remestemcel-L

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.

12.1 Mechanism of Action The mechanism of action for RYONCIL is not clear but may be related to immunomodulatory effects. Data from in vitro studies demonstrate that MSCs inhibit T cell activation as measured by proliferation and secretion of pro-inflammatory cytokines. Acute GvHD occurs when alloreactive donor-derived T cells within the donated tissue (graft) trigger an immunological response, and alloreactive donor-derived T cells play a role in mediating the systemic inflammation, cytotoxicity and potential end organ damage associated with aGvHD.

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 a

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

5 WARNINGS AND PRECAUTIONS Hypersensitivity/Acute Infusion reactions : Monitor for hypersensitivity reactions during infusion and premedicate with corticosteroids and antihistamines. ( 5.1 ) Transmission of Infectious Agents: RYONCIL may transmit infectious agents. ( 5.2 ) Ectopic Tissue Formation: Ectopic tissue formation may occur following treatment with RYONCIL. ( 5.3 ) 5.1 Hypersensitivity and Acute Infusion Reactions Hypersensitivity reactions including acute infusion reactions have occurred with RYONCIL administration [see Adverse Reactions (6.1) ] . Serious hypersensitivity reactions, including anaphylaxis, may occur due to DMSO and trace amounts of porcine or bovine proteins. Signs and symptoms may include fever, dyspnea, and hypotension during or after RYONCIL infusion. Premedicate patients with antihistamine and corticosteroids and monitor closely for signs and symptoms of hypersensitivity or acute infusion reactions. If a hypersensitivity or infusion reaction occurs, interrupt RYONCIL infusion. Do not administer RYONCIL in patients who experience serious or life-threatening reactions. 5.2 Transmission of Infectious Agents Transmission of infectious disease or agents may occur with RYONCIL administration because it contains cells from human donors and is manufactured using human, porcine and bovine-derived reagents. Donors are screened and tested for Human Immune-deficiency Virus 1 (HIV-1); Human Immune-deficiency Virus 2 (HIV-2); Hepatitis B Virus (HBV); Hepatitis C Virus (HCV); Human T-cell Leukemia-lymphoma Virus 1 (HTLV-1); Human T-cell Leukemia-lymphoma Virus 2 (HTLV-2); West Nile Virus (WNV); Cytomegalovirus (CMV); Epstein-Barr Virus (EBV); and Syphilis ( Treponema pallidum ). Only screening was performed for Creutzfeldt-Jakob disease (CJD) and communicable disease risks associated with xenotransplantation. RYONCIL cell banks are tested for human and animal viruses, retroviruses, bacteria, fungi, yeast, and mycoplasma. Human and animal-derived reagents are tested for human and animal viruses, bacteria, fungi, and mycoplasma before use. These measures do not eliminate the risk of transmitting these or other infectious diseases or agents. 5.3 Ectopic Tissue Formation Ectopic tissue formation may occur following treatment with RYONCIL due to the ability of human mesenchymal stromal cells to differentiate into mesenchymal lineage cells such as bone, cartilage and fat cells.

4 CONTRAINDICATIONS Do not use RYONCIL in patients with known hypersensitivity to dimethyl sulfoxide (DMSO) or porcine and bovine proteins. Known hypersensitivity to dimethyl sulfoxide (DMSO) or Porcine and Bovine proteins. ( 4 )