ICT talks with Dan Williams from SynaptixBio about the rare genetic disease group of leukodystrophies, how they affect the white matter of the brain, why there are currently no treatments or therapies for many of them and how this is being combatted through partnerships
ICT: What is leukodystrophy and why there are currently no curative therapies for it?
Dan Williams (DW): Leukodystrophies are a group of rare genetic diseases that affect the white matter of the brain. They are caused by abnormalities in the cells that form the myelin sheath around nerve fibres. This leads to disruption of the signals travelling along those nerve fibres, causing issues with movement, development and speech, amongst other things.
There are a number of different genes and mutations that can cause different types of leukodystrophies, such as metachromatic leukodystrophy, adrenoleukodystrophy or Alexander’s disease. There is also a range of severity. Early onset leukodystrophies, which can be particularly severe, are seen in babies – these are typically noticed when the baby fails to reach certain developmental markers; they may not be able to raise and support their heads, for instance.
Later-onset leukodystrophies, such as hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC), occur when a child develops normally up until a point, but then certain developmental markers disappear, for example an incorrect gait when learning to walk. The child’s brain is not developing in the right way because the myelin sheaths are defective, and they lose motor skills as well as developmental and learning abilities.
There’s a range of severity within this – some children don’t progress quite as quickly as others. Unfortunately, a lot of affected children don’t make it to adulthood. So, why are there very few therapies? Although there’s been a lot of research, it’s difficult even to get samples and consequently understand what’s going on in the brain. However, technology, especially sequencing, is improving, and mutations are increasingly being identified.
In some cases, it’s only quite recently that specific mutations have been associated with the causes of particular forms of leukodystrophy. For example, TUBB4A-related leukodystrophy was recognised through imaging of the brain in 2010, yet it was only in 2015 that the mutations were identified and an understanding of the impact of those mutations that were linked to the disease.
Once mutations are found, mechanisms of the disease can be identified, giving much greater insight into a what a potential therapy could look like. Currently, we have some idea of the likely mechanisms for TUBB4A leukodystrophy, and we are working towards developing a therapy that could go into trials next year. In short, there are few therapies because the mechanisms have only recently been recognised and potential therapies are only now reaching clinical trials. The clinical trials themselves present difficulties because these are rare diseases and recruitment of patients is always going to be difficult.
ICT: When planning to investigate rare diseases in such a young cohort, what steps can be implemented to ensure their safety and well-being?
DW: It is very important to consider the risks and benefits of a potential therapy, in order to provide patients with the best outcomes. Regulators and clinicians set the standards by which these are considered and ensure that a company’s non-clinical examination of the therapy is sufficient. To satisfy these requirements comprehensive preclinical planning is required.
A good starting point is to look at how the molecules being tested behave in vitro. To do this we are looking at the cell lines to see whether pathogenic pathways become activated. Planning also involves in vivo studies, but the problem with some molecules is that they are very specific to humans. So, it’s good practice to build a non-clinical package where testing is performed in a species that is as close as possible to humans.
This is often guided by the regulators and typically involves non-human primate testing. The difficulty is trying to get as close as we possibly can to a species that’s relevant and scientifically appropriate. The species not only needs to be picked but the age of the animals needs to be considered as the patients are children. Thus the animals need to be juveniles, enabling testing for developmental issues that could arise.
The next problem is how to proceed if there isn’t a model of the disease. Using a disease-relevant model that’s close to humans would be ideal. However, if there’s no disease model, there will be difficulty in picking up efficacy signals. If there isn’t similarity between the genes then there’s uncertainty around the potential to knock out those genes within that animal.
As a result, the effect in humans may be hard to simulate. So, care must be taken when looking at these and comparing what occurred in vitro, and what will occur in vivo and in patients. Generally, this can be an issue for all therapies, not just rare diseases and not just for children. The goal is to have a good mechanism of disease and mechanism of action and an understanding of all the effects of the therapy to enable a comprehensive risk-benefit analysis prior to dosing patients.
ICT: Can a virtual business model present additional difficulties for organisations trying to organise first-in-human trials?
DW: A virtual company will have difficulties anyway. When moving into the clinic there has to be a very specific plan, which can’t be changed very easily, as there’s not a team on board specifically looking after the clinical trial. What that clinical trial is going to look like has to be thought about beforehand, including things like how the Quality Management System works.
This is because there is no-one to constantly monitor the systems and all effort is placed into collaborating with third-party companies as the process moves forward. This means that any finances raised go directly into ensuring control systems work from the outset and not into all of the other things, for example personnel.
Now, one of the difficulties a virtual company comes up against is a dependency on outside organisations. Within preclinical, there can be a high dependency on chemistry, manufacturing and controls (CMC) coming from a good CMO or CDMO. There will be a dependency on clinical trial management from a CRM, as they are required to do the full study. There can also be a significant dependency on consultants.
Within a company there must be management that can handle the outsourcing of all that work. So, ultimately there is either the need to expand to enable those clinical trials to be managed within the company, or to enter into contracts with consultants that are able to help in the long term.
ICT: What are some best practices to ensure that investors, stakeholders, consultants, CROs and CDMOs, and patient groups are kept informed during the early stages of the pipeline?
DW: One of the things that takes a lot of time is setting up the stakeholders to make sure they have a good understanding of what the goals are. This difficulty depends on how far they are from the science. As such, companies should go through each of their main stakeholders individually and try to make sure there’s a good understanding of what it is that they’re trying to achieve, the timelines and the money that is required.
Then, have regular meetings with each of the different stakeholders, which can be very different depending on who it is that is being engaged. With investors, there needs to be a lot of time spent at the very beginning, outlining what’s planned, what milestones will be hit and when, for example. An idea is to meet with them on a six-monthly basis and give them an update of where you’re up to and what the next stage is going to be.
There should also be frequent board meetings, along with making sure the lead investor gets to see what’s happening on an almost day-to-day basis. The key is to be completely open for them to come back with questions and ask for updates. When dealing with leukodystrophy patients, which is such a rare population, the parents and carers want to know where treatment developments are up to and what is happening. There are multiple ways in which they can be kept informed.
Firstly, it is a good idea to talk to the advocacy groups and parents. This is also a chance for them to give some insight and input, which can be extremely useful, particularly around things like regulatory requirements or clinical trial planning. Another great space for communication is conferences. A lot of parents with rare disease patient children attend these conferences and want to know what’s going on, so updates can be given through these.
Also, quite importantly, PR work – such as press releases – can give an idea of the milestones, which then go through the advocacy groups on places such as LinkedIn and Facebook to the wider community. Ultimately, one of the best practices is to keep up to date with the patient advocacy groups because they can then go out to the parents of these patients and give them an idea of what’s happening, and create the opportunity to receive feedback as well to help move research forward. For companies and partners, you can engage them in the same way you do investors. They need to be brought up to speed and talked through the science. If the work is put in right at the very beginning to make sure everyone understands what is being done, it smooths everything out.
ICT: How important are partnerships – either within or outside of the pharma industry – in helping reach clinical trials?
DW: The short answer is extremely important, especially as a virtual company. The whole idea around a virtual company is that everything is managed internally by a small team – there has to be people that are managing the money coming in and going out, managing the sites by making sure the trials are in the right place, and driving the project forward. One way to do this is to outsource the work and through academic collaborations.
There are different types of partnerships. For one, the patients and advocacy groups. While they haven’t been able to do lots in the research and discovery side of things, they will be able to do huge amounts within regulatory and clinical – they know the patients better than anyone else. They’re able to give you a good idea of whether what you’re looking for, in terms of outcome measures, will work.
At the moment, the main advocacy groups for TUBB4A leukodystrophy are in the UK and the US, but some are springing up elsewhere. In clinical trials as well, the academic partnership is going to be very important, particularly in the US as it has the largest population of known patients. Academic partnerships are going to be very much involved in being part of the clinical trial recruitment stage, and it helps to work with experts in this area who really understand the disease and how to run clinical trials involving them.
There are also clinical partnerships with the hospitals that are seeing these patients – they have a lot of expertise, they understand the patients and they will be bringing them in, so it’s extremely important to work with them. A virtual company has to outsource everything. One example is manufacturing, where they have the expertise but they need to understand the product and the necessity of the product.
Crucially, however, they understand the actual molecule and they’re able to feed back when, for example, things are going wrong within the manufacturing process, whether the yields are coming out, what tweaks we may need. Consultants who are experts in this area can be utilised, and they can have those conversations with the manufacturer.
As a smaller, virtual, company there’s a strong likelihood that you will either need to expand or go into partnership with someone bigger who understands later-phase clinical trials, what’s required to get through to market. For any biotechs who want to push things through, those partnerships are really important. Big Pharma can to do it on their own but even they are now partnering with companies and people with more expertise or resources. Getting to market and getting through these stages will definitely require some sort of partnership in future.
About Dan WIlliams
Dan Williams is CEO of SynaptixBio. He has spent over 20 years in the industry after studying at the University of Dundee for a degree in biochemistry and physiology, and a PhD. After his PhD he entered the industry, where he worked his way up to senior scientist. Dan then took over a cell group and started his management of science, running a cell group and then a preclinical group.
He then moved into development, focusing on the organisation and management of manufacturing and clinical trials. After that particular therapy went into the clinic and was progressing within clinical trials, he moved to Adaptimmune and switched from biologics to developing cell therapies. He set up the development groups within Adaptimmune, while project managing some of the preclinical research and the move from the partnership with an academic group for their clinical trials, to taking on those clinical trials as a company.
He then managed the larger research group, and moved from that position to the VP of Research Operations. From there, Dan moved to Meatable as the Chief Product Officer. Dan co-founded SynaptixBio Ltd. in 2021 with the aim to push leukodystrophy therapies through to clinical trials.
Associated news article: https://www.calameo.com/read/006113385a1c828272bff?page=8