Priority Medicines Project

Background reviewTuberculosis

Dr Mary Moran

London School of Economics

September 2004

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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)

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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

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TB growth rates in Europe

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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)

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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

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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

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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

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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

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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

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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

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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