Obstetric anal sphincter injuries (OASIS), which involve partial or complete disruption of the anal sphincter muscles, are one of the most common causes of fecal incontinence (FI) in women [1]. Therefore, we examined the efficacy and safety of iltamiocel, a cellular therapy investigational product comprised of autologous muscle derived cells (AMDC), as a treatment for FI in adult women with a history of OASIS.

Subjects were enrolled in a prospective, multicenter, nonrandomized Phase 1/2 investigational study (study code: GIFI). Subjects received a single administration of iltamiocel at a dose of 250 million (±20%) cells. The study included subjects with primary symptoms of FI defined as baseline Cleveland Clinic Incontinence Score (CCIS) ≥9 and history of failed conservative treatment. Key exclusion criteria were presence of neuromuscular disorder, prior major sphincter augmentation procedures or anorectal operation leading to anal sphincter damage, inflammatory bowel disease, and non-viable mucosa lining along the anal tract.
Iltamiocel was manufactured from approximately 50-250mg skeletal muscle tissue harvested from the subject’s vastus lateralis via outpatient needle tissue procurement procedure. After isolation and expansion, iltamiocel suspension was evenly distributed around the external anal sphincter (EAS) through 8-12 percutaneous injections parallel to the anal canal during a subsequent outpatient procedure. For subjects with a defined sphincter defect, approximately half of the cell suspension was injected in the region of the defect with the remaining volume evenly distributed through the remainder of the EAS.
Efficacy outcomes were change in frequency of FI episodes and days with FI episodes as recorded by a 28-day diary and change in CCIS and Fecal Incontinence Quality of Life (FIQL) questionnaires. Outcomes were assessed by comparing baseline (pre-injection) parameters to those at 3, 6 and 12-months post-treatment. Anorectal manometry was used to explore changes in anal sphincter function from baseline to 12 months. Incidence of iltamiocel- or study procedure-related adverse events (AEs) and serious adverse events (SAEs) was recorded up to 12 months post-treatment.

Thirty-one women with history of OASIS including obstetric tears and/or episiotomy during labor (median age 60 years, range 31-78) received iltamiocel injection. Subjects had a median of 2 vaginal births (range 1-4), 19 (61%) and 20 (65%) presented with obstetric tear or episiotomy, respectively, and 8 (26%) presented with both. Sonographic EAS defect was present in 20 (65%) subjects; the median defect area was 60 degrees (range 30 to 180 degree), 5 (19%) subjects had an EAS defect ≥120 degree and 10 (32%) had previous anal sphincter repair. Of the 31 subjects who received iltamiocel injection, 26 (84%) completed baseline diary and had ≥1 episode at baseline diary. These subjects were included in the efficacy analysis.
The safety profile of iltamiocel treatment in the 31 OASIS subjects enrolled in Study GIFI was favorable with no SAEs related to the product, injection procedure, or tissue procurement procedure. Most AEs were determined to be unrelated to Iltamiocel or study procedures. Only one iltamiocel-related AE of injection site inflammation was reported; the event was grade 1 in severity and resolved without treatment. No secondary interventions due to AEs were necessary following iltamiocel administration.  
At 12-months follow-up, 62% of OASIS subjects reported a ≥50% reduction in number of FI episodes, 46% reported a ≥75% reduction and 27% reported 100% reduction which represents a complete restoration of continence over a 28-day period (Table 1). When analysis was restricted to the group of OASI subjects with EAS defect <120 degrees (n=20), 70% and 50% of these achieved ≥50% and ≥75% reduction in FI episodes, respectively, and 35% achieved complete continence at 12 months (Table 1). A significant reduction in both median FI episodes and days with FI episodes compared with baseline was observed in this group of subjects at all time points (Table 2). Improvements in symptom severity and quality of life over the follow-up period, were demonstrated by a statistically significant reduction of CCIS and increase of all FIQL scales at 12 months compared with baseline (Table 2). No significant changes in anorectal manometry measurements were detected at 12 months compared with baseline.

The significant reduction in both number of FI episodes and days with FI episodes, along with significant improvements in both CCIS and FIQL scales observed after 12 months, demonstrate that a single administration of iltamiocel [250 million (±20%) cells] shows promise in improving FI symptoms and quality of life in women with a history of obstetric injuries. Indeed, the efficacy of the iltamiocel treatment was even higher in the group of subjects with an EAS defect less than 120 degrees. In this group, 70% of subjects achieved at least 50% reduction of FI episode and 35% achieved complete continence (0 episodes in a 28-day diary) at 12 months post iltamiocel injection. Importantly, a ≥75% episodes reduction was previously identified by most subjects as a threshold for FI treatment success [2]. In this study, half of subjects with OASIS and EAS defect <120 degree achieved a ≥75% episodes reduction. In keeping with previous reports [3], these data suggest that patients with FI due to obstetric injury and an EAS defect <120 degrees may be ideal candidates for AMDC therapy.

Obstetric anal sphincter injury represents one of the most common cause of FI in women. AMDC therapy, which delivers autologous muscle progenitor cells to the targeted tissue, is hypothesized to increase anal sphincter functionality in patients with FI due to defined structural defects and/or generalized weakening of the EAS. Treatment with iltamiocel may therefore represent a safe, minimally invasive, and potentially transformative option for patients suffering from FI due to obstetric injuries, particularly in those that involve less than one third of the total external anal sphincter area.

Sideris M, McCaughey T, Hanrahan JG, Arroyo-Manzano D, Zamora J, Jha S, Knowles CH, Thakar R, Chaliha C, Thangaratinam S. Risk of obstetric anal sphincter injuries (OASIS) and anal incontinence: A meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2020 Sep;252:303-312.
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Frudinger A, Marksteiner R, Pfeifer J, Margreiter E, Paede J, Thurner M. Skeletal muscle-derived cell implantation for the treatment of sphincter-related faecal incontinence. Stem Cell Res Ther. 2018 Sep 13;9(1):233.

Continence 2S2 (2022) 100371
DOI: 10.1016/j.cont.2022.100371