Regulatory Decision Summary for Constella

The purpose of this Supplemental New Drug Submission (SNDS) was to obtain market authorization, pursuant to section C.08.004 of the Food and Drug Regulations, for Constella, filed by AbbVie Corporation. This Supplement was filed to (i) add a new pediatric indication for the treatment of functional constipation (FC) in children and adolescents 6 to 17 years of age, (ii) change the existing contraindicated age range from less than 6 years of age to less than 2 years of age, and (iii) update the Constella Product Monograph with new safety and efficacy data from a Phase 3b study in adult patients with irritable bowel syndrome with constipation (IBS-C), focusing on abdominal symptom improvement. Upon review of the submitted data package, Health Canada authorized Constella for the new pediatric indication as filed, and maintained the existing contraindicated age range of less than 6 years of age. During review, the Sponsor withdrew the Phase 3b study due to missing efficacy data, which will be filed at a later date.

The proposed indication was supported by efficacy and safety data from a randomized, double-blind, placebo-controlled Phase 3 clinical trial (LIN-MD-64). In this study, 328 pediatric subjects aged 6 to 17 years who met the modified Rome III criteria for FC were administered once-daily either Constella 72 µg or placebo for 12 weeks in a 1:1 ratio. The Rome III criteria defines FC in children and adolescents (4 to 17 years-old) as experiencing ≥ two of the following symptoms, with insufficient criteria for diagnosis of irritable bowel syndrome (IBS), at least once per week for at least two months prior to diagnosis: two or fewer defecations in the toilet per week, at least one episode of fecal incontinence per week, history of retentive posturing or excessive volitional stool retention, history of painful or hard bowel movements, presence of a large fecal mass in the rectum, and history of large diameter stools which may obstruct the toilet. The study was conducted in 140 sites from the United States, Canada, Europe, and the Middle East. The primary efficacy endpoint was the change from baseline in 12-week spontaneous bowel movement (SBM) frequency rate (SBMs/week). Signs and symptoms of FC were captured using a patient-reported eDiary, referred to as pediatric FC Symptom Diary (PFCSD).

The results showed that the primary efficacy endpoint was achieved. Constella led to a statistically significant increase in the SBM frequency rate at week 12 compared to baseline. The least mean square difference (LSMD) between Constella and placebo was 1.170 SBMs/week (95% confidence interval [CI], 0.651–1.689; p < 0.0001). The direct observability of SBM frequency was validated through analysis of clinical outcomes assessment (COA) administration methods (self-reported and caregiver-reported), with consistent efficacy outcomes across both approaches. The primary outcome was supported by the results from exploratory endpoints, including decrease in rescue medication use in subjects treated with Constella compared to placebo. Furthermore, the mean SBM frequency in the Constella group exceeded the Rome threshold of 3, which was not met by the placebo group. Overall, the primary efficacy changes were determined to be clinically significant. The multiplicity controlled secondary efficacy endpoint, change in stool consistency from baseline to week 12, was statistically but not clinically significantly improved following Constella treatment compared to placebo. The LSMD between the two groups was 0.423 (95% CI, 0.208-0.638; p = 0.0001).

The safety of Constella in the proposed population was characterized through data obtained from the pivotal phase 3 study (LIN-MD-64) as well as a placebo-controlled 4-week phase 2, randomized, double-blind, placebo-controlled study (LIN-MD-62). Long-term safety of Constella (72 µg and 145 µg) was assessed based on interim data from a 24-week open-label extension study (LIN-MD-66). In this study, 181 subjects received at least 24 weeks of open-label Constella 72 μg and 145 μg. Constella was well tolerated across all doses and age groups and the safety profile was consistent with prior adult Constella studies for chronic idiopathic constipation (CIC). There were no deaths. In the Phase 3 study, the most frequently reported treatment-emergent adverse events (TEAEs) (> 1% subjects) in Constella-treated subjects were diarrhea (4.3% in Constella versus 1.8% in placebo), and nausea (1.2% in Constella versus 0 in placebo). Additionally, treatment-related TEAEs of abdominal discomfort and dehydration were reported in one patient each (0.6%) for Constella and none in placebo group. The majority of cases with diarrhea were mild in severity. One subject in the Constella 72 µg treatment group experienced a treatment-related serious adverse event (SAE) of severe diarrhea accompanied by dehydration that resulted in hospitalization and permanent discontinuation of Constella treatment.

The current Supplement was also filed to support a change in the pediatric contraindication age for Constella. Constella is currently contraindicated in pediatric patients less than 6 years of age. The Sponsor proposed to change the contraindicated age from less than 6 years to less than 2 years of age. The contraindication was initially included based on non-clinical toxicology studies showing mortality in juvenile mice exposed to linaclotide. The proposed change to the contraindicated age was supported by non-clinical toxicology studies and one gene expression study. The newly submitted non-clinical studies in mice revealed that the linaclotide-associated mortality in neonatal mice (corresponding to human age of approximately 0 to 28 days) was due to rapid and severe dehydration caused by significant fluid shifts into the intestinal lumen from guanylate cyclase-C (GC-C) agonism. The non-clinical studies also showed that in older juvenile mice (corresponding to human age of approximately > 23 months) linaclotide treatment did not cause mortality, although diarrhea was still an adverse event of treatment. The Sponsor also filed a gene expression study, which assessed the mRNA expression of GC-C (GUCY2C) in duodenal and colonic pediatric (< 18 years old) specimens. This study found no significant difference in GC-C mRNA expression based on age (6 months to < 18 years old) or weight in human duodenal or colonic tissue samples. However, this study focused on mRNA expression and did not inform on the GUCY2C protein expression, localization and function in duodenal and colonic epithelium, thus limiting the clinical relevance of the results.

Clinical data was inadequate to support the proposed change. The Sponsor’s clinical trials database focused on subjects 6 years and older. Preliminary results from a single clinical trial (LIN-MD-67) was submitted, which assessed the safety of linaclotide in younger pediatric subjects 2 to 5 years of age. In this study, only 8 subjects were given the proposed marketed dose of linaclotide. This sample size is insufficient. Post-market data submitted is limited due to small sample sizes, incomplete reports, and poor generalizability, which undermined the reliability of the safety data. Children face higher risks of severe dehydration due to factors like increased body surface area, increased metabolic demands resulting in increased sensible and insensible losses, increased fluid requirements and inability to communicate needs or hydrate themselves when in need. Taken together, there is uncertainty and concern around lowering the age of the contraindication to less than 2 years without clinical data to support safety in this population. Health Canada will consider modifying the contraindicated age range only after receiving and reviewing sufficient data from clinical trials in this age group.

An updated Risk Management Plan (RMP) for Constella was reviewed by Health Canada and considered acceptable. Risks have been communicated in the approved Product Monograph and will continue to be monitored post market as outlined in the Risk Management Plan, with routine pharmacovigilance activities.

The final labelling and Product Monograph were considered acceptable.

Overall, the benefit-harm-uncertainty profile was favourable for Constella (72 µg once daily) for the approved indication and contraindication when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance (NOC) was recommended.

For further details about Constella. please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.