Positive update on Neurogene Rett gene therapy program

Neurogene update on NGN 401 gene therapy for Rett syndrome 

On 11 November 2024, Neurogene shared a long-awaited update on the ongoing clinical trial of their Rett syndrome gene therapy, NGN-401.  

The age group for the clinical trial is currently 4>10 (over four years old and before the child’s 11th birthday). The trial was initially designed to include two groups or cohorts, a low dose group and a high dose group. 

Key take aways: 

• NGN-401 well-tolerated in the first 7 participants with no serious adverse events. 

• Interim efficacy data from the first four children in the low dose group show significant improvements across all areas including:  

• Hand function/fine motor,  

• Language/communication  

• Walking/gross motor 

• New skills and milestones have increased and deepened over time. 

• A new cohort of 3 adolescent/adult patients has been added to the study. 

You can read the full press release from Neurogene dated 11 November 2024 here 

You can read Neurogene’s letter to the patient community here 

Read on below to find out more about how patients on the trial have fared and what this means in terms of next steps for the Rett community. 

Efficacy 

On their most recent investor call held on 11 Nov 2024, Neurogene shared data from a comparative group of patients from the US based Natural History Study which is a longitudinal database of more than 1000 patients with Rett syndrome.  

The NHS data shared showed that the improvements gained by all of the first four participants dosed with NGN-401 do not typically happen in girls with Rett syndrome at this stage of disease. The comparative group only included girls with the same CGI-S scores of 4-6 indicated in the eligibility criteria for the NGN 401 clinical trial. 

For clarity, the first four patients described below are part of the low-dose cohort in the trial.  

Gains included: 

Child (LD1-15 months post treatment-age 7 at baseline) previously unable to finger feed now able to self feed and has started to use a fork. Using both hands to drink on her own. Previously unable to go up and down stairs and get onto and off bed without parental support, now able to do both independently as well as getting into and out of the bath and out of her car seat to exit the car.  

Pre-treatment, the same child was unable to follow any commands or express emotions. She now follows ten commands such as ‘give a kiss’ sit down put it in the trash open the door/shut the door give it to me flush the toilet. She frowns/shouts to express displeasure and waves hello. 

Child (LD2-12 months post treatment-age 4 at baseline) previously had clenched hands and no hand use, unable to grab, reach or hold objects is now able to hold juice box and drink. She is starting to self-feed. She can pick up her security blanket and put the pacifier clipped to her shirt into her mouth to self-soothe. She can turn on her videos by tapping her tablet. 

Pre-treatment, the same child walked independently but fell frequently and could not stand from seated without being pulled up by a care giver. She could not bend over. Now she is walking faster, falling less. She can stand independently from a seated position, bend over and pick up her blanket from the floor, step off a curb with one hand held.  

Pre-treatment, the same child was unable to babble, make choices or follow commands. Post treatment she is able to say mama dada and nana clearly and in context. She can follow commands such as come here and give a kiss and make choices of preferred foods. 

Child (LD3-9 months post treatment-age 6 at baseline) previously unable to self-feed and unable to swallow anything other than pureed food is now able to swallow solid foods and drink clear liquids. She was unable to sit, stand or walk independently. She can now sit independently with improved posture. She can stand with less support and is able to advance feet forward with less support.  

Previous to treatment the same child was unable to make choices or follow commands. Post treatment she is able to make some choices and is showing an appropriate response to jokes made by caregivers. 

Child (LD-4 3 months post treatment-age 7 at baseline) previously able to use a utensil velcroed to her hand, unable to use regular utensils is now able to use regular utensils to self-feed. She can reach with more precision.   

Prior to treatment she was unable to stand or walk independently. There is not yet any substantial improvement in standing and walking likely due to the recency of dosing. Prior to treatment she was unable to follow commands and laughed out of context. She is now laughing at appropriate moments and vocalising to express discomfort or to show emotion. 

Importantly, data showed from the comparative group within the US based Natural History Study showed that in patients with Rett syndrome without treatment: 

• 82%/86% never learned to climb up/down stairs without help 

• 64% never learned to follow a command without a gesture 

• 80% never learned to use utensils (without assistance) to self feed 

• Only 4% relearned waving hello post regression 

• Only 3% relearned a raking grasp to retrieve an object 

• Only 13% relearned to reach for an object 

• Only 8% relearned to use words with meaning 

• Only 4% relearned to use a pincer grasp 

• Only 8% relearned to self feed 

• Only 7% relearned to sit independently 

Safety 

Neurogene shared the following safety information with a cut off date of October 17^th 2024: 

• NGN-401 was well-tolerated in the first seven participants, five in the low dose group and two in the high dose group. 

• There were no serious adverse events related to NGN-401. 

• There were no adverse events related to the ICV route of administration which is where the therapy is administered via a common neurosurgical procedure. 

• Most treatment-related adverse events are known potential risks of adeno-associated virus (AAV) gene therapy, and are resolved or resolving. 

The company also shared that on November 11^th 2024, they became aware of an emerging treatment-related serious adverse event (SAE) consistent with known risks of AAV gene therapy in the third high-dose participant who was recently dosed. This situation is being monitored, has been reviewed by the Data Safety Monitoring Board and will be reported on as appropriate. *

*This patient has now sadly died from a rare immune reaction. You can read more about this here.

Next steps: 

• Neurogene is on track to complete enrollment of the first patient cohort this quarter. 

• They expect to provide a regulatory update in Q1 2025. 

• They expect to provide more clinical data in Q2 2025. 

• They present a compelling efficacy profile in the low dose cohort. 

• Whilst the first four patients in the low dose cohort were very different at baseline, they are seeing consistent improvements and gains with skills lasting and deepening over time. 

• Neurogene has added a new study group (cohort 3) in adolescents/adults to the clinical trial. 

• Cohort 3 will enroll three adolescents/adults with Rett syndrome aged 16 or older. 

• Due to recent developments in the high dose cohort, a protocol amendment is being sought to enroll 3 participants at the low-dose of NGN-401. 

• This pilot cohort is expected to provide initial information on the potential of NGN-401 to treat a broader patient population 

Neurogene has opened additional clinical trial sites in the U.S., U.K. and Australia. Please see the current list of enrolling sites below: 

• U.S. 

• Children’s Hospital Colorado: [email protected] 

• Rush University Medical Center: [email protected] 

• Boston Children’s Hospital: [email protected]  

• Montefiore Medical Center: [email protected]  

• Texas Children’s Hospital:  [email protected]  

• U.K. 

• Royal Hospital for Children and Young People: [email protected] 

• Manchester University NHS Foundation Trust: [email protected] 

• Australia 

• The Children’s Hospital at Westmead: [email protected] 

If additional sites are added, site contact information will be found here

Interested families should directly contact a clinical trial site that is currently enrolling. 

To register your interest in UK clinical trials for Rett syndrome please register your loved one on the Rett Registry UK HERE

About Reverse Rett 

This news about these first UK gene therapy clinical trials for Rett syndrome has been a long time coming for the UK Rett community.  

At Reverse Rett, we are grateful to everyone who has supported our work to:  

• Fund the work of Professor Stuart Cobb at the Universities of Glasgow and Edinburgh, which led to this program  

• Develop the Rett Registry UK demonstrating UK infrastructure for successful UK clinical trials  

• Implement clinical trial support services at trial sites across the UK including Edinburgh and Manchester in order to develop clinical expertise and experience in Rett syndrome   

• Demonstrate the burden of disease and advocate for the need for treatments with UK regulators   

Without all this work and more, we would not be where we are today. Our infinite thanks goes to all our supporters, donors and fundraisers. This could not have happened without you. 

More information about the study including inclusion and exclusion criteria can be found here  

Learn more about gene therapy trials for Rett syndrome on the Reverse Rett YouTube channel here.