Gene therapy for the treatment of Angelman Syndrome: Future clinical trials
Agilis Biotherapeutics, LLC
Drs. Greg Robinson and Jodi Cook
This is gene therapy. A virus (adeno-associated virus=AAV) is used to carry (vector) the UBE3A gene into the nerve cells (neuron) of the brain and implant it into the nucleus (“manufacturing facility” of the cell), so that each cell can make the protein UBE3A (E6-AP ubiquitin ligase) that is coded by UBE3A and is missing in those individuals with Angelman Syndrome (AS). This therapy will involve a direct delivery to the brain to replace the missing or defective gene and will likely be an injection, either into the spinal fluid (intrathecal administration) or directly into the brain itself.
The benefit of AAV therapy is that the virus can infect the targeted cell and allow for long-term gene expression. The virus DNA will persist for many years in non-dividing cells (neurons). In trials conducted to date, this mechanism has been found to be very safe and well tolerated.
Since the UBE3A gene is only missing in neurons due to its imprinted nature and lack of paternal expression, replacing this gene will allow for production of the protein needed for normal cell function (e.g. ubiquitination of various proteins in neurons and at the synapses; as discussed above, to tag proteins for degradation).
The brains of individuals with AS are considered to be morphologically normal, so by giving back this gene and making this protein, the expectation is to restore many of the functions that have been lost. This fact is very unique when compared to other neurological disorders where the brain is not morphologically or anatomically normal, wherein restoration of function would be difficult or even impossible.
The DNA of UBE3A is packaged into the AAV and then delivered into the brain where it is needed. In a study published by Dr. Weeber’s lab (Dailey, et al, 2011), it was found that after the AAV was inserted into the brain of mice, Ube3a expression and E6-AP protein levels were increased and cognition was improved. One impressive fact about this study was that it was conducted in adult mice, suggesting that adults with AS could see a benefit in UBE3A recovery. In AS mice, improvements were seen in learning, memory, and neuronal/synaptic plasticity.
Agilis has the worldwide exclusive license to this technology for the treatment of AS and has partnered with Dr. Ed Weeber and Dr. Kevin Nash at the University of South Florida, two members of the FIRE Team at FAST. Collaborative research is ongoing at USF to move forward studies with the human UBE3A gene-AAV. Animal studies are underway as well as optimization of the DNA construct for expression. They are testing different AAV capsids to determine the best delivery option. Agilis expects to identify the lead AAV/gene candidate in 2016, and then focus of developing the therapeutic.
Drug development typically takes 7-10 years and Agilis will work very hard to expedite this process as much as possible. They are already in the pre-clinical phase and development process. Since this gene therapy approach was previously successfully tested in mice, they are now making the human version, which moves the process forward faster. In the development process of making a new drug, companies must show that they can make the same exact AAV-capsid package with the gene repetitively, so that the treatment produced at different times will be identical. Once this process is completed, discussions with the FDA will ensue and a safety trial will be started in individuals with AS (Phase I clinical trial). This will help to determine proper dosing to ensure safety. Then, it will move to efficacy trials (Phase II and III). Once that is complete, Agilis can file for drug approval.
Agilis is proud to announce that they have recently received Orphan Drug status by the FDA. In 1983 the Orphan Drug Act for Rare Diseases was passed to promote the development of new treatments for rare diseases affecting fewer than 200,000 people in the USA. Receiving Orphan Drug designation incentivizes companies to continue research in rare diseases as typically there is less money in this area due to the low number of patients. Some of the incentives include: 7 year market exclusivity; tax incentives for research and development costs; user fee waivers; eligibility for fast-tracking through the FDA review process; and to have more frequent interactions with regulators in the FDA to speed development into clinical trials. As of 2015, the FDA had granted orphan drug designation to 3,273 therapies; where before the year 1983 it was only granted to 10. Additionally, since 1983, nearly 500 orphan drugs have been approved for sale; with 233 of them within the last 10 years. This is a high percentage of follow-through.
Agilis’ timeline is to optimize the DNA and capsid for humans and select a lead in 2016. Expect more safety studies to maximize the dose and evaluate for side effects in more animal models over the following 6-12 months. The manufacturing process development is ongoing and will continue until perfected. While this is occurring, they are simultaneously working on the best route of direct administration to the brain (get it into the brain without going systemically as the brain has a strong network of barrier to protect the brain from drugs and toxins getting into this space) as well as focusing on the least invasive and most effective mode. They are also currently working on Phase I clinical protocol development to find appropriate outcome measures that can be used in the trial to evaluate for clinical efficacy. Then there will be regulatory discussions with the FDA. Once all of these events are complete, Phase I clinical trials can start.
Agilis is scheduling an Outcome Measure Consortium to take place later this winter in order to establish reliable biomarkers and clinical measures in Angelman Syndrome that can be used for therapeutic development and evaluation. These outcome measures are needed to get the FDA to approve any clinical trial. There are currently no outcome measures specifically for individuals with AS. We have to show the FDA that the drug improves the lives of individuals with AS, but this needs to be well thought out and executed. Simple, yet clear improvements, are needed for the FDA to let a drug move forward through the development process. This step is one of the most important for successful clinical trials.
The goal of this consortium is to invite many types of “stakeholders” to participate in the project development and as such, will include organizations, scientists, physicians, clinicians, parents, caregivers, and pharma/biotech companies. These are the people most knowledgeable about AS; and therefore, know exactly what is desired from a therapeutic for each individual with AS. This consortium will build momentum toward developing both short- and long-term objectives, raise awareness, participation, allow new data collection and more funding. The ultimate goal of this consortium is to rank order the most important symptoms needing resolution or control (e.g. seizures, anxiety, sleep, constipation, speech, motor function, etc...), and to determine if there is a sensitive and objective test for each symptom. If not, it is important to get baseline data on patient’s symptoms. This will be determined by a consensus of experts, including parents/caregivers. This data will help to plan and budget for studies in order to achieve a sensitive and objective test for each major symptom of AS.
- Will my child qualify for the clinical trial?
- When will treatment be available?
- Is there anything I can do now?
- Are we worried about overexpression of the gene with this technology?
- What is the estimate for the start of Phase I clinical trials?
- If a child/adult has co-morbidities to AS will they be excluded?
- What are we doing with the old outcome measures, data, natural history (NH) study that many families were a part of?