “All the deaths in the placebo arm of the human studies the FDA examined were linked to tuberculosis. Among the participants taking Sirturo, the causes of four deaths could not be identified, meaning that they might have been related to the drug.”

“We desperately need new TB drugs and therefore the FDA approval of Sirturo is great news. But I am concerned about introducing any new TB drug in the Indian market.” Dr Madhukar Pai Asso. Professor, McGill University, Dept of Epidemiology & Biostatistics

However Pai feels, “We desperately need new TB drugs and therefore the FDA approval of Sirturo is great news. But I am concerned about introducing any new TB drug in the Indian market. The market is completely unregulated and anyone can purchase any antibiotic over the counter (OTC). Also, several studies have shown irrational and irresponsible antibiotic use in India, including for TB. So, if the new drug is abused widely, then we will rapidly lose the drug to drug resistance, and that will be a big setback in the race to develop better TB drugs. So, new TB drugs must be introduced very carefully and regulated. Doctors must be educated on how to use them as combinations, rather than single drugs.”

Region wise global TB statistics

(Source: Cognizant Technology Solutions)

Nexus between TB and HIV

As per the WHO Global TB Report 2011, there were an estimated 8.8 million incident cases of TB globally in 2010, 1.1 million deaths among HIV-negative cases of TB and an additional 0.35 million deaths among people who were HIV positive. Major challenges to control TB in India include poor primary health-care infrastructure in rural areas of many states, unregulated private health care leading to widespread irrational use of first-line and second-line anti-TB drugs, spreading HIV infection, poverty, lack of political will, and, above all poorly managed government-driven anti-TB programmes. In 2009, there were an estimated 9.7 million children who were orphaned as a result of parental deaths caused by TB.

“While the HIV epidemic in India appears to have peaked, the total number of persons living with HIV/AIDS remains high, and with time the level of immune deficiency and TB vulnerability may increase. Malnutrition remains highly prevalent in India, and will remain a significant factor for years to come,” highlights Maya.

TB statistics of the 22 TB burden countries

(Source: Cognizant Technology Solutions)

A call to eradicate TB

India having the largest TB cases, a significant number of domestic pharma companies are engaged in manufacturing and marketing anti-TB drugs. Lupin also partners with various agencies and organisations for their TB eradication programmes. “We supply anti-TB drugs to many Government agencies, the National TB programme, the Stop TB Partnership and various other international agencies. Lupin is pre-qualified as a preferred supplier to the Global Drug Facility (GDF). These formulations are being supplied to more than 50 countries through GDF procurement. The company also supplies to various international institutions like Pan America Health Organisation (PAHO), Medicines Sans Frontier (MSF) and the Damien Foundation. We are now looking at expanding our offerings in the Anti-TB range to include APIs in the MDR TB category. The areas of MDR TB and Paediatric TB provide additional opportunity for Lupin to strengthen its global leadership,” shares Chakraborty.

He continues, “The majority of funding for RNTCP is from the Government of India (GoI) sources which includes a World Bank credit. The programme is also supported with funds from donor agencies including Department for International Development (DFID) of UK, the Global Fund and USAID. The Global Drug Facility (GDF) procures about half of the drug requirement of RNTCP using funds from DFID. Efforts have been made by the GoI to make TB treatment affordable to the poorer sections of the Indian society.”

Maya feels, “The Indian government’s Revised National TB Control Programme (RNTCP) was started in 1997 and was then expanded across India until the entire nation was covered by March 2006. The programme uses the WHO recommended Directly Observed Treatment Short Course (DOTS) strategy and reaches over a billion people in 632 districts/reporting units. In 2010 the RNTCP achieved a treatment success rate of 87 per cent of NSP patients and a detection rate of 71 per cent of the estimated NSP people in the community. In 2010 the RNTCP made a major policy decision that it would change focus and adopt the concept of Universal Access to quality diagnosis and TB treatment for all TB patients. This involves extending the reach of RNTCP services to all people diagnosed with TB, as well as improving the quality of existing services.”

Maya shares the insight that the RNTCP plans to achieve these targets by using rapid diagnostics for the diagnosis of TB and drug resistant TB; expanding services for the management of multi drug resistant TB; strengthening urban TB control; strengthening public-private mix initiatives; improving the quality of basic DOTS services; aligning with National Rural Health Mission supervisory structures. ”The RNTCP has tried to involve non public health providers in promoting TB care, but it is believed that many patients continue to seek treatment elsewhere and currently go unreported. Surveys of TB prevalence including self reporting of TB prevalence have suggested that up to 46 per cent of patients may not be currently reported. There are many reasons why people may seek care outside the RNTCP. These include poor knowledge about TB, poor knowledge about services available through the national programme, the convenience of services, a desire for confidentiality and desire for personalised care. “With the aim of improving the collection of patient care information, in May 2012 India declared TB to be a notifiable disease, meaning that in future all private doctors, caregivers and clinics treating a TB patient must report every case of TB to the government, “adds Maya.

High burden countries

TB has huge global impact, however, approximately 80 per cent of the global TB burden is concentrated in 22 high burden countries (HBCs). TB treatment has been considered primarily as a public health priority, because lengthy, supervised treatment is needed to maximise cure rates, reduce incidence, and minimise the development of resistance. A significant amount of private sector TB treatment is, however, known to exist.

Of the 22 HBCs for drug-sensitive TB, 11 countries were covered in an IMS study to assess the penetration of private sector in the TB drug market. One of these 11 HBCs, Brazil, is thought to have no private market for TB drugs. The remaining 10 HBCs (listed by 2009 HBC rank [14]) are: India (1), China (2), Indonesia (3), South Africa (5), Bangladesh (6), Pakistan (8), the Philippines (9), Russia (11), Viet Nam (12) and Thailand (18). Based on the estimated number of incident cases, these 10 countries include 60 per cent of the estimated burden of TB. IMS data were not available for other countries in sub-Saharan Africa including Nigeria (4), Ethiopia (7) and DR Congo (10). In the public sector, TB treatment policies are typically based on World Health Organization (WHO) recommendations, and for first line treatment most countries adhere to a six month course denoted, in shorthand, as 2HRZE/4RH (2 months of isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E), followed by four months of isoniazid and rifampicin). Sales of standard dosages by the Global Drug Facility (GDF) reinforce these recommendations. For a given country, these treatment policies are usually decided centrally and are uniformly applied. Thus, estimating average treatment practices in the public sector is easier than in the private sector, where decision making is made at the healthcare provider or patient level.

Four of the biggest high-burden countries — India, Indonesia, Pakistan, and Philippines — have a large private sector pharma presence, capable of producing enough TB drugs to treat all incident TB patients with a full TB drug regimen. Gajaria notes, “The problem arises in the case of MDR-TB – very few patients receive MDR-TB treatment and data reveals that the private sector seems to be still finding it’s feet in bridging the gap. The RNTCP in India focuses on affordable and effective treatment of TB.”

PPP on TB drug development

Private markets in four countries—Pakistan, Philippines, Indonesia and India – had the largest relative sales volumes; annually, they sold enough first line TB drugs to provide 65–117 per cent of the respective countries’ estimated annual incident cases with a standard 6–8 month regimen. Fixed drugs combination (FDC) markets were, however, more concentrated, with four companies capturing 69 per cent of FDC volume across the 10 countries (Sandoz, MacLeods and Lupin). Among second line drugs, fluoroquinolones were widely available, with significant volumes used for TB in India, Pakistan and Indonesia. Certain WHO-recommended drugs are not available and in general there are insufficient drug volumes to cover the majority of the expected burden of multidrug-resistant TB (MDR-TB). Private TB drug markets in several HBCs are substantial, stable, and complicated. “This calls for appropriate policy and market responses, including expansion of Public-Private Mix (PPM) programmes, greater reach, flexibility and appeal of public programmes, regulatory and quality enforcement, and expansion of public MDR-TB treatment programmes. From a public health standpoint, understanding the private market is critical to ultimately improving overall outcomes in TB. In contrast to most national TB programmes (NTPs), the private markets operate in a decentralised and largely unregulated fashion, with few mechanisms in place to monitor and ensure evidence-informed prescribing and patient adherence to a TB regimen, creating risks for developing drug resistance.” According to Stop TB an arm of the WHO, there are close to around 15 new TB drugs which are presently in various stages of development. Soon after Sirturo there is an another new drug in the pipeline for active against MDR-TB, Delamanid, developed by Otsuka, targeted for this year. These drugs provide more hope to both the industry as well as the patient, the end user, in the fight against TB.

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