Summary Basis of Decision for Daybue

Clinical Pharmacology

Trofinetide, the medicinal ingredient in Daybue, is a synthetic analog of the N-terminal tripeptide of insulin-like growth factor 1. The mechanism by which trofinetide exerts therapeutic effects in patients with Rett syndrome is unknown.

Trofinetide exhibited linear kinetics, with no time- or dose-dependent effects on pharmacokinetic parameters. Systemic exposure to trofinetide was dose-proportional across the studied dose range. Minimal to no dose accumulation was observed following twice-daily administration.

Trofinetide is rapidly absorbed after oral administration, with a time to maximum drug concentration (T_max) of 2 to 3 hours. Results of the mass balance study show that at least 84% of the administered dose was absorbed following the oral administration of 12 g trofinetide. In healthy adults, the apparent volume of distribution of trofinetide was approximately 80 L. Trofinetide is primarily excreted unchanged in urine (approximately 80% of the dose), with minor excretion in the feces (15.3%). The effective elimination half-life of orally administered trofinetide in healthy subjects is approximately 1.5 hours. This is followed by a relatively slow elimination phase with a half-life of 30 hours. Based on a population pharmacokinetic analysis, the trofinetide systemic clearance/oral bioavailability (CL/F) is estimated to be 11.8 L/h at steady state.

The effect of moderate renal impairment on the pharmacokinetics of trofinetide was studied in an open-label Phase I study. A single 6 g dose of trofinetide was administered to participants with moderate renal impairment (defined as an estimated glomerular filtration rate [eGFR] of 30 to <59 mL/min/1.73 m²) and compared to healthy participants receiving a single 12 g dose of trofinetide. Dose-normalized systemic exposure to trofinetide was approximately 2-fold higher in participants with moderate renal impairment compared to healthy participants. Time to elimination and rate of maximum elimination of trofinetide in urine was slower and lower in participants with moderate renal impairment compared to healthy participants. The physiologically-based pharmacokinetic model supported this finding, showing that a high trofinetide exposure is expected with increasing renal impairment. Based on the results from the Phase I study and pharmacokinetic analyses, a 50% reduction in trofinetide dosage is recommended for patients with moderate renal impairment. A further reduction (an additional 20% to 30% following the 50% reduction) should be considered for patients with a high degree of moderate renal impairment. A 20% to 30% dose reduction should be considered for those with a high degree of mild renal impairment (eGFR of 60 to 70 mL/min/1.73m²). Trofinetide is not recommended in patients with severe renal impairment or with end stage renal disease.

The pharmacokinetics of trofinetide have not been studied in patients with hepatic impairment. However, hepatic impairment is not expected to have a clinically meaningful effect on the exposure of trofinetide.

A dedicated QT study was conducted using single doses of either 12 g, 18 g, or 24 g trofinetide in healthy adults. This study did not provide evidence of QT prolongation, however, supratherapeutic exposures were not achieved. The upper 90%, 2-sided confidence interval for the change from baseline in the corrected QT interval (Fridericia’s formula; QTcF) (∆QTcF) and the placebo-corrected change from baseline in the QTcF (∆∆QTcF) were below 10 ms (the threshold of concern for cardiac repolarization).

No clinical drug-drug interaction studies were performed.

Trofinetide was generally safe and well-tolerated in all the studies evaluated as part of the clinical pharmacology package.

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

Clinical Efficacy

Data from six clinical studies were submitted to support the clinical efficacy of Daybue for the treatment of Rett syndrome (RTT). These include one pivotal study (ACP-2566-003), two open-label extension studies (ACP-2566-004 [40 weeks] and ACP-2566-005 [32 months]), two supportive Phase II studies (Neu-2566-RETT-001 and Neu-2566-RETT-002), and one open-label study in 2- to 4-year-old patients with RTT (ACP-2566-009) to support extrapolation of efficacy to younger patients with RTT.

The pivotal study (ACP-2566-003) was conducted in 187 female patients with RTT between 5 and 20 years of age, and had a randomized, double-blind, placebo-controlled design. Patients were required to have a documented disease-causing mutation in the methyl-CpG-binding protein 2 (MECP2) gene, a score of 10 to 36 on the Rett Syndrome Clinical Severity Scale (RTT-CSS), and a score of 4 or higher on the Clinical Global Impression of Severity (CGI-S). Patients were stratified by age and baseline severity according to the Rett Syndrome Behavioural Questionnaire (RSBQ), and then randomized in a 1:1 ratio to receive either a placebo (94 patients) or Daybue (93 patients) and were evaluated for 12 weeks.

Two co-primary endpoints were assessed: a caregiver-rated, 45-item RSBQ, and a clinician-rated Clinical Global Impression of Improvement (CGI-I) measured on a 7-point Likert scale. Statistically significant improvements were observed with respect to each endpoint. An improvement was observed in the RSBQ total score from baseline to Week 12 via the mixed-effect model for repeated measures (MMRM) least squares mean (LSM) difference of -3.1 (p = 0.0175; Cohen’s d effect size 0.37). This reflected a mean RSBQ total score change in the Daybue group of -5.1 points compared to -1.7 points in the placebo group. The CGI-I score at Week 12 yielded a treatment group difference of -0.3 (95% confidence interval [CI]: -0.5, -0.1; p = 0.0030; Cohen’s d effect size 0.47), reflecting a mean Week 12 CGI-I score of 3.5 in the Daybue group compared to 3.8 in the placebo group. The results of sensitivity analyses to account for missing data and intercurrent events were supportive of the primary analysis. However, high rates of patient discontinuations violated the missing-at-random assumption which forms the basis of the MMRM approach, and functional unblinding due to the adverse event of diarrhea introduced an additional bias.

The mean improvements on the RSBQ and CGI-I scales met the criteria for statistical significance. However, the Cohen’s d effect size, which served as an indicator of clinical improvement, was lower than the definition for medium effect size (d = 0.5) for the two primary endpoints (0.37 for RSBQ and 0.47 for CGI-I). No minimally clinically important difference (MCID) has been published for the RSBQ scale. However, the standard deviation (SD) used by the sponsor to estimate the MCID via distribution-based methods was 0.4, while the SD suggested in scientific literature was 0.5. Twelve weeks into the 32-month open-label extension study ACP-2566-005 (reflecting duration of Daybue treatment of 52 weeks in the placebo group [36 patients], and 64 weeks in the Daybue group [41 patients]), 20.5% to 23.5% of patients met the “responder” criteria of a CGI-I score of 1 (“very much improved”) or 2 (“much improved”).

The RSBQ is a well-validated instrument designed to identify core signs and symptoms of RTT, and to distinguish individuals with RTT from other females with other causes of severe to profound intellectual disability. The CGI-I is well-established in the use of neurodevelopmental disorders, and an RTT-specific anchor scale was developed specifically for the evaluation of improvement or worsening in patients with RTT. Improvement observed in both these outcome measures provided evidence of a meaningful clinical change in individual patients. At the group level, the extent to which the magnitude of change in the co-primary endpoints was clinically meaningful was modest. However, certain individuals met the “responder” criteria and experienced larger benefits. If beneficial effects are not experienced by an individual after 52 weeks of treatment with Daybue, Health Canada recommends the discontinuation of treatment as no additional benefit has been demonstrated in non-responders after one year of treatment.

Indication

Sponsor's proposed indication	Health Canada-approved indication
For the treatment of Rett syndrome (RTT) in adults and pediatric patients 2 years of age and older.	Daybue (trofinetide oral solution) is indicated for the treatment of Rett syndrome in adults and pediatric patients 2 years of age and older and weighing at least 9 kg.

As RTT primarily affects females and the pivotal study was conducted specifically in female patients between 5 and 20 years of age, Health Canada added limitations of use to accompany the approved indication for Daybue. There are limited data on Daybue for patients over 20 or under 5 years of age, male patients with RTT, individuals without a MECP2 mutation, or those who are diagnosed with atypical/variant RTT. Individuals with RTT with an underlying corrected QT (QTc) interval greater than 450 ms were excluded from clinical studies of Daybue.

For more information, refer to the Daybue Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

Safety data from 18 clinical studies with Daybue were included in this submission, conducted in clinical populations with RTT and other conditions, and in patients with renal impairment. In total, 675 individuals were exposed to Daybue in the clinical development program, including 260 unique individuals with RTT.

Although pooled safety data were provided, different formulations of Daybue were used in certain pools. Therefore, for studies included in these pools, clinical safety was evaluated in each study individually. The most relevant safety data came from the pivotal study (ACP-2566-003), the open-label extension studies (ACP-2566-004 and ACP-2566-005), and an open-label study in 2- to 4-year-old patients with RTT (ACP-2566-009). All four of these studies used the proposed marketed formulation of Daybue in the clinical population of interest.

In the pivotal study, adverse event rates were higher in the Daybue group than in the placebo group. The most commonly reported adverse events were diarrhea (80.6% vs. 19.1%), vomiting (26.9% vs. 9.6%), weight loss (12.9% vs. 4.7%) seizure (8.6% vs. 5.3%), pyrexia (8.6% vs. 4.3%), and decreased appetite (5.4% vs. 2.1%). Adverse events frequently resulted in dose modification (34% of participants on Daybue, 6% of participants on placebo). Participant discontinuation was higher than expected (24.7% Daybue, 9.6% placebo), and in the majority of cases, was adverse event-related (17.2% Daybue, 2.1% placebo). Concomitant anti-propulsive medication (loperamide) was used by 50.5% of participants in the pivotal study, and by 57.9% of participants in the pivotal study and associated open-label long-term extensions.

Serious adverse events (SAEs) were reported in 3 participants (3.2%) in each of the Daybue and placebo groups in the pivotal study, and rates of SAEs increased in the open-label extensions. Serious adverse events were reported in 19 participants (12.3%) in study ACP-2566-004, 23 participants (29.9%) in study ACP-2566-005, and 4 participants (26.7%) in study ACP-2566-009. Four deaths were reported (cardiac arrest, aspiration and vomiting, sudden unexplained death in epilepsy, and gastric ulcer hemorrhage, in one participant each), all in the open-label long-term extension study ACP-2566-005. The other most common SAEs reported in the long-term extension studies were seizure, vomiting, pneumonia, urinary tract infection, and acute respiratory failure.

As the medication is intended for continuous, life-long use, the issue of tolerability is particularly relevant. Dosing considerations and recommendations were included in the Daybue Product Monograph to mitigate the risk of adverse events. These include slow dose up-titration, temporary dose reduction to 50% of the recommended dose with onset of intolerable adverse reactions, and modified doses in cases of renal impairment. Health professionals are advised to consider discontinuation of Daybue if a patient does not experience beneficial effects after 12 months of treatment due to an unfavorable benefit-harm-uncertainty evaluation. Adverse events of special interest including QTc prolongation, diarrhea, and vomiting are described in the Warnings and Precautions section of the Daybue Product Monograph.

There are ongoing uncertainties regarding the use of Daybue in a broad population with RTT. All individuals enrolled in the 6 clinical studies in patients with RTT were females with a documented disease-causing MECP2 mutation and classic RTT diagnosed using 2010 criteria (Neul et. al., 2010). Efficacy and safety in individuals with atypical/variant RTT, males with RTT, and those with less common mutations (i.e. CDLK5, FOXG1) have not been established in the clinical development program. Additionally, there are limited data on the efficacy and safety of Daybue in female patients with RTT less than 5 years of age or older than 20 years of age. Although the Phase I Neu-2566-RETT-001 study enrolled females between 16 and 45 years of age, the marketed formulation was not used, and doses were much lower (35 mg/kg and 70 mg/kg) than those in the pivotal study, in which the recommended dose of Daybue was used. A small number of participants at younger ages (2 to 4 years) and lower weight (9 to 12 kg) were evaluated in ACP-2566-009, to establish the basis for extrapolation of Daybue use to patients with RTT 2 years of age and older. However, this study was open-label and not powered for evaluation of efficacy.

Healthcare professionals should be aware that individuals with RTT and QTc prolongation (QTc interval greater than 450 ms) were excluded from clinical studies with Daybue. Given that patients with RTT are at a higher baseline risk of developing QTc prolongation, close monitoring of cardiac status (including QTc intervals) and electrolyte disturbances (hypokalemia, hypocalcemia, hypomagnesemia) are recommended to prevent adverse cardiac events including Torsades de Pointes. Health Canada has outlined these uncertainties in the Limitations of Use in the Indication section, in the Warnings and Precautions section, and in the Clinical Trials section of the Product Monograph.

Although efficacy and safety data are lacking for rarer sub-populations with RTT, the assumption of similar underlying pathophysiology combined with labelling of risks and appropriate pharmacovigilance are considered adequate to maintain a favourable benefit-harm-uncertainty assessment.

For more information, refer to the Daybue Product Monograph, approved by Health Canada and available through the Drug Product Database.

In non-clinical pharmacokinetic studies, trofinetide was quickly absorbed and distributed throughout the body, with limited distribution to the central nervous system. It did not undergo metabolic transformation, and was excreted almost entirely intact in the urine and feces. Trofinetide is a substrate of organic anion transporting polypeptide (OATP) 1B1 within the therapeutic range, and can also inhibit cytochrome P450 (CYP) 3A4 and/or P-glycoprotein in the gut due to its expected high intestinal concentration.

In dogs, trofinetide was not associated with adverse antemortem or postmortem findings following oral administration for up to 39 weeks at doses of 50, 300, and 1,000 mg/kg/day. Increases in the incidence and frequency of fecal excretion findings (unformed stool, watery and/or mucoid diarrhea) were observed at 1,000 mg/kg/day only. However, these were not considered adverse as no impacts were observed on animal health, behaviour, or viability, and all stool effects resolved when dosing stopped. The no-observed-adverse-effect level (NOAEL) was conservatively established at 300 mg/kg/day based on a difference in uterine weights, likely attributable to biologic variability of estrous cycling, but not considered adverse. At the highest dose of 1,000 mg/kg/day, the plasma exposure achieved was less than that in humans at the maximum recommended human dose (MRHD). In rats, doses up to 2,100 mg/kg/day resulted in no adverse effects, and plasma exposure was approximately half of that observed in humans at the MRHD.

No adverse effects were observed on fertility or reproductive function in male and female rats following the oral administration of trofinetide (0, 300, 900, or 2,000 mg/kg/day) prior to and throughout mating, and continuing in females through gestation day (GD) 7. No impacts were observed on embryofetal development in pregnant rats with similar doses from GD7 to lactation day 20. At the highest dose tested (2,000 mg/kg/day), the plasma exposure (as measured by the area under the concentration-time curve [AUC]) was similar to that observed in humans at the MRHD.

Pregnant rabbits were treated with trofinetide (0, 150, 300, or 600 mg/kg/day) during the period of organogenesis. Although no adverse effects were observed on embryofetal development, maternal toxicity was reported at doses of 300 mg/kg/day and higher, with occurrences of abortions and severely reduced maternal body weight gains. Therefore, while the NOAEL for developmental toxicity was the highest dose of 600 mg/kg/day, the maternal NOAEL was determined to be 150 mg/kg/day, at which the plasma exposure was much lower than that observed in humans at the MRHD.

No adverse effects were observed on pre- and postnatal development in rats treated with trofinetide up to 2,000 mg/kg/day throughout pregnancy and lactation. At the highest dose tested, the plasma exposure (AUC) was similar to that observed in humans at the MRHD.

To evaluate juvenile toxicity, trofinetide was orally administered to juvenile rats from 2 to 28 weeks of age. No adverse effects were observed on growth or neurobehavioural function at doses of 0, 300, 600, or 2,000 mg/kg/day. Test article-related clinical signs included soft feces and increased weight gain and food consumption. Plasma exposures at the highest dose tested were similar to those observed in humans at the MRHD. No adverse effects were observed when these juvenile rats were assessed for sexual maturation or reproductive function after 10 weeks.

Trofinetide was not found to be genotoxic in dedicated in vitro and in vivo genotoxicity assays.

Studies to evaluate the carcinogenic potential of trofinetide have not been conducted.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Daybue Product Monograph. Considering the intended use of Daybue, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Daybue Product Monograph, approved by Health Canada and available through the Drug Product Database.

The quality (chemistry and manufacturing) information submitted for Daybue has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper pharmaceutical development and supporting studies were conducted and an adequate control strategy is in place for the commercial processes. Changes to the manufacturing process and formulation (if any) made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 24 months is acceptable when the drug product is stored between 2 ºC and 8 ºC. Any unused Daybue oral solution must be discarded 14 days after first opening the bottle.

The proposed drug-related impurity limits are considered adequately qualified (e.g., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH] limits and/or qualified from toxicological studies, as needed).

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy.)

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations.

None of the excipients used in the formulation of Daybue is of human or animal origin.