TB drugs R&D overview

TB drugs Research and development (R&D) is a complex, long lasting and costly process. There are specific WHO requirements for new TB drugs:

  1. Shorter and safer regimens of treatment
  2. Treatment of multidrug-resistant TB strains and atypical mycobacteria in HIV-positive patients
  3. Reduction of treatment cost and affordable TB drugs price
  4. Greater intermittency which would allow better treatment control
  5. Fewer adverse effects

For more than 40 years, there have been no new global medicines on the market for the treatment of tuberculosis. The new molecules under investigation have not succeed in meeting all of the expectations, especially in terms of shortening the treatment duration and lowering the cost of the treatment.

First line TB drugs Year of discovery
Isoniazid 1952
Rifampicin 1966
Rifapentine 1965
Rifabutin 1975
Pyrazinamide 1952
Ethambutol 1961
Streptomycin 1944

Some of the new TB molecules in development (TAG 2019 pipeline report (HIV, TB & HCV) according to mechanism of action are as follows:

Energy Production: bedaquiline, pyrifazimine (TBI-166), telacebec (Q203)

Cell Wall Synthesis: BTZ-043, delamanid, macozinone (PBTZ169), OPC-167832, pretomanid, SQ109, TBA-7371)

Protein Synthesis: contezolid acefosamil (MRX-4), delpazolid (LCB01-0371), sutezolid (PNU-100480), TBI-223, GSK3036656 (GSK-070)

DNA Synthesis: SPR720

Only a few pharmaceutical companies and NGOs are currently developing new TB medicines. The reasons could be summarized as follows:

  • Nature of the biggest TB markets – huge territories, poor countries, unreliable and irregular drug supply, complex healthcare systems (state and/or private), organizational issues, intellectual property issues, political issues, etc.
  • The price of the current first line TB drugs is very low as they are generic and have lots of global and local producers. Governmental budgets are not tuned to account for a higher price and additional funding or donations are needed to enable the introduction of new drugs. TB programs are financed by governments and by the WHO Global TB fund. To list a new TB medicine the governments and WHO have to be convinced that a particular new TB drug reduces total treatment cost and is more cost-effective than current therapy.
  • NPV/IRR– according to the publications the majority of big pharma companies prefer new drug R&D investment projects exceeding net present value (NPV) of  USD 1 billion and IRR over 35%. Nature of TB disease, markets and people suffering from TB don’t allow high prices of the TB drugs and reaching such NPV. A modern TB drug development pipeline should include NGOs, Pharma Companies, Universities, and Venture Capital Companies in order to guarantee a successful launch. A number of new drug trials have been either stopped or delayed because of insufficient funding.
  • Investment risk: early stages (pre-clinical, 1st and 2nd Phases) of drug development are high risk because very few molecules reach Marketing authorization. Currently big and mid-size pharma companies buy molecules at Phase III or completed Phase II at best. Tuberculosis is a complex disease with complex treatment which is usually conducted with 4 medicines. Here drug development is complicated because of nature of the disease and drug interaction between the medications in the human body. Also the high incidence of HIV co-morbidity require study of drug interactions with the anti-retroviral therapy. Patient adherence to the therapy is also a serious factor since the therapies last 6 or more months.
  • Production Volume – big production volume with low relative price, complicated logistics and difficult market access, since some of the biggest TB markets are low and middle income countries.
  • Time to launch – about 10 years for pre-clinical and clinical studies. As tuberculosis treatment lasts minimum 6 months and relapses require additional time. This affects the clinical studies’ time-scale and only perfect organization and funding could decrease this time to 6-7 years and only if the product has no unexpected adverse effects.
  • Increasing regulation from the authorities (FDA and EMA) regarding clinical trials – patient counts, GMP, GLP, etc. A good news here is that the FDA has introduced an accelerated procedure for the registration of pharmaceutical products which treat socially significant diseases including tuberculosis.