Source: FDA, National Drug Code (US) Revision Year: 2025
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.
Human pharmacodynamic data were obtained from analysis of blood samples in pediatric subjects with SR-aGvHD (n=40; age range 0.6-17 years) following treatment with RYONCIL at a dose of 2 x 106 cells/kg. At Baseline, elevated levels of tumor necrosis factor receptor type I (TNFR1) and suppressor of tumorigenicity 2 (ST2) were observed consistent with the inflammatory state of aGvHD. Treatment with RYONCIL reduced the levels of TNFR1 and ST2 by 79% and 75%, respectively, at Day 180 as compared to baseline values. Further, the circulating levels of CD3+CD4+CD25+HLA-DR+ T cells, which represent activated T cells, were reduced by 64% at Day 180 following treatment with RYONCIL as compared to the baseline values.
No studies have been performed to evaluate the pharmacokinetics of RYONCIL.
No animal studies have been performed to evaluate the effects of RYONCIL on carcinogenesis, mutagenesis or impairment of fertility.
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.
Table 4. Efficacy Results for Study MSB-GVHD001:
| Response at Day 28 | N=54 |
|---|---|
| Overall Response Rate n (%) 95% CIa | 38 (70%) 56.4, 82.0 |
Durationb (days) Median (range) | 54 (7, 159+) |
| Complete Response Ratec n (%) 95% CIa | 16 (30%) 18.0, 43.6 |
| Partial Response Rated n (%) 95% CIa | 22 (41%) 27.6, 55.0 |
CI=confidence interval
a Two-sided exact binomial confidence interval at the 95% level
b Duration of response was calculated from Day-28 response to either progression (worsening by one stage in any organ without improvement in other organs in comparison to prior response assessment), new systemic therapy for aGvHD or death from any cause.
c Complete response was defined as resolution of aGvHD in all involved organs as per IBMTR grading system.
d Partial response was defined as organ improvement of at least one stage without worsening of any other organ as per IBMTR grading system.
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+).
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