Responding to a critical unmet need in the treatment of pediatric SR-aGvHD

So, you know, when acute GvHD develops, the standard of care is to give steroids, but only half the children who get steroids respond.

Most therapies aren’t approved in children, even if they’re approved in adults.

Responding to a critical unmet need in the treatment of pediatric steroid-refractory acute graft-versus-host disease (SR-aGvHD).

Many doctors just try one thing and then another and then another and the children end up on multiple drugs, make the kids immune suppressed. It’s just sort of, you know, a negative sequence of events.

So we always have to balance taking away some of the Prednisone if we can and picking a therapy that fits the context of the patient at the time.

RYONCIL is the first and only FDA-approved steroid-refractory acute GvHD treatment for pediatric patients 2 months of age and older and the only approved option for patients under 12 years of age.

It’s really a cell therapy approved to treat steroid-resistant GvHD in children. So that, in itself, is a real milestone.

Important Safety Information.

Do not use RYONCIL in patients with known hypersensitivity to dimethyl sulfoxide (DMSO) or porcine and bovine proteins. Serious hypersensitivity reactions, including anaphylaxis, may occur due to DMSO and trace amounts of porcine or bovine proteins. Premedicate with antihistamines and corticosteroids and monitor closely. Interrupt infusion if hypersensitivity or a serious reaction occurs. Do not administer RYONCIL in patients who experience serious or life-threatening reactions.

RYONCIL may transmit infectious agents because it contains cells from human donors and uses human, porcine, and bovine-derived materials. Ectopic tissue formation may occur following treatment with RYONCIL due to the differentiation potential of mesenchymal stromal cells.

The most common non-laboratory adverse reactions ≥20% are: viral and bacterial infectious disorders, infection—pathogen unspecified, pyrexia, hemorrhage, edema, abdominal pain, and hypertension. Please see full Prescribing Information for complete safety information.

We don’t understand the full mechanisms of actions. What we think happens when you inject the cells, they travel into the bloodstream, they tend to modulate the immune system in a way to decrease the inflammation and hopefully help in that balance of repairing the tissues where they’re damaged and suppressing the ongoing immunological attack.

It’s actually been tested in these patients, and been shown to be effective where our other agents have not really been tested in this young pediatric population.

It’s given via IV, so we don’t have to worry about being able to take medicines, which is a challenge for a lot of our young patients.

It’s been shown to be effective with this four week course. And then for some patients, we’ll extend it for another 4 weeks if they’ve had an incomplete response.

So I was the PI for the 001 study. We treated children who really had no other options and the majority responded and improved on RYONCIL.

We are noticing the short-term improvement in outcomes but also long-term improvement outcomes, which matters that long term outcomes are pretty good.

That means children with the steroid-refractory aGvHD have a good treatment option.

RYONCIL is very well tolerated. It’s been shown to be very safe for our patients.

Most of the patients that I’ve started RYONCIL on to date started on the inpatient side and as they’ve shown responses, we’ve been able to transition this patient to the outpatient setting.

You know, sending the patient home is a celebration, and we were able to celebrate that.

In the treatment of pediatric steroid-refractory acute GvHD, redefine what’s possible with RYONCIL.

Indication. 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.

Important Safety Information.

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

Warnings and precautions.

Hypersensitivity and acute infusion reactions. Hypersensitivity reactions, including acute infusion reactions, have occurred with RYONCIL administration. 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.

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). 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.

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.

Adverse reactions — 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 × 10⁶ MSCs per kilogram 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 × 10⁶ MSCs per kilogram once a week for an additional 4 weeks. 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).

Adverse reactions ≤grade 3 occurring in ≥10% of patients in study MSB-GVHD001 up to day 100 after RYONCIL treatment included viral infectious disorders, bacterial infectious disorders, infections—pathogen unspecified, pyrexia, hemorrhage, abdominal pain, hypertension, vomiting, arrhythmia, diarrhea, rash, arthralgia, fungal infectious disorders, hypotension, cough, and respiratory failure. No grade 4 or 5 adverse reactions occurred in the study.

Grade 3 or 4 laboratory abnormalities that worsened from baseline in ≥10% of patients in study MSB-GVHD001 included elevated Gamma-glutamyl transferase, thrombocytopenia, and elevated bilirubin.

Use in specific populations.

Pregnancy. There are no available data for RYONCIL use in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with RYONCIL to assess whether it can cause fetal harm when administered to a pregnant woman. It is not known if RYONCIL has the potential to be transferred to the fetus. Therefore, RYONCIL is not recommended for women who are pregnant. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 10-20%, respectively.

Lactation. There is no information regarding the presence of RYONCIL in human milk, the effect on the breastfed infant, and the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for RYONCIL and any potential adverse effects on the breastfed infant from RYONCIL or from the underlying maternal condition.

You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Mesoblast at toll-free phone number 1-844-889-MESO (6376). Please see the RYONCIL full Prescribing Information for additional Important Safety Information.