NeuroVoices: Ponni Subbiah, MD, MPH, on the Open-Label LILAC-2 Study of Trofinetide


The senior vice president, global head of medical affairs, and chief medical officer at Acadia Pharmaceutical, gave an overview of LILAC-2, a long-term extension study assessing trofinetide (Daybue), the first approved therapy for Rett syndrome.

Ponni Subbiah, MD, MPH

Ponni Subbiah, MD, MPH

For years, those with Rett syndrome lacked an approved therapy specific to treat their condition. Rett syndrome, a neurodevelopmental disorder, is characterized by loss of mobility, seizures, cognitive problems, slowed brain and head growth, and digestive problems, among other issues. Earlier this year, the FDA gave greenlight to Acadia’s trofinetide, a novel synthetic analog of the amino-terminal tripeptide of IGF-1, as the first and only agent to treat patients with the condition.

Trofinetide works by reducing swelling in the brain, increasing the amount of a protective protein in the brain, and stopping cells from becoming too active. Months after its approval, Acadia presented new data from its phase 3 LILAC-2 study (NCT047767746), a 32-month open-label trial, at the 2023 American Epilepsy Society (AES) annual meeting, held December 1-5, in Orlando, Florida. In the trial, trofinetide was given following weight-based dosing twice daily (morning and evening, ≥8 hours apart) orally or by gastrostomy tube, with the main goal of safety.

Over the 32-month period, patients on trofinetide continued to show improved symptoms, as demonstrated by improved scores in Rett Syndrome Behavior Questionnaire and Clinical Global Impression-Improvement scores. A caregiver analysis of participants from LAVENDAR, LILAC, and LILAC-2 who were treated with trofinetide also showed improvements in child engagement, hand use, eye gaze, attention/focus, ability to make sounds, and mood.1,2

As part of a new iteration of NeuroVoices, NeurologyLive® sat down with study investigator Ponni Subbiah, MD, MPH, to learn more about the LILAC-2 data and the most important clinical takeaways. Subbiah, senior vice president, global head of medical affairs, and chief medical officer at Acadia, discussed the beneficial impacts of trofinetide from both a patient and caregiver perspective, as well as some of the specific symptoms the treatment may aid in.

NeurologyLive®: Can you provide an overview of the study findings?

Ponni Subbiah, MD, MPH: LILAC-2 is a 32-month long-term open-label study that evaluated the safety and efficacy of trofinetide in patients with Rett syndrome. Before we get into the details of the study, let me give some background on trofinetide. Trofinetide became the first and only approved treatment for Rett syndrome in March of this year. Its approval by the FDA was based on the pivotal registration phase three study called LAVENDAR, a 12-week double-blind placebo-controlled trial showing clinically significant differences between trofinetide and placebo in both a clinician-rated scale called a Global Clinical Impression of improvement, as well as a caregiver-rated scale called the RSBQ or the Rett Syndrome Behavioral Questionnaire. Those patients who completed that study had the option of participating in a long-term study, 40 weeks in duration, openly available, called LILAC-1. In those patients who then completed LILAC-1, they had the option to participate in LILAC-2. LILAC-2, as I mentioned, was 32 months in duration, and there were 77 participants with Rett Syndrome.

The mean age of these patients was 12 years; the range was between five and 22 years, the age ranges of participants in the study. The objective of the study was to look at the long-term safety, as well as the efficacy assessed using the same scales from the first phase three lavender study and LILAC-1: the Rett Syndrome Behavioral Questionnaire and the Clinician Global Impression of Improvement scale. Of the 77 participants, 79% completed the study, and safety and tolerability were key objectives. The most common adverse events observed were diarrhea in 53% of participants. COVID-19 occurred in 27%, and diarrhea occurred in about 20%. There were no new safety signals observed in this long-term study compared to the previous studies. With regards to efficacy on both the caregiver-rated scale and the clinician-rated scale, we continue to show improvements, even with the more prolonged use of trofinetide. It's essential to have long-term evaluation because Rett (syndrome) is a chronic disease, related to a genetic mutation, and is lifelong. Acadia was committed to studying beyond the 12-week pivotal study, which is why we conducted both LILAC-1 and LILAC-2. In total, some patients were on the drug for more than two and a half years.

Coming into the study, did you have any concern that trofinetide would not hold up in the long term?

Well, it's very important, especially in a chronic disease like Rett syndrome, that we continue to look at the longer-term effects. Especially with the approval, patients may continue to benefit from it. We can only show that through science and clinical studies. Acadia has been committed to that, planning from the beginning, when we were planning for trofinetide, that in addition to the initial pivotal studies, we would continue to study it beyond that. Since its approval, we are continuing to study the benefits that trofinetide could have in this population through a real-world study called LOTUS. The science doesn't stop; we will continue to learn more with trofinetide now being used in real-world practices. We'll continue to understand different populations and some benefits that may not always have been picked up. It is a very important study from that perspective. But we're not through yet. We're continuing to expand the science in this area.

How has the integration process been? Considering this is the first approved treatment for Rett.

I think the first thing is, we have been very busy since the approval, ensuring that clinicians have the correct information. That's one of the reasons we had a poster, not only at AES, on the LILAC-2 study, as of course, at the Epilepsy Society meeting. We are going to continue to communicate the science through scientific congresses, publications, website, field-based medical team, engagement with the caregiver community, and international Rett syndrome. We are very committed to ensuring that all stakeholders receive the information on Daybue. Second, we have an important resource for both clinicians and caregivers called Acadia connect. This makes the prescription and accessing the drug seamless. Caregivers and clinicians can use this resource with assistance in navigating the insurance pathway and ensuring that once the drug has received insurance approval, it seamlessly gets to the caregiver. After that, we have lots of education materials for both caregivers and clinicians, so they can start and stay on Daybue, including benefits they could see and how to manage side effects such as diarrhea.

How significant was it to see quality-of-life improvements seen from trofinetide?

FDA has been encouraging the patient voice in the drug development process. As part of LILAC-2, we did exit interviews with caregivers whose child participated in the study. This was voluntary, and 27 caregivers participated in this study, with interviews conducted via telephone for about one hour. The interviews used an Institutional Review Board approved qualitative interview guide by a qualified group called RTI. Open-ended questions were asked of the caregiver about the benefits they saw with trofinetide. The data collected through these interviews were then analyzed to look for key themes across the interviews. The results showed that the top three areas of improvement noted by these caregivers in their children were improvement in engagement, improvement in hand use, and improvement in eye gaze. Some caregivers also noted the child had new words or new sounds, aligned with an observation that communication was better after trofinetide was started. This was important because communication and hand use are common areas caregivers wanted to see improvement in their child. Caregivers themselves, 54% of them noted a positive impact on their own lives, feeling the ability to interact with their children was better. For the children to respond in turn was better. The family appeared to be happier, able to participate more often in social gatherings as a family. Engagement seemed to be noticed also by others, in addition to family members.

Are there any specific symptoms of Rett that you believe trofinetide could have an impact on?

It's important to understand that Rett syndrome is a heterogeneous disease, presenting differently for every patient. Similarly, that's why one of the endpoints was the Rett Syndrome Behavioral questionnaire, assessing the different symptoms of Rett. The benefits observed, not only through the outcome measures but also through the caregiver, can be varied. Every child can benefit differently from the drug. If you look at some of the things I mentioned related to what caregivers observed, some key areas noted with benefiting from trofinetide are engagement, interaction with others, hand use, eye gaze, all contributing to communication and interaction.

Transcript edited by artificial intelligence. Click here for more coverage of AES 2023.

1. Percy AK, Neul JL, Benke TA, et al. Trofinetide for the treatment of Rett syndrome: long-term safety and efficacy results from the open-label LILAC-2 study. Presented at: AES 2023; December 1-5; Orlando, FL.
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