1. Efficacy of Paloverotene in a Q207D mouse model of HO
Clementia – U. Penn Meeting
October 8, 2013

2. Experimental Design Injury (cardiotoxin; 10μM/50μl) Pre-treatment
Time to initial
HO formation
(5 half-lives)
Imaging
(microCT)
All animals
with HO
Functional
Assessment
(e.g., wire grasp)
Drug administration/day

3. Wire grasp test Control Treated
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.

4. Dosage calculations Calculated by formula below*
AED: animal equivalent dose in mg/kg
HED: human equivalent dose in mg/kg
Human weight: 60 kg
Average 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
𝐴𝐸𝐷=𝐻𝐸𝐷× 𝑎𝑛𝑖𝑚𝑎𝑙 𝑤𝑒𝑖𝑔ℎ𝑡 𝑖𝑛 𝑘𝑔 ℎ𝑢𝑚𝑎𝑛 𝑤𝑒𝑖𝑔ℎ𝑡 𝑖𝑛 𝑘𝑔 −0.33
E.g., for a HED of 10 mg,
𝐴𝐸𝐷=0.167 𝑚𝑔 𝑘𝑔 × 𝑘𝑔 60 𝑘𝑔 −0.33
= 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.

5. A B C *<0.05, **<0.01 1.47 2.94 Palovarotene (mg/kg) n = 16
1.47
2.94
Palovarotene (mg/kg) B
n = 16
n = 8
n = 9
*<0.05, **<0.01
1.47
2.94
Palovarotene (mg/kg) C
n = 8
n = 9
n = 16

6. Side effects and Adverse Events
Side Effects/Adverse Events
Palovarotene (mg/kg)
Mucocutaneous
(no. animals)
Dermatologic
General
Xerostomia
Xerosis
Alopecia
Weight Loss
Death
1.47
Not observed
Not observed (2/8)
Mild (6/8)
Not observed (1/8)
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

7. 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.