UK Clinical Trials Webinar. Part 1: Therapies in Development

More than 50 people have joined the webinar live on July 1st to learn about Angelman Syndrome Clinical Trials in the UK. We are very grateful to Laurent, Dora, Katie and Julien for putting the event together and providing such a comprehensive overview of the upcoming developments.

It is worth noting as well how diligent Laurent was with answering both the questions that came in advance and also the continuous Q&A throughout the webinar too.

In a series of 3 posts we will try to convey the key points from all 4 talks and also Q&As

Part 1: Therapies in Development
- How can a drug work to treat Angelman Syndrome?: Dr Katie Cunnea (Angelman UK)
- Current preclinical and clinical developments in Angelman Syndrome: Dr Theodora Markati (University of Oxford)
Part 2: Natural History Study
- The natural history study in Oxford – our readiness for clinical trials: Julien de Bournet (FAST UK)
- Q&A about the Natural History Study: Prof. Laurent Servais
Part 3: GTX-102 Clinical Trial in the UK
- GeneTX Phase 1 Trial: Prof. Laurent Servais
- Q&A about Clinical Trials: Prof. Laurent Servais

How can a drug work to treat Angelman Syndrome?

The talk will cover the key pieces of scientific information that we need to be aware of about how an Angelman Syndrome drug might work.

Angelman Syndrome Genotypes

There are different genetic types of Angelman Syndrome. Angelman Syndrome is the result of having a lack of UBE3A in the brain. But there are slightly different genetic causes of that. On a top level, when babies are created the genetic information in mum and in dad is split in half and then rejoined from mum and dad. And we can get errors occurring in this process. There are slightly different errors that all result in the same problem – Angelman Syndrome.

We can have a deletion occurring. We can have two copies coming from dad instead of one copy for dad and one copy for mum. We can have an imprinting centre defect, which basically means that although one copy has come from mum and another from dad, they act as if they both have come from dad. Then you can also have a mutation – very small changes that are different in different individuals.

The role of RNA

The genes we have within the DNA are converted into a particular type of protein. So in the case of Angelman Syndrome that protein is called UBE3A. And so what happens is the DNA is converted to protein, but that there is an intermediate step as well – RNA. That’s an important thing to know when we’re talking about these different types of drugs today. In Angelman Syndrome, the mother’s UBE3A gene is missing or it’s damaged in some way. It’s mutated, for example. While the father’s gene is inhibited, so it’s silent and not functioning. It’s there, but there’s a mechanism, which means that protein is not produced from the father’s copy of the gene.

Therapies

Most of the medicines we’re all familiar with are often what we call small molecule drugs; they activate or inhibit a cellular process. But Angelman Syndrome is a genetic condition and there are many different cellular processes thought to be affected by it. So there are lots of potential difficulties with applying these traditional type medicines. And drug companies have been looking at something that has much better theoretical prospects for treating. Angelman Syndrome. Something that is genetic that affects the genetic information within the cells of individuals with Angelman Syndrome.

But there’s a couple of really key questions here that scientists have been trying to solve. How do we activate the UBE3A protein in the brain? And how do we get the medicine into the brain? Because there’s this issue with the blood-brain barrier and that can present problems.

There are two different strategies that people are looking at. One is gene therapy. On the other one is something called oligonucleotides therapy. What’s the kind of key difference that we need to think about? And that is that gene therapy introduces a change so that the genetic information that’s being produced by the cell is altered, whereas oligonucleotides therapy introduces a small piece of genetic information into the cell that sticks on to the genetic information that’s being made by the cell all the time. With gene therapy, you will typically have one treatment and there will be quite a long time before you would need an additional treatment. Whereas with oligonucleotides therapy? that would be a continuous therapeutic that you would need to take multiple times.

Current preclinical and clinical developments in Angelman Syndrome

My name is Dora Markati. I’m a researcher at the University of Oxford. I’m a member of Laurent’s team, and we’re currently designing together the natural history study for which we’re planning to recruit patients in July. So this evening, I will try to give you a good overview of what is currently in the therapeutic pipeline for Angelman Syndrome.

Angelman Syndrome pathology

We’ll start by zooming in on the Angelman Syndrome pathology and where the treatments that we’re going to discuss actually aim. We all know that Angelman Syndrome is caused by the deficiency of a protein with a name UBE3A. For everyone, for every protein that we have in our bodies, we have a least one gene coding for this protein. And for each gene we have two copies: one we take from our mothers and one we take from our fathers. So what happens for the gene that codes for the UBE3A protein is that the paternal copy only in the nervous system is silenced. That’s a natural blocking mechanism that regulates the level of the protein in the nervous system.

However, what happens now is that in the case that there is a mutation or a deficiency of the maternal copy, the paternal cannot compensate anymore for this. And then we have UBE3A deficiency. UBE3A is a protein that actually is involved in the recycling of other proteins in the brain. When we have a deficiency, we have abnormal levels of other proteins: some proteins are increased and some other proteins are decreased when this shouldn’t happen. And that has a second consequence – a disruption in the way that the brain cells connect with each other, or the way that the brain cells communicate with each other. And this is how the disruption in functions that way see with Angelman Syndrome happens. So we have disrupted communication, disrupted sleep, or we might have other symptoms arising or conditions like epilepsy.

Now we have two main categories of treatments aiming to treat Angelman Syndrome and the first big category is the Upstream Treatments, which aim to treat the cause of the Angelman Syndrome – UBE3A deficiency. And the second big category is the Downstream Treatments. These downstream treatments are not treating the cause but are aiming at different pathways that caused the symptoms of Angelman Syndrome.

Upstream Treatments

I’m going to start by talking about the upstream treatments. The upstream treatments are mostly those that we refer to as genetic treatments as well. And these upstream treatments have two main categories. One is genetic therapy or gene therapy. And the other one is those that aim to unsilence the paternal copy.

Gene therapy

We’ll start with gene therapy. What happens here is that we are aiming to introduce a normal copy of the UBE3A gene in the neurons, so that then the cells – the neurons – can produce the UBE3A protein that is missing. We are using viruses as the delivery system. These viruses are modified in the lab, so are not pathogenic anymore. The sequences in their genetic material that make them pathogenic are replaced by the UBE3A gene that we want to introduce into the neurons. Then we inject a lot of these viruses carrying the UBE3A gene via a needle into the spinal fluid of the patients. And then these viruses find a way and actually infect, in a positive way, the brain cells. The brain cells recognise the UBE3A part of the genetic material and produce the protein.

This has already been tried in animal models, in mouse models of Angelman Syndrome, and the first proof of concept happened in 2011.

I know that it’s a bit unclear how this can be inserted into the spinal fluid of the patients. There are several ways. The one that is the most common is by injection using a needle in the lower back, and that’s a process which is called intrathecal injection. It’s also referred to as a lumbar puncture which is very commonly used in clinical medicine, and also for diagnostic purposes.

Cell therapy

There is another type of gene therapy, which is called cell therapy. And in this case, what happens is that the patient’s cells are modified outside of the body of the patient. Cells are collected from a patient’s vein. And then the gene is inserted into the cells in the lab using viruses. Then the cells that are infected are transfused back into the patient. They then find their into the brain, because they are programmed to do so. And since they have the normal copy of the gene they produce the protein and they give the protein to the neurons.

So with this type of therapy, it is not just one drug or just one institution or one company that produces the therapy. There are several programmes, and not all of them are in the same phase. Not all of them use the same exact gene or not all of them have used the same virus for the transinfection. But we can’t yet tell which one is better. That’s why it’s good that we have a lot of developments going on. The one that’s had the most progress is very close to being in Phase 1. This type of therapy has not been tried yet for Angelman Syndrome but is approved for another type of rare paediatric disease.

Antisense Oligonucleotides (ASO)

Then the other big category is those drugs that can unsilence the paternal copy and the largest category of drugs are the antisense oligonucleotides, which are already in clinical trials being tested with Angelman Syndrome patients.

The paternal copy is silenced in the nervous system, and that happens because of a long molecule that actually blocks the gene. The antisense oligonucleotides are small sequences that are complementary to this long molecule that blocks the paternal copy. When we inject antisense oligonucleotides in the patient’s spinal fluid, they find their way and they hybridise with this long molecule that blocks the paternal gene and they degrade its part and this allows the paternal gene to produce that protein that is missing from the neurons. So in this type of treatment, we actually intervene in the genetic material that already exists in patients.

ASO in Clinical Trials

This type of treatment is already in clinical trials, and we have two. One is an antisense oligonucleotide produced by GeneTX and Ultragenyx – that’s in Phase 1/2. It’s mostly we’re aiming to assess the safety, but also the preliminary efficacy. The patients that are going to be included in this clinical trial are patients who have a maternal deletion, aged between 4 and 17 years, and the treatment is going to be delivered via a lumbar puncture. It’s taking place in the United States, Canada and the United Kingdom.

And then we have the second one produced by Roche, which is in Phase 1, and it’s all also for patients who have a maternal mutation or deletion between 1 and 12 years old. And it’s also with a lumbar puncture again. This trial is taking place in United States, Netherlands, Italy and Spain.

What’s important to know right now is that the big difference between gene therapy and antisense oligonucleotide is that, we don’t know for sure but we expect that, the gene therapy will probably require a less frequent redosing compared to antisense oligonucleotide.

Other Upstream Treatments

There are also several other treatments that currently are being prepared, which also aim to unsilence the paternal copy and this includes the topoisomerase inhibitors, which are already approved as a treatment for cancer. The CRISPR/Cas technology which is also known as “genetic scissors”, and the Zink Fingers.

I’ve made a table because I know that it’s difficult to get a grasp of all the different upstream therapies. And I’ve tried to show you where we are currently, in which phase of development. At the moment we have the antisense oligonucleotides, which are the most progressed in clinical development and they are between Phase 1 and Phase 2. The gene therapy and cell therapy programs, which are basically both gene therapies, are very close to Phase 1 but are not yet there.

There are many different programmes, but not all of them are at the same stage of development. I’m just showing generally, per category, the most progressed programme and where it is at the moment. We also have topoisomerase inhibitors, CRISPR/Cas9, the Zink Fingers which are at the preclinical stage. And then we also have three extra categories aiming to treat the UBE3A deficiency which are not yet at the preclinical level, which means that they have not yet been tried in animal models. These are enzyme replacement therapy, small RNA and small molecules.

The enzyme replacement therapy is in concept similar to the gene therapy because we are aiming to introduce the protein that is missing in the neurons, not with the virus this time, but directly infusing the protein in the nervous system. The RNAs are also similar in concept with the rest of the therapies that aim to silence the paternal copy. They just use different delivery systems.

Downstream Treatments

Now, I’m going to talk about the Downstream Treatments, those that we could also call symptomatic treatments.

So these treatments are not aiming to treat the cause of Angelman Syndrome, the UBE3A deficiency,

but act at lower levels of the pathology of Angelman Syndrome.

They address symptoms, such as epilepsy
Not all are directly targeting Angelman Syndrome
They can be helpful for all different genotypes of Angelman Syndrome
Gaboxadol OV-101 was discontinued last December. It was a neural compound to improve tonic inhibition.
- CGI-I-Angelman Syndrome scale was used – a 7-point scale assessing patient’s condition in five key areas (sleep, motor function, communication, etc)

Current needs

Objective and cross-comparable measures
- Meaningful outcome measures for different domains
- Biomarkers – digital or lab-based objective markers of the disease
- This leads to better design of clinical trials, accelerated approval processes, compensation by Health Systems after approval

Key messages

Different drugs might benefit different genotypes
Genotypes not eligible at early phases might be eligible at later phases
- Current mouse models are only deletions, that’s why trials begin from deletions
Currently, developments are in phase I/II which assess mostly safety and tolerability and to a lesser extent efficacy
Genetic therapies have different advantages and disadvantages
A combination of different genetic therapies or genetic therapies + downstream treatments might potentiate the effect
Participation in natural history studies or other biomarker studies.