Priority Medicines Project Background review Tuberculosis

1. Priority Medicines ProjectBackground reviewTuberculosis Dr Mary Moran London School of Economics September 2004

2. Tuberculosis (TB) • TB is an old disease with old management tools • No novel TB drugs for 30 years • No new vaccine for 80 years • No new field diagnostic test for 120 years • (My report is also “old” – things move quickly)

3. Tuberculosis (TB) • Current TB strategy (DOTS) is superior to other approaches but is not enough in areas of: • High MDR-TB prevalence • High HIV/AIDS prevalence • TB case notifications are rising rapidly in: • Eastern Europe and Former Soviet Union • The expanded EU has 50,000 TB cases/year • 10% of these cases are resistant to one or more TB drugs • Africa • HIV-linked TB now represents >20% of all TB cases globally. • HIV-TB has quadrupled between 1995 and 2000

4. TB growth rates in Europe

5. Obstacles to TB control • Technical limitations of existing TB tools • Dx test (AFB) detects only around 50% of active TB cases • No cheap, rapid reliable tests for screening / MDR-TB* • Lengthy drug treatment with up to 80-100 observed doses* • MDR-TB treatment very poor* *An issue in both OECD and DC • Expensive and cumbersome system needed to manage old TB tools • Costs of “managing” cheap old tools make up 80-90% of treatment cost (e.g. frequent observation; repeat testing)* • The 2-year MDR-TB treatment costs up to 1,400 times more**An issue in both OECD and DC • 70% global case detection targets may not be realistic using current DOTS tools and approaches • DC infrastructure problems (common to all diseases i.e. not TB-specific)

6. Lessons from past/current research • Breakthroughs in basic research (genome/proteins) • Driven by increased public funding since early ‘90s (now $120 million/year) • The multinational pharmaceutical industry is no longer the lead player in TB • Few multinational companies have retained TB activities (~ all EU-based) • Modest but useful activity in vaccines/drug discovery • The majority of TB R&D is now done by smaller players: • Public-Private Partnerships (PPPs) • 1 drug; 1 diagnostic; 2 vaccine • Small to mid-size industry (biotechs/CROs/med technology firms), often in collaboration with public funders, PPPs or via PPP-outsourcing

7. Lessons from past/current research • The US dominates R&D for TB (funding and activity) • EC funding for new TB tools is minimal • $8.5 mill/year under FP5 for drug, diagnostics and vaccines R&D and basic research. (Latvia’s MDR costs alone are $7.7 million for 600 patients) • Additional $8 mill/year announced on World TB Day 2004 for vaccine R&D (TB and delivery systems) • Public funding is poorly targeted • No incentives to link industry activity with PPPs willing and eager to outsource to industry • Incentives poorly designed for the small to mid-size companies who are active in TB • Almost no funding of PPPs, who are driving new R&D • <$2.5 million total for drug/dx PPPs since inception

8. Current pipeline • 50 diagnostics currently on the market or in development, many promising for DC adaptation • FIND (PPP) co-developing DC tests with small industry (biotechs/medical technology) • Expected around 2005-2008 • ~13 novel drug compounds in known development for TB (as of end 2003) • Ten compounds by the TB Alliance (PPP) • Half a dozen small company/biotech projects • 3 active TB collaborations (NIAID, other nfp) • Several commercial projects (e.g. immune regulators), but looking for public partners for possible TB development • Plus early discovery activity, academic and industry • Expected around 2010 • 3 vaccines in Phase I trials • Public or PPPs • Expected around 2015 or later

9. Gaps/opportunities for R&D • New diagnostics • Adapt existing Dx’s to poor settings • Cheap ($5-20 million); fast (1-3 years); EU small industry very active; US not a big player • New drugs • Current new pipeline compounds!! (MDR and TB) • Adapt existing antibiotics for a TB indication: could halve treatment times (not MDR) • Follow-up early compounds with promising anti-TB activity (>200 hits) • Cost of new drug development: around $76-115 million (from lead compound up to registration); industry outsourcing opportunities+++; opportunity to increase role of EU biotechs/academics/CROs

10. Gaps/opportunities for R&D • New delivery mechanisms and approaches • Depot and slow-release drugs (greatly reduce observations) • Skin patch and “electronic nose” diagnostics • Mucosal vaccines (recent EC funding boost) • Develop supportive technologies • Surrogate markers that will cut drug/vaccine trial times and costs • Vaccine adjuvants • Follow-up the basic research needed for new tools • Molecular targets for drugs/vaccines • Better understanding of latency, reactivation and the human immune response to TB

11. Filling the gaps • Systematic approach to compounds with anti-TB promise (e.g. an EU consortium supported by a public screening facility) • Use PPPs to act as a conduit/co-ordinator: • Identify gaps, seek out and prioritise R&D opportunities, link academia/industry to these R&D gaps (see following) • Outsource identified R&D needs to industry (e.g. pre-clinical, medicinal chemistry) • Potentially lucrative for industry • Keeps industry activity tightly focussed on R&D gaps • Reduces risk for government funders • Link industry incentives to R&D on identified pipeline “gaps” (e.g. drug discovery; adjuvant technologies) rather than lower priority areas • Develop incentives tailored to small and mid-size industry

12. Conclusions • TB and MDR-TB are on the increase, including in the EU • Current TB tools and approaches are insufficient to manage resurgent HIV-TB and MDR-TB • There are many promising new TB diagnostic and drug leads • A major obstacle to developing these is the lack of appropriate incentives to link industry activity (small and large) to desired TB R&D outcomes and pipelines • PPPs offer a useful link between government funding and industry activity; and between industry activity and health outcomes • Well-designed funding strategies can: • Deliver high-impact new TB tools within 3-6 years • Support EU industry and academia