Remestemcel-L-Rknd

1 INDICATIONS AND USAGE RYONCIL is indicated for the treatment of steroid refractory acute graft versus host disease (SR-aGvHD) in pediatric patients 2 months of age and older. RYONCIL is an allogeneic bone marrow-derived mesenchymal stromal cell (MSC) therapy indicated for the treatment of steroid-refractory acute graft versus host disease (SR-aGvHD) in pediatric patients 2 months of age and older.

2 DOSAGE AND ADMINISTRATION For intravenous use only. For intravenous use only. The recommended dosage of RYONCIL is 2 × 10 6 MSC/kg body weight per intravenous infusion given twice per week for 4 consecutive weeks. Infusions should be administered at least 3 days apart. Assess response 28 ± 2 days after the first dose and administer further treatment as appropriate as described in the table below. Recommended Treatment Based on Day 28 Response Response Recommendation Complete Response (CR) No further treatment with RYONCIL Partial or Mixed Response Repeat administration of RYONCIL once a week for additional 4 weeks (4 infusions total) No Response Consider alternative treatments Recurrence of GvHD after CR Repeat administration of RYONCIL twice a week for an additional 4 consecutive weeks (8 infusions total) 2.1 Recommended Dosage The recommended dosage of RYONCIL is 2 × 10 6 mesenchymal stromal cells (MSC)/kg body weight per intravenous infusion given twice a week for 4 consecutive weeks for a total of 8 infusions. Administer infusions at least 3 days apart. Assess response 28 ± 2 days after the first dose and administer further treatment as appropriate as described in Table 1 based on Day 28 response. Table 1: Recommended Treatment based on Day 28 Response Response Recommendation Complete Response No further treatment with RYONCIL Partial or Mixed Response Partial response defined as organ improvement of at least one stage without worsening in any other organ, whereas mixed response was defined as improvement of at least one evaluable organ with worsening in another organ as per International Blood and Marrow Transplantation Registry Severity Index Criteria grading system. Repeat administration of RYONCIL once a week for additional 4 weeks (4 infusions total) No Response Consider alternative treatments Recurrence of GvHD after complete response Repeat administration of RYONCIL twice a week for an additional 4 consecutive weeks (8 infusions total) 2.2 Preparation and Administration Instructions Receipt and Storage of RYONCIL RYONCIL is shipped directly to the clinical facility in a liquid nitrogen dry shipper maintained at a temperature of ≤ -135°C. RYONCIL must remain frozen at ≤ -135°C in liquid nitrogen vapor phase until thawed immediately prior to administration [see How Supplied/Storage and Handling (16) ] . Preparation RYONCIL and Plasma-Lyte ® A should be prepared following aseptic technique in a Biological Safety Cabinet (BSC). Spray and wipe down the following materials with 70% alcohol prior to transferring them into the BSC preparation area. All materials should remain in the BSC preparation area unless discarded. Prepare a sterile water bath to a minimum depth of 4 inches and warm to 37°C (± 2°C) at least 30 minutes prior for thawing. Supplies needed for preparation of RYONCIL and Plasma-Lyte ® A RYONCIL vials Plasma-Lyte ® A Infusion bag Interlink blood bag spikes (2) Interlink threaded lock cannula (1 per syringe) 60 mL luer-lock syringe (1) 5 mL luer-lock syringe (1 per each thawed vial) 18-gauge needle (1 per each thawed vial) Note: Use a 1mL syringe if volume to be removed from vial is less than 1mL Airtight zip seal plastic bag(s) (1 per each vial for thaw) Water bath Alcohol wipes Note: Plasma-Lyte ® A may be substituted by Plasma-Lyte ® 148 (pH 7.4 with no glucose). Preparation of Plasma-Lyte ® A 1- Insert the Interlink blood bag spike into the Plasma-Lyte ® A bag. 2- Aseptically attach the threaded lock cannula to a 60 mL syringe. 3- Use an alcohol wipe to scrub the membrane of the Plasma-Lyte ® A bag interlink spike injection site. 4- Attach the threaded lock cannula/syringe assembly to the Plasma-Lyte ® A bag to the injection site. 5- Measure and withdraw 40 mL of Plasma-Lyte ® A from the bag Note: DO NOT remove the syringe containing Plasma-Lyte ® A from the Plasma-Lyte ® A bag. Set aside for later use. Preparation of RYONCIL 1. Prior to RYONCIL thaw, verify that the pre-arranged time for the RYONCIL administration is still feasible. Patient infusion must occur within 5 hours from the start time of first vials of RYONCIL thaw. 2. Remove RYONCIL vial(s) from cryo-storage. 3. Place vial(s) into an airtight zip seal plastic bag(s) and immerse closed bag(s) into the water bath (37ºC), maintaining the top closure above the water line. Use a separate zip seal plastic bag for each vial of RYONCIL. Note: A maximum of 4 vials can be thawed in the water bath at the same time. 4. To thaw, gently agitate the sealed zip seal bag(s) with the vial(s) for approximately 5 to 8 minutes to thaw. 5. Remove vials from the water bath prior to the last visible crystal of ice melting. Note: Do not exceed 15 minutes for each set of four vials. 6. Inspect vial(s) while still in the bag(s) to identify there is no leakage of vial contents. 7. Remove the RYONCIL vial(s) from the sealed plastic bag(s). 8. Inspect for foreign particulate matter (FPM). If FPM is found via visual inspection – DO NOT USE! Retain the offending vial(s). Call the Mesoblast contact number 844-889-MESO (6376). 9. Remove the tab from the RYONCIL vial cap to expose the vial stopper and wipe the exposed surface of the stopper with one provided sterile alcohol wipe. 10. Promptly withdraw the required amount of RYONCIL (based on actual patient body weight) from the vial(s). One syringe and an 18-gauge needle per thawed vial is required. 11. Carefully remove the needle from the syringe containing RYONCIL. 12. Attach the threaded lock cannula to the syringe. 13. Retrieve the infusion bag. 14. Wipe the membrane of the infusion bag interlink spike injection site with sterile alcohol wipe. 15. Insert 1 interlink blood bag spike into the outermost port on the infusion bag (leave the middle port for the infusion line.) 16. Attach the syringe to the spike and transfer the RYONCIL into the infusion bag. 17. Remove the syringe with the threaded lock cannula and discard the syringe and the threaded lock cannula. 18. Repeat for each syringe until the required volume of RYONCIL is added to the infusion bag. Transfer of Plasma-Lyte ® A into Infusion Bag 1. Retrieve the bag and 60 mL syringe containing Plasma-Lyte ® A. 2. Verify the syringe contains 40mL of Plasma-Lyte ® A. 3. Aseptically remove the 60 mL syringe with the threaded lock cannula containing the 40mL Plasma-Lyte ® from the bag of Plasma-Lyte ® A. 4. Use alcohol wipes to clean the membrane of the infusion bag interlink spike injection site. 5. Aseptically attach the 60mL syringe containing the Plasma-Lyte ® A to the spike. 6. Slowly transfer the 40mL Plasma-Lyte ® A into the infusion bag. 7. Gently mix cells with the Plasma-Lyte ® A. 8. Remove the syringe with the threaded lock cannula and discard the syringe and threaded lock cannula. 9. Label the bag according to Institutional Policy. 10. Transport infusion bag to patient infusion area. Administration Note: Patient infusion must occur within 5 hours from the start time of first vial(s) of RYONCIL thaw. Administer RYONCIL under the supervision of a qualified health professional experienced in the management of SR-aGvHD. Administer RYONCIL using an infusion pump. Use blood filter with a pore size of 40-260 microns for infusion of RYONCIL. Flush lines per institutional practice and/or policy for cellular infusions. Pretreatment Premedicate patients with corticosteroids and antihistamines 30-60 minutes prior to administration of RYONCIL to reduce the potential for infusion reactions. Infusion Rates For patients weighing 35 kg or more, infuse RYONCIL at a rate of no more than 6mL/ minute. For patients weighing less than 35 kg, infuse RYONCIL over the course of 60 minutes. Discard unused, thawed RYONCIL vials per institutional policy.

6 ADVERSE REACTIONS The most common non-laboratory adverse reactions (incidence ≥20%) are: viral infectious disorders, bacterial infectious disorders, infection – pathogen unspecified, pyrexia, hemorrhage, edema, abdominal pain and hypertension ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Mesoblast at toll-free phone #1-844-889-MESO (6376) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The safety data described in this section reflect exposure to RYONCIL in 54 patients in Study MSB-GVHD001 for the treatment of SR-aGvHD. Patients received intravenous infusion of RYONCIL at a dosage of 2 x 10 6 MSCs/kg twice a week for four consecutive weeks, for a total of eight infusions. Patients with partial or mixed response at Day 28 received additional infusions of RYONCIL 2 x 10 6 MSCs/kg once a week for an additional four weeks [see Clinical Studies (14) ] . The median number of doses administered were 10 (range 1 to 16), and the treatment was administered over a median of 43 days (range 1 to 104 days). Serious adverse reactions occurred in 35 patients (65%) including pyrexia (n=5;9%), respiratory failure (n=5;9%), pneumatosis intestinalis (n=4;7%) and staphylococcal bacteremia (n=2;<5%). Eight patients had discontinuation of RYONCIL treatment due to the following: acute infusion reactions (n=3), hypotension (n=1), gastroenteritis (n=1), and death (n=3). Table 2 summarizes most common adverse reactions that occurred in ≥10% patients in Study MSB-GVHD001. Table 2: Adverse Reactions** Occurring in ≥10% of Patients in Study MSB-GVHD001 (N=54) a Based on National Cancer Institute Adverse Event Common Toxicity Criteria version 4.03 b No grade 4 or 5 adverse reactions occurred in the study *Is a composite that includes multiple related terms **Includes adverse reactions up to 100 days following RYONCIL treatment Adverse Reactions All Grades a n (%) Grade 3 b n (%) Viral infectious disorders* 30 (56) 8 (15) Bacterial infectious disorders* 24 (44) 10 (19) Infections - pathogen unspecified* 22 (41) 8 (15) Pyrexia 19 (35) 2 (4) Hemorrhage* 15 (28) 4 (7) Edema* 12 (22) 1 (2) Abdominal pain 11 (20) 4 (7) Hypertension 11 (20) 3 (6) Vomiting 10 (19) 3 (6) Arrhythmia* 9 (17) 2 (4) Diarrhea 9 (17) 1 (2) Rash* 9 (17) 0 (0) Arthralgia 8 (15) 0 (0) Fungal infectious disorders* 8 (15) 2 (4) Hypotension 8 (15) 2 (4) Cough 7 (13) 0 (0) Respiratory Failure 6 (11) 6 (11) Table 3 presents the most common grade 3 or 4 laboratory abnormalities that worsened from baseline in ≥10% of patients Table 3: Grade 3 or 4 Laboratory Abnormalities that Worsened from Baseline in ≥ 10% of Patients in Study MSB-GVHD001 (N=54) Laboratory Parameter Grade 3 or higher a % a Based on National Cancer Institute Adverse Event Common Toxicity Criteria version 4.03 Gamma-glutamyl transferase increased 32 Thrombocytopenia 28 Blood bilirubin increased 11

12.3 Pharmacokinetics No studies have been performed to evaluate the pharmacokinetics of RYONCIL.