Ryoncil: ODAC/FDA Meeting Discussion, page-1057

Fourth Speaker Afternoon Session: Dr Grossman

“We agree with that they conclusion that results in study 0014 specifically significant, the response was durable and the results were consistent across subpopulations and secondary endpoints”

“We also agree with the FDA that there were no safety signals of concern identified in the studies of really stem cells and that there were no remarkable differences between Remi stem cells and Siebel.”

“Let me share learnings from the two randomized controlled trials that did not meet their primary end points."

Protocols 65 and 280 role primarily adult patients.

Additionally the primary endpoint in both studies were different than study 001.

“In May of 2009 scientifically leaders discussed acute GvHD clinical trial endpoints at the NIH FDA public workshop.

They concluded that day 28 overall response was a valid efficacy outcome trials of acute GvHD treatment. Additionally several studies have demonstrated day 28 overall response is highly correlated with long-term survival.”

“When we looked at the prespecified analysis of the pediatric population using day 28 overall response we saw a signal of efficacy.”

“While the sample sizes is small the analysis provided a signal of potential efficacy and survival with Remi stem cell in children with severe steroid refractory acute GvHD.”

“Based on these findings expanded access protocol 275 continue to enroll pediatric patients.”

“Expanded access protocol 275 represents a real-world population with the most severe patients who failed to respond to multiple lines of additional therapy.”

The survival rate in responders was 82% compared to 38% in nonresponders.

These clinical meaningful results in learning from study 280 informed the design of pivotal study 001 in children with steroid refractory acute GvHD .

Based on advice from the FDA trial 001 eliminated potential confounding from all other agents by excluding additional treatment other than steroids during the first 28 days.

Additionally there is agreement on the inclusion exclusion criteria, disease severity and study endpoints.

Moving to pivotal study 001 and 002 as noted earlier we agree with the FDA conclusion of study 001

That there was a statistically significant, measured response was durable, and the results were consistent across subpopulations and secondary efficacy endpoints.

The FDA considers single arm trials support for marketing approval in instances where there are no available therapies that would be considered standard of care.

Anywhere the effect of response is presumed to be attributable to the investigational product.

We have already established that there are no available therapies that would be considered standard of care.

I

I will begin to by describing the appropriate external controls that justify and validate the hypotheses used for the 001 pivotal trial.

As the FDA briefing states external appropriate controls can be a group of patients treated at an earlier time or during the same time period but in another setting.

We use the international conference on harmonization guide to identify the appropriate external controls using similar baseline characteristics between the controls and the study patients.

Was also essential that the standard of care used in the control cohort included freedom for the physician to choose alternative therapies to align with study 001 design potential control cohort in this patient populations.

The top three are most relevant because patients were treated first line after steroids.

The studies use the same primary endpoints as the pivotal study 001 and allowed use of best available therapies. The three cohorts on the bottom tested single experimental agents and had very endpoints

All three external controls justify and validate the 45% null hypothesis used in study 001.

External cohorts of studies to determine controls range from 34% to 45%.

All three of these external cohorts aligned with the patient population in study 001 and are appropriate controls that justify a no hypothesis of 45% used in study 001.

Study 001 was a Phase 3 single ARM open label trial intended to show significant increases in day 28 overall response attribute to any stem cell as initial second line therapy following steroids.

55 children between two months and 17 years of age with acute GVHD grace [ Indiscernible ] enrolled in the study

Eligible patients received Remi stem cell twice per week for four consecutive weeks and for response at day 28.

At that point patients who had a complete response or no response stopped receiving Remi stem cell but continued assessments.

A new 100 mark the end of study 001 in the beginning of study 00 two for patients who continued into the extension through 180 days.

The primary endpoint was overall response rate.

Defined as complete or partial response at the 28.

Response category was evaluated based on improvement in symptoms of rash, just systems of diarrhea and [indiscernible].

The key secondary endpoint was overall survival at a 100.

Study 002 was primarily a safety studies looking at adverse events and survival through Day 180 as well as duration of response.

Of the 55 patients who enrolled in study 001 54 were treated with Remi stem cells.

For the patients were 74% completed the study alive.

32 of the 40 eligible patients from study 001 enrolled in study 002 and 97% completed to date 180.

We were able to gain vital status to a 180 for all but two of the 54 patients treated in study 001.

Study 001 met the primary endpoint was 70% response at the 28 day

As the FDA points out duration of response is an important consideration to the clinical meaningfulness of response outcomes in a single arm trial.

With the knowledge there are differences and how this can be calculated but we agree with the FDA that Remi stem cell provided a durable response when looking at our calculations or any of the Relation used by the FDA.

Conclusion:

the data demonstrate that the effect of the clinical response is attributable to remestemcel-L

The primary endpoint of day 28 overall response is study 001 was statistically significant

The FDA is asking how to interpret the positive results from studies 001 amongst the context of other remestemcel-L studies. “let's review the relationship between manufacturing enhancements and the GvHD studies.

We will focus the subsequent analysis of manufacturing enhancements and clinical outcomes the studies of just steroid refractory acute GV HG which include 280, 275 and 001.

Phase 3 study showed increase in product TNFR1 due to optimized product”

/ Basically, after the company optimized the product, survival rates sky-rocketed. This is revealed in one quarted of EAP 275 and the entirety of 001. /

“I would like to go back to the criteria in FDA's guidance for singlearm trial to support approval.”

“We have shown you that Remestemcel meets the criteria.”

“there are no available therapies that would be considered standard of care in children and shown that the effective date 28 overall response is attributable to remestemcel”

“The totality of data demonstrate substantial evidence of efficacy as a board approval of Remi stem cell for children suffering the steroid refractory acute GvHD who urgently need a treatment to increase survival.”

“about two weeks ago we held an advisory board meeting with global experts in adult GvHD to discuss potential trial design to provide robust and clinical meaningful and useful data.”

“Planning is underway for a randomized control of Remi stem cells versus standing of care that is showing improved response and survival.”

“We will focus on adults with a continued high unmet need despite approval therapy for who have not responded to existing therapy.”