508 Compliant - ICD-10-PCS Application for Cresemba (isavuconazole)

1. ICD-10-PCS Application for Cresemba (isavuconazole)
Tawanda Gumbo, MD
Baylor Research Institute,
Baylor University Medical Center,
Dallas, Texas

2. Isavuconazonium Sulfate (Isavuconazole)
* Mold active triazole antifungal agent
* Highly water soluble prodrug
o IV formulation: no cylodextrin
* Under FDA review for Invasive Aspergillosis and Invasive Mucormycosis

3. Isavuconazole Development Program
2002 – Start of Isavuconazole Development
2002-2014 – 40 Phase I Studies
2007 – Phase 3 Trails Begin
2010 – Astellas Licensed ISA Development
2013-2014 – QIDP & Orphan Drug Status Granted
2014 – NDA Submitted, 44 studies, 2166 subjects, 1692 Received ISA
2015 – FDA AC Jan 22

4. Administration of CRESEMBA® Cannot Be Described by Current Codes
Issue/Request
* There is not a unique ICD-10-PCS code to describe the intravenous (IV) and oral administration of CRESEMBA® (isavuconazonium) to treat patients with invasive fungal infections, in particular invasive aspergillosis and mucormycosis
* Astellas requests to establish new ICD-10-PCS codes to better identify both IV and oral isavuconazonium administration for the treatment of invasive aspergillosis and mucormycosis
NTAP Application
* Astellas submitted a New Technology Add-On Payment (NTAP) application for isavuconazonium for fiscal year (FY) 2016
FDA Approval 
* A New Drug Application (NDA) for isavuconazonium was submitted to the FDA and accepted by the agency on September 6, 2014.  Based on PDUFA regulations, the target date of regulatory approval is March 8, 2015

5. Disease Background and Unmet Medical Need

6. Invasive Mold Infections
* Typically occur in severely immunocompromised patients
o High comorbidities
* Rare infections
o ~12,000 / year aspergillosis (Tong 2009; Warnock 2007)
o ~500 / year mucormycosis (Rese et al., 1998)
* Difficult to diagnose
o High morbidity and mortality
* Limited therapeutic options
7. Aspergillus (Aspergillosis)
* Aspergillus is widely found in soil, dust, plants, food, and air vents
* Most common mold pathogen causing invasive fungal infections
* Opportunistic pathogens: it’s the host!
* High mortality ranging from 50%-90%
* Difficult to isolate organism, diagnosis primarily based on clinical factors

8. Primary Host Condition and Risk Factors Drive the Risk for Invasive Aspergillosis
* Factors Related to Underlying Condition 1-5
o Neutropenia
o Progressive disease
o Graft-vs-host disease
* Medications 1-5
o Corticosteroids
o Chemotherapy
o Immunosuppressive agents
* Innate Immune Status 1,5
o Polymorphisms in:
o Toll-like receptors
o Interleukin-10
o Mannose-binding lectin
o Plasminogen
o Others
* Other Factors 1,2,4,5
o Age
o Diabetes mellitus
o Metabolic acidosis
o Iron overload
o Renal impairment
o Respiratory disease/infection
o CMV disease
* Environmental Factors 1,5
o Season
o Construction
o Composting, gardening
o Contaminated water, food
o Contaminated air handling systems
o Tobacco/marijuana use
* Primary Host Factor 1,4
o Acute hematologic malignancy
o Aplastic anemia and myelodysplasia
o Allogeneic HSCT
o Solid organ transplantation
o Solid tumor
o Other immune disorder
o IMMUNOSUPPRESSION

1. Adapted from Herbrecht R, et al. Ann N Y Acad Sci. 2012;1272:23-30. 
2. Steinbach WJ, et al. J Infect. 2012;65(5):453-464.
3. Garcia-Vidal C, et al. Clin Infect Dis. 2008;47(8):1041-1050.
4. Girmenia C, et al. Clin Infect Dis. 2009;49(8):1226-1236. 
5. Pagano L, et al. J Antimicrob Chemother. 2011;66 Suppl 1:i5-14

9. Mucormycosis – (a.k.a. Zygomycosis )
* Ubiquitous; usually present in decaying matter
* Primary route of infection is via the respiratory tract
* Extremely aggressive infection; 
* Rapidly progressive and fatal unless prompt action taken

Kontoyiannis DP. In: Goldman’s Cecil Medicine, 24th ed. Philadelphia, PA: Saunders Elsevier; 2012.
 

11. Difficult to diagnose and Differentiate Mold Infections
* Report of autopsy data from 1,017 patients with hematologic malignancies 1
o 31% found to have IFD at autopsy
* 75% not diagnosed prior to death
* Autopsy of 38 allogeneic stem cell patients 2
o 10 dies with IFD
* 4 proven / probably before death
* 6 deep mycoses were missed
* 3 with invasive aspergillosis

1. Chamilos et al., 2006
2. Sinko et al., 2008

12. Voriconazole: Standard of Care in Invasive Aspergillosis

13. Voriconazole: Pharmacologic Characteristics 
* Excellent activity against Aspergillus spp.
o No activity vs. Mucorales
* IV and oral formulations
o IV formulation requires cyclodextrin
* Pharmacokinetic characteristic
o Non-linear PK
o Genetic variability in metabolism (CYP2C19)
o Food effect
o Potential drug-drug interactions
* CYP3A4, CYP2C9, CYP2C19

14. Sulfobutylether???cyclodextrin (SBECD): Sequence of progressive degeneration of Renal proximal tubule cells.

(A) Histology of normal proximal tubule cells. (B) Histology of ??cyclodextrin renal necrosis
Journal of Pharmaceutical Sciences
Volume 99, Issue 8, pages 3291-3301, 8 MAR 2010 DOI: 10.1002/jps.22109
http://onlinelibrary.wiley.com/doi/10.1002/jps.22109/full#fig2

15. Voriconazole: Limitations
* Dose limiting safety risks
o Hepatic adverse effects
o Dermatological reactions
o QT prolongation
* Safety risk specific to voriconazole
o Visual disturbances

Prescribing information Voriconazole April 2014

16. Mucormycosis Treatment: Amphotericin B
* IV formulation only
o Infusion reactions
o Renal toxicity
* Associated with prolonged stay in hospital and mortality (Bates, 2001; Ullmann, 2016)
* Only FDA approved therapy for mucormycosis
* Lipid formulations
o Reduce toxicities
o Recommended as first line therapy (Cornely et al., 2014)

17. Unmet Medical Need for Additional Therapeutic Options
* Difficult to diagnose and differentiate mold conditions clinically 
* Voriconazole 
o PK and safety limitations
o No activity against mucormycetes 
* Amphotericin B deoxycholate 
o Only approved option for mucormycosis
o Toxicity limitations
o Active against invasive aspergillosis and invasive mucormycosis

18. Isavuconazonium Sulfate (Isavuconazole)

19. Isavuconazole Mechanism of Action

20. Isavuconazole: Spectrum of Activity

Moulds				ISA	AmB	Vori
* A. fumigatus		x	x	x
* A. flavus			x	x	x
* A. terreus			x		x
* A. niger			x	x	x
* A. nidulans			x	x	x
* Fusarium spp		x	x	x
* Phaeohypomycoses		x		x
* Scedosporium apiosperum	x	x	x
* Scedosporium prolificans				
* Mucorales			x	x	

In vivo reduction in fungal tissue burden and increase in survival
* Disseminated and pulmonary aspergillosis
o AUC / MIC correlated with outcome
* Pulmonary mucormycosis
21. Clinical Pharmacology Characteristics
* 40 Clinical pharmacology studies 
o Dose proportional increases in exposure
o Rapidly absorbed with 98% oral bioavailability
o No pH or food effect 
o Large volume of distribution (450L) 
o CYP3A4 metabolism 
o  <1% of unchanged drug excreted by kidneys 
o Long terminal elimination half-life (~ 130 hrs)
o No dose adjustment required in elderly or renally impaired 

22. Complexity of Achieving Adequate Drug Levels 1 With Triazoles
* Patient Factors				
o Immunocompetence
o Risk of stress ulcers
o Renal function
o Hepatic function
o Mucosal integrity
o Genetics
o Comorbidities 
o Concomitant medications
* [Drug] at therapeutic target 
* Drug Factors
o Administration
o Formulation
o Dosing
o Absorption 
o Metabolism 
o DDIs
o Distribution
o Elimination

DDI, drug-drug interaction; MPC, mutant prevention concentration.
1. Brunton LL, Lazo JS, Parker KL, eds. Goodman and Gilman’s The Pharmacological Basis of Pharmacotherapy. 11th ed. 
New York, NY: McGraw-Hill Book Company; 2006:1-39. 
2. Blondeau JM, et al. Antimicrob Agents Chemother. 2001;45(2):433-438.

23. CYP450 Inhibitors and Inducers Increase Risk of Poor Response or Toxicity

MPC, mutant prevention concentration.
1. Brunton LL, Lazo JS, Parker KL, eds. Goodman and Gilman’s The Pharmacological Basis of Pharmacotherapy. 11th ed. 
New York, NY: McGraw-Hill Book Company; 2006:1-39. 
2. Blondeau JM, et al. Antimicrob Agents Chemother. 2001;45(2):433-438.

24. Drug – Drug Interaction Potential

CVP			Substrate		Isavuconazole		Voriconazole
3A4			Midazolam		^ 2.05 fold		^ 10.3 fold
1A2			Sirolimus		^ 1.84 fold		^ 11.9 fold
2C8			Caffeine		NCS			NCS
2C9			Rapaglinide		NCS			NCS
2C19		Warfarin		NCS			^ 2-fold (PT)
2B6			Omeprazole		NCS			^ 4-fold
2B6			Bupropion		-42%			^ 1.3 fold
2D6			Dextromethorphan	NCS			NCS

25. Phase 3 study Design and efficacy result

26. Phase 3 Program Overview
* Study 0104
o Primary support for treatment of Invasive Aspergillosis
* Study 0103
o Primary support for treatment of Invasive Mucormycosis

27. Study 0104: Study Overview
   Isavuconazole
IV 200 mg TID (Days 1 & 2); IV or oral 200 mg QD (Day 3 onwards)

Randomization		Treatment duration: 84 days			Follow-up
1:1			Efficacy & safety assessments:		              28 days (±7) after EOT 
       Days 1, 2, 3, 7, 14, 28, 42, 63 & 84

   Voriconazole
IV 6 mg/kg BID (Day 1); IV 4 mg/kg BID (Day 2); IV 4 mg/kg or oral 200 mg BID (Day 3 onwards)

Patients were stratified by:
Geographic region, Allogeneic BMT/HSCT, and Uncontrolled malignancy status

Maertens J. ECCMID Oral presentation 2014

28. Study 0104: Primary Endpoint
* All-cause mortality (ACM) through Day 42
o Pre-specified non-inferiority margin: 10%
o Assumed ACM: 20% (Herbrecht 2002)
o Power: 80%
o Sample size: 510

29. Study 0104: Primary endpoint met – all cause mortality at Day 42

30. Study 0104: Overview of Safety
       Isavuconazole; N=257	Voriconazole; N=259
							%			%
AEs leading to death				24.1			27.8
SAE							52.1			57.5
AEs							96.1			98.5
Study drug-related AEs				42.4			59.8
AEs leading to permanent discontinuation		14.4			22.8
of study drug

Astellas. Study 0104.  Clinical Study Report

31. Significantly fewer treatment discontinuations due to adverse reactions

32. Study 0104: AEs by System Organ Class (SOC) (>5%) *P<0.05

System Organ Class (%)				Isavuconazole; N=257	Voriconazole; N=259
Gastrointestinal Disorders					67.7			69.5
Infections and infestations					59.1			61.0
General Disorders and Admin. Site Conditions		57.6			55.6
Respiratory, Thoracic, and Mediastinal Disorders		55.6			56.8
Metabolism and Nutrition Disorders				42.0			46.7
Nervous System Disorders					37.0			34.4
Investigations						33.1			37.1
Skin and Subcutaneous Tissue Disorders			33.5*			42.5
Blood and Lymphatic System Disorders			30.0			31.7
Psychiatric Disorders					27.2			33.2
Musculoskeletal and Connective Tissue Disorders		26.8			29.7
Vascular Disorders						26.1			29.7
Renal and Urinary Disorders					21.4			22.4
Cardiac Disorders						16.7			22.0
Eye Disorders						15.2*			26.6
Injury, Poisoning and Procedural Complications		12.8			15.1
Hepatobiliary Disorders					8.9*			16.2
Immune System Disorders					7.8			9.7
Neoplasms Benign, Malignant and Unspecified		7.4			12.0
Ear and Labyrinth Disorders					5.4			5.0

Astellas.  Study 0104.  Clinical Study Report

33. Clinically relevant transaminase elevation: Isavuconazole vs. Voriconazole  

34. Study 0103: Study Overview

Dose: Isavuconazole 200 mg TID PO or IV followed by Isavuconazole 200 mg  QD PO or IV 
Key endpoints: All Cause Mortality
Day 42, 84, 120, and 180 
Other species included:  Aspergillus, Dimorphic fungi, Non-Candida yeast, Mixed infection, other filamentous fungi

   003 Clinical Study Report.

35. Study 0103: All-cause mortality through Day 42
Astellas. Study 0103. Clinical Study Report

36. Fungiscope Registry: Mortality data is consistent with the historic data in the literature

All-cause Mortality Through Day 42 for 9766-CL-0103 Cases and Fungiscope Matched-case Controls

9766-CL-0103 Cases, n=21
Crude mortality rate, 95% CI

Fungioscope controls, n=33
Crude mortality rate, 95% CI

Fungioscope controls, n=33
Weighted mortality rate, 95% CI

Range of all-cause mortality of amphotericinB or posaconazole based on literature review

All-cause Mortality through Day 42 for Patients with Invasive Mucormycosis

Source: Section 4.2.3.1; Module 5 Mucor Literature Review; Module 5 Fungiscope Matched-case Control Analysis


37. Summary – Isavuconazole
* Not inferior efficacy to Voriconazole;  Fewer AEs
* Dose isavuconazole represent important clinical advance? 
o A Pro-Drug:  can be solubilized without renal toxic cyclodextrin
o Can be used in patients with renal Impairment
o Moderate Drug –Drug Interaction
o Spectrum of coverage
o No dosage adjustments in special populations
o No food effect and pH effect
o Offer IV/PO bioequivalence 

38. ICD-10 Procedure Code Request

39. Coding Request: IV Formulation

* To capture the intravenous administration of isavuconazonium, Astellas requests the creation of the following new ICD-10-PCS codes by establishing a new, separate qualifier in table 3E0 as is shown below.  This option is limited to 3 Peripheral Vein and 4 Central Vein body system/region values and a percutaneous approach.

Section: 		3 	Administration
Body System: 	E 	Physiological Systems and Anatomical Regions
   Operation: 		0 	Introduction: Putting in or on a therapeutic, diagnostic, nutritional, 
       physiological, or prophylactic substance except blood or blood products
Body System/Region	Approach		Substance		Qualifier
3 Peripheral Vein		3 Percutaneous		2 Anti-infective		8 Oxazolidinones 
4 Central Vein								9 Other Anti-infective
       ADD R 
       isavuconazonium

40. Coding Request: Oral Formulation

* To capture the oral administration of isavuconazonium, Astellas requests the creation of the following new ICD-10-PCS code by establishing a new approach for oral treatments as well as a new, separate qualifier in table 3E0 body system/region D Mouth and Pharynx, as is shown below.  

Section: 		3 	Administration
Body System: 	E 	Physiological Systems and Anatomical Regions
Operation: 		0 	Introduction: Putting in or on a therapeutic, diagnostic, nutritional, 
       physiological, or prophylactic substance except blood or blood products
Body System/Region	Approach	Substance	Qualifier
D Mouth and Pharynx	ADD Z Oral	2 Anti-infective	ADD R Isavuconazonium

41. Summary
* A NDA for isavuconazonium was submitted to the FDA and accepted by the agency on September 6, 2014
* Astellas submitted a NTAP application for isavuconazonium for fiscal year 2016
* There is not a unique ICD-10-PCS code to describe the IV and oral administration of CRESEMBA® to treat patients with invasive fungal infections, in particular invasive aspergillosis and mucormycosis
* Astellas requests to establish new ICD-10-PCS codes to better identify both IV and oral isavuconazonium administration for the treatment of invasive aspergillosis and mucormycosis:
1. To capture the intravenous administration of isavuconazonium, Astellas proposes to create new ICD-10-PCS codes by establishing a new, separate qualifier in table 3E0 .  This option is limited to 3 Peripheral Vein and 4 Central Vein body system/region values and a percutaneous approach
2. To capture the oral administration of isavuconazonium, Astellas proposes to create a new ICD-10-PCS code by establishing a new approach for oral treatments as well as a new, separate qualifier in table 3E0 body system/region D Mouth and Pharynx