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.

For intravenous use only.

RYONCIL is available as a cell suspension for intravenous infusion in a target concentration of 6.68 X 106 MSCs per mL in 3.8 mL at cryopreservation contained in a 6 mL cryovial.

Each 6 mL cryovial contains approximately 25 x 106 MSCs.

Cryopreserved MSCs are combined with Plasma-Lyte® A for administration.

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

RYONCIL is provided as a frozen cell suspension in a cryogenic vial. The active ingredient in RYONCIL is comprised of culture-expanded mesenchymal stromal cells (MSCs) isolated from the bone marrow of healthy human adult donors. Each cryovial contains nominally 25 x 106 MSCs in 3.8 mL (a target concentration 6.68 x 106 cells/mL) formulated in Plasma Lyte®-A (70% v/v), Human Serum Albumin (HSA) Solution (25%) (20% v/v) and Dimethyl sulfoxide (DMSO) (10% v/v). The product is thawed and combined with Plasma-Lyte® A prior to intravenous administration.

The efficacy of RYONCIL was evaluated in a multicenter, prospective, single-arm study (MSB-GVHD 001; NCT02336230). The study enrolled pediatric patients with SR-GvHD Grade B to D (excluding Grade B skin alone) as per International Blood and Marrow Transplantation Registry Severity Index Criteria (IBMTR) after receiving allogeneic hematopoietic stem cell transplantation (HSCT). SR-aGvHD was defined as aGvHD that progressed within 3 days or did not improve within 7 consecutive days of treatment with methylprednisolone 2 mg/kg/day or equivalent. Patients who received a second line therapy for aGvHD prior to screening were excluded.

RYONCIL was administered by intravenous infusion at a dosage of 2 x 106 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 106 MSCs/kg once a week for an additional four consecutive weeks. Patients with complete response at Day 28 who experienced recurrence of aGvHD received infusions of RYONCIL 2 x 106 MSCs/kg twice a week for an additional four consecutive weeks.

A total of 55 patients were enrolled, and 54 were treated with RYONCIL. Among the treated patients (n=54), the demographic characteristics were as follows: median age was 7 years (range: 7 months to 17 years); 36% were females; 56% were White, 19% reported “other” race, 15% were Black, 6% were Asian, 6% American Indian or Alaska Native, 33% were Hispanic and 65% were non-Hispanic. Among enrolled patients, hematologic malignancies (67%) and non-malignant diseases (33%) were the underlying reasons for allogenic HSCT. SR-GvHD severity was as follows at baseline: Grade B (11%), Grade C (43%), Grade D (46%). Organ involvement at baseline were as follows: skin alone (26%), lower gastrointestinal tract only (39%), multi-organ involvement (35%). The median duration of prior corticosteroid treatment at baseline was 8 days (range: 2 to 46 days).

The main efficacy outcome measures were Day-28 overall response rate (complete response rate and partial response rate) and the duration of response.

The efficacy results are summarized in Table 4.

Overall response rate at Day 28 by baseline disease severity is as follows: Grade B (3/6; 50%), Grade C (16/23; 70%), and Grade D (19/25; 76%).

Among the 38 responders, the median time from Day-28 response to either death or need for systemic therapy for aGvHD (non-RYONCIL systemic therapy for aGvHD or increase in the dose of corticosteroids to methylprednisolone 2 mg/kg or equivalent) was 111.5 days (range 9, 182+).

RYONCIL is supplied as a sterile, cryopreserved cell suspension of ex-vivo culture-expanded allogeneic bone marrow-derived mesenchymal stromal cells (MSC) in vials.

RYONCIL is provided as a customized kit to meet dosing requirements for a single dose for each patient [see Dosage and Administration (2.1)], with each kit containing:

• Cartons containing sufficient RYONCIL for one infusion based on the patient weight (see Table 5)
• Sufficient alcohol wipes for preparation of the RYONCIL infusions.

Kit sizes and National Drug Codes (NDC) are provided in Table 5.

RYONCIL is shipped to the clinical facility in a liquid nitrogen dry shipper maintained at a temperature of ≤ -135°C.

Storage conditions: RYONCIL must remain frozen at ≤ -135°C in liquid nitrogen vapor phase until thawed immediately prior to administration.

Handling: Restrict preparation and administration of RYONCIL to a medical facility in which the medical personnel are trained in aseptic technique.

Disposal: Dispose empty or partially used RYONCIL vials according to the institutional guidelines for disposal of biohazard materials.

Do not save thawed RYONCIL vials for future use.

Discuss the following with patients and/or caregivers.

• Hypersensitivity and Acute infusion reactions: Inform patients and/or caregivers that hypersensitivity and acute infusion reactions due to the presence of porcine and bovine protein, and DMSO may occur with RYONCIL infusion. Advise patients and/or caregivers to seek immediate medical evaluation if any signs and symptoms of hypersensitivity or acute infusion reactions occur, such as fever, rash or hives, low blood pressure, breathing problems [see Warnings and Precautions (5.1].
• Transmission of Infectious Agents: Inform patients and/or caregivers about the possible risk of transmission of infectious agents with RYONCIL administration [see Warnings and Precautions (5.2)].
• Ectopic Tissue Formation: Inform patients and/or caregivers about the possible risk of ectopic tissue formation with RYONCIL administration [see Warnings and Precautions (5.3)].

Manufactured for:
Mesoblast, Inc.
1114 Sixth Avenue, Fourth Floor
New York, NY 10036
US License number: 2140

RYONCIL is a registered trademark of Mesoblast. All rights reserved.
©2024 Mesoblast, Inc. All rights Reserved
V 2.1

remestemcel-L-rknd

Ryoncil®

Target 25 X 106/ 3.8mL
(6.68 x 106/mL)

For intravenous administration after thaw
and resuspension
See Prescribing Information for directions for use.
Store at ≤ -135°C
Single–use vial
Discard unused portion

Manufactured for Mesoblast Inc.

Rx only

NDC 73648-154-01

remestemcel-L-rknd

Ryoncil®

Suspension for IV Infusion

Allogeneic bone marrow-derived mesenchymal stromal cells
Target 25 X 106/ 3.8mL (6.68 x 106/mL)
Single–use vial. Discard unused portion.

For intravenous administration after thaw and resuspension

Rx only
Sterile. No preservative.

NDC 73648-154-04

remestemcel-L-rknd

Ryoncil®

Suspension for IV Infusion

Allogeneic bone marrow-derived mesenchymal stromal cells
Target 25 X 106/ 3.8mL (6.68 x 106/mL)
Single–use vial. Discard unused portion.

For intravenous administration after thaw and resuspension

Rx only
Sterile. No preservative.

NDC 73648-111-01
remestemcel-L-rknd
Ryoncil®
Suspension for IV Infusion
Allogeneic bone marrow-derived mesenchymal stromal cells
Target 25 X 106/ 3.8mL (6.68 x 106/mL)

Kit for Patient Weight:
<12.5 kg

Kit Contents:
1 X single vial carton
1 Alcohol Wipe

Single–use vial. Discard unused portion.
For intravenous administration after thaw and resuspension
Rx only
Sterile. No preservative.
See Prescribing Information for directions for use.
Complete infusion within 5 HOURS of thawing and resuspension
of RYONCIL®.
Each vial contains a target of 25 x 106 cells / 3.8 mL.
Cryopreserved in: Human Serum Albumin Solution 20% v/v
(containing 5% w/v Human Serum Albumin), Plasma Lyte-A 70 %
v/v, dimethyl sulfoxide (DMSO) 10% v/v.
Contains known sensitizing substances DMSO or Porcine and
Bovine proteins (see Prescribing Information, WARNINGS AND
PRECAUTIONS).
Store at ≤- 135°C; vapor phase of liquid nitrogen
No U.S. standard of potency.

Manufactured for Mesoblast Inc.
1114 Sixth Avenue, Fourth Floor
New York, NY 10036
U.S. License number: 2140

LOT:
EXP:

PNTC-1154.024

NDC 73648-112-02
remestemcel-L-rknd
Ryoncil®
Suspension for IV Infusion
Allogeneic bone marrow-derived mesenchymal stromal cells
Target 25 X 106/ 3.8mL (6.68 x 106/mL)

Kit for Patient Weight:
12.5 kg – <25 kg

Kit Contents:
2 X single vial cartons
2 Alcohol Wipes

Single–use vial. Discard unused portion.
For intravenous administration after thaw and resuspension
Rx only
Sterile. No preservative.
See Prescribing Information for directions for use.
Complete infusion within 5 HOURS of thawing and resuspension
of RYONCIL®.
Each vial contains a target of 25 x 106 cells / 3.8 mL.
Cryopreserved in: Human Serum Albumin Solution 20% v/v
(containing 5% w/v Human Serum Albumin), Plasma Lyte-A 70 %
v/v, dimethyl sulfoxide (DMSO) 10% v/v.
Contains known sensitizing substances DMSO or Porcine and
Bovine proteins (see Prescribing Information, WARNINGS AND
PRECAUTIONS).
Store at ≤- 135°C; vapor phase of liquid nitrogen
No U.S. standard of potency.

Manufactured for Mesoblast Inc.
1114 Sixth Avenue, Fourth Floor
New York, NY 10036
U.S. License number: 2140

LOT:
EXP:

PNTC-1154.025

NDC 73648-113-03
remestemcel-L-rknd
Ryoncil®
Suspension for IV Infusion
Allogeneic bone marrow-derived mesenchymal stromal cells
Target 25 X 106/ 3.8mL (6.68 x 106/mL)

Kit for Patient Weight:
25 kg – <37.5 kg

Kit Contents:
3 X single vial cartons
3 Alcohol Wipes

Single–use vial. Discard unused portion.
For intravenous administration after thaw and resuspension
Rx only
Sterile. No preservative.
See Prescribing Information for directions for use.
Complete infusion within 5 HOURS of thawing and resuspension
of RYONCIL®.
Each vial contains a target of 25 x 106 cells / 3.8 mL.
Cryopreserved in: Human Serum Albumin Solution 20% v/v
(containing 5% w/v Human Serum Albumin), Plasma Lyte-A 70 %
v/v, dimethyl sulfoxide (DMSO) 10% v/v.
Contains known sensitizing substances DMSO or Porcine and
Bovine proteins (see Prescribing Information, WARNINGS AND
PRECAUTIONS).
Store at ≤- 135°C; vapor phase of liquid nitrogen
No U.S. standard of potency.

Manufactured for Mesoblast Inc.
1114 Sixth Avenue, Fourth Floor
New York, NY 10036
U.S. License number: 2140

LOT:
EXP:

PNTC-1154.026

NDC 73648-114-01
remestemcel-L-rknd
Ryoncil®
Suspension for IV Infusion
Allogeneic bone marrow-derived mesenchymal stromal cells
Target 25 X 106/ 3.8mL (6.68 x 106/mL)

Kit for Patient Weight:
37.5 kg – <50 kg

Kit Contents:
1 X 4-vial carton
4 Alcohol Wipes

Single–use vial. Discard unused portion.
For intravenous administration after thaw and resuspension
Rx only
Sterile. No preservative.
See Prescribing Information for directions for use.
Complete infusion within 5 HOURS of thawing and resuspension
of RYONCIL®.
Each vial contains a target of 25 x 106 cells / 3.8 mL.
Cryopreserved in: Human Serum Albumin Solution 20% v/v
(containing 5% w/v Human Serum Albumin), Plasma Lyte-A 70 %
v/v, dimethyl sulfoxide (DMSO) 10% v/v.
Contains known sensitizing substances DMSO or Porcine and
Bovine proteins (see Prescribing Information, WARNINGS AND
PRECAUTIONS).
Store at ≤- 135°C; vapor phase of liquid nitrogen
No U.S. standard of potency.

Manufactured for Mesoblast Inc.
1114 Sixth Avenue, Fourth Floor
New York, NY 10036
U.S. License number: 2140

LOT:
EXP:

PNTC-1154.027

NDC 73648-115-02
remestemcel-L-rknd
Ryoncil®
Suspension for IV Infusion
Allogeneic bone marrow-derived mesenchymal stromal cells
Target 25 X 106/ 3.8mL (6.68 x 106/mL)

Kit for Patient Weight:
50 kg – <62.5 kg

Kit Contents:
1 X single vial carton
1 X 4-vial carton
5 Alcohol Wipes

Single–use vial. Discard unused portion.
For intravenous administration after thaw and resuspension
Rx only
Sterile. No preservative.
See Prescribing Information for directions for use.
Complete infusion within 5 HOURS of thawing and resuspension
of RYONCIL®.
Each vial contains a target of 25 x 106 cells / 3.8 mL.
Cryopreserved in: Human Serum Albumin Solution 20% v/v
(containing 5% w/v Human Serum Albumin), Plasma Lyte-A 70 %
v/v, dimethyl sulfoxide (DMSO) 10% v/v.
Contains known sensitizing substances DMSO or Porcine and
Bovine proteins (see Prescribing Information, WARNINGS AND
PRECAUTIONS).
Store at ≤- 135°C; vapor phase of liquid nitrogen
No U.S. standard of potency.

Manufactured for Mesoblast Inc.
1114 Sixth Avenue, Fourth Floor
New York, NY 10036
U.S. License number: 2140

LOT:
EXP:

PNTC-1154.028

NDC 73648-116-03
remestemcel-L-rknd
Ryoncil®
Suspension for IV Infusion
Allogeneic bone marrow-derived mesenchymal stromal cells
Target 25 X 106/ 3.8mL (6.68 x 106/mL)

Kit for Patient Weight:
62.5 kg – <75 kg

Kit Contents:
2 X single vial cartons
1 X 4-vial carton
6 Alcohol Wipes

Single–use vial. Discard unused portion.
For intravenous administration after thaw and resuspension
Rx only
Sterile. No preservative.
See Prescribing Information for directions for use.
Complete infusion within 5 HOURS of thawing and resuspension
of RYONCIL®.
Each vial contains a target of 25 x 106 cells / 3.8 mL.
Cryopreserved in: Human Serum Albumin Solution 20% v/v
(containing 5% w/v Human Serum Albumin), Plasma Lyte-A 70 %
v/v, dimethyl sulfoxide (DMSO) 10% v/v.
Contains known sensitizing substances DMSO or Porcine and
Bovine proteins (see Prescribing Information, WARNINGS AND
PRECAUTIONS).
Store at ≤- 135°C; vapor phase of liquid nitrogen
No U.S. standard of potency.

Manufactured for Mesoblast Inc.
1114 Sixth Avenue, Fourth Floor
New York, NY 10036
U.S. License number: 2140

LOT:
EXP:

PNTC-1154.029

NDC 73648-117-04
remestemcel-L-rknd
Ryoncil®
Suspension for IV Infusion
Allogeneic bone marrow-derived mesenchymal stromal cells
Target 25 X 106/ 3.8mL (6.68 x 106/mL)

Kit for Patient Weight:
75 kg – <87.5 kg

Kit Contents:
3 X single vial cartons
1 X 4-vial carton
7 Alcohol Wipes

Single–use vial. Discard unused portion.
For intravenous administration after thaw and resuspension
Rx only
Sterile. No preservative.
See Prescribing Information for directions for use.
Complete infusion within 5 HOURS of thawing and resuspension
of RYONCIL®.
Each vial contains a target of 25 x 106 cells / 3.8 mL.
Cryopreserved in: Human Serum Albumin Solution 20% v/v
(containing 5% w/v Human Serum Albumin), Plasma Lyte-A 70 %
v/v, dimethyl sulfoxide (DMSO) 10% v/v.
Contains known sensitizing substances DMSO or Porcine and
Bovine proteins (see Prescribing Information, WARNINGS AND
PRECAUTIONS).
Store at ≤- 135°C; vapor phase of liquid nitrogen
No U.S. standard of potency.

Manufactured for Mesoblast Inc.
1114 Sixth Avenue, Fourth Floor
New York, NY 10036
U.S. License number: 2140

LOT:
EXP:

PNTC-1154.030

NDC 73648-118-02
remestemcel-L-rknd
Ryoncil®
Suspension for IV Infusion
Allogeneic bone marrow-derived mesenchymal stromal cells
Target 25 X 106/ 3.8mL (6.68 x 106/mL)

Kit for Patient Weight:
87.5 kg – <100 kg

Kit Contents:
2 X 4-vial cartons
8 Alcohol Wipes

Single–use vial. Discard unused portion.
For intravenous administration after thaw and resuspension
Rx only
Sterile. No preservative.
See Prescribing Information for directions for use.
Complete infusion within 5 HOURS of thawing and resuspension
of RYONCIL®.
Each vial contains a target of 25 x 106 cells / 3.8 mL.
Cryopreserved in: Human Serum Albumin Solution 20% v/v
(containing 5% w/v Human Serum Albumin), Plasma Lyte-A 70 %
v/v, dimethyl sulfoxide (DMSO) 10% v/v.
Contains known sensitizing substances DMSO or Porcine and
Bovine proteins (see Prescribing Information, WARNINGS AND
PRECAUTIONS).
Store at ≤- 135°C; vapor phase of liquid nitrogen
No U.S. standard of potency.

Manufactured for Mesoblast Inc.
1114 Sixth Avenue, Fourth Floor
New York, NY 10036
U.S. License number: 2140

LOT:
EXP:

PNTC-1154.031