Efficacy of Paloverotene in a Q207D mouse model of HO

Clementia – U. Penn MeetingOctober 8, 2013

Experimental Design

All animalswith HO

Imaging(microCT)

FunctionalAssessment(e.g., wire grasp)

Time to initialHO formation

Pre-treatment

Injury(cardiotoxin; 10μM/50μl)

Drug administration/day

(5 half-lives)

Control Treated

Wire grasp test

Unimpaired mice grasp the wire with all four limbs (simultaneously) while mice with impaired mobility of a joint can only grasp the wire with three limbs simultaneously.

Dosage calculationsCalculated by formula below* AED: animal equivalent dose in mg/kgHED: human equivalent dose in mg/kgHuman weight: 60 kgAverage mouse weight: 0.01 kg (based on avg. weight over 18 days) Calculations for AED based on 5 and 10 mg dosages of palovarotene in humans was 1.47 and 2.94 mg/kg, respectively

E.g., for a HED of 10 mg,

= 2.94 mg/kg

* Based on: FDA (2005). Guidance for Industry, Estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. Center for Drug Evaluation and Research, US Department of Health and Human Services.

0 1.47 2.9405

10152025303540

*

**

Palovarotene (mg/kg)

Bo

ne

Vo

lum

e [m

m3]B

0 1.47 2.94

Palovarotene (mg/kg)

C

A

0 1.47 2.94

Palovarotene (mg/kg)

n = 16

n = 8

n = 16

n = 8 n = 9

n = 9

Side effects and Adverse Events

Side Effects/Adverse EventsPalovarotene

(mg/kg)

Mucocutaneous(no. animals)

Dermatologic(no. animals)

General(no. animals)

Xerostomia Xerosis Alopecia Weight Loss

Death

1.47 Not observed Not observed (2/8) Mild (6/8)

Not observed (1/8)Mild (6/8)

12 % (0/8)

2.94 Mild (1/11)Moderate (5/11)

Severe (5/11)

Moderate (2/11)Severe (9/11)

Moderate (11/11) 25 % (2/11) [Day 15]

Xerosis & alopecia

Xerostomia

Xerosis & alopecia

Summary• Paloverotene at HEDs of 5mg and 10mg substantially reduced or

virtually eliminated HO formation in a Q207D mouse model, respectively, consistent with a positive proof-of-principle study.

• Mucocutaneous and dermatologic side effects were mild or not observed at the HED of 5mg, but were moderate or severe at the HED of 10 mg.

• Weight loss was observed at both HEDs, more severe at the higher dose.

• Death occurred in 2 out of 11 animals at the higher HED.• Based on these experiments, we expect that levels of CD-RAP

will be close to, or at baseline, in the serum ofanimals treated with the 5mg and 10mg HEDs.