20th Anniversary Meeting of the Fungal Research Trust

Development of new antifungal drugs & combination therapy

Professor David Denning

June 2011London, UK

Development of new antifungal drugs & combination therapy

Professor David DenningScientific Advisor

Fungal Research TrustThe University of Manchester

The National Aspergillosis Centre

Priorities for novel antifungal agents for the treatment of invasive fungal infections

Oral agent for treatment of systemic and mucosal candidiasis, with activity against all common Candida species (including fluconazole resistant strains). Parenteral/ oral agent with activity against Cryptococcus neoformans and penetration into the central nervous system Parenteral and oral agent with potent activity against Aspergillus spp., including triazole resistant species. Ideally there should be few drug interactions and safety in patients with renal or hepatic impairment. Parenteral and oral agent active against rare, but medically important moulds (e.g. Mucorales, Scedosporium spp.). Oral agent(s) for the treatment of chronic pulmonary and allergic aspergillosis, with few drug interactions (especially corticosteroids) and favourable intrapulmonary pharmacokinetics.

The echinocandins

The azoles

Amphotericin B and its formulations

Abelcet Amphocil AmBisome

Priorities for novel antifungal agents for the treatment of invasive fungal infections

Oral agent for treatment of systemic and mucosal candidiasis, with activity against all common Candida species (including fluconazole resistant strains). Parenteral/ oral agent with activity against Cryptococcus neoformans and penetration into the central nervous system Parenteral and oral agent with potent activity against Aspergillus spp., including triazole resistant species. Ideally there should be few drug interactions and safety in patients with renal or hepatic impairment. Parenteral and oral agent active against rare, but medically important moulds (e.g. Mucorales, Scedosporium spp.). Oral agent(s) for the treatment of chronic pulmonary and allergic aspergillosis, with few drug interactions (especially corticosteroids) and favourable intrapulmonary pharmacokinetics.

Mechanism of drug action

Only 4 mechanisms of actionand only the azoles and flucytosine are oral

Priorities for novel antifungal agents for the treatment of invasive fungal infections

• New treatment for systemic and mucosal candidiasis, with activity against all common Candida species (including fluconazole resistant strains).

Early treatment critical to good outcome in candidaemia

Morrell, Antimicrob Agents Chemother 2005;49:3640. Garey, Clin Infect Dis 2006;43:25

Mortality rate from time of blood draw that later turns positive

Rx in <12 hrs

Rx in 12-24 hrs

Rx in 24-48 hrs

Rx >48 hrs Rx >72 hrs

Morell, 2005 11.1% 30% 32.6% 34.5% -

Garey, 2006 15.4% 23.7% 36.4% 41.4%

25%

25%

Importance of getting treatment right in candidaemia

Parkins, J Antimicrob Chemother 2007;60:613.

Su

rviv

al (%

)

Empirical therapy correct?Yes No

100

73

44

P=0.02

Micafungin versus Ambisome randomised study

Important to monitor blood cultures during therapy

Unpublished data Kuse, Lancet 2007;369:1519

Laboratory surveillance of invasive fungal infections England 1990-

2004

0

400

800

1200

1600

2000

1990

1992

1994

1996

1998

2000

2002

2004

*

nu

mb

er o

f re

po

rts

invasive candidosis

invasive aspergillosis

* provisional data

Laboratory surveillance of candidaemia age distribution 2008

Voluntary surveillance of candidaemia in England, Wales, & N. Ireland: 2008

Candidaemia - species distribution 2008

Fluconazole insensitive or resistant

Echinocandin insensitive or resistant

Priorities for novel antifungal agents for the treatment of invasive fungal infections

• New treatment for systemic and mucosal candidiasis, with activity against all common Candida species (including fluconazole resistant strains).• Parenteral/ oral agent with activity against Cryptococcus neoformans and penetration into the central nervous system

Cryptococcal meningitis treatment

Nussbaum et al, Clin Infect Dis 2010;50:338

Priorities for novel antifungal agents for the treatment of invasive fungal infections

• New treatment for systemic and mucosal candidiasis, with activity against all common Candida species (including fluconazole resistant strains).• IV & oral antifungal with activity against Cryptococcus and penetration into the central nervous system• IV & oral antifungal with potent activity against Aspergillus spp., including triazole resistant species. Ideally there should be few drug interactions and safety in patients with renal or hepatic impairment.

Impact of voriconazole in real life for invasive aspergillosis

Nivoix et al, Clin Infect Dis 2008;47:1176

Combination therapy – invasive aspergillosis

RetrospectiveAmB failuresMost HSCT30/47 proven IA

Multivariate analysisP=0.008 for combination and survival

Curves came together later

Marr et al, Clin Infect Dis 2004:39:797

Priorities for novel antifungal agents for the treatment of invasive fungal infections

• New treatment for systemic and mucosal candidiasis, with activity against all common Candida species (including fluconazole resistant strains).• IV & oral antifungal with activity against Cryptococcus and penetration into the central nervous system• IV & oral antifungal with potent activity against Aspergillus spp., including triazole resistant species. Ideally there should be few drug interactions and safety in patients with renal or hepatic impairment.• Oral agent(s) for the treatment of chronic pulmonary and allergic aspergillosis, with few drug interactions (especially corticosteroids), excellent safety and favourable intrapulmonary pharmacokinetics.

Chronic pulmonary aspergillosis and posaconazole

Unpublished

Jan 2010 Oct 2008

DC (♂, age 73) was commenced on posaconazole 400mg twice daily following progression of CPA despite itraconazole and voriconazole. CPA had developed on a background of asthma and ABPA.

Acneiform rash with posaconazole

Unpublished

Within 48hrs of commencing posaconazole he developed a severe acne-like rash, typical of folliculitis, across his face.His treatment had to stop, and we have n more oral treatments available for him.

Patient LT

www.aspergillus.org.uk

LT (♀, age 49) lifelong asthma and atopy, with ABPA diagnosed in 1993.

Recognised to have CPA complicating ABPA in 2001, but the CPA diagnosis was apparent in 1993.

Patient LT

Better pulmonary status on voriconazole initially, but then slow deterioration,

On 4l/min oxygen dependent 24 hours a day.

Mild photosensitivity on voriconazole, even with little sun exposure. As wheelchair bound very little outside time, so mostly indoor light.

She developed rough scaly patches over her face, neck and lower arms. Dermatological review indicated “multiple solar keratoses”.

www.aspergillus.org.uk

Patient LT

Skin biopsy from the right forearm showed low grade premalignant change.

She was treated with local 5-fluorouracil cream (Efudix) (3 cycles) to the affected lesions.

www.aspergillus.org.uk

Patient LT

www.aspergillus.org.uk

Patient LT

www.aspergillus.org.uk

Patient LT

These photos were taken when her skin was at its worst. The inflammation resolved after discontinuing the cream. This reaction is expected with application of this mild chemotherapy agent.

Following treatment her skin was much softer and considerably improved. Voriconazole has been stopped, and posaconazole substituted.

Patient LT

So voriconazole is a potent photosensitising drug with malignant potential

18 months later, new lesion on her forearm. Biopsy showed squamous cell carcinoma in situ.

What is coming?

• Isavuconazole [similar to voriconazole with fewer drug interactions and photosensitivity. Once daily, phase 3]•Nikkomycin Z [oral, coccidioidomycosis, phase 2] • Candida vaccine [to prevent invasive candididiasis and MRSA, phase 1/2]• FG3409 series [New mode of action, Aspergillus and moulds, IV & oral, phase 1]• Nanoparticle preparations of amphotericin B [oral, preclinical]• Others

Thank you for supporting the work of the Fungal Research Trust