GeneTx Biotherapeutics LLC and Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE), companies partnered in the development of intrathecally administered GTX-102, an investigational treatment for Angelman syndrome, today announced positive interim data from the Phase 1/2 study of GTX-102. Preliminary results from the first five patients treated indicate substantial improvements in all patients in at least two disease domains including communication, behavior, sleep, gross motor function, and fine motor function as measured by the Clinical Global Impression of Improvement Scale for Angelman Syndrome (CGI-I-AS) at day 128. At the highest doses, all five patients experienced a serious adverse event (SAE) of lower extremity weakness believed to be related to local inflammation due to GTX-102. Following these events, the companies paused enrollment and dosing. These SAEs were assessed as mild or moderate in severity and have generally improved over a period of a few weeks while disease domain improvements have been sustained for three months. The study protocol will be amended to reduce the dose-level range and modify the administration process, which is expected to reduce further drug-related SAEs.

“The work that the GeneTx team and Dr. Scott Dindot and his lab have conducted over these last years provided the opportunity to impact Angelman syndrome in a fundamental manner with a potent antisense oligonucleotide,” noted Emil D. Kakkis, M.D., Ph.D., CEO and President of Ultragenyx. “These initial GTX-102 findings raise the possibility of improving some of the significant symptoms of Angelman syndrome.”

“The UBE3A antisense transcript targeted by GTX-102 is a viable target for treatment,” stated Scott Stromatt, M.D., Chief Medical Officer of GeneTx. “The results observed to date are encouraging and we look forward to resuming dosing at lower doses to help avoid side effects.”

“So far we are seeing rapid improvements in multiple areas, including some kids doing things they’ve never done before, and I don’t believe this rate of progress in development skills has been seen before in Angelman syndrome,” commented Elizabeth M. Berry-Kravis, M.D., Ph.D., Professor of Pediatrics, Neurological Sciences and Biochemistry, Rush University Medical Center, and investigator in the GTX-102 clinical study. “It is especially amazing that families are asking me repeatedly when they can start treatment again despite the side effects that their child experienced. That speaks to the value of what they were seeing in their child.”

Interim Efficacy Results

The study design includes five dosing cohorts in which patients were to receive four monthly doses of GTX-102 on an intra-patient dose escalation scheme. Five patients between the ages of 5 and 15 with deletions in the maternal UBE3A gene region were enrolled in the first three cohorts and are included in the interim data analysis.

Initial indications of benefit have been observed in all five treated patients across the key domains of communication, fine and gross motor skills, behavior, and sleep as measured by the CGI-I-AS. In some patients these initial indications of clinical improvement were observed by the investigator early in the study at the two lowest dose levels and began within weeks of the first dose.

At day 128, all patients had a meaningful improvement in their individual global CGI-I-AS score, which evaluated overall improvement across five domains specific to the symptoms of Angelman syndrome. All five patients were assessed as ‘much improved’ or ‘very much improved’ on the 7-point global scale of -3 to +3 with a mean change of +2.4. All patients had at least two symptom domains that were assessed as ‘very much improved’ or ‘much improved’ and at least three domains that were ‘minimally improved’ or better (Score of 3, 2, or 1).

Patient-by-patient CGI-I-AS results by domain and overall are as follows:

*Patients 002, 003, and 004 had gross motor impairment at time of assessment due to the ongoing SAE

Note: CGI-I-AS scale ratings: +3: very much improved, +2: much improved, +1: minimally improved, 0: no change, -1: minimally worse, -2: much worse, -3: very much worse.

Data as of day 128, except day 86 for patient 005.

Supporting the CGI-I-AS improvements were changes in other domain-specific measurable endpoints. All patients experienced numerical increases in the sub-scale growth scores of expressive and/or receptive communication of the Bayley Scales of Infant and Toddler Development (Bayley-4) domains, and three patients showed improvements in the Observed Reported Communication Ability (ORCA) measure of expressive, receptive, and pragmatic communication.

The interim analysis did not include data from other exploratory outcome measures such as seizure frequency, sleep diaries, EEG patterns, UBE3A protein levels in the CSF, ambulation by wearable device, and adaptive behaviors.

Caregiver reports, via functional domain questionnaire, of improvement in the patients also support the changes seen in CGI-I-AS and the other endpoints. Notable caregiver-reported changes include:

• Acquisition of spoken words, signs and gestures, and augmentative and alternative communication abilities; two previously nonverbal patients began using words, one reaching nine words
• Ability to respond to their name, follow commands, and focus on tasks
• Acquisition of independent capabilities, such as self-feeding with a fork
• Increased abilities in physical activities, such as patients swimming on own and catching/throwing a ball
• Dramatically improved sleep
• Decreased maladaptive behaviors
• Increased social engagement
• Improved gait and posture

Interim Safety Results

Significant but reversible lower extremity weakness has been observed as a grade 1 or 2 SAE in four patients after administration of the highest dose, which was approximately 10 times higher than the initial low dose of cohort 1, and in one patient after administration of a single dose at the second highest dose level assessed, which was approximately 6 times higher than the initial low dose of cohort 1. The SAE was not observed after the two lower starting doses in the first four patients.

The onset began between approximately one to four weeks after the last dose. In two patients the lower extremity weakness progressed to an inability to walk or bear weight. No patients experienced upper extremity weakness. The companies paused all dosing beginning at the time of the first SAE, and patients were treated with intravenous immunoglobulin (IVIg) and corticosteroids. The most severe aspects of the neurologic findings steadily and substantially resolved within a few weeks of the dosing pause and implementation of treatment. The adverse event has completely resolved in four patients (occurring between 19 and 70 days from onset), while the findings in the one remaining patient substantially improved by three to four weeks and is now almost fully resolved.

The lower extremity weakness was associated with an elevation of cerebrospinal fluid (CSF) protein, which has been reported in studies of other intrathecally administered antisense oligonucleotides. Magnetic resonance imaging (MRI) shows findings consistent with local inflammation in the meninges and nerve roots in the region of intrathecal administration in the lower back (lumbosacral region) at the higher doses of GTX-102. The lower extremity SAE was not observed at lower doses and the delayed events of lower extremity weakness were not observed in preclinical GLP toxicity studies at similar and higher doses.

There have been no other SAEs reported to date with GTX-102. Other adverse events have included transient ataxia, headache, and fatigue. The acute, transient ataxia was reported in all five patients, occurred two to six hours after the intrathecal injection, lasted for 24 to 72 hours, and was dose dependent. No patients have withdrawn from the study.

Study Next Steps

The companies paused dosing and enrollment in the study after first observing the lower extremity SAE to evaluate the event, assess efficacy, and monitor recovery. After review of all findings and nonclinical evaluations, the study protocol will be amended to try to reduce exposure to GTX-102 at the point of local contact during intrathecal administration. The dose will be lowered to the observed safe range at which clinical improvement was first observed and a slower titration regimen will be implemented that is dependent on individual patient response and age. The administration method will be modified to help reduce local drug contact time. The companies will obtain agreement on these modifications with the U.S. Food and Drug Administration (FDA) prior to resuming enrollment and dosing. Further detail from the first five patients will be presented at the Foundation for Angelman Syndrome Therapeutics (FAST) Global Summit in December 2020. Additional safety and efficacy data from the study are expected in 2021.

Investor Conference Call and Webcast Information

Ultragenyx will host an investor conference call today, Monday, October 26, 2020, at 2 p.m. PT / 5 p.m. ET to discuss the results. The live and replayed webcast of the call will be available through the company’s website at https://ir.ultragenyx.com/events.cfm. To participate on the live call by phone, dial (855) 797-6910 (USA) or (262) 912-6260 (international) and enter the passcode 5684773. The replay of the call will be available for one year.