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PALOVAROTENE

1. What is palovarotene?

ANSWER: Palovarotene is a retinoic acid receptor gamma (RARγ) agonist and is in a class of compounds called systemic retinoids. These compounds have been shown to block bone formation in a variety of mouse models of FOP. Palovarotene is being investigated as a potential treatment for FOP.

2. Has palovarotene been tested in animals?

ANSWER: Yes, palovarotene has been tested in both healthy animals and in animal models of FOP. The testing in healthy animals helped to determine what some of the potential side effects of palovarotene may be in humans. When tested in mouse models of FOP, palovarotene prevented new bone growth after injury in a dose related manner; that is, the higher the dose the more bone is prevented.

3. What is the expected effect of palovarotene on humans with FOP?

ANSWER: Palovarotene prevented the formation of new bone in a variety of mouse models of FOP, but whether it will do the same in humans is not known. The Phase II clinical trial that Clementia is conducting is designed to evaluate the effect, if any, that palovarotene will have on new bone formation during and following a flare-up in patients with FOP, and at what dose. Additionally, this clinical trial will evaluate the side effects associated with palovarotene in patients with FOP.

4. Have any people ever taken palovarotene? Were any of these patients afflicted with FOP?

ANSWER: Eight hundred and twenty-five people, including healthy volunteers and patients with emphysema, have taken palovarotene as of June 2014, but none of these were FOP patients.

PVO-1A-201, THE PHASE II CLINICAL TRIAL OF PALOVAROTENE IN PATIENTS WITH FOP

5. What is the purpose of the Phase II palovarotene trial?

ANSWER: The purpose of this clinical trial is to investigate whether palovarotene has an effect on new bone formation during and following a flare-up in patients with FOP, at what dose and with what associated side effects.

6. Who can participate in the Phase II clinical trial?

ANSWER: This clinical trial is designed to observe the effects of palovarotene in FOP patients with the R206H mutation and will enroll up to 40 patients. Patients who are at least 6 years old and are able to complete examination and enrollment within 7 days of a flare-up that is located in the shoulders, chest, abdomen, arms, hips, or legs may be considered for enrollment in the Phase II clinical trial. Patients must be willing to consider treatment with prednisone per the FOP treatment guidelines; not have any of the clinical trial exclusion criteria; and must be able to attend all protocol scheduled visits during the 3-month trial. Further details and enrollment criteria of the clinical trial can be found on www.clinicaltrials.gov and www.orpha.net.

7. What is required of participants who are enrolled in the Phase II clinical trial?

ANSWER: Patients will undergo a complete history and a physical examination plus laboratory assessments to determine if they meet all the enrollment criteria for the clinical trial. Patients who meet the enrollment criteria and are enrolled in the clinical trial will then be randomly assigned to receive either palovarotene or placebo, which will be taken by the patient every morning after breakfast for 6 weeks. These patients will continue to be followed for an additional 6 weeks after study medication has stopped, so the total participation in the clinical trial is 12 weeks.

There will be a number of assessments performed during the clinical trial to determine whether palovarotene will have an effect on new bone formation during a flare-up, and what the side effects are. These include x-ray, CT scan, and MRI (or ultrasound for any subject unable to undergo MRI) of the flare-up site, patient rating of pain and swelling symptoms, patient assessment of movement at the flare-up site, and range of motion at the flare-up site. In addition, patients will complete questionnaires meant to assess physical limitations and other general health measures. Finally, side effects will be assessed. In general, these assessments will be performed at baseline (at the time of enrollment), at week 6 (at the end of treatment) and at week 12 (after the 6-week follow-up).

Further details of the clinical trial can be found on www.clinicaltrials.gov and www.orpha.net.

8. What does it mean to be randomly assigned to receive a placebo treatment in the Phase II clinical trial?

ANSWER: Patients who are enrolled in the Phase II clinical trial will be randomly assigned (a process similar to flipping a coin) to receive either palovarotene or placebo. In this clinical trial you will have a 25% (one in four) chance of receiving placebo and a 75% (three in four) chance of receiving palovarotene.

9. What is a placebo treatment and why is it being used in the Phase II clinical trial?

ANSWER: Placebo is a product with no therapeutic action that looks like the experimental compound but is not and does not contain palovarotene. Placebo treatments are usually required in clinical trials in order to determine whether an experimental compound provides any treatment benefit, and to determine the side effects. Using a placebo group in a clinical trial helps determine whether the effects seen are from the experimental compound, or are due to patients being carefully monitored as part of a clinical trial, or are by chance.

10. Will participants in the Phase II clinical trial be able to receive their usual care, like prednisone for a flare-up, other medications and/or devices like oxygen or CPAP (continuous positive airway pressure)?

ANSWER: Yes, although the clinical trial protocol does not allow some medications because of potential interactions with palovarotene, it is permissible to use prednisone, oxygen, and CPAP. More details of the clinical trial, including acceptable medications, can be found on www.clinicaltrials.gov and www.orpha.net. Also, the clinical trial personnel will discuss this information with you.

11. What if a patient enrolled in the Phase II clinical trial experiences side effects to the treatment?

ANSWER: The most frequent side effects associated with palovarotene include effects on skin and mucous membranes (e.g. the inside of your nose and mouth) including dry skin, dry lips, itching, rash, redness of the skin, flaking and peeling skin, inflammation of the lips, dry mouth, and dry eyes.

There are other potential side effects associated with the class of medications palovarotene is a part of – called retinoids, and these will be described in the informed consent process when being considered for enrollment in the clinical trial. There will be an opportunity to discuss these potential health risks with the clinical trial personnel.

If a patient experiences a side effect during the clinical trial, he/she will be carefully evaluated by the clinical site physician and treated appropriately. Also, patients can choose to stop participating in the clinical trial at any time.

12. Where is the Phase II clinical trial being conducted?

ANSWER: The clinical trial is being conducted at four sites as listed below. There will be clinical trial personnel at each clinical site who are knowledgeable about FOP and well trained on the clinical study protocol. Site readiness details can be found on www.clinicaltrials.gov and www.orpha.net.

13. Will a patient who does not live in the US, UK or France be able to enroll in this clinical trial?

ANSWER: Yes, patients who live outside the US, UK or France may be considered for enrollment into the trial. Any subject interested in participating should contact study personnel as described on www.clinicaltrials.gov (NCT02190747) and www.orpha.net (ORPHA419970) or call one of the participating sites directly.

14. Will Clementia provide funding for transportation and housing to participants in the Phase II clinical trial that live too far to drive to the clinic site?

ANSWER: Yes, all reasonable costs associated with participating in this trial will be covered, including travel and accommodations for the patient and caregiver.

15. If this Phase II clinical trial is successful, will it lead to marketing approval?

ANSWER: This Phase II clinical trial is exploring whether palovarotene will have an effect on new bone formation during a flare-up in patients with FOP and at what dose. It will also assess the side effects of palovarotene in patients with FOP. Additional studies will be required before a regulatory agency such as the US Food and Drug Administration and the EU European Medicines Agency will review the marketing application for palovarotene as a treatment for FOP.

16. What is the timeline for palovarotene marketing approval?

ANSWER: The timeline for marketing approval is not yet known.

17. What happens to patients after their participation in the Phase II clinical trial is complete?

ANSWER: Clementia is conducting an open-label extension for any patient who completes the 12-week double-blind clinical trial.

Open-label means a patient enrolled in this extension clinical trial who experiences an eligible flare-up would be treated with palovarotene whether or not that patient received placebo or palovarotene in the first study. Details about this study are posted at www.clinicaltrials.gov (NCT02279095) and at www.orpha.net (ORPHA442910).