Rare diseases represent a significant unmet medical need, impacting the lives of millions of patients and their caregivers worldwide. At WuXi AppTec, we believe that our ongoing collaborative efforts to raise disease awareness and foster innovative thinking will lead to better and faster breakthrough treatments to address the healthcare challenges of rare diseases. As we continue this exciting journey to bring transformative medicines to patients, we are thrilled to share with you a new interview series from worldwide leading experts, “Delivering on the Promise of New Therapies for Rare Diseases.”

Hi David! Thank you for joining our interview. To kick off, could you please introduce yourself?

David: Hello, my name’s David Walker and I’m the Director of Chemistry at Sentinel Oncology. Sentinel is a Cambridge, UK-based drug discovery company focused on treating diseases with high levels of unmet medical need. I’m also the technical lead on Sentinel’s program to develop a therapeutic for Fragile X syndrome.

As a company which is mostly focused on cancer treatments, what inspired Sentinel to work on Fragile X and what issues are you trying to address?

David: I’m often asked why an oncology company is working on Fragile X syndrome! Well, we were driven by the science. Sentinel originally set out with a focus on developing selective inhibitors of the kinase S6K1 to treat triple-negative breast cancer. Triple-negative breast cancer is a particularly invasive subtype of breast cancer accounting for 10 to 20% of all breast cancers. Prognosis is generally poor and treatment options remain limited. One of the reasons for such a poor prognosis is the common formation of brain metastases which evade treatment. It has been published that S6K1 is responsible for driving the metastasis.

To address this huge unmet medical need, we set about developing a series of brain penetrant S6K1 inhibitors. Then, in 2012, Professor Eric Klann and Dr. Aditi Bhattacharya at New York University published in the journal Neuron, showing that S6K1 plays a key driving role in the pathology of Fragile X syndrome. In short, Fragile X Syndrome is caused by a mutation of the gene Fmr1, leading to the absence of the protein product FMRP. FMRP acts as a repressor of protein synthesis so that in its absence, protein synthesis is always on and elevated. Klann and others have shown that in Fragile X patients and model mice, S6K1 is over-activated in the brain compared to healthy counterparts, and this drives excessive protein synthesis leading to pathology.

S6K1 is a master regulator of protein synthesis and Klann and Bhattacharya showed that genetic deletion of S6K1 in a Fragile X model mouse restores healthy protein synthesis in the brain, as well as correcting associated pathologies. This led us to hypothesize that if a small molecule inhibitor of S6K1 could achieve the same effect, it could potentially be a viable treatment option for Fragile X patients. Indeed, we went on to collaborate with Klann and Bhattacharya to test our S6K1 inhibitor in their Fragile X model mice. This work was published in Neuropsychopharmacology in 2016.
In short, our S6K1 inhibitor was able to correct a wide range of deficits in the Fragile X mouse. This included dampening down the activity of S6K1 in brain to healthy levels, decreasing protein synthesis in the brain and correcting neuronal spine morphology. Furthermore, we showed efficacy in behavioral models, including the social novelty test, Y-maze, and audiogenic seizure model.

Overall, this strong scientific rationale underpinned our choice to invest in the Fragile X space. We are also driven by the high level of unmet medical need with Fragile X. All the existing therapies of Fragile X treat the symptoms only, whereas with our S6K1 inhibitor, we have the opportunity to treat the underlying disorder itself.

What is the greatest value of your modality or technical approach to Fragile X syndrome, compared with existing treatments to these patients?

David: Today, the drugs available to Fragile X patients treat symptoms only. Probably, the greatest value of our approach is that we have the potential to treat the underlying root cause of the disease. This in turn has a potential to improve profound aspects, such as cognition. To date, there has never been an S6K1 inhibitor in the clinic for Fragile X syndrome, so our approach is differentiated over what has come before.

Could you share with us the current progress of your Fragile X program and its upcoming milestone?

David: So, our candidate drug SOL784 has shown promising preclinical effects in several models of Fragile X Syndrome, giving us good confidence in taking this molecule forward. We have plans to put SOL784 into a Phase I clinical trial. Right now, SOL784 is in late stage development, undergoing a number of preclinical tests necessary for it to enter clinical trials.

Let’s talk about the future. In your opinion, where might the next breakthrough in the field come from?

David: In my view, the next paradigm shift looks to be the implementation of new measurable outcomes for drugs in Fragile X clinical trials. Some of this is happening already. Clinical development clearly is not easy in this field and there are challenges such as the placebo effect to contend with; however, outcome measures such as the EEG and eye gaze tracking are now finding their place in Fragile X clinical trial design. We are hopeful that an S6K1 inhibitor which treats the underlying pathology of the disease will show meaningful effect under these measures.

From your point of view, how will AI transform the field of Fragile X research?

David: I think it probably still remains to be seen. There are groups already using AI to predict rational combination therapy for Fragile X syndrome. These combinations are already in the clinic, so we should see results in due course.

Could you highlight how collaborations and partnerships affect your Fragile X program and the field?

David: Collaborations and partnerships are very important to this field. Ever since Sentinel got into this field, FRAXA has provided tremendous support to us in terms of advice and practical drug testing. This was not our original field of expertise and it’s fair to say that without that relationship, we wouldn’t have taken this program forward. So, huge thanks to Michael Tranfaglia and Patricia Cogram of FRAXA. Our research collaboration with Professor Eric Klann and Dr. Aditi Bhattacharya at New York University was also instrumental in generating proof-of-concept data on our S6K1 inhibitor in Fragile X model mice. We are very grateful to all our collaborators for their support. Finally, we are excited to be in alliance with MSRD to take our Fragile X program forward.

In your opinion, what does patient-centric drug development mean for the Fragile X field?

David: This is an important question. Patient-centric drug development means understanding the Fragile X patient population and the makeup of patients in any clinical trial. This will have a bearing on the outcome of said trial. There are important factors to consider such as age, sex, and genetic disposition amongst others. For example, in our case, there’s an argument to start treatment with an S6K1 inhibitor in young patients to target the pathology during development. Furthermore, genetic disposition affects severity of disease. For example, males with full mutation are generally considered the most severely affected group. We know from the world of oncology that patient populations tend to be divided into certain subgroups that respond differently to a drug. We’d like to explore that parallel in Fragile X Syndrome.

In 2021, the FDA approved 50 new drugs. If we imagine 2030 and think beyond Fragile X, would we collectively be able to achieve 100+ new drug approvals at half of today’s cost? And in achieving so, do you foresee any major gaps to bridge or any upcoming breakthroughs which you are most excited about?

David: Well, the drug discovery landscape has changed a lot in the last five years with biologics and gene therapies and others being added to the portfolio. In other words, the landscape is no longer small molecules. So, probably these additional therapies will supplement numbers, but I don’t think that net cost is necessarily the key question – rather, it’s where is the innovation coming from? In my view, nothing will replace the development cost of a drug, and experiments will get more costly as they get more complicated.

In terms of major gaps to bridge; well, innovation starts early. It remains difficult to raise early stage finance, and innovators must have access to good finance to get the work done. Breakthroughs rely on high quality new science. There will be new ways to treat disease besides small molecule. AI may help with areas such as repurposing, but we still need to find those new drugs.

Thank you very much for your time, and for sharing your valuable insights with us .

David: Thank you.

 

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David Walker

DIRECTOR OF CHEMISTRY, SENTINEL ONCOLOGY

David is a medicinal chemist with over 20 years’ experience in Biotech & Pharma. David has held positions at Pfizer, Cambridge Discovery Chemistry, Millennium Pharmaceuticals & Astex Therapeutics. Whilst at Sentinel Oncology, David has spent over 14 years managing small molecule drug discovery and development projects via an outsourcing model. David is technical lead on Sentinel’s program to develop a therapeutic for Fragile X Syndrome. David is a named inventor on multiple patents and co-author on several scientific publications.