Report of the Expert Advisory Panel on Prochymal®

January 26, 2012

The Expert Advisory Panel on Prochymal^® was convened at the request of the Biologics and Genetic Therapies Directorate (BGTD), Health Canada. The panel's mandate was to provide advice to BGTD on the benefits and risks of a new mesenchymal stem cell (MSC) therapy, Prochymal^®, manufactured by Osiris Therapeutics Inc. Prochymal^® is intended for the treatment of acute graft versus host disease (GvHD) in children who have failed all previous therapies for GvHD following bone marrow transplantation.

The Prochymal^® New Drug Submission was initially given a priority review status based on very preliminary evidence of efficacy that did not come from well-designed controlled trials. Based on BGTD's initial assessment, the drug manufacturer was notified that the Prochymal^® submission would be eligible for filing under the Notice of Compliance with Conditions (NOC/c) policy. The drug manufacturer agreed to comply with the pre- and post-authorization requirements that fall under this policy when they filed the submission.

The expert advisory panel was convened via a full day face-to-face meeting in Ottawa on January 26, 2012. In advance of the meeting, the panel was provided with the terms of reference, questions posed by BGTD, and background materials provided by BGTD and Osiris Therapeutics Inc. The background materials included information intended to address the issues raised in the risk-benefit assessment and interpretation of the efficacy and safety data of Prochymal^®. The panel was tasked with conducting an unbiased scientific review of the data provided on safety and efficacy in order to provide independent and objective advice to BGTD. The final regulatory decision on Prochymal^® remains with BGTD.

The panel members were:

• Harry Atkins, MD, FRCPC (Chair)
• Max Coppes, MD, PhD, MBA
• Allan Donner, PhD, FRSC
• Adam Gassas, MD, MBChB, MRCP, DCH, MRCPCH
• Michelle Mullen, PhD
• Bernard Thébaud, MD, PhD

This meeting was attended by six panel members, representatives from Health Canada, Osiris Therapeutics Inc, two Principal Investigators for Prochymal^®, and a Medical Monitor for Prochymal^®. Panel members provided verbal declarations of their affiliations and interests at the beginning of the meeting. These declarations had been previously provided in writing to BGTD on the Affiliations and Interests Forms.

Health Canada provided a presentation on its assessment of the New Drug Submission for Prochymal^® based on the review of the supporting quality and clinical data submitted by the drug manufacturer. A summary of study 280 and the study 275 (which is considered pivotal), the efficacy and safety analyses, the issues and questions identified during the review were presented.

A Principal Investigator for Prochymal^® provided an overview of graft versus host disease (GvHD) and the continuum of care for a patient with refractory acute GvHD. Osiris Therapeutics Inc. presented on the clinical trial design, patient population, and treatment plan of the studies 275 and 280. The differences in severity of acute GvHD in the patients enrolled in protocol 275 versus protocol 280 were discussed. In addition, the overall response efficacy results for studies 275 and 280 were presented. The Medical Monitor for Prochymal^® provided an overview on the clinical safety of the drug. Another Principal Investigator presented the risk management plan developed by Osiris Therapeutics for the post-market pharmacovigilance and surveillance of Prochymal^®. At the end of the presentations, Health Canada and Osiris Therapeutics answered questions from the panel members.

The panel discussed the questions posed by BGTD; the panel discussion was attended only by Health Canada representatives. The following are the Expert Advisory Panel's advice and recommendations on the questions.

Question 1: The submission for Prochymal^® rests on a small number of children: Are the studies as reported adequate to arrive at a decision on the efficacy and safety (benefits vs. risks) for Prochymal^® as a cell therapy in the treatment of acute GvHD?

a. Is the series of children adequate to define the efficacy of Prochymal^®?

Panel Discussion:

The panel noted that severe Grade D GvHD is an extremely serious disease that affects a very small patient population. A few panel members have seen in their clinical experience how pediatric patients dramatically responded to treatment with Prochymal^®. However, this positive anecdotal evidence is not adequately reflected in the efficacy data.

The panel further noted that there is very limited efficacy data; the data is suggestive but not definitive with respect to efficacy. There is a very small post-hoc analysis (in children) from a randomised trial, protocol 280 that demonstrated a small change in effects between the Prochymal^® arm and the placebo arm. In addition, protocol 275 is a cohort study for severe refractory GvHD with limited efficacy endpoints and vague inclusion criteria. In protocol 275, the survival probability through 180 days post onset of acute GvHD in refractory Grade D pediatric patients is 56.2% for the Prochymal^® group and 31.0% for the historical control group. From a clinical perspective, this is a positive effect; however, it is not a conclusive indication of efficacy.

The panel commented that Phase IV protocol 295 should be opened to international enrolment in order to increase the number of pediatric patients. According to the Center for International Blood and Marrow Transplant Research (CIBMTR) website, over 4,000 allogenic bone marrow transplants are registered in the database per year in pediatrics.

Based on this number, it is reasonable to expect that approximately 500 pediatric patients per year will be eligible to enrol in protocol 295. Thus, protocol 295 should be able to provide within a reasonable timeframe (4 - 5 years) confirmatory efficacy results for Prochymal^®.

On the other hand, given the complexity of the transplant field, how ill these patients are, and the many competing risks these patients suffer from, it is challenging to determine the baseline level of death or debility from GvHD and use it as a benchmark of comparison with Prochymal^®. Comparing registry data from protocol 295 to retrospective registry data from CIBMTR will not likely generate answers on the drug's efficacy. A registry of patients treated with Prochymal^® should be established and maintained to monitor safety, but it will not provide robust data on efficacy.

The panel discussed the issues of determining the efficacy of Prochymal^® at length. Given the limited efficacy data, it was challenging for the panel to draw definitive conclusions on the drug's efficacy. There were different views on the level of efficacy; most of these differences resulted from personal clinical experiences that panel members have had with either Prochymal^® and/or the standard of care in their transplant centres.

The options for obtaining further efficacy data, as discussed by the panel are summarized below.

Option 1:

A randomised controlled trial between the best standard of care (control) and Prochymal^® should be conducted in adults and children at the same time. Due to the low incidence of severe refractory GvHD in children, there will not be sufficient patients enrolled in a randomised controlled trial. However, assuming that the disease is the same in adults and children, the trial can be opened to adult enrolment as well. The data can then be analysed for the pediatric population or independent of the age of the patients.

Option 2:

A proper case-controlled study with concurrent or historical controls should be carried out. A 1:1 match does not require an exact match on all factors. The relevant factors to be considered are: gender, age, race, regimen that was given, and the type of GvHD. Exact age matching might not be required, so an age range could be used, such as matching within: 0 to 6 months, less than 3 years, 4 to 7 years, etc. The goal is not to find perfect matches, but to find matches that make biological sense and produce reasonably comparable groupings for new patients that will be entered in the post-market protocol 295. A statistical analysis can adjust for other factors that have prognostic importance but were not matched on.

The panel would like the company to submit a clear comprehensive explanation of why 1:1 matching cannot be implemented prospectively by peer-matching. In addition, all recommendations from the panel concerning the confirmatory post-market protocol 295 described in Option 2 should be considered when developing the study proposal in the Letter of Undertaking of the NOC/c.

Panel Recommendations:

The panel commented that the NOC/c is a very innovative approach to authorize a drug into the market safely and determine its broader efficacy for a severe disease that affects a very small population. The data for Prochymal^® is limited but the panel deemed it acceptable to demonstrate that the drug is safe and most probably effective.

As a NOC/c commitment, the panel recommends that Osiris Therapeutics Inc. develop a strong clinical trial design that will demonstrate efficacy of Prochymal^® in the pediatric or steroid refractory GvHD population. This could take the form of either a randomised clinical trial comparing Prochymal^® versus the best standard of care (Option 1) or a proper case control study with appropriately matched concurrent or historical controls (Option 2). Osiris Therapeutics must commit to provide substantial data that show statistical significance in the efficacy of Prochymal^® in a GvHD patient population that is steroid refractory. Osiris Therapeutics must provide this data to Health Canada within a reasonable timeframe as agreed upon with Health Canada.

b. Is there adequate information to define the safety of the product?

Panel Discussion & Recommendation:

The panel noted that the data on Prochymal^® adequately define its safety, with the exception of long term safety, which is important in a pediatric population.

The panel recommended that Osiris Therapeutics Inc. develop a formal long term registry to monitor the safety of Prochymal^®. In specific cases where patients are autopsied, a screening of lungs should be done to look for the potential presence of residual Prochymal^® cells.

Question 2: Based on the clinical studies as presented:

a. What is the most appropriate timing for initiating treatment with Prochymal^® in acute GvHD in the pediatric population?

Panel Discussion & Recommendation:

The definition of "most appropriate time for treatment" varies in practice from one transplant centre to another. Generally, high-dose steroids are given to patients diagnosed with GvHD. The patient is assessed after five days; if there is progression of the disease or the patient is non-responsive to steroids, the 2^nd line treatment is initiated at day 6 to day 7. Protocol 280 demonstrates that treatment with Prochymal^® should be given within 14 days of failure to respond to steroids.

The panel recommended that Prochymal^® should be available as a 2^nd line treatment to a patient with steroid refractory GvHD within 14 days of failing steroids. Prochymal^® may be used for Grades C and D acute GvHD of any organ (including skin) and for Grade B acute GvHD involving any visceral organ (includes gastrointestinal tract, liver but excludes skin involvement).

b. What age ranges should be considered for therapy? Should this be for the full age range proposed by Osiris?

Panel Discussion & Recommendation:

The panel agreed with the age range of pediatric patients up to 18 years as proposed by Osiris Therapeutics Inc. The panel recommended that Osiris be encouraged to establish a Special Access Program for adult patients as a means to collect data for GvHD cases in adults.

c. Are there any special considerations for starting and discontinuing therapy where the experience of the panel can add to the considerations for Dosage and Administration?

Panel Discussion & Recommendation:

The panel agreed with the dosage proposed by Osiris Therapeutics: 2 × 10⁶hMSC/kg body weight administered intravenously. Pre-medications may be given to patients to minimize infusional reactions for this type of product as it contains dimethyl sulfoxide (DMSO).

d. What are the long-term considerations in terms of the efficacy of Prochymal^®?

Panel Discussion & Recommendation:

In terms of efficacy, the panel recommended a one year follow up beyond the timeframe where patients convert from acute GvHD to chronic GvHD. The panel also recommended the following to be added to the Warnings section of the product monograph: "The long term effects of Prochymal^® in growing children are unknown."

Question 3: Concerning the safety of Prochymal^®:

a. What considerations would the panel wish to include in defining the profile of Prochymal^®?

Panel Discussion & Recommendation:

If Health Canada grants a NOC/c for Prochymal^®, the panel made a strong recommendation to limit the distribution of this product to only the pediatric blood and marrow transplant centres in Canada. This limited distribution should be in place as long as the only indication for the use of Prochymal^® is acute steroid refractory GvHD in children. This approach will limit the off-label use of this product for other diseases where mesenchymal stem cells (MSCs) are being studied but where their safety and efficacy have not yet been proven.

If Prochymal^® is authorized, the panel was of the opinion that there will be a strong desire in the general patient population to use this drug very broadly for indications that are not even remotely connected to treatment of GvHD. Given the extent of stem cell tourism, the general public may put pressure on their physicians to prescribe this drug for off-label uses such as myocardial infarction, diabetes, multiple sclerosis and other more controversial uses such as autism, dementia, genetic development abnormalities, where it could cause harm.

There are many other diseases where MSCs have been considered as an alternative therapy. These illnesses have more appropriate treatments or treatments with a known efficacy and safety profile. The risk-benefit ratio is not in favour of a drug without documented efficacy. Acute GvHD is such a devastating illness that the risk-benefit ratio would be acceptable even with the current efficacy data.

For the above reasons, the panel strongly advised that this limited distribution condition must be agreed to by the sponsor before Prochymal^® could be granted a NOC/c. The panel recommended that Health Canada explore regulatory options under its authority to place this condition under the NOC/c commitments.

b. What is the actual or perceived (real or theoretical) risk for tumorigenicity from mesenchymal cell therapy?

Panel Discussion

The panel commented that the short-term data from Prochymal^® does not demonstrate a risk of ectopic tissue formation from mesenchymal cell therapy.

c. What are the considerations for longer-term follow-up in relation to the safety of the product?

Panel Discussion & Recommendation:

In terms of safety, the panel recommended a long term registry that would monitor the patients for 15 years follow up or until the patient reaches 30 years of age (whichever one comes first). Tumour monitoring could be part of this registry.

d. What are the long-term outcomes that need to be monitored?

Panel Discussion & Recommendation:

From a post-market surveillance perspective, the areas that Health Canada should specifically focus on are: tumourigenicity, the occurrence of unusual infections or an increase in the number of infections, and the presence of Prochymal^® in autopsy or biopsy specimens.

In the proposed post-market protocol 295, a CT scan should be carried out for each patient at baseline and one at the time at which the primary endpoint is measured.

In addition, the sponsor needs to clarify the following: In the assessment of biopsies for the presence of third party markers, how far beyond 18-days post-infusion was this assessed? How many patients were assessed?

Question 4: Please outline any specific or special considerations for the labelling of the product.

Panel Discussion & Recommendation:

The panel proposed a revised version of the company's indication for Prochymal^®.

"Prochymal^® is indicated in the management of acute GvHD in pediatric patients. Acute GvHD or the disease should be refractory to treatment with systemic corticosteroid therapy and/or other immunosuppressive agents.

Prochymal^® may be used for Grades C and D acute GvHD of any organ (including skin) and for Grade B acute GvHD involving any visceral organ (includes gastrointestinal tract, liver but excludes skin involvement)."

The data from protocol 275 should be included in the product monograph. This is preliminary data that will be confirmed in a post-market confirmatory trial.

Report submitted by the Expert Advisory Panel on Prochymal^®