Report on FDA Listening Session on STXBP1
FDA Listening Session on STXBP1-Related Disorders
On April 12, 2022, the STXBP1 Foundation (Foundation), a non-profit advocacy organization, along with members of the STXBP1 community, participated in a one-hour Listening Session with representatives from the U.S. Food and Drug Administration (FDA). STXBP1-related Disorder (STXBP1) is a neurodevelopmental disorder, with an incidence of approximately 1:30,0000 births, associated with mutations in the STXBP1 gene (also known as MUNC-18) resulting in severe deficiencies in neurotransmitter release.
The goal of this listening session was to provide FDA representatives with a broad overview of the lived experience of people with STXBP1-related Disorders, the requirements for daily caregiving of affected individuals, and treatment priorities.
The key objectives of the meeting were to highlight the following:
Seizures are a prominent symptom of the disease; however, STXBP1 is a devastating disorder characterized by a diverse spectrum of symptoms, which must be addressed in therapy development.
There is a tremendous unmet need for viable treatments. Targeted, precision approaches that address the disease at its genetic level and effective therapies that address the spectrum of symptoms are urgently needed and would be welcomed by the community.
There is significant heterogeneity in the patient population. Improvement in one disease aspect may significantly improve the quality of life of an individual, and that aspect may differ among patients.
Meeting Participants
STXBP1 Foundation and Community participants:
Melissa Hioco, Parent of Alex, a child with STXBP1
Jennifer Clatterbuck, Parent of Emma, a child with STXBP1
Michael Boland, Parent of Lukas, a child with STXBP1
Russ Novy, Parent of Katie, a child with STXBP1
Charlene Son Rigby, President of STXBP1 Foundation & Mom
Jackie Steinberg, Vice President of STXBP1 Foundation & Mom
James Goss, PhD, Scientific Director of STXBP1 Foundation
John Oldenhof, PhD, Scientific Advisory Board Member & Dad
Cristina Brennan, Board Member of STXBP1 Foundation & Mom
Terry Jo Bichell, PhD, Executive Director of COMBINEDBrain
Ingo Helbig, MD, Department of Neurology, Children’s Hospital of Philadelphia
Zachary Grinspan, MD, Department of Pediatrics, Weill Cornell Medical Center
Sarah Guggiero, MS GCG, Children’s Hospital of Philadelphia
James Valentine, JD, MHS, Regulatory Advisor
FDA representatives from the following Centers were present:
Center for Drug Evaluation and Research (CDER), including Office of Neuroscience, Division of Neurology 2, and Professional Affairs & Stakeholder Engagement
Center for Biologics Evaluation and Research (CBER)
Summary of Topics Discussed
The meeting comprised of four statements by parents sharing the experiences of their children living with STXBP1, a presentation from a pediatric neurologist who provided a clinical perspective of the disease, a question-and-answer session to allow the FDA representatives to address the parents, and opening and closing statements by the FDA and the STXBP1 Foundation. The discussion is summarized below, including select representative quotes from the meeting participants.
Burden of Living with STXBP1-Related Disorders
There is a broad phenotypic spectrum of STXBP1-related Disorders. In an opening statement, the FDA affirmed that they understood STXBP1 is a complex medical condition that can present with a variety of symptoms. The Foundation presented caregiver survey data collected by the Foundation and Simons Searchlight pertaining to symptom burden and most challenging daily activities of STXBP1 patients. Caregivers reported that the symptoms with the highest impact are communication challenges, intellectual and cognitive disabilities, impaired motor control, and epilepsy. These symptoms are reflected in the most challenging aspects of daily life for patients which are independence and need for constant everyday care, speech and communication, toileting, learning, and using their hands.
Communication challenges. The majority of STXBP1 patients are non-verbal or have speech that is limited to a few words. Communication challenges represent a major impact to patients and caregivers; speech and communication was highlighted as the top most difficult symptom in a caregiver survey from the STXBP1 Foundation. One mother described how her son’s language skills disappeared. “At the age of 3 he lost all the words that he had fought so hard to gain. As his mom I watched with dread as [he] lost skills. The few words he once had, have now forever disappeared.” A father of a 4-year-old discussed how his son’s communication ability is lagging behind normal milestones, “His verbal skills are under 6 months as he vocalizes but is not yet babbling.” Another father discussed his 18-year-old daughter, “She has no communication skills; it is a total guessing game to determine what [she] wants or needs.”
Intellectual and cognitive disabilities. As a developmental encephalopathy, STXBP1 patients suffer from cognitive and intellectual deficits, which can lead to autism and behavioral problems. As one father described it, “[She] has a severe cognitive impairment and her development plateaued at 13-months, which has left [her] living as an adult-sized toddler.” One mother described her son’s behavioral problems, “He has always displayed sensory seeking behaviors since he was a young child … He obsessively seeks out food and will stuff his mouth with no regard to the size or amount … We have had to stop him from constantly biting himself, or intensely hitting his limbs causing bruising … Currently he holds his breath over and over again to the point that his oxygen levels dangerously drop.”
Impaired motor behaviors. STXBP1 patients suffer from hypertonia, hypotonia, spasticity, gross motor, and fine motor control issues, which as the pediatric neurologist acknowledged also “leads to gastrointestinal and respiratory problems in patients.” The motor difficulties and the impact on patients and caregivers were mentioned by several parents. The father of a toddler noted, “By six months of age [his] global delay was starkly evident. He struggled with head control, had no interest in grasping or mouthing toys, and did not readily smile back at his caretakers…Due to his extremely limited fine motor control, sign language is not a good option for communication… [He] has gastroesophageal reflux disease and severe constipation. His reflux was so severe it significantly interfered with his sleep.” A mom of a teenager stated, “[He] had both high tone and low tone as a baby and as a toddler he developed a terrible tremor in his hands.” Another mother noted of her preteen daughter, “She can’t hold a pencil, can’t draw, and chokes and throws up regularly.” The father of an adult child said, “She cannot feed herself and cannot transition from sit to stand…She tripped on the carpet and knocked her 4 front teeth loose; [she] has no protective reflex when falling.”
Seizures. STXBP1-related disorder was first identified in patients with severe forms of infantile epilepsy. Approximately 85%-90% of patients experience seizures, which, as described by the pediatric neurologist “is highly dynamic, ebbing and flowing over time.” Seizures are a major concern of parents and, more often than not, difficult to adequately control. As a mother with a daughter with intractable epilepsy remarked, “From partial focal to infantile spasms to generalized to clusters, the seizures have stolen years’ worth of time with her friends, time at school, and time with her family. They have stolen learning opportunities, potential memories, and chances at fun. They steal sleep, feelings of safety and security, and hope for the future.” And, as a dad noted about his daughter, “[She] suffers 2-3 seizures per day, she is on her 15th seizure med, and we worry about SUDEP and any other possible long-term effects.” Even if seizure activity is eventually controlled in a child, the experience is traumatic. A dad described his feelings during his son’s first 6 months, when he suffered severe seizures, “After five days in the NICU we took [him] home. My wife and I were almost scared of him, he seemed so fragile. Despite the Keppra, he continued to have about 30 seizures a day…My memories of the first six months with [him] are dominated by feelings of love tempered with fear, uncertainty, and inexplicable sadness.”
Independence and constant care. STXBP1 patients have severe developmental delay which robs them of any independence. They require nearly constant attention and aid in almost all daily activities, as addressed by several parents. “His lack of safety awareness makes it so that we can never let down our guard...he sleeps in an enclosed bed with multiple latches, so that he is safe”, “She needs help with all aspects of daily living from dressing to eating to getting in and out of the car”, “As [she] is older now, we worry mostly about [her] long-term care, especially since she needs support with all aspects of daily life. Who’s going to care for [her] when we are old and unable? Where is the safest place for her to live? When will we no longer be able to care for her ourselves? And how are we going to pay for all this?”
The Unmet Medical Need in STXBP1 and Treatment Goals
During its opening and closing statements, the Foundation pointed out that there is a large unmet medical need for STXBP1 therapies as there is no FDA-approved therapy specifically for any STXBP1-related disorder. Current therapies are largely antiseizure medications, and 1/3 of patients are refractory. There are no treatments for the other hugely impactful symptoms. Given the broad phenotypic patient population, it is difficult to establish clinical measures to use as endpoints, especially given that a specific symptom improvement may be meaningful for one patient but not necessarily another.
The FDA was interested in hearing further clarification from caregivers on balancing the benefits of a drug with the risk associated with it, and if a therapy was worth pursuing if it diminished the quality of life for the patient; as one parent had stated “As a parent of a child with intractable epilepsy, you are constantly weighing the risks and benefits of a treatment. What will need to be sacrificed to obtain seizure freedom or even just less seizure activity? Is seizure freedom worth losing quality of life in other ways?” The consensus view of the parents was that there are some small improvements that could have a huge impact on the children and any risks or benefits should be weighed by the parent and physician. One mom mentioned how placing their son on the keto diet “took a lot away from him, but the family is afraid of SUDEP and the decision was based on saving [his] life versus some loss of quality of life.” As one dad put it, “The frustrating part is seeing the only therapeutic option is seizure control. I would be OK with some seizures if I saw significant improvement in other aspects. If I could hear the words ‘I love you dad’ that would be very significant.”
The bottom line is that new treatments are urgently needed for these patients who have very limited options.