Example for an early drug-device development plan

Dr. Barbara SchugSocraTec R&D, Oberursel

www.socratec-pharma.de

Joint Conference of European Human Pharmacological Societies and 20th Anniversary of AGAH

Berlin, Germany, March 31 – April 01, 2011

Why early drug-device combinations ?

Potential reasons for early drug-device combinations

intended drug targeting due toimproved therapeutic effect when the site of action is difficult to reachimproved tolerability when the side-effect pattern constrains regular use

intended local application for locally acting drugs

necessity to overcome drug substance limitationshigh–first pass metabolismpoor absorption due to solubility problems or molecule size

Locally acting / applied: ciclesonide

A. Weinbrenner: J Clin Endo 87(5): 2160-2163, 2002

Structural formula of ciclesonide

Metered dose inhaler for treatment of asthma

R-epimer

Locally acting / applied: ciclesonide

RM1 has approximately 100-fold greater affinity for glucocorticoid receptor

Metered dose inhaler for treatment of asthma

Proposed metabolic pathway of ciclesonide R-epimer

CDER Document: Application Number: 21-658

B9207-015

B9207-021(M1)

B9499-010(16-hydroxyprednislone)

M3 familyM2

anidentified metabolites

CYP3A4CYP2C8

CYP3A4CYP2D6

Esterase

CYP3A4CYP2D6

CYP3A4CYP2C8

Questions answered for ciclesonide (1)

Pharmacokinetic development program of ciclesonide with assessment of

absolute oral bioavailabilityabsolute inhaled bioavailabilitysingle dose (inhaled) dose proportionality (40-3250µg) in healthy subjects and asthmaticssteady state (inhaled) dose proportionality(250-1000µg)

Absolute oral bioavailability

Contribution of swallowed ciclesonide to be assessed primarily for safety reasons

single dose administrations6.9mg (oral) vs 0.64mg (i.v.) [14c] – ciclesonide separated by wash-out phase of 14 days6 healthy male subjects aged 19 to 40 yearsassessment of total radioactivity …… and of ciclesonide and RM1 in whole blood, plasma, urine and faeces

Absolute oral bioavailabilityStudy results

ciclesonide < 1%budesonide 10.7%fluticasone ≅ 1%

conclusion: swallowed ciclesonide of minor importance

after oral administration the parent compound was not detectable in plasma …… only traces of RM1 were determined resulting oral bioavailability below 1% for the parent compound

Absolute oral bioavailability

Nave R. et al: Int J Clin Pharm (2006) , 1-7

Fig 2. Cumulative excretion of radioactivity in urine and faeces after administration of 0.64mg of [14C]ciclesonide as a 10-minute intravenous infusion (IV) or 6.9mg of [14C]ciclesonide as an oral capsule (PO). Values are means ± standard error.

Due to poor systemic availability evaluation focuses on urine and faeces data

Oral systemic availability

in contrast to orally administered drugs with intended systemic availability, exposure after administration of such a drug-device combination for locally acting / locally applied drugs is only of relevance for the swallowed fraction

Conclusions from study results

thus, absolute bioavailability after oral administration in this case is assessed for safety reasons onlyabsolute bioavailability after inhaled administration is also determined for safety reasons

Questions answered for ciclesonide (2)Clinical pharmacology development program of ciclesonide with assessment of

absolute oral bioavailability (safety)absolute inhaled bioavailability (safety)single dose (inhaled) dose proportionality (40-3250µg) steady state (inhaled) dose proportionality(250-1000µg)PK in asthmatics and healthy subjectsPK in adults, children, male, female, whites, Japanese, black, elderly, patients with renal or hepatic impairment

PK after inhalation – patients ?

underlying disease influences site of absorption (obstruction and inflammation)PK may be different in patient population

Comparison healthy vs. asthmatics

12 patients with persistent asthma were matched with 12 healthy subjects (sex, age, BMI)single inhaled dose of 1280µg (8 puffs)

Target population is a special PK population per definition

Parallel group study performed for ciclesonide

PK after inhalation

R. Nave: Clin Pharm 43 (7): 479-486, 2004

Fig 1. Mean ± standard error of the mean serum concentrations of ciclesonide and desisobutyril ciclesonide in healthy subjects and patients with asthma after receiving a single inhaled dose of ciclesonide 1,280 µg.

Primary parameter:AUC of des-CIC1.003 (0.815-1.234)

Questions answered for ciclesonide (3)

Clinical pharmacology development program of ciclesonide with assessment of

“classical” drug-drug interaction studies with erythromycin, ketoconazole and formoterolsingle dose lung deposition with 99mTc-labeled ciclesonide in adults with moderate asthmasingle dose lung deposition with 99mTc-labeled ciclesonide in healthy volunteers

Lung-deposition

Local Pharmacokinetics to be assessed in addition

99mTc-labeled ciclesonide administered to healthy subjects and asthmaticsassessment of percent deposition in mouth and pharynxassessment of percent deposition in the lungcharacterisation of deposition pattern for peripheral and lower central regions of lung

Lung-deposition: efficacy

C. Leach: J Aero Medi 19(2): 117-126, 2006

Fig 3. Representative two-dimensional lung deposition pattern of 99mTc ciclesonide-hydrofluoroalkane (HFA) in a healthy male volunteer.

Deposition in healthy subjectsmouth/ pharynx: 38% ± 14%

lung: 52% ± 11%central: 17% / 30%peripheral: 47% / 34%

2D-imaging

3D-SPECT

Questions answered for ciclesonide (4)

HPA-axis suppression determined in adults12 healthy male volunteers4-period-changeover design over 7 days each

800 µg morning administration800 µg evening administration400 µg BID

Cortisol suppression as safety marker

Hypothalamic-Pituitary-Adrenocortical-axis suppression also assessed in asthmatic children

comparison with placebo

Influence on HPA-axis

Cortisol suppression as safety markerprimary endpoints (cortisol in serum)

24h mesor (AUC(0-24h) / 24h)24h amplitude (1/2 Δ max / min)acceptance criterion: 80 – 125%assay: fluorescence polarisation immunoassay

A. Weinbrenner: J Clin Endo 87(5): 2160-2163, 2002

Dose Ratio / Confidence intervalmorning dose 800µg 0.94 / 0.86 – 1.02evening dose 800µg 0.98 / 0.90 – 1.07BID 400µg 0.93 / 0.86 – 1.02

study results (PE in comparison to placebo)

Cortisol suppression: safety

A. Weinbrenner: J Clin Endo 87(5): 2160-2163, 2002

Fig 2. Mean 24-h profiles of serum cortisol of 12 healthy volunteers treated for 7 d with (A) placebo twice daily, (B) 800 µg ciclesonide in the morning and placebo in the evening, (C) 800 µg ciclesonide in evening and placebo in the morning, and (D) 400 µg ciclesonide in the morning and 400 µg ciclesonide in the evening in a randomized, double-blind, change-over, equivalence study with at least 7 d wash-out.

Deficiency letter for HPA-axis in children

Comments to sponsorreferring to study in children with mild persistent asthma

more than 40% of the subjects included had a 24h-urine volume < 250mlanalytical method for cortisol in urine showed no adequate validationpatient compliance could not be a assured

new study requested with children aged 4-11 y24h urine cortisol and24h serum cortisol

CDER Document: Application Number: 21-658

Summary ciclesonide (1)Early development plan – major steps

underlying disease interferes with site of absorption

“bridging” study healthy vs. patients necessary

characterisation of site-of-action deposition in addition to systemic availability needed

99mTc-marker lung deposition study needed

“classical” pharmacokinetic program, but primarily for safety reasons

established PD-model for safety assessment commonly required

HPA-axis study regulatory requirementCDER Document: Application Number: 21-658

Deficiency letter refers to basic methodologicalissues

Summary ciclesonide (2)Development plan strongly influenced by site of action

ciclesonide has also been developed as nasal formulation (“seasonal allergic rhinitis”) with (different) study package necessary

systemic availability (safety reasons)influence of underlying disease not characteriseddeposition at site of action commonly not assessed…but local tolerabilitymetabolism in human epithelial cells for activation of the pro-drug needed (and assessed in cell cultures)

Product monograph “Omnaris”, Nycomed Canada

SMPC Nycomed: “Interactions with food have not been assessed… and are unlikely with nasal corticosteroids”

rhBMP-2 for bone tissue induction

treatment of acute, open tibial shaft fractures stabilized with intramedullary nail fixationafter appropriate wound management

Recombinant human bone morphogenetic protein

within 14 days after the initial fracturepatients must be skeletally mature

above 18 yearsradiographic evidence of epiphyseal closure

no active infection at the operative site

INFUSE® bone graft induces new bone tissue at the site of implantation

Summary of safety and efficacy data, INFUSE ® bone graft, Whyeth Pharmaceutical Inc., Pennsylvania

rhBMP–2: therapeutic principle

disulfide – linked dimeric proteintwo major subunit species of 114 and 131 amino acidseach subunit glycosylated with high mannose–type glycansproduced by genetically engineered Chinese hamster ovary cell line

rhBMP-2 as active moiety

Need for local, but not systemic availability

placed to bone within 15min after preparationsolution applied to absorbable collagen spongelyophilised drug + excipients for reconstitution

rhBMP–2: absorbable collagen sponge

rhBMP-2 / ACS – pre-clinical tests

single/ multiple dose general toxicity studies after intravenous administration

no treatment related toxicityno disseminated bone formation when systemically appliedpotent bone inducing activity only at implantation site

no evidence for carcinogenicity / genotoxicity

no delayed skin sensitizationno intracutanous toxicity / no dermal irritation

no mortality / no systemic toxicity

no cell lysis (cytotoxicity tests)no hemolysis / no cellular mutagenicityhard, granular formation in muscle irritation test

Animal studies

rh BMP-2: PK in animals

extensive metabolismrapid uptake in highly perfused tissues

rapid elimination from systemic circulationf ½ (rat) : 16 minf ½ (primates) : 6.7 min

rapid renal excretion

local retention of rh BMP-2 / ACS

Studies with iv-administration and implantation

Several / comprehensive pre-clinical trials conducted

rh BMP-2: PK in animals

Retention and clearance from systemic circulation:iv administration (left) and after implantation (right)

Presentation Gerard Riedel, Wyeth-Genetics Institute

rhBMP-2: clinical trials

safety / effectiveness in patient population150 subjects per treatment group ( 2 doses of rhBMP-2 vs. control)follow-up: 12 months after wound closureclinical endpoint: fracture healingtesting for antibodies (9 / 149) antibody formation depends on location of implantation

Summary of clinical trials

No further studies in human for initial submission

rhBMP-2: deficiency letter

in-vitro investigations – tumor promotionrabbit studies - embryonic development better in-vitro release characterisationtraining plan for surgeons requested

Additional investigations requested Centre for Devices and radiological health at FDA

No further prospective clinical trials requested !

Summary: rhBMP-2

comprehensive in vitro testscomprehensive animal tests1 clinical trial with a total of 2*150 patients with efficacy and safety assessments

(Pre-)Clinical development plan

Additional post-approval studies to be performed for characterisation of immunological response

Rotigotine: dopamine receptor agonist

Initial development as transdermal therapeutic systemPfeiffer RF, Neurology 2005, 65 6-10

structural similarity with dopamine(also) high first-pass metabolismoral administration not meaningful

Rotigotine – development programSummary of study designs

sequential repeated measurement design with increasing i.v. doses in PK/PD trial (patients)

dose finding done with i.v. administrationtitration against the L-dopa dose needed

ADME with i.v. administration in healthy subjectsearly characterisation of absorption site

abdomenflankupper armshoulderthighhip

CDER Document: Application Number: 21-658

All absorption sites demonstrate adequate systemic availability

PK – characterisation of rotigotine

“Classical” PK-program due to systemic action after patch administration

single dose

multiple dosedrug-drug interactionsspecial populationsdifferent patches: bioavailability / bioequivalence

Summary: rotigotine

Relevant aspects of the clinical development program

systemic availability is prerequisite for efficacyi.v. administration for proof-of-concept study and early dose findingtransdermal administration to overcome first-pass metabolism“classical” PK program“classical” PD programcharacterisation of route of administration incl. influence of body area used for application

Conclusion: early drug-device

Development program strongly depends on necessity of systemic availability

Systemic availability means high similarity to classical development programs with additional assessment of specific influence of deviceLocally acting means comprehensive evaluation of application site and systemic exposureProgram also depends on classification “drug-device-combination” vs “medical device”

No “cookery book” approach …

… “playing field” for human pharmacology instead

Many thanks to …

Dr. Ramón Villalobos Hernández, SocraTec R&D

Katrin Jäger, SocraTec R&D