I've been giving consideration to the question of efficacy of trofinetide in Rett syndrome.
Phase 3 Pivotal TrialThis 12-week, double-blind, randomized, placebo-controlled study (LAVENDER;
NCT04181723) evaluated trofinetide in 187 females, aged 5–20 years, with RTT.
Trofinetide met the co-primary efficacy endpoints requested by the FDA, demonstrating statistically significant improvement over placebo in both the caregiver-assessed Rett Syndrome Behaviour Questionnaire (RSBQ) (p=0.0175) and the clinician-assessed Clinical Global Impression of Improvement (CGI-I) (p=0.0030).
On the RSBQ, improvements were seen in all subscales, indicating that the overall effect on RSBQ was not driven by one or two of the domains, but seemed to be a more generalized pattern of improvement.
On both RSBQ and CGI-I scores, results were consistent across all age groups - 5 to 11, 12 to 16, and 17 to 20 – and across all severities of disease.
The key secondary endpoint was also met. Trofinetide demonstrated statistically significant improvement over placebo in the Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist Social Composite Score (CSBS-DP-IT Social) (p= 0.0064). This is a caregiver scale that measures the ability to communicate through the modalities most commonly used by people with RTT – e.g., emotion, eye gaze, gesture, sounds, words and object use.
https://ir.acadia.com/events-and-presentations/Phase 2 TrialsPaediatric StudyA 6-week, double-blind, randomized, placebo-controlled Phase 2 paediatric study evaluated trofinetide in 82 girls aged 5 -15 years, with RTT.
The highest dose (200mg/kg) group achieved statistically significant clinical improvement compared with placebo in the Rett Syndrome Behavior Questionnaire (RSBQ), the Clinical Global Impression of Improvement (CGI-I), and the Rett Syndrome Domain Specific Concerns (RTT DSC).
The approximate 15% improvement from treatment baseline was considered clinically meaningful by leading physicians.
There was evidence of biological activity across multiple symptom areas.
https://hotcopper.com.au/threads/ann-investor-presentation-3-april-2017.3338574/Adult StudyA 4
-week, double-blind, randomized, placebo-controlled Phase 2 trial evaluated trofinetide in 56 subjects aged 16-46 years, with RTT.
The higher dose (70mg/kg) exceeded the pre-specified criteria for improvement in core efficacy measures, observed in both clinician and caregiver assessments, compared with placebo.
Both doses given in the trial showed trends of increasing effect with duration of treatment.
https://hotcopper.com.au/threads/ann-investor-presentation-3-april-2017.3338574/
Effect Size in Phase 3 Pivotal TrialEffect size in the pivotal trial, as measured by Cohen’s d, was 0.37 on RSBQ, 0.47 on CGI-I and 0.43 on CSBS-DP-IT Social.
A commonly used interpretation is to refer to effect sizes as small (d = 0.2), medium (d = 0.5), and large (d = 0.8) based on benchmarks suggested by Cohen (1988). However, these values are arbitrary and should not be interpreted rigidly (Thompson, 2007). Small effect sizes can have large consequences, such as an intervention that leads to a reliable reduction in suicide rates with an effect size of d = 0.1https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3840331/Clinical Benefit/Relevance of Phase 3 Pivotal Trial resultsIn the pivotal trial,
the greatest changes from baseline in the RSBQ were seen in the domains of fear/anxiety, body rocking and expressionless face, hand behaviours and breathing problems.Rett Mum and advocate, Mel Lancaster, has explained the potential impact that an even small improvement on
anxiety/fear can mean to a Rett patient and her family
The other area was the significant improvement in anxiety/fear. There seemed to be a disconnect between the areas the other agencies on the (investor conference)
call concentrated on and the things that seemed to me to be far more important. One point some callers made was- Is 5 points really enough? Dr. Pichard (CSO of the International Rett Syndrome Foundation and mother of a child with Rett)
echoed my feelings when she said, “if there’s just one improvement that makes our lives easier, that’s enough.” I completely agree. During Katelin’s trial, I could not imagine a more chill child. I could take her anywhere without her becoming overwhelmed; she didn’t scream; she engaged with the other children and adults around her. I have no way of knowing if every child/adult will have this benefit, but for those that do, this IS life changing. I can see babysitters, family gatherings that so often exclude us soon being possible; I can see date nights for couples; I can see people being able to go to work or work from home. But, most of all, I see siblings that aren’t gipped out of a childhood or have their social lives impacted so severely. Not all families face these obstacles, but there are many that do and the quality of their lives would be utterly changed.Not only would a decrease in anxiety/fear affect the general health of the family, maybe, just maybe we could take our children off of all those meds that often leave them sleepy, foggy, or barely help. This is one thing that would offset the cost, as well. Less need for multiple meds and behavioral therapy would be a huge savings for states.https://trailtoatexastrial.wordpress.com/2021/12/20/a-chat-with-dr-pichard-of-irsf/Dr. Pichard has explained the impact of
repetitive hand movements for patients and families.
What’s the impact if someone with Rett can’t control their hand movements?- Can’t pick up objects and learn how to use them
- Can’t take a shower or dress or feed themselves
- Can’t play with toys
- Can’t open doors, turn on music or movies, get a drink of water
The caregiver must always be the hands for their childIn the pivotal trial, trofinetide also demonstrated statistically significant improvement over placebo on the key secondary endpoint, the CSBS-DP-IT Social scale, which measures ability of people with RTT to
communicate through emotion, eye gaze, gesture, sounds, words and object use.Dr. Pichard has explained the impact of inability to
communicate for patients and families.
- Repetitive hand movements prevent sign language, writing, typing
- Trapped in a body that can hear, smell, feel, taste but not speak
- Cannot communicate needs, wants, pain, and more
- Mental health affected: frustration, anxiety, loneliness, depression
- Potential for abuse or neglect to go undetected
- Education and learning suffers: receptive far higher than expressive
For caregivers, relentless anticipation of every need all day, every dayhttps://ir.acadia.com/events-and-presentations/Finally, in her comments on the trofinetide pivotal trial results, Dr. Pichard commented that even a seemingly small change can make a big difference to both patient and family.
Clinical Benefits rated as most important by Rett familiesIn March this year, the FDA held an online Rett Syndrome Externally-Led Patient-Focused Drug Development Meeting to allow patient families to share the impact that Rett syndrome has on their family and how symptom improvements would affect them and their loved one’s quality of life.
Participants were asked to select the top 3 aspects of Rett syndrome which they would rank as the most important for a possible new therapeutic to improve.
Communication was ranked first (30%), repetitive hand movement/hand use was ranked second (18%) and mobility/balance third (11%).
CommentI believe there is adequate evidence of efficacy to support approval of trofinetide in Rett syndrome.
- There are currently no approved treatments for Rett syndrome.
- Trofinetide has demonstrated efficacy across one Phase 3 and two Phase 2 trials in a total of 325 child and adult patients.
- All trials have been double-blind, randomized and placebo-controlled.
- The pivotal trial design and endpoints were agreed with the FDA prior to commencement.
- In the pivotal trial, the FDA set a high bar of co-primary endpoints. Both co-primary endpoints were met along with a key secondary endpoint.
- The pivotal trial results were highly statistically significant - RSBQ (p=0.0175); CGI-I (p=0.0030); CSBS-DP-IT Social (p= 0.0064).
- Effect size in the pivotal trial, as measured by Cohen’s d, was small to moderate - 0.37 on RSBQ, 0.47 on CGI-I and 0.43 on CSBS-DP-IT Social.
- Results were consistent - on the RSBQ, improvements were seen in all subscales and on both RSBQ and CGI-I scores and results were consistent across all age groups and across all severities of disease.
- Statistically significant improvement was seen in the two most important aspects of Rett syndrome that families wished to see addressed by any new therapeutic.
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