Next, to test tolerability, we evaluated the same doses of NGN-401
that demonstrated efficacy in a female mouse model. These mice are genotypically comparable to Rett female patients, and therefore a good model to demonstrate tolerability where 50% of cells have normal levels of MeCP2 expression. As you can see, NGN-401 shown in green was well tolerated, with no negative effects on survival. However, when we conducted a similar experiment using unregulated conventional gene therapy as depicted in purple, these mice
experienced immediate toxicity and were dead or reached the humane endpoint within 2-3 weeks. The deaths were associated with significant overexpression of MECP2, illustrating how the EXACT technology is able
to control MeCP2 levels to a tolerable level.
Slide 18
Earlier this year, the U.S. FDA cleared the IND application for our planned Phase 1/2 trial, and, notably, is allowing us to dose pediatric Rett female
patients for our first in human study.
Traditionally, the FDA requires sponsors to demonstrate safety in adults prior to advancing into children. In
order to overcome the high regulatory bar, we successfully demonstrated to the FDA that we had a strong scientific rationale, a positive benefit-risk framework, and preclinical evidence that support a prospect of direct benefit in children with
Rett syndrome.
Key pillars of that preclinical evidence are: (1) NGN-401 delivers controlled MeCP2 levels,
as is evidenced by the strong efficacy and safety profile; (2) There is a strong translational foundation, as our data show robust MeCP2 expression in key areas of the brain underlying Rett pathology (3) we are maximizing the therapeutic
potential of our product by delivering the highly conserved full length gene and (4) we have a comprehensive safety package, with no evidence of transgene toxicity or any off-target effects. There is more
detailed preclinical data included in the appendix for those of you interested in learning more.
Slide 19
The Phase 1/2 trial is an open-label, single-arm, multi-center clinical trial that is designed to assess the safety,
tolerability, and efficacy of a single dose of NGN-401 delivered using a one-time ICV procedure in female pediatric patients with Rett syndrome.
The first cohort is expected to enroll a total of five girls with a confirmed genetic diagnosis of classic Rett syndrome ages
4-10 years, with dosing commencing in the back half of 2023. The starting clinical dose is bracketed by the two efficacious mouse doses shown earlier in the mouse models and as a result would be expected to be
efficacious. In addition, we are making plans to dose escalate and expand the study given the safety margin of >4x from our GLP toxicology study. Key assessments will be taken at 3, 6, and 12 months, with efficacy assessments of interest
including autonomic function, hand function, communication, and gross motor function.
We expect to report preliminary data from the study from patients
dosed in our first cohort in the fourth quarter of 2024, with additional data from a greater number of patients in the back half of 2025. It is worth noting that the FDA generally requires in a gene therapy study a stagger in between patient dosing,
along with the adjudication of safety by an independent data safety monitoring board, or DSMB, before we can proceed to the next patient dosing. This stagger applies to all of the patients in the first cohort. Therefore, we would expect that the
2025 dataset will also have more extensive follow up on these first few patients, as well as an expanded dataset from additional patients.
Slide 20
I will now turn to NGN-101, which we are currently developing for CLN5 Batten disease.
Slide 21
Batten disease is a family of rare
neurodegenerative diseases caused by pathogenic changes in one of a series of genes that results in the accumulation of toxic deposits across multiple organ systems. CLN5 Batten disease is a rare, pediatric-onset and rapidly progressive condition
caused by a pathogenic mutation in the CLN5 gene, leading to loss of function. It is characterized by loss of vision, seizures, and progressive decline in intellectual and motor capabilities beginning in childhood, leading to substantial impairments
and early mortality. Unfortunately, CLN5 disease has no disease specific treatment options.
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