Trofinetide

Adapted from iStock, zizar2002 As both Taysha Gene Therapies and Neurogene warm up for an important year of readouts, the Rett syndrome community is pinning hopes on a smooth finish—and possibly, a result in line with Novartis’ spinal muscular atrophy gene therapy Zolgensma. Patients with Rett syndrome have historically had few treatment options—but 2027 could change that. Two gene therapies are at the FDA’s doorstep with strong data showing they can alter the trajectory of the rare neurodevelopmental disorder. While experts are cautious to avoid using the word “cure,” the excitement is palpable. Monica Coenraads, founder and CEO of the Rett Syndrome Research Trust (RSRT), which previously helped to fund the academic science behind both Taysha’s and Neurogene’s candidates, made an optimistic comparison to Novartis’ spinal muscular atrophy (SMA) gene therapy Zolgensma. “My hope is that something is so dramatic that we end up with a Zolgensma situation, where kids that would have been dead by two are taking ballet lessons,” Coenraads said. “You don’t need sophisticated statistics to understand that that was transformative.” Zolgensma was greenlit by the FDA in 2019 as the first gene therapy for SMA after infants in Novartis’ Phase 1 START trial achieved motor milestones never seen before in the natural history of the disease, according to Novartis’ approval announcement . Rett syndrome is a genetic neurodevelopmental disorder mainly affecting girls and women that causes a loss of motor and speech skills over time. In this space, it is now a “two-horse race” to bring a gene therapy to market, BMO Capital Markets analysts said. Candidates from Neurogene and Taysha Gene Therapies are each in the final stretch of late-stage development. Taysha announced in August that it has completed dosing of TSHA-102 in 17 girls in the pivotal REVEAL trial that could support a regulatory submission in the first half of 2027. Neurogene has similarly completed dosing of its own gene therapy, NGN-401, in the registrational Embolden trial with data expected in the second half of 2027. The company has dosed 25 female patients three years and older in the Phase 3 trial, according to a June press release . Rare diseases FDA Signs Off on Neurogene’s ‘Best-Case Scenario’ Pivotal Study Design for Rett Syndrome The pivotal trial for Neurogene’s Rett syndrome gene therapy makes use of baseline controls and a rigorous endpoint that could help ensure a broader label for the drug product, if approved, according to analysts. July 1, 2025 · 2 min read · Tristan Manalac Read more Trials from both companies have demonstrated long-term efficacy from ongoing early-stage trials, with the one-time treatments resulting in 100% response rates—every patient met more than one developmental milestone. For patients and caregivers in the Rett community, the headway marks a more hopeful period following many years with limited available treatments. Coenraads is the mother of Chelsea, a 30-year-old woman living with Rett syndrome who has never walked independently. Coenraads has witnessed her daughter’s lifetime of symptom-based medications and has seen this approach begin to give way to the potential for root-cause genetic treatments. “It’s difficult to imagine a [small molecule] drug that works on a particular pathway having a dramatic effect on Rett syndrome, but if we could somehow target the root cause of the disease, the symptoms should go away,” Coenraads told BioSpace . “It was incredibly important for these companies to take these programs forward as the first genetic medicines to go to clinical trials,” she said, adding that this brought a lot of hope and excitement to the field. With Taysha and Neurogene soon to be knocking on the regulatory door with their gene therapies, experts and caregivers are watching closely to determine whether both will find a place in the Rett syndrome landscape, with an eye particularly toward safety and long-term efficacy. Finding an objective outcome Originally described by Austrian physician Andreas Rett in the 1960s , Rett syndrome did not have an officially approved therapy until just a few years ago. In March 2023, Acadia Pharmaceuticals secured the regulatory greenlight for Daybue (trofinetide) for patients 2 years and older after the small molecule oral drug significantly improved Rett symptoms compared to placebo in the Phase 3 Lavender study . In a testament to the difficulties of objectively assessing outcome measures in neurological conditions, Daybue entered the scene with some controversy concerning its efficacy in real-world settings. In a fact sheet written by RSRT leadership, including Coenraads, the organization noted that 61% of patients taking Daybue did not improve, while only 13% were rated as “much improved.” Drug Development Acadia Wins FDA Approval for First Rett Syndrome Medicine Acadia Pharmaceuticals announced the approval of Daybue (trofinetide) as the first and only drug to treat Rett Syndrome, a rare, neurodegenerative disorder affecting primarily girls. March 9, 2023 · 3 min read · Heather McKenzie Read more The Lavender and open-label Lilac-1 trials lacked data regarding specific symptoms, and adverse effects such as diarrhea and vomiting affected many patients, according to the RSRT’s findings. Acadia itself reported diarrhea in 82% of Daybue-treated patients vs. 20% of placebo comparators and vomiting in 29% on Daybue vs. 12% taking placebo. Because of the challenges elicited by subjective outcomes, Coenraads is looking to gene therapies for a potential game-changing moment. For that, she takes cues from Zolgensma, with optimism that the data will speak for itself in a more objective manner. Taysha and Neurogene While Rett syndrome has been classified as a neurodevelopmental disorder, it is perhaps more accurately defined as a “neural network disorder” for the widespread effects of the central gene at its core, MECP2 , Sukumar Nagendran, head of R&D at Taysha, told BioSpace . “ MECP2 is teleologically a very ancient gene and essentially acts as an orchestra conductor, controlling up to 4,000 genes in the central nervous system and elsewhere in the body,” Nagendran said. “That master orchestra conductor, which is the MECP2 gene, has fallen asleep in patients with Rett syndrome, and the orchestra doesn’t know what to do, but if the conductor wakes up, the music starts.” Nagendran, who served as chief medical officer at AveXis—now Novartis Gene Therapies —during the development of Zolgensma, pointed to the similarities between that product and TSHA-102, particularly as both are one-time treatments. “This program could be a very useful therapeutic option for patients with Rett syndrome and could transform the regulatory landscape if it works out that way,” leading to prioritization of single-arm comparators, Nagendran said. This could include natural history controls and comparisons to a patient’s own baseline—as is the case in Taysha’s REVEAL trial—to show individual patient progress. This would ensure a trial’s results don’t succumb to potential placebo effects, overcoming some of the objectivity challenges in the space. TSHA-102 is delivered into the spinal cord, which BMO analysts said could provide a meaningful advantage for future uptake if approved, given the relative “ease of administration and common availability in the community” as compared with Neurogene’s therapy, which is delivered directly into the brain. While Taysha and Neurogene are neck and neck in the race to bring the first gene therapy to patients with Rett syndrome, Neurogene has had the higher mountain to climb, particularly with regard to safety. The company abandoned a higher dose of NGN-401 after a patient in its Phase 1/2 trial died. The death was attributed to the adeno-associated virus (AAV) used to deliver the genetic material. Neurogene subsequently built in a biomarker protocol to avoid further safety signals while also pursuing doses that would be effective, CEO Rachel McMinn told BioSpace . Taysha’s gene therapy is also delivered via AAV, but has avoided the fatal safety issue that compromised Neurogene’s trial. Despite the efficacy seen so far from these treatments, both McMinn and Nagendran are careful not to offer false hope. “For CNS diseases, we are not in a place where it is remotely responsible to use the word ‘cure,’ McMinn said, “even though what we’re seeing are very encouraging signs of improvements. The gains in developmental milestones are very divergent from the natural history of the disease, and the promise [is] there, but there needs to be technological innovation to get closer to what you and I would truly consider a cure.” She continued, “These girls seem to be markedly different little girls as they’ve been followed over time, but that doesn’t mean they’re going to college.”