NGLY1 Deficiency

MENLO PARK, Calif.--(BUSINESS WIRE)-- Grace Science, LLC announced today that the first patient was dosed in an open-label Phase 1/2/3 clinical trial of GS-100, an AAV9 gene replacement therapy for the treatment of NGLY1 Deficiency. Part 1/2 of the study will investigate dose-escalation and the safety and efficacy of a single intracerebroventricular (ICV) infusion of GS-100 in NGLY1 Deficiency patients aged 2-18 years. Part 3 of the study will assess the co-primary outcomes at 52 weeks following treatment at the selected dose: 1) change from baseline of the NGLY1 Deficiency Primary Disease Activity Biomarker, GlcNAc-Asn (GNA, or N-acetylglucosamine) in cerebrospinal fluid, and 2) change from baseline in the motor subdomain of the Bayley Scales of Infant and Toddler Development, Fourth Edition (BSID-4). Further details regarding the Phase 1/2/3 study can be found at . Matt Wilsey, CEO & Co-Founder of Grace Science, LLC, stated that "Treating the first patient is a tremendous milestone for our company and the NGLY1 Deficiency patients we strive to cure. We believe this drug will improve the lives of individuals living with this devastating disease. Time is precious as our community has lost sixteen individuals since January of 2020.” “This study is a true partnership between the scientific community and the NGLY1 patient community,” said Carolyn Bertozzi, Co-Founder of Grace Science, LLC. Dr. Bertozzi went on to say “The team has worked incredibly hard to reach the goal of treating the first NGLY1 Deficiency patient with this potentially life-changing therapy. We are so thankful to the patients and their families for helping Grace Science turn this treatment into a reality.” About GS-100 GS-100 is a recombinant, single-stranded AAV9 vector that encodes a full-length version of the human NGLY1 gene. GS-100 was previously granted Orphan Drug Designation (ODD) by both the FDA and the European Medicine Agency (EMA) in 2021, Rare Pediatric Disease Designation by the FDA in 2021, and Fast Track Designation by the FDA in 2023. About NGLY1 Deficiency NGLY1 Deficiency is a serious, life-threatening disease with no approved therapy. Patients with this disease suffer from debilitating symptoms that present early in life, including global developmental delay, cognitive impairment, (hypo)alacrima, movement disorders, and other neurological symptoms. About Grace Science Grace Science, LLC is a biotechnology company founded in 2017 by Matt Wilsey and Dr. Carolyn Bertozzi to develop novel therapies based on the function of NGLY1, a key enzyme involved in proteostasis. The company’s deep knowledge of the NGLY1 pathway is key to its ability to identify new ways of treating NGLY1 Deficiency as well as more common diseases. For more information about Grace Science, LLC and NGLY1 Deficiency, please visit gracescience.com.

Pictured: Randomized data over a strand of DNA/Nicole Bean for BioSpace Rare diseases, by their very nature, don’t fit the mold—so neither should the trials for therapies designed to treat them nor the regulatory process to approve them. This was the tone set during a recent panel discussion where Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, argued that non-randomized, single-arm trials could be the best option when testing certain gene therapies for rare diseases. Peter Marks “There are many rare diseases affecting dozens to a few hundred individuals in the United States where the concept of trying to do a randomized trial is very challenging at best and impossible at worst,” Marks told BioSpace. When it comes to trialing gene therapies, it’s not possible to efficiently enroll sufficient numbers of patients, either because there aren’t enough patients or because those patients won’t agree to be randomized, he explained. “It’s a situation where you can’t get the job done.” While single-arm trials may seem like an efficient path to approval of therapies for diseases with high unmet need, experts told BioSpace that this approach is not always appropriate. As they explained, there are several variables to consider when deciding whether having a control arm is important. When Single-Arm Trials Can Work There is no typical trial design for rare disease gene therapies, according to Suyash Prasad, a genetic medicine consultant and former chief medical officer in the biotech industry. He told BioSpace that for a single-arm trial to be effective, certain parameters need to be met. These include significant clinical efficacy in a reasonable number of patients, a non-heterogeneous patient population with a consistent disease progression and a mechanistic or biological endpoint. “If you have those three things in position, then . . . I think a single-arm study is fine,” he said, but added that the converse is also true. “If you have a subtle improvement, if you see only the improvement in one or two endpoints . . . if there’s a very heterogeneous disease population, then it becomes much harder to run a single-arm study.” Suyash Prasad Marks concurred, saying that one of two conditions needs to be met for CBER to consider approval of a gene therapy based on a single-arm trial. “The treatment has to create a large enough effect that it is apparent to a non-statistician that something has happened significantly to those individuals, such that having a control group is not necessary,” he explained, or measurement tools must show that “a parameter has changed enough so that we feel comfortable that it is reasonably likely to predict that something good down the line is going to happen.” Biomarkers in Question Marks has long been a proponent of regulatory flexibility and has overseen drug approvals in this vein. In June 2023, the FDA granted Accelerated Approval to Sarepta Therapeutics’ Elevidys, the first gene therapy for Duchenne muscular dystrophy (DMD). This followed a narrow 8-6 advisory committee vote in favor of Elevidys and FDA briefing documents that questioned evidence of “a pharmacologic effect on a biomarker in the pathway of the disease.” The FDA’s Accelerated Approval pathway allows for the approval of medicines for serious or life-threatening diseases based on surrogate endpoints that are reasonably likely to predict clinical benefit. Marks said this pathway provides a way to get around the need for randomization in gene therapy trials. If a gene therapy is targeting a disease where a protein is deficient, and it’s possible to test for increases in protein production, that can act as a biomarker, he explained. Patients essentially act as their own controls, Marks said, as investigators look for the affected protein to reach levels thought to allow “normal or near normal function.” There is some question, however, both inside and outside of regulatory circles, about the scientific rigor of certain biomarkers. Holly Fernandez Lynch, assistant professor of medical ethics at the University of Pennsylvania’s Perelman School of Medicine, pointed to dystrophin in DMD as an example. The FDA in 2016 greenlit Sarepta Therapeutics’ Exondys 51 under Accelerated Approval based on a dystrophin increase in skeletal muscle observed in some patients treated with the drug. “Seven years after the first approval on the basis of that endpoint, we still don’t know whether that endpoint actually is supporting clinical benefit that is meaningful in patients’ lives,” Fernandez Lynch said. Holly Fernandez Lynch She stressed that she supports Accelerated Approval but believes confirmatory trials should be underway before it is granted—something the FDA is taking strides toward. However, she said, “This question about what counts as an acceptable surrogate, I think still needs more refinement.” Particularly in the case of subtle changes, Marks said biomarkers would ultimately need to be connected to a clinical endpoint in a post-approval study. Using biomarkers in this way gets the ball rolling ahead of a confirmatory trial, he said. “Honestly, for parents of children with very serious diseases . . . it’s a way of intervening with something that is well scientifically justified and where the chances are it’s reasonably likely to predict that they will have clinical benefits,” he said. Getting Gene Therapies to Patients One approach for these types of studies is to run a trial with both clinical and biomarker endpoints. Menlo Park, Calif.-based Grace Science recently received FDA clearance for an open label, single-arm Phase I/II/III trial for GS-100, an AAV9 gene replacement therapy for NGLY1 deficiency, a rare metabolic disease. This trial’s co-primary endpoints are change in motor subdomain on the Bayley Scales of Infant and Toddler Development and change from baseline in a disease-specific pharmacodynamic biomarker of enzymatic activity, the molecule GNA. GNA accumulation is directly linked to the absence of functional NGLY1, according to a 2021 article published in The Journal of Biochemistry and co-written by Grace Science co-founder and CEO Matt Wilsey. Wilsey told BioSpace in an email that this trial design was “absolutely essential given the severity of NGLY1 Deficiency as well as the rarity. We had to create a trial that used a small number of patients to select the highest safe dose.” For Wilsey, the ideal trial design for an ultra-rare pediatric disease is “a study with no placebo control that leverages a disease-specific biomarker and allows a sponsor to dose as young as two years old as quickly as possible.” Prasad shared that at his former employers, Taysha Gene Therapies and Audentes Therapeutics, he argued for just one single-arm trial for approval of therapies for ultra-rare diseases with an unmet need where a clinically significant improvement is expected. However, he said, “Most of the time, I have ended up in a compromise situation,” with randomization between immediate and delayed treatment arms. Ultimately, Prasad continued, disease prevalence and availability of other treatments should factor into the trial design decision. “When you’ve got a very rare disease where there’s only a hundred or a few hundred patients, and the patients are dying at the age of three, four or five years of age, for example. . . then there’s much more urgency.” Marks echoed that sentiment. It’s important, he said, “not to be hamstrung in trying to move things forward. We’re here to try to alleviate suffering of kids with bad diseases. Will we get it right all the time? Probably not. But as long as we get it right 90 or 95% of the time, I think that’s plenty good.” Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Also follow her on LinkedIn.

MENLO PARK, Calif.--(BUSINESS WIRE)-- Grace Science, LLC announced today that it has received FDA clearance of its Investigational New Drug (IND) application for GS-100, an AAV9 gene replacement therapy for the treatment of NGLY1 Deficiency. The clinical trial will utilize a single-protocol and an innovative Phase 1/2/3 trial design that includes an open-label, single arm, dose-finding study to investigate the long-term safety and efficacy of GS-100 administered by intracerebroventricular (ICV) infusion to NGLY1 Deficiency patients 2-18 years of age. “Dr. Bertozzi and I started Grace Science to save lives across the rare disease community — and beyond. We knew that the best way to do that was to approach science and drug development in a different way,” said Matt Wilsey, Co-Founder and Chief Executive Officer of Grace Science, LLC. “Today’s news is an exciting validation of that approach. We would not be here without the hundreds of people who developed the drug from patients, families, and our incredible partners.” “We are thrilled to obtain FDA clearance to advance GS-100 into the clinic and are excited about the prospect of what this new treatment may mean for NGLY1 Deficiency patients and families,” said Dr. Carolyn Bertozzi, Co-Founder of Grace Science, LLC. “This is an important milestone for NGLY1 Deficiency families, as well as for our company. This is the first Grace Science program to receive FDA clearance to enter the clinic and the first gene therapy clinical trial for NGLY1 Deficiency.” About GS-100 GS-100 is a recombinant, single-stranded AAV9 vector that encodes a full-length version of the human NGLY1 gene. GS-100 was previously granted orphan drug designation (ODD) by the FDA and by the European Medicine Agency (EMA) in 2021. GS-100 was also granted Rare Pediatric Disease Designation by the FDA in 2021, providing the potential for a Priority Review Voucher upon marketing approval. About NGLY1 Deficiency NGLY1 Deficiency is a serious, life-threatening disease with no approved therapy. Patients with this disease suffer from a lifetime of debilitating symptoms, including global developmental delay, cognitive impairment, (hypo)alacrima, movement disorders, and other neurological symptoms. About Grace Science Grace Science, LLC is a biotechnology company founded in 2017 by Matt Wilsey and Dr. Carolyn Bertozzi to develop novel therapies based on the function of NGLY1, a key enzyme involved in proteostasis. The company’s deep knowledge of the NGLY1 pathway is key to its ability to identify new ways of treating NGLY1 Deficiency as well as more common diseases. For more information about Grace Science, LLC and NGLY1 Deficiency, please visit gracescience.com.