Angelman Syndrome Market: Insights Into The Recent Late-Stage Drug Failures And Novel Approaches To Treating This Rare Neurogenetic Disorder

Angelman syndrome (AS) is a complex genetic rare disorder that affects the nervous system. The first sign of a child suffering from Angelman syndrome is a delay in development, such as the inability to sit without support or making incoherent babbling sounds. The hallmarks of the syndrome constitute severe physical disabilities, delayed development, intellectual disability, severe speech impairment, and problems with movement and balance (ataxia). Often affected children experience recurrent seizures (epilepsy) and have a small head size (microcephaly). 

Angelman syndrome is a result of the missing or dysfunctional gene known as UBE3A. The gene is responsible for the normal and healthy development of an individual physically as well intellectually. Usually, only a single copy of the gene is required that too from the mother, however, in cases of AS, either the child does not get any copy, or the child receives two copies – each from mother and father. 

As per Delveinsight’s estimates, the total Angelman syndrome prevalent cases in the 7MM (the US, EU5 (the UK, Germany, Spain, Italy and France) and Japan) was estimated to be 57,716 in 2017. However, many cases go undetected or underdiagnosed since, the diagnosis is usually based on the behavioral phenotype, particularly combinations of movement disorder, absent speech, and happy demeanor. Besides underdiagnosis, a lack of standardized treatment option forms a huge clinical unmet need. The present Angelman syndrome treatment market revolves around the management of symptoms rather than curing the condition. 

However, DelveInsight’s Angelman syndrome market analysis report estimates that several approaches focused primarily on the Gene Therapies, Topoisomerase Inhibitors, Cannabidiol, Protein Phosphatase 2A inhibitor, among others are under development to find a cure for the Angelman syndrome. Several pharmaceutical and biotech companies in the Angelman syndrome market are exploring the novel curative approaches. With high hopes from GeneTx’s therapy after the doors were closed for Ovid, Roche and Sarepta/StrideBio, the AS market is still a risky affair. 

Of all the Angelman syndrome pipeline therapies, the most touted treatment was Gaboxadol (OV101 or THIP), a product of Ovid Therapeutics. The company was running Phase III trials of the therapy for AS; however, the therapy flunked in the trial failing to meet its primary endpoint. As a consequence, Ovid halted everything related to OV101 and Angelman syndrome. The late-stage failure of the therapy has once again tumbled down the hopes and have shown how tough of a nut neurological disorders are to crack. 

Gaboxadol (OV101 or THIP) is an investigational oral therapy that is derived from muscimol, which selectively activates GABAA receptors present on the surface of nerve cells but away from the site where these cells communicate called a synapse. What made it different from the rest of the Angelman pipeline therapies was that it was the first compound targeting disrupted tonic inhibition, and the company hoped that its candidate would be able to restore tonic inhibition. This failure of the Ovid has left the Angelman syndrome market landscape wide open for other pharmaceutical and biotech companies to explore the waters. 

Although, it can be relieving that other players turned to different approaches for finding a cure for Angelman syndrome. For instance, GTX-102, an antisense therapy silencing the gene expression by binding to the RNA molecule behind the regulation of its expression, has also secured USFDA Fast Track Designation. GeneTx and Ultragenyx are co-developing the therapy. In AS patients, the UBE3A gene is only missing in neurons due to its imprinted nature and lack of paternal expression and otherwise morphologically normal. Thus, restoring the presence of this particular gene can help to restore several of the functions of the brain. Preclinical studies undertaken to evaluate the drug have shown that GTX-102 activates the paternal copy of the UBE3A gene in neurons in vitro, and can ease certain disease symptoms in a mouse model of Angelman syndrome. 

However, the journey to secure the FDA nod in the Angelman syndrome market landscape does not seem to be all flowery. The companies had to pause the trials of GTX-102 after the patients temporarily lost the ability to walk. Although the issue was resolved with the full recovery of the affected patients, the drug will be in close scrutiny of agency regulators due to safety concerns. 

PTC Therapeutics is taking homage under AAV vectors to develop its investigational gene therapy GT-AS (initially developed by Agilis Biotherapeutics). GT-AS uses a modified virus, called an adeno-associated virus (AAV) as a carrier to deliver a normal copy of the UBE3A gene to specific central nervous system cells, thereby, maintaining the production of the E6-AP enzyme. The company hopes that this will help to improve cell function and rescue neurological defects, thus will emerge with a cure in the Angelman syndrome therapeutics market. Sarepta Therapeutics and StrideBio collaborated to try their hands in vivo AAV-based therapies for up to eight central nervous system (CNS) and neuromuscular targets. 

With another approach, Biogen is  evaluating ubiquitin-protein ligase E3A (UBE3A) protein levels in cerebrospinal fluid (CSF) in a clinical trial (NCT04103333) under the study “Angelman Syndrome (AS) Biomarker Study.” The primary objective of this study is to measure ubiquitin-protein ligase E3A (UBE3A) protein levels in cerebrospinal fluid (CSF) and to evaluate its utility as a biomarker in support of the development of therapies for AS. 

Further, Roche and Biogen/Ionis are also working on two independent programs in their quest to find a cure in the Angelman syndrome market landscape. Biogen is leading a study, called the AS CSF and Biomarker Study, to find potential biomarkers, biological signs of disease, that can be measured in CSF. These biomarkers could then be used to check if a drug affects AS. Another study, called the AS Endpoint Study, led by Roche, aims to find ways to measure disease impact in the home and clinic and use new technologies to learn about AS. These measurements (endpoints) and technologies focus on areas such as sleep, communication and brain activity. 

Thus, it is essential to wait and watch which theory will manage to touchdown and which will be left in tatters. In the wake of late-stage trial failures, trial pauses, it is yet to see which pharmaceutical or biotech company will manage to emerge as trendsetter salvaging the AS patients.

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Healx uses AI to find drugs for Angelman Syndrome

The UK-based AI technology company Healx has begun a partnership with the Foundation for Angelman Syndrome Therapeutics (FAST), focusing on developing new therapies for the rare neurogenetic disorder.

The latest project will focus on quickly identifying and progressing novel treatments for Angelman syndrome, which is caused by several genetic mutations.

But the most significant is loss of function in a protein-making gene called UBE3A, which leads to complications in the nervous system and severe issues with movement, balance and speech.

There are no approved treatments – something that the Cambridge company aims to change by using patient insights during the development process.

Healx said that by working with FAST, it aims to create a “collaborative model” of drug discovery.

Dr Bruce Bloom, chief collaboration officer at Healx, said: “(Patients) are the ones driving forward research efforts to find new treatments, and have a wealth of experience and insight about what it’s actually like to live with these conditions.

“By integrating their expertise early on, and connecting to their well-developed scientific and clinical network, we have a better chance of finding critical new therapies.

“We’re really excited about working with FAST and hope to move our AI predictions towards preclinical validation in the second half of the year.”

Healx already has a collaboration with the UK’s muscular dystrophy research, support and advocacy charity Muscular Dystrophy UK.

The project will focus initially on a condition called facioscapulohumeral muscular dystrophy (FSHD), which causes muscle-weakening in the face, shoulder blades and upper arms.

In April Healx also began working with the Children’s Tumor Foundation to develop new therapies for neurofibromatosis, another rare genetic disorder affecting one in 3,000 people worldwide.

Earlier this year the company started using its technology to uncover combinations of drugs that could be used against the SARS-CoV-2 coronavirus.

The company hoped to use data to find out why mortality is higher in patients with comorbidities and problems with respiratory and cardiac systems.

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Ovid Therapeutics and University of Connecticut Collaborate to Accelerate the Development of OV101 (gaboxadol) for Angelman Syndrome


  • Ovid will collaborate with UConn’s Stormy J. Chamberlain and secures exclusive access to identified genetic sequences for shRNA-based therapy. Ovid plans to leverage its translational medicine capabilities and drug development expertise in Angelman syndrome to advance OV101 into clinical
  • Ovid is developing OV101 for Angelman syndrome to restore tonic inhibition addressing several core symptoms of the disease. OV101 is currently being evaluated in P-III NEPTUNE study with expected results in Q4’20
  • Additionally, Ovid is exploring OV881, a microRNA approach that may reduce the expression of UBE3A-antisense and restores UBE3A expression while the company is developing OV935 (soticlestat) in collaboration with Takeda for rare developmental and epileptic encephalopathies (DEE)

Click here to read full press release/ article | Ref: Ovid Therapeutics | Image: Ovid Therapeutics