Women with persistent or recurrent stress urinary incontinence (SUI) symptoms following anti-incontinence surgery are a challenging population due to higher safety risks and diminished efficacy from additional surgical procedures [1].  Additionally, these women reported more leaks and worse QOL at baseline in investigational studies of Autologous Muscle Derived Cells (AMDC) compared with women without prior surgery [2].  In 2020, the FDA granted Regenerative Medicine Advanced Therapy (RMAT) designation to AMDC which acknowledges that this complicated SUI sub-population meets the definition of a serious condition with unmet medical need.

Therefore, we examined if AMDC treatment for SUI is effective and improves QOL in women with persistent or recurrent SUI and a history of prior anti-incontinence surgery.

Preliminary data are reported from post-hoc analyses of a pooled subset of women with history of ≥1 prior surgeries for SUI >6 months prior to enrollment in 2 individual Phase 3 investigational studies of AMDC (UIAD, N=17 and IND2, N=75).  All subjects had either a prior sling surgery and/or a bladder neck suspension.  Women ≥18 years with primary symptoms of SUI and ≥3 SUI episodes over a 3-day period at screening were randomized 2:1 (AMDC:placebo) at 25 sites.  

The AMDC investigational product was manufactured from 50-250mg of skeletal muscle harvested in clinic from the subject’s vastus lateralis via biopsy, expanded to 150 million (±20%) cells, and delivered into the urinary sphincter using the Cook® Multi-Injection Needle during a subsequent clinic procedure.  Subjects were followed 2 days and 1, 3, 6, 12, and 24 months post-injection. Stress incontinence episode frequency (SIEF) was measured using 3-day bladder diary, and QOL and symptom severity were measured using validated, subject questionnaires (I-QOL, IIQ-7, GQOL, UDI-6, and ISI).  The primary outcome measure was SIEF at 12 months. Responders were defined as subjects with ≥75% reduction in SIEF at 12 months.  The incidence of product-related serious adverse events (SAEs) and product-related, injection and biopsy procedure-related adverse events (AEs) were assessed.  AEs were considered related if assessed by the Investigator as possibly, probably, or definitely related to the product/procedure. 

Investigators and subjects remained blinded through the 12-month visit. After unblinding, subjects who received placebo could elect to receive open-label AMDC treatment.  These subjects and those originally randomized to AMDC were followed for 2 years after initial blinded treatment.

92 women (61 AMDC, 31 placebo) were included in this subset analysis.  At baseline, women were 58.1±11.8 years old, experienced 1.7±0.8 surgeries, 18.7±13.4 SUI episodes over 3 days, and recorded 61.8±88.6 g leakage during 24-hour pad test (mean±standard deviation). All women completed the blinded 12-month visit.  AMDC treatment effect of ≥75% SIEF reduction at 12 months was significant when compared with placebo in the pooled analysis from the UIAD and IND2 studies (44.3% vs. 16.1%; p=0.007, power=0.8, Figure 1), and independently in IND2 (40.0% vs. 16.0%; p=0.037).  The association across all subjects at 12 months exceeded a clinically meaningful threshold of ≥10-point improvement in I-QOL total score at ≥75% reduction in SIEF (Figure 2) [3].  In addition, there was significant correlation between change in SIEF and change in all QOL and symptom severity scores in AMDC subjects at 12 months (p≤0.009).  Significant differences in mean QOL and symptom severity score changes at 12 months were observed between SIEF responders and non-responders in the AMDC group but not in the placebo group in all 5 scores (p<0.01). 

Twenty-four-month diaries were completed by 73.8% (45/61) of the subjects who received AMDC. Only subjects with completed 24-month 3-day diaries were included in the durability assessment (N=45).  Treatment durability, determined as the percentage of SIEF responders at 12-months who maintained this effect at 24-months, was observed in 66.7% (16/24) of subjects (mean SIE change 0.1±0.9 between 12 and 24 months).  Additionally, 14.3% (3/21) of subjects who were non-responders at 12-months became responders by the 24-month visit.

After unblinding, 90% (28/31) of placebo subjects elected to receive open-label AMDC, 100% (28/28) of these subjects completed the 24-month final study visit and 39.3% (11/28) achieved SIEF responder status at 24 months (mean change in SIE -7.9±7.0 between 12 and 24 months).  Of these 11 responders at 24-months, 7 (63.6%) were new responders (i.e., were non-responders at 12-months).  This open-label crossover responder rate was similar to that observed in AMDC subjects at the 12-month blinded visit (Figure 1).

AMDC was well tolerated with no AMDC-related SAEs. During the blinded treatment period, the rates of subjects with any AE related to AMDC/placebo or injection procedure between groups were similar. Dysuria was the most frequently reported AE related to AMDC (3.1%) or placebo (5.8%).  The most frequently reported injection procedure-related AEs during the blinded period were injection site pain (7.7% AMDC, 0% placebo), dysuria (4.6% AMDC, 5.9% placebo), and urinary tract infection (4.6% AMDC, 5.9% placebo).  There were 3 subjects who reported urinary retention, one following placebo injection which required catheterization and resolved in 2 days, and 2 following open-label AMDC injection which did not require catheterization.  One subject experienced a biopsy procedure-related SAE of procedural pain which required hospitalization for 2 days and resolved in 4 days.  Procedural pain, post procedural contusion, and post procedural haematoma were the most common biopsy procedure-related AEs (4.8%, 3.8%, and 2.9%, respectively).

Unlike anti-incontinence sling and suspension surgeries and bulking agent injections which all produce an immediate mechanical effect that may decrease over time, augmentation of muscle function by AMDC is not expected to be immediate due to regenerative mechanisms.  Clinical data from the UIAD and IND2 studies presented here suggest that functional integration may occur over time, as additional improvements in SUI symptoms were observed in some subjects 12+ months after AMDC administration. 

The reduction in SIEF during AMDC treatment is associated with improvement in QOL and symptom severity scores in this complex population.  In particular, SIEF responders had mean score improvement well beyond an established clinically meaningful threshold with I-QOL, the most comprehensive instrument designed to capture individuals’ perception of their SUI as a serious medical condition and its impact on ability to perform day-to-day functions [3].

Women with persistent or recurrent SUI following prior surgical treatment have a serious unmet medical need which substantially impacts day-to-day functioning and quality of life.  Clinical evidence from 2 double-blind, randomized, multicenter, placebo-controlled trials indicates that AMDC treatment may be safe and effective at reducing SIEF and improving QOL in these women.

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