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Candida Past, Present, & Future: A Clinical Perspective

Candida Past, Present, & Future: A Clinical Perspective. John H. Rex, MD AstraZeneca Pharmaceuticals Vice President, Medical Director for Infection University of Texas Medical School-Houston Adjunct Professor of Medicine.

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Candida Past, Present, & Future: A Clinical Perspective

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  1. Candida Past, Present, & Future: A Clinical Perspective John H. Rex, MD • AstraZeneca Pharmaceuticals • Vice President, Medical Director for Infection • University of Texas Medical School-Houston • Adjunct Professor of Medicine The slides contain many references. Should you want the exact cite, a copy of the talk will be available soon at www.doctorfungus.org

  2. Anidulafungin Caspofungin Ravucon XMP Sordarins Micafun Voricon Posacon Medical Mycology:The Last 50 Years # of drugs L-AmB ABCD ABLC Terbinafine Amphotericin B (1958) Itraconazole Griseofulvin Fluconazole Ketoconazole Miconazole Nystatin 5-FC

  3. Anidulafungin Caspofungin Ravucon XMP Sordarins Micafun Voricon Posacon Medical Mycology:Patient Groups as Drivers of Demand L-AmB ABCD ABLC • Having toenails! Terbinafine • Chemotherapy Amphotericin B (1958) Itraconazole Griseofulvin Fluconazole • HIV Infection Ketoconazole Miconazole Nystatin 5-FC • ICU Care

  4. Anidulafungin Caspofungin Ravucon XMP Sordarins Micafun Voricon Posacon New Tools Open New Doors • Do I need a pill? • Novel Diagnostics L-AmB ABCD ABLC • Which pill? • Susceptibility Testing Terbinafine • An easy pill! • Fluconazole Amphotericin B (1958) Itraconazole Griseofulvin Fluconazole • A pill! • Ketoconazole Ketoconazole Miconazole Nystatin 5-FC • Amphotericin B • Lives are saved!

  5. Medical Mycology: The Next 10 Years • That’s a lot of progress • But, there is more to do • Not a lament for the sake of lament • Invasive aspergillosis • Mortality > 30% Herbrecht NEJM 2002 347:408 • Much higher in some settings • E.g., CNS aspergillosis • Candidiasis • Persistent candidemia rate ~10% • Even in the most recent studies! • Onychomycosis • 20%+ fail Drake LA, J Am Acad Derm ‘97 37:740

  6. Survey Results • Big Clinical Advances • Echinocandins • Understanding resistance mechanisms • Clinical Wish List • Adequate diagnostic tests • “Fungicidal azoles.”  New drugs • Susceptibility methods that better predict response • Better understanding of virulence factors, pathogenesis, & ways to predict colonization  disease As I thought about where we need to go next, it was interesting to hear your thoughts on things that mattered

  7. Molecular Diagnostics • Current state of the art • Fungal metabolites • Can work, but distinctive (unique) metabolites have been hard to find • PCR for fungal DNA • Plausible, but standardization has been a problem • Antibody detection • Epidemiological value, but • Really frustrating overall • Antigen detection • Generally the strongest approach • Diagnostics • Best Drug Use • Runaway Hits • Finding Drugs

  8. What about Candida? • Metabolites • D-arabinitol: Limited, but not bad • Not produced by C. glabrata or krusei • Must adjust for renal clearance • Candidemia: 74% +ve (Walsh, Am J Med, ‘95) • PCR: Plausible • Works for candidemia, ~= blood culture • Not clear if helpful beyond that • Antigens: The great hope • Undefined antigens? Variable data • Cand-Tec, mannan(s): not so good • Defined antigens? More promise • Enolase, glucan: let’s look at these Good reviews (all in Clin Micro Reviews): Yeo SF, 15:465-84, 2002 Reiss E, 6:311-323, 1993 (old, but instructive) Jones JM, 3:32-45, 1990 (old, but instructive)

  9. Candida Enolase • Enolase: 48-kd cytoplasmic antigen • Walsh 1991: High-risk cancer pts • With repeat testing, found in 18 of 24 pts (75%) with proven fungal infection • Deep tissue or blood, not mucosal • Not present in 140/146 who lacked proven disease (specificity: 96%) • Mitsutake ‘96: 39 pts w/ candidemia Sensitivity Specificity • Enolase 72 100 • Glucan* 88 84 • Pastorex mannan 100 26 • Cand-Tec 88 77 *This is not any current test but a homebrew For details, see: Walsh, NEJM 324:1026-31, 1991 Mitsutake, J Clin Micro 34:1918, 1996

  10. Beta-D-Glucan • Two kits for this cell wall component • Fungitec-G (marketed in Japan) • Obayashi, Lancet 345:17-20, ’95 • “Definite fungal infections”: 90% sensitive • Glucatell (approaching US licensure) • Various abstracts (see at left) • Same antigen, different assay • Principle for Fungitec-G & Glucatell • Limulus amebocyte lysate reaction • Endotoxin triggers clot through Factor C • Beta-D-glucan triggers through Factor G • Kits: Factor C removed  Glucan specific • Kits: Different species of horseshoe crabs! • South China Sea vs. North America • Cut-offs differ, results NOT identical! Glucatell abstracts ICAAC 2001, #841 ICAAC 2002, #M-902 ICAAC 2003, #M-1028 ICAAC 2003, #M-1021 ICAAC 2002, #M-1034a (latebreaker)

  11. Glucatell for b-D-glucan: Performance • Positive cut-off: 60 pg/ml • Established from candidemia pts • Ostrosky, ICAAC ’03, #M1034a • Multicenter study of 189 with and 170 w/o IFI (invasive fungal infection)* • Based on a single sample/patient • Sensitivity: 70%; Specificity 87% • Odabasi (Clin Infect Dis, in press) • 283 during chemo for leukemia/MDS • Samples 2x/week (7.3 samples/pt) • One +ve sample: 100% sensitive for IFI* • Two +ve samples: 96% specific for IFI* Sampling frequency is critical! *IFI by EORTC/MSG (Ascioglu et al. CID 34:7, 2002

  12. All beta-D-glucan assays share certain properties • Other fungi • Beta-D-glucan is present in & released from Aspergillus, Fusarium, & many other moulds • (ICAAC ’03, M-1021 & Miyazaki, J Clin Micro 33:3115, ‘95) • But, not from Cryptococcus • It mostly uses an alpha-glucan • So, a positive result requires thought: What fungus is likely? • False positives: Still learning. • Gauze, some hemodialysis filters, some cellulose-filtered drugs

  13. Candida & Molecular Diagnostics: Summary • It is possible • Beta-D-glucan, enolase, and even Cand-Tec do detect disease • Glucan is not Candida-specific • You have to think a little with it! • What is needed next? • Commercial support • Validation, validation, validation • Data in a variety of patient groups, various clinical settings, etc. • And finally: Can one of these become a surrogate marker for use in clinical trials? The real goal for advancing the field: Be able to use to diagnose and monitor therapy. A high hurdle!

  14. Surrogate markers: Some background • Our current tools for diagnosis are poor. Miserable, to be honest. • This cripples clinical studies • Solid proof of infection and response is very hard to demonstrate. Enrollment is slow. Costs are high. • A surrogate marker would help • But, just having a diagnostic test is not enough! You must prove that the test links to disease. How? • ICH E9 (Stats), Section 2.2.6 • Biological plausibility (YES) • Link of marker to outcome (Not yet) • Treatment effects on marker match clinical outcome (Not yet) Personally, I think this is the central problem of clinical mycology at present ICH = International Conference On Harmonisation

  15. Best use of existing drugs • Now playing at local theatres • Amphotericin B, multiple flavors • Fluconazole, itraconazole, voriconazole, & ketoconazole • 5-FC • Terbinafine • Caspofungin • Coming attractions • Micafungin, anidulafungin • Posaconazole, ravuconazole • Rumors & intrigues • Sordarins, other azoles, PLD-118, nikkomycin, Mycograb and other antibodies, and more…. • Diagnostics • Best Drug Use • Runaway Hits • Finding Drugs

  16. But, none of this helps today’s patients • What studies would really make a difference? (Multicenter, please!) • Validation of serodiagnostic kits • Make every effort to tie to outcome! • Candidal prophylaxis in ICU • Placebo-controlled & with reproducible entry rules & outcome measures • Would also validate a predictive rule! • Combination therapy • Aspergillosis: Combine drugs • Caspofungin vs. vori vs. C + V • It’s not Candida, but we need it! • Candida: Combine with cytokine? • Hypothesis & need less clear at present Those drugs may or may not come to pass. What more we do with our current set of tools?

  17. Brouwer et al. ISHAM #0292003 • 64 adults, HIV, cryptococcal meningitis • Serial quantitative CSF cultures • Four therapy arms, 16 patients each • AmB, AmB + flucytosine, AmB + fluconazole, & all three together • All drugs at full therapeutic doses • Measured mean rate of fall of colony forming units (CFU) for crypto in CSF • Greatest for AmB + flucytosine • It beat the other arms: • Better than AmB alone, P = 0.004 • Better than AmB + fluconazole, P = 0.04 • Better than triple combo, P = 0.02 • This result is especially meaningful due to data linking CFU clearance to outcome This shows the power of a surrogate marker!

  18. Immune System &Fungal Infections • Pappas et al. (JID, in press) • IFN-gamma as adjuvant therapy for cryptococcal meningitis • CSF cultures more often neg. at 2 wk • Serum crypto antigen lower Big hurdle: must show superiority of the adjuvant therapy This is just one example of work in this area

  19. A comment on susceptibility testing • “Better susceptibility testing” was a frequent wish in the survey • Surprise! Susceptibility testing for fungi is ~ as good as for bacteria! • At least for fluconazole and Candida • Other bug-drug pairs are coming • Key: an MIC can only do so much • The 90-60 rule • Susceptible isolate? 90% response • Resistant isolate: 60% response • Or, in short • Some improve despite our therapy • Some won’t improve with any therapy I really don’t have time to do this topic justice. Please see these papers for more: Clin Infect Dis 2002;35:982-989 Antimicrob Agents Chemother 2004;48:693-715

  20. Future Drugs: What next? • Another view: Where are the holes? • PO drug + echinocandin-likeCandida coverage • Stunning. Vaginitis, OPC, IV follow-up • If IV, could overtake IV candins • IV & PO for Aspergillus, Zygomycetes • Without all the high-end azole quirks • E.g., no interactions with vincas, cyclosporin, rifampin • With Candida coverage, would rule cancer prophylaxis • Better onychomycosis therapy • Even just different would be good! • Diagnostics • Best Drug Use • Runaway Hits • Finding Drugs

  21. Why is finding new drugs so hard? • The desire for new antimicrobial drugs is intense • CDC in 2001 • 2001: Public Health Action Plan to Combat Antimicrobial Resistance • Action Item: “facilitate … development by industry of novel therapeutic agents” • IDSA in 2003 • 12 March: The Impending Crisis • “Since 1998, only 7 new antibacterial agents have been approved” • Of 290 agents listed in current major pharmaceutical pipelines, only 4 (1.4%) are antibacterial agents • But, why is it still so slow and hard? • Diagnostics • Best Drug Use • Runaway Hits • Finding Drugs

  22. IND Submitted NDA Submitted Discover a drug Phase 1 Clinical Studies Phase 2 FDA FDA Phase 3 From a distance, drug development looks like this PK Studies Slide courtesy Francis Tally

  23. IND Submitted NDA Submitted Chem & Mfg Synthesis & Purification Mfg Scale-up Formulation Development This is just shy of 1 billion real dollars. No group or company can make this investment casually. Short Term Animal Animal Studies Long Term Animal Phase 1 Clinical Studies FDA FDA Phase 2 Phase 3 PK Studies Time 5-10 years at a cost of ~$900 million But, there’s more Microbiology Studies Discover drug Slide courtesy Francis Tally

  24. Example Hurdle #1 Consider just one of those other components • Formulation development • Tablet? Capsule? • Salt? Prodrug? • Even worse if you must account for two circulating forms of the drug • Stability • If it is going to sit on the shelf for 2 years, you have to prove it is stable • Accelerated stability testing (heat, cool, repeat) gives some clues, but… • The real studies take 2 years • Final formulation must go through full stability and safety testing It is really hard to make changes once you are even part way down this path

  25. Example Hurdle #2 Why are (safe) antibiotics so difficult to find? • Are there special issues here? • Non-human target: should be easy! • But, curiously, it is not • Can avoid mechanism-based toxicity by picking targets well • Need to hit intra-microbial targets adds another barrier (efflux, etc.) • Thus, we often use drug levels that are high relative to other drugs • Digoxin: typical levels ~1 ng/ml • Beta-lactams: up to 100-200 mg/ml • This puts you at risk for non-mechanism side-effects (hERG, etc.)

  26. Net effect of all those hurdles Paying for it all (1) • How do CEOs make choices? • How do you choose what to fund? • Net Present Value (NPV) • NPV is current value of future profits • It can be risk-adjusted to account for relative likelihood of failure • NPV of an antibiotic is often less than in other areas. Why? • Antibiotics are used only briefly • Unlike chronic use of (say) insulin • Areas with greatest need may have less ability to afford • Big problem for TB and malaria • Government pricing pressures A sensitive area, but one that must be addressed.

  27. Paying for it all (2) • Risk-adjusted NPV (million $US) for a new • Musculoskeletal agent: 1,150 • Oncology agent: 300 • IV-only Gram-positive agent: 100 • Effect of possible requirement for tighter statistics (10% delta rule) • Increase in time & cost of project • This causes significant drop in NPV • Musculoskeletal agent: 1,150 • Oncology: 300 • IV-only Gram-positive agent: 35 A positive NPV means that you do make a profit. Bigger NPV is better. Projan S. Curr Opin Microbiol 2003;6:427-30

  28. Paying for it all (3) • Now, there is more to it than NPV • Companies do want to spread risk • All your drugs can’t be in one class • Antibiotics have the nice feature of low risk of development failure once you’ve shown them to be non-toxic Antibiotics Other drugs Source : Pharmaprojects, McKinsey & Co. Graphic courtesy Francis Tally

  29. Paying for it all (4) • There is more to it than NPV (cont.) • Companies do want to fill unmet needs • Social responsibility • Ultimately, we are all patients! • But, profit is required • Without profit on drug #1, there will be no drug #2 • Recall that cost of $900 million to bring ONE drug to market • Lots of failures along the way • The process takes years and people • And lots of optimism! It is frustrating to hear “The drugs are too expensive.” Actually, the disease is expensive—good drugs are both life-saving and often a relative bargain. New drug: $800 + $95 post-approval commitments = $895. DiMasi JAJ Health Econ 2003;22:151-85.

  30. Early Discovery Develop for launch Paying for it all (5): Balance! • First, be curious! • Drugs can create a niche • Caspofungin: $200m/yr to $1bn/yr? Science & Unmet need Avoid paralysis by analysis! First is not always best. Me-Too can have value (NEJM 350:211, ’04) Commercial Analysis

  31. Finding new drugs: Summary • Drug discovery and development is • Hugely expensive • Always a gamble • It is also a partnership • Regulatory requirements & process • The agencies have an impossible job – there is no way to guarantee perfectly safe drugs at perfectly affordable prices • Government pricing agreements • Antimicrobial discovery & development is indeed underway • But it must be carefully nurtured! There are a lot of efforts ongoing to regularize and smooth the overall process

  32. Thank you! Any solution to a problem changes the problem. — R. W. Johnson Life would otherwise be boring, no?

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