The landscape of antifungal development, present and future

Ref ID: 19355

Author:

J. H. Rex

Author address:

AstraZeneca, Waltham, USA

Full conference title:

6th Trends in Medical Mycology 2013

Date: 11 October 2014

Abstract:

What is the unmet need? New antifungal agents are needed to
address emergence of resistance, to treat fungi for which current
therapies are as yet inadequate, and to provide options to current
therapy in settings where safety or drug-drug interaction issues limit
the utility of current drugs.
Candida The azoles remain limited for selected non-albicans species
(C. glabrata in particular). Resistance to the echinocandins is appear-
ing in multiple species and cross-resistance with the azoles is also
noted.
Aspergillus Azole resistance has emerged in recent years, most
notably in Europe.
Other fungi Current agents are not consistently reliable (e.g., little
is available for S. prolificans, curative therapy is not routine in some
of the chronic forms of coccidioidomycosis).
General Enhanced immune function (e.g., therapy with G-CSF) may
ameliorate disease, but effective drug therapy is usually required.
Does the current pipeline address these unmet needs? The cur-
rent pipeline is small, with more activity reported for novel small
molecules than for other approaches. Based on review of industry
pipeline reports and abstracts from recent meetings, there are 3 CYP
inhibitors, 2 glucan synthesis inhibitors, 1 chitin synthesis inhibitor,
and ~5 agents with a variety of MOAs both known and unknown.
Only 6 agents appear to be in clinical development at phase 1 or
beyond (3 CYP inhibitors, 1 glucan synthesis inhibitor, 2 other
Figure 1 Trends in fungal disease alerts in the PROMED database.
ª 2013 The Authors
Mycoses © 2013 Blackwell Verlag GmbH, 56 (Suppl. 3), 11-42 13
Plenary Sessions
mycoses
Diagnosis,Therapy and Prophylaxis of Fungal Diseases
agents). The most advanced agent is a CYP inhibitor in Phase 3 with
a trial program focused principally on invasive aspergillosis and can-
didiasis. Antibody-based therapeutics and vaccines have been
described, with recent activity reported in vaccines for candidiasis
and coccidioidomycosis.
How will development of newer agents differ from development
of older agents? In 2012, antifungal agents were specifically
recognized in the United States as being eligible for Qualified Infec-
tious Disease Pathogen (QIDP) status and thus for the development
incentives created by the GAIN Act embedeed within FDASIA (the
renewal legislation for the FDA). In addition, newer antifungal
agents seem likely to be able to take advantage of changes made to
facilitate development of antibacterial agents to address unmet needs.
These pathways should permit registration based on clear demonstra-
tions of the PK-PD driver, the ability to achieve adequate PK in
patients, and single Phase 3 trials. PK-PD-based arguments for dose
selection are beginning to appear for the mycoses and seem likely to
become very important in a fashion similar to its current use in anti-
bacterial development where limited clinical data can be notably
strengthened by good PK-PD support. Pharmacometric analyses of
clinical trial data will further strengthen the utility of PK-PD as a
support for dose selection and proof of efficacy. Finally, new diagnos-
tic technology will increase trial efficiency by enabling clear patient
selection – as an example of this, detection of galactamannan appears
to be accepted for patient qualification for studies of invasive
aspergillosis.
Summary Although evolving more slowly than unmet need for anti-
bacterial agents, there remains a meaningful and growing unmet
need for new antifungal agents. The development pipeline is limited
and does not address the full range of gaps. Combined with advances
in diagnostics and our understanding of PK-PD, recent changes in
the regulatory landscape should facilitate development of new
agents.

Abstract Number: ps4.1

Conference Year: 2013

Link to conference website: NULL

New link: NULL

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