Community FAQs about recent patient death in Neurogene gene therapy trial

12/12/2024

Since the recent announcement that a child taking part in the Neurogene Rett syndrome gene therapy clinical trial has died following complications from a rare and life-threatening hyperinflammatory syndrome associated with high doses of the virus used to deliver the gene therapy, we have received many questions from the UK Rett syndrome community.

In the first instance, families share their heartfelt sadness for the family whose young daughter has died. They also share their gratitude for all families taking part in clinical trials of potential treatments for Rett syndrome. 

These families live with the burden of Rett syndrome daily, they know firsthand the challenges, illnesses and restrictions it places on their loved one and on the family as a whole. 

They have unique insight too into an almost undefinable magic that our children, young people and adults with Rett bring into our lives. Whilst not being able to say anything, they say everything, somehow grounding us, bringing an integrity to our world with just a look or slight gesture and bring so much love to our families.

This is what gives each of us the empathy to really sense the magnitude of the loss of this child’s family and of all who have lost their beloved family members with Rett. 

Although we may not have experienced this tremendous loss, we have all imagined it. 

You can’t avoid imagining it when you know your child is at increased risk of sudden death, respiratory infections, seizures and cardiac instability at any age or any stage of the disease. 

Rett families worldwide live under this shadow. We hope for better. That’s why at Reverse Rett, we actively work to support the acceleration of treatments that can improve the lives of everyone living with Rett syndrome today and for future generations of children with Rett.

The questions of UK Rett syndrome families are listed below in their own words. These questions have been answered by Rachael Stevenson, CEO of Reverse Rett in consultation with Reverse Rett Trustee, Jocelyn LeBlanc Ph.D., and Dr Jay Shetty, Consultant Neurologist at the Royal Hospital for Children and Young People in Edinburgh

If you have further questions, please reach out and we will answer them as best we can.

Thank you.

Will the gene therapy trials for Rett syndrome be stopped now?

No. Rett syndrome gene therapy trials will continue.

There are currently two Rett syndrome gene therapies in clinical trials and both will continue.

This particular clinical trial, which is Neurogene’s NGN-401 clinical trial, was studying two different dose levels of the gene therapy, 1E15 vg  (low dose) and 3E15 vg (high dose).

The rare, serious adverse reaction happened at the 3E15 vg dose, and is associated with high doses of the virus used to deliver the gene therapy; the virus is called adeno-associated virus (AAV). 

The company has stopped dosing at the 3E15 vg dose level and has been given permission to continue at the low dose level (1E15 vg).

Surely what’s in the high dose is in the low dose?

The design of Neurogene’s gene therapy is the same, no matter the dose. 

The problem is associated with the dose level.

For background, a gene therapy is delivered into the cells by using a virus, called   AAV9.

Viruses are good at invading all our cells. In current gene therapy models, scientists use the shell of a virus, called a vector, and put in a copy of whatever healthy gene is needed. 

The vector is then sent into the body and delivers a copy of the healthy gene into the cells.

In this situation, the reaction was related to the amount of virus used to deliver the healthy gene in the 3E15vg dose. In clinical trial terms, a reaction like this  is referred to as a Serious Adverse Event (SAE). 
In this particular SAE, The girl experienced systemic hyperinflammatory syndrome, a rare and life-threatening immune response that has been reported with systemic exposure to high doses of AAV.

This reaction is similar to the rare immune reactions some children had to the Coronavirus during the Pandemic which were also severe and life threatening.

These reactions have also been seen in high dose AAV use in other disease groups in both clinical trials and in approved treatments.

Why is the US regulator happy for Neurogene to continue the trial at the low dose if the vector has caused the immune reaction?

NGN-401 at the 1E15 vg dose (low dose) was well-tolerated with a favorable safety profile in the first five participants; all treatment-related adverse events (AEs) in these participants were mild. 

The first four participants at the 1E15 vg dose (those had been dosed long enough ago to show efficacy data) showed consistent improvements across key Rett syndrome scales, and all achieved meaningful gains of function and developmental milestones in hand function/fine motor, communication/language, and ambulation/gross motor. The SAE was seen in one of the 3 girls who received the 3E15 vg dose (high dose), and is associated with high doses of AAV.

This reaction has not been seen in other AAV9 gene therapies (in any disease) at the lower dose (1E15 vg).

There have been no other treatment-related serious side effects in the clinical trial in either the 1E15 vg (low dose) or the 3E15 vg (high dose) groups.

Why did the company try a high dose and a low dose? Why didn’t they do double instead of triple dose?

This is a common practice in any new treatment, and particularly in gene therapy, to determine a tolerable and efficacious dose. Gene therapy is a one-time treatment, and  because there is no opportunity to re-dose,  establishing the optimal dose is critical. Neurogene chose the 1E15 vg dose to start, which was expected to be tolerable and efficacious based on studies done in animals. The 3E15 vg dose also showed tolerability as well as better efficacy in animal models, so that was chosen as the second dose. 

The dosing level is set by sponsors (the companies making the gene therapies) and that dosing plan is approved for use in the clinical trial by regulatory agencies based on preclinical data (including animal studies) and, when applicable, clinical data (human studies). This would have been thoroughly thought through and the high dose was well-tolerated by the first two participants.

How many other trials using this vector have resulted in a participant dying?

This reaction is associated with the dose level. Thousands of people have been treated with AAV9, the type of virus used in the Neurogene clinical trial. 

Is the Taysha Gene Therapies Rett syndrome trial using the same sort of vector and if so, is there a risk of a similar SAE in that trial as well?

Yes, the Taysha Gene Therapies trial of TSHA-102 for Rett syndrome is using the same AAV9 vector. 

The Taysha Gene Therapies trial also has two dose levels, however, the high dose of TSHA-102 is the same (1e15) as the low dose of NGN-401 (also 1e15). 

There are other differences between the products and a direct comparison of the two products cannot be made at this time.

There have been no reports of hyperinflammatory response in the field of AAV gene therapy at or below the dose levels used in Taysha’s trials.

The two dose levels being tested in Taysha’s trial (5.7E14 total vg and 1E15 total vg) are significantly less than the high dose used in Neurogene’s trial (3E15 total vg).

To date, there have been no serious adverse events related to TSHA-102 reported at either dose level in a total of 7 participants. 

Is there a way to test how a virus/vector will specifically affect the immune response a patient may have (outside of the body, by taking a blood sample etc) before being given the gene therapy? 

At the moment, this is not possible. No one knows why some people have this reaction and others do not.

If the SAE is caused by an immune reaction, what is the immune suppression regimen and why didn’t it work?

Neurogene used a prophylactic, or pre-emptive, immunosuppression regimen in the 3E15 vg cohort, which included corticosteroids, rituximab and sirolimus. The other two participants in this dose cohort did not experience this rare hyperinflammatory response. Why this participant in this specific case had this reaction will be studied further by the team involved and the sponsor. We also know from other AAV9 vector gene therapy trials that this sort of rare immune reaction may occur. Why some people respond and others don’t is unknown. The numbers of gene therapy recipients who have had this kind of response are too small to be able to easily identify any specific factors.

Where did this child live/where did the SAE happen?

Information about where the child and family live has not been shared publicly. In a rare disease clinical trial, sharing information about location can unblind the trial and so it is essential that this information is kept confidential. Speculation/rumours about the location of the patient/trial site involved are unhelpful and potentially damaging to the community and to the program moving forward.

How will the improvements seen so far on low dose affect our children’s lives positively in the long term?

Significant improvements have been seen in the first four patients in the 1E15 vg (low dose) cohort of the Neurogene trial. These improvements strengthen over time since initial dosing which is reflected in the data shared. You can read more about this here.

Could Neurogene go back to the higher dose level if we see even greater improvements in the two children who were dosed prior to the SAE?

At this point in time, Neurogene has discontinued the 3E15 vg dose and will be moving forward with the 1E15 vg dose, which showed a favorable safety profile and meaningful improvements across Rett syndrome scales and acquisition of developmental milestones and skills. 

Families with questions and concerns about the clinical trial can contact Neurogene here:

001-877-237-5020

[email protected]