banter and General Discussion, page-11050

Just A Few Reasons for Confidence/Optimism Regarding Mesoblast’s GVHD Treatment Approval. Let’s hope it’s sooner than later.

1. FDA Protocol Changes: The FDA initially approved Mesoblast’s trial protocol but later requested a second trial, despite the first meeting its primary endpoint.

2. Current Treatment Limitations: The existing treatment, Ruxolitinib (RUX), has flawed 28-day endpoints that do not correlate with long-term survival.

3. High Non-Response and Adverse Events with RUX: RUX demonstrated a 60% non-response rate by Day 56 and significant adverse events in severe cases.

4. Trial Population Differences: Mesoblast’s trial focused exclusively on severe cases, while RUX included lower-risk patients, potentially skewing RUX’s results.

5. Limited Long-Term Survival with RUX: RUX showed minimal differences in 12-month survival compared to the Best Available Therapy, indicating limited long-term efficacy.

6. Shorter Endpoints Recommended: Research from the MAGIC Consortium suggests that shorter endpoints, such as 14 days, may better reflect outcomes in severe acute GVHD (SR-aGVHD).

7. Manufacturing Readiness: Mesoblast successfully passed an FDA Pre-Approval Inspection (PAI) in Singapore, demonstrating consistent production capabilities for commercial use.

8. Poor Outcomes for RUX-Refractory Patients: Real-world data indicate dismal outcomes for patients who do not respond to RUX, with median survival as low as 28 days.

9. Impact of FDA Delays: Delays in FDA approval are likely contributing to preventable deaths in severe GVHD patients. Meanwhile, remestemcel-L has been used under compassionate use programs at a high cost to the company.

10. Support from Clinicians and Advisory Panels: Mesoblast’s product has received support from clinicians and the FDA’s ODAC Advisory Panel, acknowledging its efficacy and addressing unmet medical needs.

11. Approval in Japan: The treatment is already approved in Japan, showcasing clinical success and providing real-world validation.

12. Global Recognition: International approvals, particularly in Japan, bolster the safety and efficacy data for Mesoblast’s product.

13. Long-Term Benefits in Japan: Data from Japan confirm long-term survival benefits, strengthening the case for FDA approval in the U.S.

14. Pediatric Success: The treatment has shown significant benefits for pediatric patients with GVHD in Japan, addressing a critical need.

15. Strong Mechanism of Action: Mesoblast’s mesenchymal stem cells (MSCs) effectively modulate immune responses and reduce inflammation, targeting SR-aGVHD.

16. Efficacy in Multi-Organ GVHD: The product has demonstrated efficacy in treating multi-organ involvement in GVHD, a challenge for existing therapies.

17. Need for Effective Treatments: There are limited effective options for severe SR-aGVHD, making Mesoblast’s therapy a crucial addition.

18. FDA Urgency for Unmet Needs: The FDA aims to expedite treatments for high unmet medical needs, aligning with Mesoblast’s therapy for SR-aGVHD patients.

19. Potential for Combination Therapy: Mesoblast’s treatment may be combined with other therapies, improving outcomes for patients unresponsive to current treatments.

20. Improved Quality of Life: Beyond survival, Mesoblast’s product can enhance quality of life by alleviating severe GVHD symptoms.

21. Regulatory Expertise on Board: Philip R. Krause, M.D., joined Mesoblast’s Board of Directors in 2022, bringing valuable regulatory experience to guide the company’s FDA interactions.

Best of luck to all Shareholders