A new multi-pharma company collaboration is intended to dramatically speed development of new combination regimens for tuberculosis, but efforts to accelerate development may be hindered by the lack of biomarkers for TB.

The "Critical Path to TB Drug Regimens" initiative, unveiled March 18, is a creation of the Bill & Melinda Gates Foundation, the Critical Path Institute and the TB Alliance. It is intended to make it easier for pharmaceutical companies to work together and get TB drugs approved more quickly than is possible today.

Already several Big Pharma companies are on board, including Johnson & Johnson, AstraZeneca, Sanofi-Aventis, Otsuka, Pfizer, GlaxoSmithKline, Bayer, and Novartis. Of the nine drugs in development for TB, eight will be part of the CPTR (see chart: "¹ Global TB Drug Portfolio: Drugs In Registration Programs"). (Aside from Lupin Limited of India, developers of all TB drugs in clinical development are participating in the program.)

As is the case with AIDS and cancer, TB requires treatment with combinations of drugs to tackle disease on a number of fronts. Standard treatment for drug-susceptible TB today is a cocktail of four elderly generics: rifampacin, isoniazod, pyramidizide and ethambutol.

Treatment lasts six months or more, resulting in compliance problems and drug resistance. According to the World Health Organization, about 1.1 million people had the active form of TB in 2008 and 500,000 had multidrug-resistant disease. Half of the cases of resistant disease were found in India and China.

The pipeline includes chemical classes that have been approved for treatment of other bacterial infections, such as fluoroquinolones, macrolides, oxazolidinones and nitroimidazoles. Furthest along in development are two antibiotics from the fluoroquinolone class that are approved for other indications - Kyorin's gatifloxacin and Bayer's moxifloxacin. Both are in Phase III for TB. J&J subsidiary Tibotec and the TB Alliance are jointly developing TMC-207, a member of the diarylquinoline class, now in Phase II. And Otsuka and the same TB Alliance are trying nitroimidazoles in Phase II (OPC-67683 and PA-824 respectively).

Ideally, the CPTR wants to create drugs for TB as rapidly as has been possible in the R&D world of HIV/AIDS, where the creation of the accelerated approval mechanism for approval based on surrogate endpoints slashed the time it took to get HIV medications to market.

But there is one important difference in these two therapeutic spaces. Rapid development of AIDS drugs was made possible by the use of established biomarkers, namely CD-4 cell counts and viral loads.

With TB, on the other hand, there are no accepted biomarkers and it takes considerable time to figure out whether drugs are working. A number of tests have been developed and the "scramble is on" to generate data to satisfy the FDA that efficacy is good enough for use in clinical trials, said William Bishai, co-chair of the WHO Stop TB Partnership Working Group for New Drugs and co-director of the Center for Tuberculosis Research at Johns Hopkins.

Wanted: Biomarkers For TB

An important part of the CPTR's mission involves helping to establish biomarkers for TB drug development.

FDA appears willing to fast-track this effort. The agency is hosting a workshop on the development of diagnostic tests and biomarkers for TB on June 7 and 8, in conjunction with the Centers for Disease Control and Prevention and the National Institute of Allergy and Infectious Diseases.

Furthermore, FDA is also drafting guidance to pave the way for testing of novel drugs in combinations. Testing multiple new drugs in combination is not prohibited currently, nor is it unprecedented, but the regulatory path is murky. (It may be easier to accomplish this in a neglected disease area; Novartis' malaria drug Coartem , approved in 2009, is a combination of two novel agents.)

Two sets of guidance on testing investigational drugs in combination are now being drafted, according to the agency, one for TB specifically and another for TB and other serious diseases.

Having the regulators' official okay to test investigational drugs in combination would "break down a huge hurdle," for developing drugs in TB, said Raymond Woosley, CEO of the Critical Path Institute.

Slashing Multidrug Regimen Development Time

Drug developers have traditionally tested investigational drugs as single new agents and then, following approval, run trials as part of combination regimens.

In the current environment, it might take 24 years to get a combination of four new drugs on the market (six years for each drug). A single drug would go through the regulatory process and then find its way into a combination regimen. Now the thinking is that "multiple drugs are mandatory" for TB, as well as other diseases, and "let's think about combinations at the very beginning," Bishai said.

Under the forthcoming guidance and with a range of standard biomarkers, four drugs could be tested at the same time, and in theory a new multidrug combination could become available in six years, or even faster.

Drug companies have already been working together on in vivo studies of TB drug combinations, but details are not publicly available about which agents are likely to be tested together.

Clinically, the process of testing drugs at the same time is complex, because it is necessary to study the effects of the combination while also teasing out side effects for individual drugs, said Paul Stoffels, global head of pharmaceutical R&D at J&J. Identifying side effects for various drugs is easier to do in combinations that involve known entities.

It is also an expensive prospect. For diseases that are common in the developed world, the "pot at the end of the rainbow is large enough" that drug companies are sure to find ways to collaborate, do deals, and conduct studies that show the benefits of combination regimens, Bishai pointed out.

The commercial imperative for drug developers to work together is less clear for diseases that primarily afflict people in developing countries. So the regulatory guidance is much more crucial for neglected diseases such as TB, Bishai said.

Pharma companies that get involved in the research of neglected diseases are mainly aiming to break even, while making a big contribution to public health and attracting some good PR, he said.

However, as innovation becomes more of a challenge and as the industry explores new business models to supplant the dwindling era of the blockbuster, emerging markets have become more attractive.

Some of the emerging economies are growing fast and there are affluent parts of their populations that would be "exceedingly eager to pay for branded pharmaceuticals for a chance at a cure for diseases like TB, malaria and Dengue fever," Bishai said.

The inroads made with TB drugs could also give companies a foothold for other marketing efforts.

In a report issued this month, IMS Health advised that Big Pharma needs to target emerging markets more aggressively, beyond the important developing markets of Brazil, Russia, India and China. About 17 countries will contribute 48 percent of annual market growth in 2013, up from the 37 percent they contributed last year, according to the report (² [A#0720120005]).

Drugs developed through the CPTR initiative will be made available at affordable prices to all who need them, but the agreements also allow for charging at a profit for countries able to pay, according to Mel Spigelman, president of the TB Alliance.

Companies that take part can also have the chance to take advantage of FDA's priority review voucher program. That scheme offers a voucher that can be used to gain a faster review for traditional commercial products in the U.S. for companies that develop drugs for neglected diseases (³ Also see "Treat and Trade: The New Priority Review Voucher Market" - In Vivo, 1 July, 2008.). Novartis was the first to take advantage of the program with Coartem (artemether/lumefantrine) (⁴ Also see "The Coartem Story: Novartis Workers In NY Feel Uplift In Battling Malaria" - Pink Sheet, 22 June, 2009.).

The priority review voucher and tax benefits for orphan drugs help offset costs of development, Stoffels noted. However, J&J's main mission is to contribute to public health and there is no commercial plan for TB drugs in development, he said.

As yet, it's undecided how development costs going forward will be shared by the various companies and philanthropic organizations involved in the CPTR, Spigelman said.

- Emily Hayes ( ⁵ e.hayes@elsevier.com )

Big Pharmas Come Together On TB, But Effort To Accelerate Development May Hit Speedbump From Lack Of Biomarkers

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