Oncology Oral Drug Development

Challenges and Opportunities

Mark J. Ratain, MD

University of Chicago

FierceLive! Webinar

Novel Technologies to Deliver Oral

Oncology Therapies

March 29, 2016

Oncology Oral Drug Development

Challenges and Opportunities

Clin Pharmacol Ther, 2013

Russian Roulette (from wikipedia.org)

• Russian roulette is a

potentially lethal game

of chance…

Black Box Warning for Nilotinib

Tasigna® [package insert]. East Hanover, NJ. Novartis Pharmaceuticals Corp.; 2015

Center for Drug Evaluation and Research. Clinical Pharmacology and Biopharmaceutics Review(s). Application number: 22-068.

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf

Nilotinib labeled to be taken

fasting

Tasigna® [package insert]. East Hanover, NJ. Novartis Pharmaceuticals Corp.; 2015

In other words, if you take nilotinib

with breakfast, you might die!!!

Tasigna® [package insert]. East Hanover, NJ. Novartis Pharmaceuticals Corp.; 2015

Reddy, N, Cohen, R, Whitehead, B et al, A phase I, open-label, three period, randomized crossover study to evaluate the effect of food on the

pharmacokinetics of lapatinib in cancer patients. Clin Pharmacol Ther. 2007;81:S16–S17 (Abstract PI-15).

Median and upper ranges of plasma lapatinib concentrations versus time following a 1,500-mg dose administered after fasting overnight, after a low-fat breakfast, and after a high-fat

breakfast.

Koch K M et al. JCO 2009;27:1191-1196

©2009 by American Society of Clinical Oncology

• Compared three

prandial conditions

consistent with the

label (i.e., not within

1 hr of a meal)

Biopharmaceutics Classification System (BCS)

(from Custodio, 2008)

Most kinase inhibitors are

Class 2 compounds

• Low solubility to bind to hydrophobic

backpocket

• High permeability to reach intracellular

target

Access to the HYDROPHOBIC pocket

adjacent to the ATP-binding site is crucial for activity

HYDROPHILIC (hydrogen) bonding to the substrate-

binding site confers selectivity Zhang J, et al. Nature Reviews Cancer. 2009; 9: 28-39

CCR, 2010

Focus on 23 drugs with marked (+50%) food effect

Kang SP and Ratain MJ. Clinical Cancer Research. 2010; 16: 4446-4451.

©2010 by American Association for Cancer Research Kang SP and Ratain MJ. Clinical Cancer Research. 2010; 16: 4446-4451.

lapatinib

nilotinib

erlotinib

deferasirox

posaconazole

The value of a healthy

breakfast… Drug Estimated 2011

US monthly cost

Approximate food

effect on AUC

Monthly savings

with food

Lapatinib $3400 150% increase $2040

Nilotinib $8800 100% increase $4400

Erlotinib $4800 50% increase $1600

Pazopanib $6000 100% increase $3000

Abiraterone $5000 >300% increase $3750

Internal analysis

Zykadia® [package insert]. East Hanover, NJ. Novartis Pharmaceuticals Corp.; 2015

Center for Drug Evaluation and Research. Cross Discipline Team Leader Review Application number: 205755Orig1s000.

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205755Orig1s000CrossR.pdf

Center for Drug Evaluation and Research. Summary Review. Application Number: 205755Orig1s000.

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205755Orig1s000SumR.pdf

• 750 mg (5 CAPSULES) orally once daily on an

empty stomach (i.e., do not administer within 2

hours of a meal)

• OR 450 mg (3 CAPSULES) orally once daily

with food

???????????

Zykadia® [package insert]. East Hanover, NJ. Novartis Pharmaceuticals Corp.; 2015

Oncology Oral Drug Development

Challenges and Opportunities

• Reducing gastrointestinal toxicity

• Greatly enhancing bioavailability

• Eliminating revenue risks associated with

relabeling, if drug is initially labeled

under conditions that result in

suboptimal bioavailabity

Oncology Drug Development Challenges and Opportunities

©2016 Catalent Pharma Solutions. All rights reserved.

JEFF BROWNE

JULIEN MEISSONNIER

03.29.16

26

Class II Class I

Class IV

~35% ~30%

~25% ~10%

Class III

Source: Dr. S. Page, Roche, CRS Meeting July 12-16, 2008, NY

Class II

Class III

Class I

Class IV

~5% ~70%

~5% ~20%

1 1000000 10 100 1000 10000 100000

10

100

1

Cell

Perm

eab

ilit

y

(x1

0-6

cm

/sec)

Volume needed to dissolve anticipated dose (ml)

Compounds in Development

The Trend for Oral Cancer Drugs is Similiar to all NCE‘s... Need for Solubility Enhancing Technologies

Source: Catalent.com, Oct2014

Taking a Closer Look at Approved Oral Cancer Drugs – Protein Kinase Inhibitors

Tyrosine Kinase Inhibitors

Product (Active)

Labelling Solubility (FaSSIF)

Food Effect

Meals Black Box (high fat meal)

Nilotinib Fast Yes

Low

82% AUC Increase

Dasatinib Fast/Fed No 14% AUC Increase

Ceritinib Fast No 73% AUC Increase; 41% Cmax Increase

Lapatinib Fast Yes 4X AUC; 3X Cmax

Erlotinib Fast No 60% fasting AUC; 100% fed AUC

Pazopanib Fast Yes 2X AUC; 2X Cmax

Gefitinib Fast/Fed No 60% oral BA; non-significant fed

BRAF Inhibitors

Product (Active)

Labelling Solubility (FaSSIF)

Food Effect

Meals Black Box (high fat meal)

Vemurafenib Fast/Fed No Low

5X AUC; 2.5X Cmax

Dabrafenib Fast No 95% oral BA; 31% AUC decrease; 51% Cmax decrease

MEK Inhibitors Product (Active)

Labelling Solubility

(FaSSIF)

Food Effect

(high fat meal) Meals Black Box

Cobimetinib Fast/Fed No Med 40% oral BA; Non-significant

Trametinib Fast No Low 24% AUC decrease; 70% Cmax decrease

Taking a Closer Look at Approved Oral Cancer Drugs – Other Classes of Compounds

HDAC Inhibitors

Product (Active)

Labelling Solubility (FaSSIF)

Food Effect

Meals Black Box (high fat meal)

Farydak (panobinosat)

Fast (rec) Fast/Fed Yes High

16% AUC Reduction; 44% Cmax Reduction

Farydak (panobinosat)

Mekinist (trametinib) Fast No Low 24% AUC decrease; 70% Cmax decrease

Androgen Enzyme/Receptor Inhibitors

Product (Active)

Labelling Solubility (FaSSIF)

Food Effect

Meals Black Box (high fat meal)

Enzalutamide Fast/Fed No Low

Non-significant

Abiraterone Fast No 10X AUC; 17X Cmax

Some Observations Regarding These Products

Food Effect

Most exhibit a positive food effect (AUC and Cmax)

Variability in Absorption

Safety: a number of these products have Black Box Warnings (Efficacy…exposure)

Majority are labeled to be taken fasted

Potential for poor patient compliance

- 1-2 hours before and after meals

Some are labelled simply based on administration during clinical trials

- Without regard to food

Labelled to take on empty stomach even though a clinically significant (PK) effect does not exist

80+ % Poorly Soluble Drugs

What Would an Ideal Target Product Profile for Orally Delivered Cancer Drugs Look Like?

Simple Dosing Regimen

High patient adherence

Without regard to food

Infrequent dosing… once daily

Wide Therapeutic Window

Minimal side effects

No Black Box Warnings

Less Variability Intra- and inter-patient

Consistent absorption

No Drug Interactions

Reduced transporter and metabolic effects

Target specific mechanism of action

Reduced lipophilicity

Bridging Drug Compound Properties to Formulation Approaches… Developability Classification System

Courtesy of R. Savla

32

… How does it help us select a suitable Formulation ?

We All Know The BCS But…

http://goo.gl/3v6GCq; https://goo.gl/DG0knr; https://goo.gl/6UaB59; https://goo.gl/D14HTV

Gordon’s Real BCS

Solubility High Low

Perm

eability

Hig

h

Low

Formulation Purgatory

Bioavilability Limbo

Developing a Modified Classification System

BCS – a regulatory tool

• Conservative, efficacy and patient safety in mind

— When is there no bio-inequivalence risk?

• Useful in late development and post-launch

DCS – a developability tool

• Aim: realistic, product development issues in mind

— What factors are likely to control the extent of oral absorption?

• Permeability, solubility/dose, dissolution rate

• Particularly useful in evaluating potential new drug candidates

Butler & Dressman 2010 J. Pharm. Sci. 99 (12) 4940–4954 33

BCS classification of compounds

BCS Classification

PE

RM

EA

BIL

ITY

H

L

SOLUBILITY H L

34 Source: Butler, J. The optimal use of biorelevant media & simple modeling for the prediction of in-vivo oral behaviour (http://www.apsgb.co.uk/Events/PastEvents/20110609/James%20Butler.pdf)

I

III IV

Good solubility and permeability

Good solubility Poor permeability

Poor solubility and permeability

IIa

IIb Solubility limited

Dissolution rate limited

Poor solubility Good permeability

II

DCS vs. BCS Classification of Compounds

DCS (Developability) vs. BCS Classification

Source: Dr. S. Page, Roche, CRS Meeting July 12-16, 2008, NY

Some Key Features of the DCS

Solubility limited absorbable dose (SLAD)

• Assumes a 500ml volume available for drug dissolution.

• Peff >1x10-4 cm/sec assumed to proportionally increase the effective volume available for dissolution of highly permeable drugs

• Represents the dose above which absorption is solubility limited. i.e. beyond this:

• Linear exposure/dose response may be lost

• Solubility related food effects are likely

• Reducing particle size alone cannot achieve complete absorption

Recommended particle size

• Derived from “dissolution number” equation

• Approach: set target dissolution number to 1, solve the equation for particle diameter, use this as the target x90.

Dn concept from Oh et al, Pharm Res 1993 10 (2) 264-270

35 J. Butler, 2013 Phys Chem Forum

Formulation strategies for DCS IIb compounds

PE

RM

EA

BIL

ITY

H

L

SOLUBILITY H L

I

IIa

IIb

III IV

Setting the Right Formulation Strategy for the Right Compound

36

*DCS: developability classification system

Source: Butler, J. The optimal use of biorelevant media & simple modeling for the prediction of in-vivo oral behaviour (http://www.apsgb.co.uk/Events/PastEvents/20110609/James%20Butler.pdf)

Increase Intrinsic Solubility -Lipid systems

-Solid dispersions

Increase dissolution rate -Milling

-Micronization

-Co-Micronization

Neat drug, powder in capsule/tablet

Lipid systems:w/o emulsions with permeation enhancers

Lipid systems with permeation enhancers

Solubility: Many compounds in Quadrant II!

37 J. Butler 2013 Phys Chem Forum

Why are We Still Playing Russian Roulette with Oncology Compounds…

All listed molecules are solubility limited at target dose

FeSSIF solubility drives a significant change in SLAD

Why are We Still Playing Russian Roulette with Tyrosine Kinase Inhibitors… Nilotinib

39

Weak base, highly insoluble max. dose 150-200 mg

FaSSIF solubility 0,2 µg/mL FeSSIF solubility 0,9 µg/mL

Estimated permeability 6.9 x10-4 cm/sec

BCS II, DCS IIb

Highly solubility limited

Recommended max particle size: 5 µm (d90) Solubility Limited Absorbable Dose 1 mg (FeSSIF 3 mg)

34 - 72% inter variability 31% intr variability 82 % positive food effect Marketed formulation is granulated API in capsule with poloxamer (DCS IIa option)

DCSIIb system cancel food effect (solid dispersions)

Why are We Still Playing Russian Roulette with Tyrosine Kinase Inhibitors… Erlotinib

40

Weak base, highly insoluble max. dose 150 mg

FaSSIF solubility 5 µg/mL FeSSIF solubility 200 µg/mL

Estimated permeability 7.4 x10-4 cm/sec

BCS II, DCS IIb

Solubility limited

Recommended max particle size: 20 µm (d90) – 110 µm under FeSSIF Solubility Limited Absorbable Dose: 17 mg (FeSSIF 720 mg)

60% exposure (fasted) 100% exposure (fed) Marketed formulation is API in tablet with surfactant, prescribed with an empty stomach

Why are We Still Playing Russian Roulette with Oncology Compounds???

Drug Marketed

Dose Form Dose (mg)

DCS Dose/

Solubility Ratio

SLAD (mg) Particle Size

(µm)

Nilotinib Capsule 400 IIb 2,000,000 1 3.5

Ceritinib Capsule 750 IIb

11,177 219 63.3

Lapatinib Tablet 1250 IIb

192, 308 22 19.7

Erlotinib Tablet 150 IIb

32,609 17 16.6

Pazopanib Tablet 800 IIb

53,333 53 29.9

Gefitinib Tablet 250 IIa 1,688 535 94,1

Marketed Protein Kinase Inhibitors Overview Formulation to Differentiate PKIs under Development

Catalent Pharma Solutions data analysis from 29 marketed PKIs, August 2015

82% low

solubility

40%

narrow therapeutic index

31%

HAVE A NON ADEQUATE DOSING

REGIMEN

78% non-

optimized DDS

22% milled

API and surfactants

7 Black Labels

42

SIMILAR PROPERTIES

SIMILAR FORMULATION RECEIPES

SUBOPTIMAL OUTCOMES

Take Abiraterone vs Enzalutamide as an example…is good enough good enough???

43

Both Compounds are Highly Similar Neutral, highly insoluble

Solubility 2 µg/mL

Estimated permeability 7,4 x10-4 cm/sec

BCS II, DCS IIb

Highly solubility limited

Recommended max particle size: 11 µm (d90) Solubility Limited Absorbable Dose: 7 mg

Enzalutamide suspension and solid form in early clinical evaluation always below lipid solutions Lipid solution removes food effect and enables linear escalation up to 600 mg

Phase I-II: Liquid filled hard gelatin capsule Market ready: Soft gelatin capsule

Zytiga® vs Xtandi® as an example…is good enough good enough???

Abiraterone acetate DCSIIa formulation

API in Tablet Formulation

− Indication: Treatment of patients with metastatic castration-resistant prostate cancer (CRPC) in combination with prednisone

− Dosage: 1,000 mg (4 X 250 mg) once daily

− Product Administration Directions: Must be taken on an empty stomach (no food at least 2 hours before and 1 hour after consumption)

− Food Effects: Approximately 17-fold and 10-fold higher, Cmax and AUC respectively, when a single dose of abiraterone acetate was administered with a high-fat (57% fat, 825 calories) meal compared to overnight fasting

Enzalutamide DCSIIb formulation

Lipid in Softgel & Spray Dried Dispersions

− Indication: Treatment of patients with metastatic castration-resistant prostate cancer (CRPC)

− Dosage: 160 mg (4 X 40 mg) once daily

− Product Administration Directions: Can be taken with or without food

− Food Effects: A high-fat meal did not alter AUC to enzalutamide or N-desmethyl enzalutamide

44

Comparability in DCSIIB Formulations Performance Rp Scherer Softgel vs Spray Dried Dispersions

45

Reference: PCT/US2013/059223

46

Fig from Porter CJH et al. , Nature Reviews | Drug Discovery, 2007, 6:231-248

Dispersion

Digestion

The rationale behind lipid-based solutions: dispersion – digestion for pre and post administration solubility

Avoid drug substance precipitation upon dispersion and digestion

Digested solution: Drug precipitation?

Fine o/w dispersion: Drug precipitation?

TG DG MG + FA

Formation of colloidal structures with endogenous biliary lipids

Digestion

Lipid Solution

Solid amorphous dispersions for DCS IIb drugs…

47

• Amorphous form of drug are high energy forms.

• Since there is no crystal lattice structure (no long range order), the energy barrier to dissolution is much reduced.

• Inherently unstable, and will tend to revert to the stable and usually least soluble form. Need to be stabilized (solid solutions, dispersions) with polymers.

— Hot Melt Extrusion and Spray Drying as processing technologies

47

DRUG DELIVERY SOLUTIONS

OPTIFORM® SOLUTION SUITE Enhanced Bioavailability in 12 Weeks

Early development followed by Phase 1 and Beyond…

1 ASSESS

2 ENHANCE

3 DELIVER

PRE-CLINICAL

Lipid Formulation

Particle Size Reduction

Solid Dispersion

• Molecule Characterization

• Assess Salt Form Benefits

• Preliminary Consultation to

select formulation technologies for ENHANCE

• Expert Consultation

• Extensive analytical data report

• 1-4 animal PK study material

1.Lipid system 2.Solid dispersion 3.Micronized Material 4.Salt Form (optional)

PHASE I & BEYOND

CU

STO

MER C

ON

DU

CTS A

NIM

AL S

TU

DIE

S

Salt Form Optimization

• Viable dose form prototypes for Phase I

• Optimized dose form development for Phase II and beyond

• CMC and Analytical

• Clinical and Commercial supply

48

Important Points to Take Home Today

1) Many of today’s oral cancer compounds fall into DCS IIb and conventional solid dose forms may not provide optimal bioavailability, i.e. poor absorption, marked food effect and significant variability

2) DCS is a valuable tool for aiding in the selection of suitable formulation strategies early in the development of these compounds

3) For DCS IIb cancer compounds, often an enabling formulation technology which allows pre-absorption drug solubility is required to assure enhanced bioavailability

4) Optiform® Solution Suite is a platform offered by Catalent incorporating 2) and 3) above which can be executed in 12 weeks or less

discover more. CATALENT PHARMA SOLUTIONS 14 SCHOOLHOUSE ROAD SOMERSET, NJ 08873

+ 1 866 720 3148

www.catalent.com