Drugs, Health Technologies, Health Systems
Indication: For the treatment of Rett syndrome in adults and pediatric patients 2 years of age and older and weighing at least 9 kg
Sponsor: Acadia Pharmaceuticals Canada Inc.
Final recommendation: Do not reimburse
Summary
What Is the Reimbursement Recommendation for Daybue?
Canada’s Drug Agency (CDA-AMC) recommends that Daybue not be reimbursed by public drug plans for the treatment of Rett syndrome in adults and pediatric patients 2 years of age and older and weighing at least 9 kg.
Why Did CDA-AMC Make This Recommendation?
Evidence from 1 clinical trial demonstrated that Daybue resulted in improvements in caregiver-reported behavioural symptoms of Rett syndrome and overall clinical improvement according to clinicians, when compared to placebo.
Caregivers of patients with Rett syndrome identified a need for treatments that improve communication skills, motor skills, health-related quality of life (HRQoL), caregiver burden, and other conditions associated with Rett syndrome. However, based on the evidence reviewed in the initial meeting and the reconsideration meeting, the Canadian Drug Expert Committee (CDEC) could not determine if Daybue addresses these needs. The uncertainty was mainly due to a lack of information on whether the results were clinically meaningful, missing data in the study, and a lack of HRQoL data.
Additional Information
What Is Rett Syndrome?
Rett syndrome is a rare genetic condition affecting the development of the nervous system that often results in a loss of language skills, purposeful hand use, and ability to walk. Rett syndrome mostly affects females and is estimated to affect between 1 in 20,000 and 1 in 40,000 people worldwide.
Unmet Needs in Rett Syndrome
There are no therapies available for Rett syndrome that treat the underlying cause of the disease, and current therapies are only supportive and do not sufficiently manage the symptoms. There is a need for safe and effective treatment options that address individual patient needs (e.g., improvements in communication, ability to move, behaviour, and sleep), as well as better HRQoL, caregiver support, and comorbidities of Rett syndrome (e.g., seizures).
How Much Does Daybue Cost?
Treatment with Daybue is expected to cost between $427,331 and $1,335,754 per patient per year, depending upon patient weight.
The Canadian Drug Expert Committee (CDEC) recommends that trofinetide not be reimbursed for the treatment of Rett syndrome in adults and pediatric patients 2 years of age and older and weighing at least 9 kg.
Rett syndrome is a rare, incurable, neurodevelopmental disorder with substantial morbidity that predominantly affects females. There is a lack of effective disease-modifying treatments available, and current supportive therapies do not sufficiently manage the disease. CDEC acknowledged that there is considerable disease heterogeneity, and the absence of standardized outcomes used in clinical practice contribute to the uncertainty in the clinical evidence available to assess the effects of trofinetide. Patients, caregivers, and clinicians identified a need for safe and effective treatments that improve communication skills, motor skills, health-related quality of life (HRQoL), caregiver burden, and symptoms of Rett syndrome; however, based on the available evidence, CDEC could not conclude that trofinetide meets these needs.
Evidence from 1 double-blind randomized controlled trial (the LAVENDER trial, N = 187) in female patients aged 5 to 20 years, weighing at least 12 kg, and diagnosed with classic or typical Rett syndrome, with a documented MECP2 variant, demonstrated that, compared with placebo, 12 weeks of treatment with trofinetide resulted in improvements in neurobehavioural symptoms associated with Rett syndrome as measured by the Rett Syndrome Behaviour Questionnaire (RSBQ) (–3.1 points; 95% confidence interval [CI], –5.7 to –0.6 points) and overall clinical improvement as measured by the Clinical Global Impression – Improvement (CGI-I) scale (–0.3 points; 95% CI, –0.5 to –0.1 points). Although the results for RSBQ and CGI-I scores were statistically significant in favour of trofinetide over placebo, it was uncertain whether the results were clinically meaningful, as no minimal important differences (MIDs) were established. Additionally, 24.7% of patients who received trofinetide and 9.6% of patients who received placebo discontinued from the LAVENDER trial, and up to 16% of patients in the trofinetide group and 9% of patients in the placebo group had missing data for the coprimary end points. There is also limited evidence supporting the use of the RSBQ in measuring treatment effects, and the instrument is not used in clinical practice. Results for other outcomes of importance to patients, caregivers, and clinicians — including communication, motor skills, and caregiver burden — were uncertain due to the lack of standardized measures and a validated MID. Because of these limitations, the committee could not determine if trofinetide addressed these unmet needs or if the results from the trial translate to meaningful benefits in a real-world setting. There was also no comprehensive measure of HRQoL — which is a primary goal of treatment for patients with Rett syndrome and for caregivers — in the pivotal LAVENDER trial, and any impact of trofinetide on this outcome for either patients or caregivers remains unsupported by the current evidence.
Request for reconsideration from the sponsor: The sponsor requested a reconsideration of the initial draft recommendation to not reimburse trofinetide for Rett syndrome. There were 4 issues outlined by the sponsor in the request for reconsideration that were discussed by CDEC: the relevance of the RSBQ as an end point in the trofinetide clinical development program, the meaningfulness of the primary outcomes (RSBQ and CGI-I scores) with respect to the duration of the trial, the totality of the evidence with respect to the unmet needs of patients with Rett syndrome, and the tolerability profile of trofinetide.
Criteria for significant unmet need: CDEC noted that there was uncertainty with the clinical evidence; therefore, the committee deliberated on trofinetide considering the criteria for significant unmet need described in the CDA-AMC Procedures for Reimbursement Reviews. CDEC acknowledged the rarity of this condition and challenges with evidence generation, and concluded that the criteria allowing for additional uncertainty in the evidence were met. However, CDEC concluded that the submitted evidence was insufficient to determine the value of trofinetide as a treatment option for patients with Rett syndrome in Canada. This was also discussed at the reconsideration meeting and CDEC upheld their initial conclusion.
Unmet needs: During the initial and reconsideration meetings, CDEC considered the patient population as well as the rarity and severity of the condition, which requires lifelong treatment; the natural history of the disease; and the lack of disease-modifying treatments indicated for Rett syndrome; all of which represent a significant unmet need for this population. CDEC noted that currently available therapies are only supportive in nature and only partially manage the multisystem symptoms of the disease. Beyond the lack of disease-modifying treatment options, the committee also acknowledged that nonpharmacologic supportive care (e.g., speech therapy, physiotherapy) may not currently be insured for Rett syndrome through public health plans. As such, they discussed how accessing supportive care can add additional financial strain for families unable to access public coverage through alternative diagnoses (e.g., autism spectrum disorder) or without a private insurance plan. While this may create significant inequities in accessing care for all patients with Rett syndrome, the committee noted how this was likely exacerbated for people living in rural or remote locations where specialized supportive care may not be readily available even if funding exists.
Patient and clinician group feedback on the draft recommendation: During the reconsideration meeting, CDEC reviewed feedback on the draft recommendation from 3 patient groups and 2 clinician groups. This feedback emphasized the significant unmet need in treating this rare disease, which currently has no alternative therapeutic options. They also highlighted the consistent and sustained benefits observed with trofinetide, both in the trial evidence and in their own experience, expressing concern that CDEC had not given sufficient weight to caregiver-reported outcomes in its initial assessment. During the reconsideration meeting, CDEC recognized the lived experiences of caregivers, who emphasized that even small improvements can have a profound impact on HRQoL, and that caregivers may be the most accurate interpreters of these changes. CDEC acknowledged the patient and clinician group perspectives, but concluded that the available evidence did not adequately substantiate that trofinetide meets the identified needs, given the considerable disease heterogeneity in Rett syndrome and natural history of the disease; limitations of the available real-world evidence (RWE), with which CDEC was unable to conclude that any treatment effect in the RWE could be attributed to trofinetide; and the experiences of caregivers and clinicians that were not supported by the evidence reviewed by the committee. Further, CDEC was apprehensive about the reproducibility and objectivity of the evidence base, particularly given the limitations identified in the LAVENDER trial, including the short trial duration, high discontinuation rates, potential for functional unblinding, lack of HRQoL measurement, and modest magnitude of benefit.
Relevance of trial outcomes and trial duration: During the initial and reconsideration meetings, CDEC deliberated on the appropriateness of the trial outcomes. CDEC acknowledged that RSBQ score is a disease-specific, caregiver-focused outcome frequently used in clinical trials, which has been accepted by regulatory agencies; however, the committee noted that none of the outcomes used in the trial are standard in clinical practice in Canada, and upheld their initial conclusion that the lack of standardized measures of treatment effect challenges the interpretation of the effect of trofinetide on Rett syndrome. The clinical experts consulted for this review agreed with the FDA assessment that the RSBQ would not be used in isolation (due to its various limitations) and would be used as part of a multidimensional evaluation of treatment effect, including such measures as the CGI-I scale, caregiver reporting, and functional assessments to contextualize changes in RSBQ score. CDEC acknowledged that, given the disease heterogeneity in Rett syndrome, in clinical practice, stabilization or improvement of disease would likely rely on clinician and caregiver judgment. Furthermore, there was a lack of evidence on the impact of trofinetide on HRQoL — which is 1 of the main goals of treatment for this patient population, the lack of which CDEC considered to be a major limitation of the evidence base — or if the drug provides relief of the comorbidities related to Rett syndrome. CDEC also noted that Rett syndrome is a lifelong disease and emphasized that the 12-week duration of the LAVENDER trial was not adequate to determine meaningful, long-term changes in important outcomes such as motor skills, communication, and potential harms. Although there was evidence from the open-label extension (OLE) studies, which provided data for up to 104 weeks, the open-label design, lack of comparator, and potential attrition bias contributed to the uncertainty of the evidence.
Certainty of evidence: CDEC discussed the pivotal evidence submitted for this review, which consisted of 1 phase III randomized controlled trial (the LAVENDER trial). The results for the coprimary end points of change from baseline in RBSQ and CGI-I scores were statistically significant in favour of trofinetide over placebo at 12 weeks (least squares mean difference = –3.1 points [95% CI, –5.7 to –0.6 points] for the RSBQ and –0.3 points [95% CI, –0.5 to –0.1 points] for the CGI-I scale). CDEC highlighted that the Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment of the evidence suggested that the certainty of these results was very low, primarily due to missing data, differences between the trial population and reimbursement request, and lack of established MIDs. During the initial and reconsideration meetings, the committee noted that there were no established or validated MIDs for the coprimary end points, but recognized the thresholds suggested by the clinical experts of a 3-point between-group difference for change from baseline in RBSQ score — which CDEC noted could be as high as 6 points, according to Health Canada — and 1-point between-group difference for CGI-I score. CDEC questioned whether a 3-point change on the 90-point RSBQ is meaningful, given the heterogeneity in Rett syndrome manifestation; the large number of questions and domains, many of which overlap in domains that are difficult to quantify objectively (i.e., potential for differential responses in individual domains of the RSBQ); and the internal validity concerns of the LAVENDER trial (e.g., potential for unblinding and missing data), which challenge the magnitude of effect observed. Furthermore, given the lack of HRQoL measures from the LAVENDER trial, CDEC was unable to contextualize whether a 3-point change resulted in improvements in HRQoL, which is an outcome that is important to patients and caregivers. CDEC noted that while the clinical expert–suggested threshold of 3 points for the RSBQ was reached, the threshold for the CGI-I scale was not achieved. The 95% CI for the RSBQ included the possibility of benefit and no benefit, and for the CGI-I scale there was no benefit. This, in addition to the reasons for the very low certainty of evidence rating, precluded CDEC from making firm conclusions on the effectiveness of trofinetide in patients with Rett syndrome. Furthermore, given that Rett syndrome requires lifelong treatment, CDEC emphasized the uncertainty in the long-term efficacy and safety of trofinetide. CDEC noted that, despite the evidence from the LAVENDER trial and longer follow-up of the OLE studies (the LILAC and LILAC-2 studies), as well as supportive studies and real-world experience, the duration of treatment effect and long-term safety remain unknown.
Harms and treatment withdrawal: During the initial and reconsideration meetings, CDEC discussed the adverse event (AE) profile of trofinetide from the LAVENDER trial, emphasizing the high incidence of diarrhea and vomiting, which occurred in 80.6% and 26.9% of patients in the trofinetide group, compared to 19.1% and 9.6% in the placebo group, respectively. Additionally, CDEC noted the high rate of discontinuation due to AEs in the trofinetide group compared to placebo (17.2% versus 2.1%). Elevated rates of diarrhea and vomiting were also observed in the LILAC and LILAC-2 extension studies, as well as the supportive DAFFODIL and LOTUS studies, with AEs being the primary reason for discontinuation. During the reconsideration meeting, CDEC reviewed the input from the sponsor and patient and clinician groups on the tolerability of trofinetide. The committee acknowledged the various support programs and AE management strategies currently offered by the sponsor, and noted that based on clinician input, the gastrointestinal AEs are typically considered manageable. While CDEC recognized these efforts, the harms and discontinuations reported in the trofinetide clinical development program, as well as the potential unblinding due to AEs in the LAVENDER trial, remain a concern with respect to study validity, magnitude of benefit, and reproducibility. However, CDEC emphasized that these harms were not the primary reason for the “do not reimburse” recommendation; rather, the decision was driven by the uncertainty of the evidence and lack of meaningful clinical benefit associated with trofinetide.
Supportive studies: CDEC discussed the results of 2 OLE studies (the LILAC and LILAC-2 studies) and 2 studies addressing gaps in the evidence (the DAFFODIL and LOTUS studies). Results of the additional supportive studies were generally consistent with the LAVENDER trial. However, CDEC noted limitations of the OLE studies, including the lack of comparator, likelihood of selection bias (the population consisted of patients who had completed the LAVENDER trial [i.e., patients who experienced a response to the treatment and patients who tolerated the treatment]), and high discontinuation rate, which limit the interpretation and generalizability of the results. CDEC noted that the evidence from the DAFFODIL study (N = 15) (a phase II/III study of females aged 2 to 5 years with Rett syndrome and a documented disease-causing MECP2 variant) and the LOTUS study (N = 154) (an ongoing, real-world study of patients with Rett syndrome who have been prescribed trofinetide and are under routine clinical care in the US) may provide information on patients outside of the LAVENDER population. However, the open-label designs, lack of blinding, and lack of comparator group in both studies, as well as the small sample size in the DAFFODIL study, prevented CDEC from making firm conclusions on the treatment effect of trofinetide on patients outside of the LAVENDER population.
New data and totality of evidence: As part of the reconsideration meeting, CDEC discussed the totality of evidence provided during the initial review of trofinetide (including the LAVENDER, LILAC, LILAC-2, DAFFODIL, and LOTUS studies), as well as new information submitted by the sponsor, which included a survey of an externally-led, patient-focused meeting; a natural history study of patients with Rett syndrome; a post hoc, domain-level analysis of the RSBQ from the LAVENDER study; and 9 months of data from the LOTUS study. CDEC considered the additional evidence provided by the sponsor, acknowledging that it was supportive of the findings reviewed during the initial meeting; however, CDEC did not consider the additional evidence provided to be sufficient to support a recommendation to reimburse trofinetide.
Rett syndrome is a rare neurodevelopmental disorder characterized by normal early development followed by a progressive loss of speech, purposeful hand use, and motor skills. Rett syndrome is most often caused by genetic variants in MECP2 located on the X chromosome, primarily affecting females, although it can occur in males in rare cases. The disorder progresses through 4 stages, which are categorized based on speed of development, regression of learned skills, appearance of symptom stabilization, and late motor deterioration. According to a natural history study of females with genetically-confirmed disease who contributed data to the Australian Rett Syndrome Database between 2000 and 2019, RSBQ scores were shown to gradually decline (i.e., suggesting behavioural improvements) with increasing age over a 10- to 14-year observation period. Patients living with Rett syndrome require lifelong care and assistance with daily activities, significantly impacting both the patients and their caregivers. Rett syndrome is clinically diagnosed based on criteria that differentiate between classic and atypical disease. Although mutations in MECP2 are neither necessary nor sufficient for the diagnosis of Rett syndrome, the majority of individuals with Rett syndrome have an MECP2 variant. Detection of pathogenic MECP2 variants confirms the diagnosis; however, MECP2 variants may not be detected in up to 5% of typical Rett syndrome cases and approximately 25% of atypical cases. A one-time genetic test for MECP2 mutations is recommended by Rett syndrome specialists for establishing or confirming a molecular diagnosis in patients with suspected Rett syndrome. The availability and reimbursement status of MECP2 testing vary across jurisdictions in Canada, and this information was not readily available for all provinces and territories. Rett syndrome is estimated to affect 1 in 10,000 females aged 12 years and younger, with a worldwide prevalence of 1 in 20,000 to 1 in 40,000. According to the sponsor, the estimated prevalence is between 600 and 900 cases in Canada, based on extrapolation of US epidemiological data.
The panel of experts consulted for this review stated that improving HRQoL is 1 of the main goals when treating Rett syndrome. Currently there are no Health Canada–approved therapies or disease-modifying treatments indicated for this disease. Available therapies are supportive in nature and only partially manage the multisystem symptoms of the disease. Pharmacological treatments for symptom management can include drugs for seizures, bone health, contractures, gastrointestinal disturbances, sleep, anxiety, and pain. Nonpharmacological treatments are used to optimize developmental potential, promote communication, and treat musculoskeletal complications, and can include physical and occupational therapy, speech therapy, and surgery.
Trofinetide has been approved by Health Canada for the treatment of Rett syndrome in adults and pediatric patients aged 2 years and older and weighing at least 9 kg. Trofinetide is a synthetic analogue of the N-terminal tripeptide of insulin-like growth factor 1. It is available as a 200 mg/mL solution for oral or gastrostomy tube administration twice a day, and the dosage recommended in the product monograph is based on body mass. The twice daily recommended dose for patients weighing 9 kg to less than 12 kg is 4 g, 12 kg to less than 20 kg is 6 g, 20 kg to less than 35 kg is 8 g, 35 kg to less than 50 kg is 10 g, and 50 kg or greater is 12 g.
To make its recommendation, the committee considered the following information:
a review of 1 phase III, double-blind, placebo-controlled clinical trial in patients aged 5 to 20 years with classic or typical Rett syndrome and a documented disease-causing MECP2 variant (the LAVENDER trial); 2 long-term extension studies (the LILAC and LILAC-2 studies); and 2 open-label studies included in the Studies Addressing Gaps in Systematic Review Evidence section (the DAFFODIL and LOTUS studies)
patients’ perspectives gathered by 3 patient groups, including the Ontario Rett Syndrome Association, Cure Rett Canada, and the International Rett Syndrome Foundation
input from public drug plans that participate in the Reimbursement Review process
input from 3 clinical specialists with expertise diagnosing and treating patients with Rett syndrome
input from 1 clinician group, the Canadian Rett Syndrome Consortium (including Acadia Pharmaceuticals Inc. advisory board members for trofinetide)
a review of the pharmacoeconomic model and report submitted by the sponsor
a review of relevant ethical issues related to trofinetide
information submitted as part of the sponsor’s request for reconsideration (described subsequently)
feedback on the draft recommendation.
CDA-AMC received patient group input from 3 organizations. The Ontario Rett Syndrome Association — with support from Rett syndrome advocacy groups from Quebec, Manitoba, Saskatchewan, Alberta, and British Columbia — provided an overview of the challenges experienced by patients living with Rett syndrome in Canada and their caregivers, with data gathered from a series of surveys for caregivers to share their unique experiences related to caring for an individual living with Rett syndrome in Canada. Input received from Cure Rett Canada and the International Rett Syndrome Foundation included information from families and caregivers of patients with Rett syndrome about their experiences with trofinetide.
The groups stated that Rett syndrome is a rare and devastating neurodevelopmental disorder that impacts nearly every aspect of an individual’s life, including their ability to speak, walk, eat, and breathe, with about 80% to 90% of patients experiencing epilepsy. Patients often have severe physical and cognitive impairments, communication difficulties, sensory sensitivities, and behavioural issues (such as anxiety, agitation, and mood disorders), as well as respiratory problems, gastrointestinal issues, cardiac abnormalities, and osteoporosis. Caregivers not only face emotional and physical exhaustion but also financial challenges, as they may need to reduce working hours or quit their jobs to provide full-time care. Rett syndrome can disrupt family dynamics, put a strain on relationships, and affect the well-being of siblings and other family members.
The input received from caregivers described how current treatments for Rett syndrome in Canada focus on symptom management, with the use of antiseizure medications and surgical interventions, as well as physical, occupational, and speech therapies. Caregivers reported dissatisfaction with the slow progress of symptom management, particularly with respect to motor skills and communication.
The patient groups stated that any new therapies that result in minor improvements in motor function would result in HRQoL benefits for patients living with Rett syndrome. There is also a need for better treatment options that could lead to improvements in communication abilities and behavioural and emotional stability, as well as a reduction in seizures, gastrointestinal issues, and respiratory problems. According to the groups, trofinetide may represent a novel treatment option for patients who have not experienced an adequate response to existing therapies or who are seeking alternatives to current management strategies. Among patients who have had experience with trofinetide, there were reported improvements in patient motor function and hand use, communication abilities, behaviour, and HRQoL, as well as a reduction in seizures. Common side effects included gastrointestinal disturbances, fatigue, and irritability, which may have impacted drug tolerability and adherence to treatment.
According to the panel of experts consulted for this review, 1 of the main unmet needs of patients with Rett syndrome is that there are no approved disease-modifying treatments in Canada, and current supportive therapies do not sufficiently manage the disease. In general, there is a need for treatment that promotes better HRQoL and addresses the individualized needs of a patient (which may include treatment for seizures and issues with communication, motor skills, cognition, behaviour, feeding, and sleep). Therapies that better support families as well as patient and caregiver daily activities are also important.
The experts stated that patients would not have to exhaust supportive therapies before accessing trofinetide. Once a diagnosis of Rett syndrome is confirmed, trofinetide would be used as a first-line therapy along with other drugs and nonpharmacological supportive therapies to manage symptoms, as outlined in the care management guidelines.
The clinical experts stated that, at this time, there are no specific characteristics or markers that would identify a group of patients who would benefit more from trofinetide. Despite the available evidence from the LAVENDER trial, the experts indicated that patients aged 2 years or older with a confirmed clinical diagnosis of classic Rett syndrome (with or without a disease-causing MECP2 variant) or atypical Rett syndrome (with a disease-causing MECP2 variant) would be suitable candidates for receiving trofinetide. The clinicians also noted that there is a small part of the population that is clinically diagnosed with Rett syndrome but does not have an MECP2 variant, and if these patients are diagnosed by Rett syndrome experts, they may also be candidates for trofinetide. However, the experts agreed that they would not treat patients with atypical Rett syndrome without a confirmed MECP2 variant. The experts explained that Rett syndrome may be suspected clinically as early as 2 years of age, and once a patient has a confirmed diagnosis, it would be reasonable to start treatment at that time. One expert also highlighted that they would not treat patients who weigh less than 9 kg with trofinetide, as there are added concerns with diarrhea, hydration, and nutrition.
Clinicians routinely record developmental and functional history to track changes in a patient and to help determine if there are clinical responses to treatment. The family’s perspective, caregiver reports (including the primary care physician, specialists, therapists, and educational assistants in the school), and physician symptom assessments were highlighted as being valuable for providing detailed insight into a patient’s day-to-day wellness and needs that lead to changes in care management. The experts stated that they would assess whether a drug was beneficial in a meaningful way to the patient and caregivers and if HRQoL improved while being balanced with the adverse effects patients can experience. The clinical experts confirmed that there are currently no standard outcomes used in clinics across Canada for measuring response to treatment, and that the outcomes used in the LAVENDER trial are not used in clinical practice.
When deciding to discontinue treatment, the experts stated that adverse effects (specifically vomiting, diarrhea, dehydration, and weight loss), hospitalization due to adverse effects, and the impact on the patient’s HRQoL are factors to consider and discuss with the caregivers. There were different perspectives on deciding when to discontinue treatment, with 1 expert suggesting an adequate trial of trofinetide at the target dose for 3 months (based on the duration of the LAVENDER trial) and others suggesting 6 to 12 months at the target dose to avoid premature discontinuation, should benefits only be observed after at least 3 months of use. The experts also suggested that if there were no improvement or clinical change despite an adequate trial of trofinetide at the target dose, it would be reasonable to trial off the medication and evaluate if there is a difference. If there were an abrupt decline in the patient’s health during the trial off the medication, the experts suggested restarting treatment. The clinical experts noted that this approach would also be taken for patients outside of the LAVENDER population (i.e., males, patients older than 20 years). Overall, they agreed that most families would not continue treatment with trofinetide if they believed that the patient was not benefiting from the treatment.
The experts noted that they may follow up with patients more often when starting a new treatment or if the disease is not stable. Additionally, they stated that consultation with the patient’s primary care team, who the patient and caregivers have more regular interactions with (particularly for monitoring and treating adverse effects), is important. They suggested that patients starting trofinetide may see Rett syndrome specialists at 1 month after initiation, at 3 months, and less frequently if they are stable.
The experts indicated that Rett syndrome specialists, as well as pediatricians and neurologists with expertise in Rett syndrome, would prescribe trofinetide at first because it is a new medication. However, it was noted that as experience with the drug increases, it may be possible for other physicians to prescribe the drug to improve access to patients in remote areas and outside major cities where specialists practice.
The Canadian Rett Syndrome Consortium (including Acadia Pharmaceuticals Inc. advisory board members for trofinetide) provided input for this review. The input included 6 clinicians consisting of pediatric neurologists, developmental pediatricians, and medical geneticists in Canada.
The clinician group stated that, in Canada, there is currently no approved treatment for Rett syndrome (aside from trofinetide) and existing medications focus on managing disease symptoms only. The group stated that no medications to date have targeted the underlying biology or course of the disease and the deteriorating developmental trajectory characteristic of Rett syndrome. According to the group input, trofinetide is unique in this space and first in class, although its exact mechanism of action is unknown. The clinician group input was consistent with the clinical experts consulted for this review, noting that trofinetide would be used as a first-line treatment and that other medications may be added to address associated symptoms tailored to an individual patient's needs.
Outcomes used to determine whether a patient is experiencing a response to trofinetide would rely on caregiver reports. A clinically meaningful response to treatment would include improvements in communication, alertness, engagement, and respiratory symptoms; the ability to move independently; and decreases in repetitive movements or stereotypies. The clinician group anticipates that trofinetide would initially be prescribed in specialized medical centres on an outpatient basis, and then over time, with education and experience, by community physicians, such as pediatricians or internists. Considerations for discontinuing trofinetide include no improvement in symptoms after 6 to 12 months of therapy, and persistent moderate to severe diarrhea or vomiting with weight loss that is not controlled with appropriate medications or by lowering the dose of trofinetide.
Input was obtained from the drug programs that participate in the Reimbursement Review process. The following were identified as key factors that could potentially impact the implementation of a recommendation for trofinetide:
considerations for initiation of therapy
considerations for continuation or renewal of therapy
considerations for discontinuation of therapy
considerations for prescribing of therapy
generalizability of trial populations to the broader populations in the jurisdictions
care provision issues
system and economic issues.
The clinical experts consulted for the review provided advice on the potential implementation issues raised by the drug programs.
One phase III, double-blind, randomized controlled trial (the LAVENDER trial; N = 187) of female patients aged 5 to 20 years and weighing at least 12 kg, diagnosed with classic or typical Rett syndrome with a documented disease-causing MECP2 variant, assessed the efficacy and safety of trofinetide 200 mg/mL (n = 93), twice a day, compared to placebo (n = 94) at 12 weeks. Efficacy was measured through coprimary end points of RSBQ total score and CGI-I score, while other clinically relevant outcomes included communication (through nonverbal means and symbolic behaviours). Outcomes relating to physical function, HRQoL, and caregiver burden were noted as being important to patient and clinician groups and were included as supportive evidence (GRADE was not applied), where data were available from the sponsor’s submission.
The LAVENDER trial included only females with Rett syndrome, and the mean age of patients was 11.0 years (standard deviation [SD] = 4.7) and 10.9 years (SD = 4.6) in the trofinetide and placebo groups, respectively. Clinical characteristics were generally balanced between the groups and the mean Clinical Global Impression – Severity (CGI-S) score was 4.9 points (SD = 0.8) for both groups, indicating that patients were moderately or markedly ill. Disease history was generally similar between the groups.
The RSBQ is a 45-item, caregiver-completed assessment with 8 subscales evaluating various neurobehavioural symptoms known to affect patients with Rett syndrome, with ratings of 0 (not true), 1 (somewhat or sometimes true), and 2 (very true). A total score is calculated as the sum of the ratings for all 45 items and ranges from 0 to 90, where higher scores indicate symptoms are more frequent. No MID was identified from the literature, and clinical expert opinion indicated that a between-group difference of 3 would be meaningful.
The mean change from baseline in RSBQ score was –4.9 points (standard error [SE] = 0.9) and –1.7 points (SE = 0.9) in the trofinetide and placebo groups, respectively, resulting in a between-group difference of –3.1 points (95% CI, –5.7 to –0.6; P = 0.0175).
The CGI-I scale is a clinician-rated scale ranging from 1 (very much improved) to 7 (very much worse), used to assess improvement or worsening compared to baseline. Disease-specific anchors were used to guide the assessor, and anchor descriptions included characterization of impairment levels across core Rett syndrome signs and symptoms. No MID was identified from the literature and clinical expert opinion indicated that a between-group difference of 1 would be meaningful.
The mean CGI-I score at week 12 was 3.5 points (SE = 0.1) for the trofinetide group and 3.8 points (SE = 0.1) for the placebo group, resulting in a between-group difference of –0.3 points (95% CI, –0.5 to –0.1; P = 0.0030).
The Rett Syndrome Clinician Rating of Ability to Communicate Choices (RTT-COMC) is a clinician-completed instrument that assesses a patient’s ability to communicate choices (including through nonverbal means), using a Likert scale ranging from 0 (normal functioning) to 7 (most severe impairment). No MID was identified from the literature and there was no suggested meaningful threshold based on clinical expert opinion.
The mean change from baseline in RTT-COMC score was –0.4 points (SE = 0.1) and 0.0 points (SE = 0.1) in the trofinetide and placebo groups, respectively, resulting in a between-group difference of –0.3 points (95% CI, –0.6 to 0.0).
The Communication and Symbolic Behaviour Scales Developmental Profile Infant-Toddler (CSBS-DP-IT) checklist is a caregiver-completed assessment for communication and prelinguistic skills in young children and older children with developmental delays. Each item is rated on a scale of 0 (not yet), 1 (sometimes), or 2 (often). The Social Composite score of the checklist (including emotion and eye gaze, communication rate and function, and gestures) consists of items 1 to 13, and scores range from 0 to 26, where higher scores indicate better social communication development. No MID was identified from the literature and there was no suggested meaningful threshold based on clinical expert opinion.
The mean change from baseline in the CSBS-DP-IT checklist social composite score was –0.1 points (SE = 0.3) in the trofinetide group and –1.1 points (SE = 0.3) in the placebo group, resulting in a between-group difference of 1.0 points (95% CI, 0.3 to 1.7; P = 0.0064).
There was no information on HRQoL in the LAVENDER trial.
The Rett Syndrome Clinician Rating of Hand Function (RTT-HF) (measuring the ability to use hands for functional purposes), Rett Syndrome Clinician Rating of Ambulation and Gross Motor Skills (RTT-AMB) (measuring the ability to sit, stand, and ambulate), and Rett Syndrome Clinician Rating of Verbal Communication (RTT-VCOM) (measuring the ability to communicate verbally) scales are clinician-completed, disease-specific instruments that rate a patient’s abilities from 0 (normal functioning) to 7 (most severe impairment). The between-group difference for the RTT-HF score was –0.1 points (95% CI, –0.3 to 0.1), for the RTT-AMB score was –0.1 points (95% CI, –0.3 to 0.1), and for the RTT-VCOM score was 0.0 points (95% CI, –0.2 to 0.2).
The patient’s overall quality of life was rated from 1 (poor) to 6 (excellent). The between-group difference for the overall quality of life rating was 0.1 points (95% CI, –0.1 to 0.4).
The Rett Syndrome Caregiver Burden Inventory (RTT-CBI) is completed by the caregiver to assess the burden of caring for the patient on their daily life in 4 areas (physical burden, emotional burden, social burden, and time dependence). Caregivers rate how often a statement describes their feelings or experiences, with frequency rated on a Likert scale from 0 (never) to 4 (nearly always). Items 1 to 24 yield a total burden score from 0 to 96, and items 25 and 26 make up the optimism index (which were not used in the analyses). Higher scores indicate greater burden on the caregiver. The between-group difference for the RTT-CBI total score was –0.8 points (95% CI, –3.5 to 2.0).
In the LAVENDER trial, 92.5% of patients in the trofinetide group and 54.3% of patients in the placebo group experienced at least 1 treatment-emergent adverse event (TEAE). Diarrhea and vomiting were the most common TEAEs and were imbalanced between the treatment groups: 80.6% of patients in trofinetide group and 19.1% of patients in the placebo group reported diarrhea, while 26.9% of patients in the trofinetide group and 9.6% of patients in the placebo group reported vomiting. In the trofinetide group, 2.2%, 36.6%, and 41.9% of patients experienced severe, moderate, and mild diarrhea, respectively, while 1.1%, 6.5%, and 19.4% of patients experienced severe, moderate, and mild vomiting, respectively. In the trofinetide group, 3 patients (3.2%) reported 5 serious adverse events (SAEs), and in the placebo group, 3 patients (3.2%) reported 3 SAEs. During the study, 17.2% of patients in the trofinetide group and 2.1% of patients in the placebo group stopped treatment due to TEAEs; the most frequently reported TEAE leading to treatment discontinuation was diarrhea (12.9% in the trofinetide group and 0% in the placebo group). There were no deaths in the study.
TEAEs considered clinically important by the clinical experts and noted in the product monograph included diarrhea and vomiting, which have been described.
Reports of TEAEs were imbalanced between the treatment groups, particularly for diarrhea and vomiting. This most likely resulted in functional unblinding and may impact the ratings of assessors who were aware of a patient’s TEAEs (e.g., caregivers, clinicians). Furthermore, efficacy outcomes were subjective in nature and there is the potential for overestimation of the treatment effect if the suspected treatment assignment was revealed to the assessors. The RSBQ was originally developed as a diagnostic tool rather than a measure of treatment effect. The RTT-COMC and the CSBS-DP-IT checklist’s Social Composite score have not been validated in patients with Rett syndrome, and both Health Canada and the FDA indicated that the latter was not adequate for establishing efficacy of trofinetide. No MIDs were identified from the literature for any of the trial outcomes. Moreover, the clinical experts consulted for this review stated that the trial outcomes are not commonly used in practice, and there are no standardized measures used across clinics in Canada. The greatest number of patients who discontinued study treatment was from the trofinetide group, and the difference between groups was large. This introduces the potential for bias against the null, as the data driving the model were largely from those who stayed in the study and were likely better responders and had fewer TEAEs. The investigators assumed data were missing at random, which is not supported by the differential losses to follow-up and reasons for discontinuations.
The Health Canada indication is broader than the trial population. The LAVENDER trial did not enrol patients who were male, aged younger than 5 years or older than 20 years, did not have classic or typical Rett syndrome, did not have a confirmed disease-causing MECP2 variant, were not at least 6 months postregression, did not have a CGI-S score of at least 4, and did not have stable standard therapies or a stable pattern of seizures. The panel of experts consulted for this review indicated that patients would be treated with trofinetide if there were a confirmed clinical diagnosis of classic Rett syndrome (with or without a disease-causing MECP2 variant) or atypical Rett syndrome (with a disease-causing MECP2 variant). Patients without an MECP2 variant would have to have a confirmed clinical diagnosis of classic Rett syndrome to receive trofinetide, but those without an MECP2 variant and with an atypical Rett syndrome diagnosis would not receive trofinetide, due to lack of evidence in this population. Because none of the LAVENDER outcomes are used in clinical practice, it is challenging to apply the results to a real-world setting. There was no comprehensive measure of HRQoL, and it is uncertain how trofinetide impacts this outcome, which is an important treatment goal in managing Rett syndrome. The LAVENDER trial had a duration of 12 weeks, which is not long enough to assess meaningful, long-term changes in motor skills, communication, and harms in patients with Rett syndrome.
For pivotal studies and randomized controlled trials identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to inform expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group.
Following the GRADE approach, evidence from randomized controlled trials started as high-certainty evidence and could be rated down for concerns related to study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.
When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null.
The selection of outcomes for GRADE assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members:
RSBQ total score
CGI-I score
RTT-COMC score
CSBS-DP-IT checklist Social Composite score.
Table 1: Summary of Findings for Trofinetide vs. Placebo for Patients With Rett Syndrome
Outcome and follow-up | Patients (studies), N | Absolute effects | Certainty | What happens | ||
|---|---|---|---|---|---|---|
Placebo | Trofinetide | Difference (95% CI) | ||||
RSBQ total score | ||||||
RSBQ total score (0 [less frequent symptoms] to 90 [more frequent symptoms]) Follow-up: 12 weeks | 187 (1 RCT) | –1.7 | –4.9 (SE = 0.9) | –3.1 (–5.7 to –0.6) | Very lowa | The evidence is very uncertain about the effect of trofinetide on RSBQ total score when compared with placebo. |
CGI-I score | ||||||
CGI-I score (1 [very much improved] to 7 [very much worse]) Follow-up: 12 weeks | 187 (1 RCT) | 3.8 | 3.5 (SE = 0.1) | –0.3 (–0.5 to –0.1) | Very lowb | The evidence is very uncertain about the effect of trofinetide on CGI-I score when compared with placebo. |
RTT-COMC score | ||||||
RTT-COMC score (0 [normal functioning] to 7 [most severe impairment]) Follow-up: 12 weeks | 187 (1 RCT) | 0.0 | –0.4 (SE = 0.1) | –0.3 (–0.6 to 0.0) | Very lowc,d | The evidence is very uncertain about the effect of trofinetide on RTT-COMC score when compared with placebo. |
CSBS-DP-IT checklist Social Composite score | ||||||
CSBS-DP-IT checklist Social Composite score (0 [worst] to 26 [best]) Follow-up: 12 weeks | 187 (1 RCT) | –1.1 | –0.1 (SE = 0.3) | 1.0 (0.3 to 1.7) | Lowe | Trofinetide may result in an increase in prelinguistic communication skills when compared with placebo. The clinical importance of the increase is unclear. |
HRQoL | ||||||
NR | NA | NA | NA | NA | NA | There is no evidence for the effect of trofinetide on HRQoL. |
CI = confidence interval; CGI-I = Clinical Global Impression – Improvement; CSBS-DP-IT = Communication and Symbolic Behaviour Scales Developmental Profile Infant-Toddler; HRQoL = health-related quality of life; MID = minimal important difference; NA = not applicable; NR = not reported; RCT = randomized controlled trial; RSBQ = Rett Syndrome Behaviour Questionnaire; RTT-COMC = Rett Syndrome Clinician Rating of Ability to Communicate Choices; SE = standard error; vs. = versus.
Note: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.
aRated down 1 level for serious study limitations (risk of bias due to missing data [results missing for 16% and 9% of trofinetide and placebo groups, respectively], potential for functional unblinding due to differences in harms, and instrument not being widely used in clinical practice for measuring treatment effect). Rated down 1 level for serious indirectness (trial population is narrower than the Health Canada indication and requested reimbursement population; results based on the trial population may not be generalizable to the Health Canada–indicated population). Rated down 1 level for serious imprecision (based on a clinical expert–suggested meaningful threshold of 3; CI for difference between groups includes possibility of a difference that is not clinically meaningful).
bRated down 1 level for serious study limitations (risk of bias due to missing data [results missing for 15% and 8% of trofinetide and placebo groups, respectively] and instrument not being widely used in clinical practice for measuring treatment effect). Rated down 1 level for serious indirectness (trial population is narrower than the Health Canada indication and requested reimbursement population; results based on the trial population may not be generalizable to the Health Canada–indicated population). Rated down 2 levels for very serious imprecision (based on a clinical expert–suggested meaningful threshold of 1; CI for difference between groups suggests no difference).
cRated down 1 level for serious study limitations (risk of bias due to missing data [results missing for 16% and 12% of trofinetide and placebo groups, respectively]; potential for functional unblinding due to differences in harms; lack of evidence supporting the instrument’s validity, reliability, or responsiveness; and instrument not being widely used in clinical practice for measuring treatment effect). Rated down 1 level for serious indirectness (trial population is narrower than the Health Canada indication and requested reimbursement population; results based on the trial population may not be generalizable to the Health Canada–indicated population). Rated down 2 levels for very serious imprecision (no known MID, so the target of certainty appraisal was any effect; CI for difference between groups includes the possibility of no difference).
dStatistical testing for this outcome was not adjusted for multiplicity. The results are considered as supportive evidence.
eRated down 1 level for serious study limitations (risk of bias due to missing data [results missing for 20% and 13% of trofinetide and placebo groups, respectively]; potential for functional unblinding due to differences in harms; lack of evidence supporting the instrument’s validity, reliability, or responsiveness; and instrument not being widely used in clinical practice for measuring treatment effect). Rated down 1 level for serious indirectness (trial population is narrower than the Health Canada indication and requested reimbursement population; results based on the trial population may not be generalizable to the Health Canada–indicated population). There was no known MID, so the target of certainty appraisal was any effect.
Source: LAVENDER Clinical Study Report and sponsor’s Summary of Clinical Evidence. Details included in the table are from the sponsor’s Summary of Clinical Evidence.
Two OLE studies, the LILAC (N = 154) and LILAC-2 (N = 77) studies, have been summarized to provide evidence regarding the long-term safety and tolerability of trofinetide in females with Rett syndrome. Patients who completed the LAVENDER trial could enrol in the LILAC study (a 40-week OLE study), and upon completion, could continue in the LILAC-2 study, an OLE study of up to 32 months of additional treatment time. Inclusion and exclusion criteria were consistent with those of the LAVENDER trial. All patients received trofinetide in these studies. Seventy patients (45.5%) withdrew early from the LILAC study, primarily due to TEAEs, with 84 patients (54.5%) completing the study. In the LILAC-2 study, most patients (79.2%) discontinued due to the study's termination following market approval, while 5 patients (6.5%) discontinued due to TEAEs and 4 patients (5.2%) died.
Demographic characteristics in the LILAC and LILAC-2 studies were similar to those in the LAVENDER trial. The mean age of patients was 11.0 years (SD = 4.6) in the LILAC study and 12.0 years (SD = 4.4) in the LILAC-2 study. The mean baseline CGI-S score was 4.8 (SD = 0.8) in the LILAC study and 4.8 (SD = 0.9) in the LILAC-2 study, and most patients were moderately ill (36.4% and 41.6%) or markedly ill (41.6% and 31.2%) in the 2 studies, respectively. Dosing in the OLE studies was weight-based, using the same weight bands that were used in the LAVENDER trial.
The primary outcomes in both the LILAC study and the LILAC-2 study focused on safety, including TEAEs, SAEs, withdrawals due to TEAEs, and potentially clinically important changes in other safety assessments. Relevant secondary and exploratory efficacy outcomes included RSBQ score, CGI-I score, RTT-COMC score, CSBS-DP-IT checklist Social Composite score, RTT-HF score, RTT-AMB score, RTT-VCOM score, overall quality of life rating, and RTT-CBI score at various time points across both studies. For both OLE studies, all results were summarized using descriptive statistics, performed using the safety analysis set unless otherwise noted.
Patients who received trofinetide in the LAVENDER trial showed a decrease in RSBQ total scores from the LAVENDER baseline, with a mean change of –7.3 points (SD = 10.7) at week 40 in the LILAC study (N = 44) and –9.8 points (SD = 11.2) at week 104 in the LILAC-2 study (N = 10). Patients who received placebo in the LAVENDER trial also experienced decreases from the LAVENDER baseline after switching to trofinetide in the LILAC study, with mean changes of –7.0 points (SD = 10.7) at week 40 in the LILAC study (N = 44) and –13.8 points (SD = 12.0) at week 104 in the LILAC-2 study (N = 11). Overall, patients who tolerated trofinetide showed at least a 5-point decrease in RSBQ total score, which persisted throughout the extension studies.
For both OLE studies, changes in CGI-I score were assessed relative to the patient’s baseline state of illness in the LILAC study. As such, there were no CGI-I scores assessed for the baseline visit in the LILAC study. Overall, mean CGI-I scores remained stable over time among patients in the OLE studies.
Other efficacy outcomes, including RTT-COMC score, CSBS-DP-IT checklist Social Composite score, RTT-HF score, RTT-AMB score, RTT-VCOM score, overall quality of life rating, and RTT-CBI score, generally remained stable over time among patients who continued in the OLE studies.
In the LILAC study, 132 patients (85.7%) reported at least 1 TEAE, with diarrhea (59.1%), vomiting (25.3%), and COVID-19 (11.0%) being the most common. SAEs occurred in 19 patients (12.3%), and 48 patients (31.2%) had TEAEs leading to drug discontinuation, primarily due to diarrhea (19.5%) and vomiting (5.8%). In the LILAC-2 study, 68 patients (88.3%) reported at least 1 TEAE, with COVID-19 (26.0%), diarrhea (16.9%), pyrexia (16.9%), and urinary tract infection (15.6%) being the most common. SAEs occurred in 23 patients (29.9%), and 6 patients (7.8%) discontinued the drug. The most common SAEs were seizures (6.5%), followed by vomiting, pneumonia, urinary tract infection, and acute respiratory failure (2.6% each). A total of 4 deaths were reported, of which 3 (3.9%) were reported as TEAEs (cardiac arrest, aspiration and vomiting, and sudden unexpected death in epilepsy in 1 patient each).
The OLE studies provided longer-term efficacy and safety data on trofinetide for up to 104 weeks. The open-label design increases the potential for bias, particularly in subjective outcomes and reporting of AEs. Because completion of the pivotal trial was required for enrolment, patients who discontinued from the LAVENDER trial were excluded, resulting in a patient population that was more tolerant of and responsive to trofinetide and introducing selection bias. Additionally, with a high discontinuation rate in the LILAC study (45.5%), mainly due to TEAEs, the impact of patient dropout on outcomes is unclear, as analyses were not conducted to assess how discontinuation affected treatment results.
No indirect treatment comparisons were submitted for the review of trofinetide.
Two studies have been summarized to provide additional evidence to the systematic review. The DAFFODIL study was a multicentre, open-label, long-term, phase II/III study in the US that provided evidence regarding the efficacy and safety of trofinetide in females aged 2 to 5 years with Rett syndrome. The LOTUS study is an ongoing, phase IV, observational, real-world study of patients prescribed trofinetide under routine clinical care in the US for up to 24 months, with interim results at 6 months submitted by the sponsor.
The DAFFODIL study enrolled 15 female patients in the US living with Rett syndrome, with an MECP2 variant, and with a CGI-S score of 4 or greater at screening and baseline. Eligible patients were aged 2 to 4 years with a body mass ranging from 9 kg to less than 20 kg, or aged 5 years with a body mass ranging from 9 kg to less than 12 kg. Aside from the age restriction, the inclusion and exclusion criteria were comparable to those used in the pivotal trial. The mean age at the time of diagnosis was 1.9 years (SD = 0.1). Trofinetide was dosed by weight and administered orally or by gastrostomy tube.
In total, 154 patients were included in the interim analysis of the LOTUS study. Most patients had classic Rett syndrome (66.7%) and were female (96.1%), and the age of patients in the study ranged from 2 to 60 years. The mean age at the time of diagnosis was 5.2 years (SD = 5.37), and the mean age at the time of trofinetide initiation was 16.5 years (SD = 11.16). There are no exclusion criteria in the study.
Relevant exploratory efficacy outcomes in the DAFFODIL study included CGI-I score from baseline to week 104 and overall quality of life rating. In both studies, safety assessments were based on the proportion of patients experiencing TEAEs, SAEs, and withdrawals due to TEAEs. Efficacy and safety data were summarized using descriptive statistics in both studies.
In the DAFFODIL study, the mean CGI-I score decreased from week 2 (n = 13) through to week 78 (n = 9), from 3.5 (SD = 0.66) to 2.2 (SD = 0.67). The mean change from baseline in overall quality of life rating at week 12 was 0.3 (SD = 0.72) and continued to increase through to week 78, with a mean change of 0.7 (SD = 0.95).
In the DAFFODIL study, safety outcomes were similar to those of the pivotal and OLE studies. In total, 14 patients (93.3%) experienced at least 1 TEAE, the most common being diarrhea (73.3%) and vomiting (46.7%). Four patients (26.7%) reported SAEs and 2 patients (13.3%) experienced TEAEs leading to drug and study discontinuation. As of the latest LOTUS interim analysis (with data up to June 26, 2024), 22 patients (11.5%) reported 57 TEAEs, with diarrhea, vomiting, constipation, and insomnia being the most common. Six patients (3.1%) reported SAEs (constipation, diarrhea, vomiting, viral gastroenteritis, pneumonia, pneumonia aspiration, and dehydration) and 14 patients (7.3%) withdrew due to a TEAE. No deaths were reported in either study.
The longer-term harms data from both the DAFFODIL study and the LOTUS study are generally consistent with those from the pivotal trial, with diarrhea and vomiting being the most common. While the 2 studies attempted to fill the evidence gaps for patients aged 2 to 5 years (in the DAFFODIL study), or patients aged 20 years or older, diagnosed with atypical disease, or who are male (in the LOTUS study), there remains uncertainty in the study results due to various limitations with the data. Neither study was designed to assess the efficacy and safety of trofinetide in a statistically rigorous manner. Other limitations include potential selection bias, lack of blinding, small study population (in the DAFFODIL study), and lack of comparator group, which may have affected the internal validity of the safety and efficacy results. In addition, the lack of blinding could have introduced bias in the reporting of subjective AEs in favour of trofinetide, if patients and/or caregivers believed the drug was beneficial.
In addition to consultation with clinical experts, patient group, clinician group, and drug plan input was reviewed to identify ethical considerations specific to the use of trofinetide for the treatment of Rett syndrome in adults and pediatric patients aged 2 years and older weighing at least 9 kg.
Diagnostic complexity and equity concerns: Rett syndrome includes classic and atypical forms, which differ in patterns of regression and severity. While 95% to 97% of classic cases and 50% to 70% of atypical cases are associated with pathogenic MECP2 mutations, some individuals lack identifiable genetic variants, adding complexity to diagnosis and treatment planning. Although it is not required for the diagnosis of Rett syndrome, clinical experts indicated that genetic confirmation is commonly pursued and generally accessible in Canada. Patient group input noted that families in rural areas may face greater challenges in accessing genetic testing, raising concerns about equity. The phenotypic variability of Rett syndrome, even among those with MECP2 mutations, further complicates efforts to predict disease progression and develop equitable and broadly applicable treatment options. This variability also poses challenges for defining treatment eligibility, as relying solely on clinical diagnosis or genetic status may inadvertently exclude some individuals who could benefit.
Challenges in caregiving and burden of illness: Caring for individuals with Rett syndrome is challenging due to the condition’s complexity and unpredictability. Patient group input highlighted acute concerns (e.g., seizures, respiratory distress, feeding difficulties, and mobility issues), which place a heavy emotional, physical, and financial burden on families. The regression following an initial period of typical development is especially distressing, with some caregivers describing it as if “someone pulled the plug on everything.” Many caregivers reported reducing work hours or leaving employment entirely to provide care, further exacerbating financial strain. Patient group input also underscored a lack of societal resources to support families in managing these burdens, contributing to feelings of isolation and unmet need.
Lack of disease-modifying treatments and barriers to care: Currently, there are no disease-modifying treatments for Rett syndrome, and care is focused on symptom management to improve HRQoL. Interventions include pharmacological treatments for seizures, gastrointestinal disturbances, and sleep issues. They also include nonpharmacological approaches like physical therapy for motor impairments, speech therapy to address communication challenges, and occupational therapy to support daily activities. This multidisciplinary care often requires coordination across multiple specialists. There are only 5 Rett specialty clinics in Canada — all located in urban centres — and families without access to these clinics are frequently left to organize and manage these complex care pathways themselves. Delays in accessing care, particularly for families in rural or remote areas, may limit opportunities to mitigate complications or improve outcomes. Symptom management approaches also fail to address the underlying disease mechanisms, leaving families without the hope of slowing disease progression. This may contribute to emotional distress and a sense of unmet need. Access to supportive services (e.g., speech therapy, physiotherapy) is further complicated by funding structures that often require alternative diagnoses (e.g., autism spectrum disorder) for coverage. This can lead to out-of-pocket costs and/or additional advocacy from families. These barriers highlight significant inequities in accessing timely, comprehensive care for a population already managing substantial burdens.
Therapeutic needs and expectations: Clinical experts and patient groups both emphasized the urgent need for therapies that address ability to communicate, motor function, cognition, and seizure management. Caregivers consistently highlighted communication — whether through speech, gestures, or assistive technologies — as a top priority, as even small improvements could significantly enhance their ability to understand and respond to the patient’s needs. As such, they believed that these small improvements would improve the patient’s quality of life. Additionally, patient group input suggested it would also foster greater autonomy for individuals with Rett syndrome by enabling them to better express their needs and preferences.
Pivotal trial evidence and limitations: The sponsor submitted evidence from the phase III, double-blind, randomized, placebo-controlled LAVENDER trial (N = 187), which evaluated trofinetide in female patients aged 5 to 20 years with typical Rett syndrome and an MECP2 variant. The coprimary outcomes (change from baseline to week 12 in RSBQ and CGI-I scores) showed greater decreases (indicating improvement) compared to placebo. However, the absence of validated MIDs for these outcomes limits the ability to interpret what constitutes a clinically meaningful change. Similarly, missing data and concerns about the utility of RSBQ score as an outcome assessment further reduced confidence in the findings. AEs, particularly diarrhea and vomiting, were frequently reported and contributed to trial dropouts, raising the importance of balancing potential benefits against the burdens of treatment.
Long-term safety, efficacy, and evidence gaps: The long-term safety and efficacy of trofinetide were assessed in 2 OLE studies, the LILAC (N = 154) and LILAC-2 (N = 77) studies, which were intended to follow patients from the LAVENDER trial for up to 3.5 years. The mean duration of exposure to trofinetide across the pivotal trial and 2 OLEs was approximately 2 years. While this follow-up period offers some insight into long-term use, Rett syndrome is a lifelong condition; thus, uncertainty remains regarding long-term clinical benefit and safety. Both studies demonstrated continued decreases in RSBQ and CGI-I scores through week 104; however, improvements in CGI-I score were modest at less than a 1-point change over the OLE period. The studies were also limited by high dropout rates in the LILAC study due to AEs and the early termination of the LILAC-2 study following US market approval. As these studies included only patients who completed the LAVENDER trial, they excluded individuals who dropped out of the pivotal trial. This potentially skewed results toward a more favourable representation of the clinical effectiveness of trofinetide by focusing on participants who are more likely to tolerate and benefit from the treatment.
Representation and generalizability: The pivotal trial and OLE studies excluded males, patients younger than 5 years or older than 20 years, individuals without an MECP2 variant, and those with atypical Rett syndrome. This creates uncertainty regarding the safety and efficacy of trofinetide in these populations. Additionally, clinical experts noted that the predominance of white participants in these studies does not reflect the diversity of patients seen in Canadian clinical practice, raising concerns about the generalizability of the findings. This is particularly important given that the proposed Health Canada indication includes all individuals aged 2 years and older with Rett syndrome, regardless of sex, clinical diagnosis (i.e., atypical or classic Rett syndrome), or genetic status. To address some of these gaps, the sponsor submitted data from 2 additional studies: the DAFFODIL study, an open-label study evaluating trofinetide in females aged 2 to 5 years, and the LOTUS study, an ongoing observational study assessing real-world use of trofinetide in individuals under routine care in the US. However, both studies have notable limitations, including the absence of control groups, potential for selection bias, and open-label designs, which introduce challenges in objectively interpreting results. These factors limit the reliability of the data and contribute to ongoing uncertainty about the safety and efficacy of trofinetide in populations not included in the pivotal trial. These gaps in evidence underscore the importance of robust informed consent processes to ensure patients and families are aware of uncertainties and potential risks, especially for those whose clinical profiles fall outside the trial population. Providers navigating these complexities will need to engage in shared decision-making and weigh potential benefits and harms on a case-by-case basis. Post-market data collection will be critical to address these gaps, ensuring equitable and evidence-based access to trofinetide across all populations living with Rett syndrome.
Balancing benefits and risks: Trofinetide represents the first Health Canada–approved therapy targeting the underlying disease course of Rett syndrome. As such, clinical experts and clinician group input expect it to become the first-line treatment option for Rett syndrome if recommended for public reimbursement. Despite the Clinical Review report’s very low certainty regarding improvements as assessed by the primary outcomes (RSBQ and CGI-I scores) in the LAVENDER trial and the OLE trials, clinical experts and clinician group input indicated a willingness to prescribe trofinetide to their eligible Rett patients. While diarrhea and vomiting were primary side effects leading to trial withdrawals, clinical experts believed that these could be managed more effectively in clinical practice than in the trial setting.
Caregivers cited in patient group input emphasized that even modest improvements in the patient’s communication, cognition, or mobility could have a meaningful impact on their quality of life. However, the potential caregiving challenges posed by side effects like diarrhea underscore the need for providers to work closely with families to ensure that expectations are aligned with treatment realities. Given the trade-offs between potential benefits and caregiving burdens, clinical experts stressed the importance of robust shared decision-making processes. Additionally, there are limited data on the long-term safety and effectiveness of trofinetide. Providers must prioritize patient and caregiver autonomy by presenting clear, comprehensive information about risks, benefits, and uncertainties to enable informed choices.
Eligibility: The heterogeneity of Rett syndrome — including distinctions between classic and atypical forms and variability in MECP2 status — complicates questions of eligibility for trofinetide. Clinical evidence from the pivotal trial is limited to females aged 5 to 20 years with typical Rett syndrome and a confirmed MECP2 variant. As a result, there is uncertainty regarding the safety and efficacy of trofinetide for atypical patients, males, and those without MECP2 variants. While the DAFFODIL and LOTUS studies provide some evidence on the use of trofinetide in a broader population, their design limitations leave residual uncertainty regarding populations excluded from the pivotal trial. Given these uncertainties, clinical experts suggested limiting eligibility to patients aligned with the trial population, classic Rett patients without a known MECP2 variant, and atypical patients with a confirmed MECP2 variant. In contrast, clinician group input supported the broader Health Canada indication, which includes all patients aged 2 years and older with Rett syndrome, regardless of sex, clinical diagnosis (i.e., typical or atypical), or genetic status. Caregivers may also advocate for trofinetide access for patients who fall outside narrower eligibility criteria, creating ethical and emotional challenges for providers navigating these conversations. Clinical experts emphasized the need for clear prescribing guidance beyond the parameters of the pivotal trial, alongside robust shared decision-making processes to facilitate informed decisions. Without such guidance, inconsistencies in prescribing practices may lead to inequitable access across providers and jurisdictions.
Prioritization: Clinical experts suggested that individuals with lower disease burden, often younger patients, may be more likely to benefit from trofinetide. As a noncurative treatment, they expected trofinetide to have greater impact when introduced earlier in the course of disease, before significant progression occurs. However, there is no clinical evidence to support this claim. As such, the experts emphasized that eligibility criteria should not rely solely on age or disease burden, as some older patients or those with more advanced disease may still see meaningful improvements in communication, mobility, or overall quality of life. Overly rigid prioritization criteria could inadvertently exclude patients who fall outside the typical profile of trial participants but could still derive significant benefit from treatment.
Geographic and access disparities: Clinician group input and clinical experts recommended that trofinetide initially be prescribed only by specialists with expertise in Rett syndrome, likely based in specialized medical centres. While this approach may help ensure appropriate use during early implementation, it could create geographic access barriers for patients living in rural or remote areas without access to Rett specialists or specialty clinics. Over time, broader familiarity with trofinetide may enable prescribing and management of treatment by a wider range of providers, potentially reducing these inequities. Families with fewer resources or limited access to specialized care may face greater challenges in managing treatment protocols. Addressing these barriers will be crucial to promoting equitable outcomes for all individuals with Rett syndrome.
Impact on health system budgets and equitable resource allocation: Expensive drugs for rare diseases, such as trofinetide, raise ethical considerations regarding equity, distributive justice, and the sustainability of health care budgets. Although there is a significant unmet need for effective, targeted therapies for Rett syndrome, the uncertainty surrounding the clinical value of trofinetide, as described previously, complicates decisions about resource allocation. The conclusion from the Pharmacoeconomic Review report by CDA-AMC that trofinetide is not cost-effective intensifies these concerns. As a result, establishing equitable and sustainable eligibility criteria is crucial, ensuring that those who stand to benefit most have access while maintaining a fair distribution of health resources.
Changes in Rett specialists’ roles and workloads: The introduction of trofinetide would shift Rett specialists’ roles and workloads. Currently, these specialists guide the treatment of Rett syndrome’s diverse symptomatic presentations. With the approval of trofinetide, they would likely take on more direct care responsibilities, requiring additional follow-up visits for monitoring and collaboration with primary care providers. This shift could strain specialist availability and increase administrative costs, potentially creating bottlenecks in care delivery. Implementing clear protocols and investing in education for nonspecialist providers could help mitigate these challenges over time.
Table 2: Summary of Economic Evaluation
Component | Description |
|---|---|
Type of economic evaluation | Cost-utility analysis Markov model |
Target population | Adults and pediatric patients with Rett syndrome aged 2 years or older and weighing more than 9 kg |
Treatment | Trofinetide plus BSC |
Dose regimen | Patients aged 2 years and older:a
|
Submitted price | Trofinetide: $13,714.11 per 450 mL bottle of 200 mg/mL oral solution |
Submitted treatment cost | Annual cost:a,b
|
Comparator | BSC, defined as concomitant medicationsc that were taken by at least 10% of subjects from the LAVENDER and LILAC CSR data |
Perspectives | Publicly funded health care payer Societal perspective |
Outcomes | QALYs, LYs |
Time horizon | Lifetime (79.1 years, until age of 90 years) |
Key data sources | LAVENDER trial, and long-term extension LILAC-1 and LILAC-2 studies |
Submitted results | ICER = $5,864,321 per QALY gained (incremental costs = $3,386,675 and incremental QALYs = 0.578) for both the publicly funded health care payer perspective and societal perspective |
Key limitations |
|
CDA-AMC reanalysis results |
|
BSC = best supportive care; CDA-AMC = Canada’s Drug Agency; GERD = gastroesophageal reflux disease; ICER = incremental cost-effectiveness ratio; LY = life-year; NOC = Notice of Compliance; QALY = quality-adjusted life-year; RSBQ = Rett Syndrome Behaviour Questionnaire.
aThe Health Canada product monograph recommends that trofinetide be titrated starting with 50% of the recommended dose taken twice daily, then the dose be increased over 4 to 8 weeks until the recommended dose is reached.
bRanges reflect the annual costs from year 1 and beyond. The range reflects dose titration in year 1 (where the cost is less to account for titration) and potential changes in the patient’s weight.
cAdrenergics, antidepressants, antiepileptics, anxiolytics, laxatives, antipropulsives, drugs for peptic ulcer and GERD, muscle relaxants, other alimentary track and metabolism products, and psychostimulants.
Trofinetide is being reviewed by CDA-AMC through the complex review pathway; as such, CDA-AMC has appraised 2 cost-effectiveness analyses submitted by the sponsor, 1 adopting a publicly funded health care payer perspective and 1 adopting a societal perspective.
CDA-AMC identified the following key limitations with the sponsor’s analysis: the number of patients with Rett syndrome in Canada is uncertain; the cost of treatment with trofinetide was not adequately derived, which likely underestimates the total costs associated with trofinetide as assumed by the sponsor; the proportion of patients eligible for public drug coverage was underestimated due to the assumption that patients with Rett syndrome would be eligible for public reimbursement at the same rate as the general population; the assumption that the use of trofinetide alters the cost of BSC was inappropriate; the relative dose intensity for trofinetide is uncertain; long-term discontinuation rates and time points for trofinetide are uncertain; and the estimated uptake of trofinetide is uncertain and may be underestimated.
CDA-AMC reanalyses revised the sponsor’s submitted analysis by assuming dosing consistent with the distribution of patient weights of modelled patients, by increasing the proportion of patients who will be eligible for public funding, and by assuming that BSC does not change due to the addition of trofinetide therapy.
Results of the CDA-AMC reanalyses suggest that the reimbursement of trofinetide for the treatment of Rett syndrome in patients aged 2 years or older, weighing at least 12 kg, and with a confirmed Rett syndrome diagnosis as described in Table 1 may be associated with a 3-year incremental budgetary cost of $166,461,725 (year 1: $53,775,386; year 2: $53,706,466; year 3: $58,979,873). As the size of the population with Rett syndrome and the uptake of trofinetide within that population remain uncertain, the estimated budget impact of trofinetide is uncertain. Scenario analyses resulted in budget impacts of up to $333 million.
The sponsor filed a request for reconsideration of the draft recommendation for trofinetide for Rett syndrome. In their request, the sponsor identified the following issues:
The sponsor requested that CDEC reconsider the clinical significance of the RSBQ as an outcome measure for capturing treatment effects in a trial setting. The sponsor also provided new information to further support the relevance of the RSBQ to caregivers and their perspectives on measures of importance.
The sponsor requested that CDEC consider the 12-week duration of the LAVENDER trial as appropriate, given the immediate needs of patients with Rett syndrome, the heterogeneous nature of the disorder, its ethical implications, and the compelling evidence observed in as little as 12 weeks. Additionally, the sponsor requested that the committee consider the supporting analyses provided to help further contextualize the results and interpretation of the evidence, and reconsider their position on the meaningfulness of trofinetide in the treatment of patients with Rett syndrome.
The sponsor requested that CDEC reconsider their conclusion based on the totality of the evidence submitted and in recognition of the significant clinical need in patients with Rett syndrome, the onset of which is in childhood, requiring lifelong care and assistance with everyday activities that significantly impact both the patients and their caregivers.
The sponsor requested that CDEC consider the various support measures implemented by the sponsor to improve diarrhea management and overall tolerance, thereby improving persistence with treatment in the real-world setting, and that the tolerability profile of trofinetide should not be cited as a reason to preclude use in patients for whom the benefits outweigh the risks.
In the meeting to discuss the sponsor’s request for reconsideration, CDEC considered the following information:
information from the initial submission related to the issues identified by the sponsor
new information provided by the sponsor to address an important clear gap in the evidence identified by CDEC
feedback from 2 clinical specialists with expertise in diagnosing and treating patients with Rett syndrome
feedback on the draft recommendation from 3 patient groups, the Ontario Rett Syndrome Association of Canada, the Manitoba Rett Syndrome Association, and the Rett Syndrome Society of British Columbia
feedback on the draft recommendation from 2 clinician groups, the Canadian Rett Consortium and SickKids Hospital
feedback on the draft recommendation from the public drug plans that participate in the Reimbursement Review process
feedback on the draft recommendation from the sponsor.
All feedback received in response to the draft recommendation is available on the CDA-AMC website.
Dr. Peter Jamieson (Chair), Dr. Sally Bean, Daryl Bell, Dan Dunsky, Dr. Trudy Huyghebaert, Morris Joseph, Dr. Dennis Ko, Dr. Christine Leong, Dr. Kerry Mansell, Dr. Alicia McCallum, Dr. Srinivas Murthy, Dr. Nicholas Myers, Dr. Krishnan Ramanathan, Dr. Marco Solmi, Dr. Edward Xie, and Dr. Peter Zed.
Regrets: Three expert committee members did not attend.
Conflicts of interest: None
Dr. Peter Jamieson (Chair), Dr. Sally Bean, Daryl Bell, Dan Dunsky, Dr. Ran Goldman, Dr. Trudy Huyghebaert, Morris Joseph, Dr. Dennis Ko, Dr. Christine Leong, Dr. Kerry Mansell (Vice Chair), Dr. Alicia McCallum, Dr. Srinivas Murthy, Dr. Nicholas Myers, Dr. Krishnan Ramanathan, Dr. Marco Solmi, Dr. Edward Xie, and Dr. Peter Zed.
Regrets: Two expert committee members did not attend.
Conflicts of interest: None
ISSN: 2563-6596
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