Written by Matthew McCann, edited by Lauren Eades, Farisha Colbourne
The Problem with Anticoagulant Therapies
Anticoagulants are an essential class of medications that are primarily used to prevent thrombotic events in individuals classified as at high risk of blood clot formation [1]. Several risk factors can increase an individual’s risk of developing a blood clot, including a previous history of blood clots (venous thromboembolism), a previous history of myocardial infarction or stroke, cardiac valve replacement, genetic clotting disorders and comorbidities such as atrial
fibrillation [2].
Although blood clots are a natural haemostatic response to stem bleeding, the development of pathological blood clots proves problematic for proper blood flow, especially in the brain, heart and lungs. As a result, the aforementioned risk factors that increase the probability of blood clots, can also increase the susceptibility of individuals to potentially fatal pathological clots and thrombotic events, including heart attacks and strokes. In the UK alone, an individual suffers from an atrial fibrillation associated stroke every 18 minutes [3].
High-risk individuals with one or more of the previously mentioned risk factors are usually prescribed anticoagulants to prevent the development of blood clots and the occurrence of thrombotic events. Anticoagulants work by altering the clotting cascade; a complex pathway consisting of multiple protein factors and interactions that lead to the formation of blood clots. Through altering the clotting cascade, anticoagulants are able to inhibit blood clot formation.
Traditionally, vitamin K antagonists, including warfarin, have been used as anticoagulant therapies [4]. This approach targets many proteins of the coagulation cascade however, more recent anticoagulants that have come to the market, the Direct Oral Anticoagulants (DOACs), target a single enzyme of the coagulation cascade. Nevertheless, all these current approaches target enzymes in the coagulation cascade responsible for pathological clot formation and the stemming of bleeding. Consequently, individuals are at risk of bleeding as a potential side-effect of current anticoagulant treatment. Additionally, vitamin K antagonists have several documented drug interactions with some of the most commonly used medications, notably with nonsteroidal anti-inflammatory drugs including ibuprofen and anti-platelet agents, that increase the risk of bleeding [5]. A 2018 report found that avoidable adverse drug reactions involving anticoagulants caused an increased risk of admission to hospital by 64% [6].
With the combined risk of excessive bleeding and adverse drug interactions, anticoagulants are hugely underutilised despite their life-saving potential in individuals at risk of pathological clot formation and thrombotic events. In 2018, 19% of eligible atrial fibrillation patients were not receiving anticoagulant therapy [7].
Anticoagulant therapy has now been identified as a patient safety priority area for NHS England and is included in one of six headline issues addressed in the NHS Improvement Medicines Safety Programme [8]. There is an urgent need to develop next-generation anticoagulant therapies that overcome the risks associated with those currently on the market.
A Promising Solution - LUNAC Therapeutics
LUNAC Therapeutics is a spinout company from the University of Leeds, built upon the findings of world-leading experts including Professor Helen Philippou and Dr Richard Foster. Through targeting a specific protein of the clotting cascade, activated Factor XII, LUNAC is developing a new class of Direct Acting Oral Anticoagulants that prevent life-threatening thrombotic events whilst removing the risk of bleeding associated with current anticoagulant therapies.
I had the absolute pleasure of chatting with Professor Helen Philippou (Co-founder and Board Member) about all things LUNAC.
Q: First things first, can you tell me a little bit about your background?
I started my PhD in London and worked at Imperial College for 10 years before I moved up to Leeds where I am now a Professor of Translational Medicine. Essentially, I’ve been working in coagulation since 1992. My aim since I have been at Leeds, about 10 years ago, was to actually use the knowledge I had acquired in coagulation to address unmet clinical needs, and anticoagulant therapy was an obviously pressing one.
As an academic, I felt that you can't really do drug discovery within academia but when I went on the Yorkshire Forward Fellowship Programme it gave me the confidence to marry the two together. That's really when I got quite serious about it and in our environment at the time, it was a challenge to do this sort of thing. I think our work is helping to change the ethos of translational medicine at the University with respect to therapeutics.
Q: What’s the LUNAC story so far?
The idea was an inspiration that I got from seeing a presentation (by Dr Thomas Renne) at a German Thrombosis and Haemostasis meeting where it was identified that mice lacking a particular coagulation factor, Factor XII, couldn’t form clots. That was the first insight that this particular coagulation factor was responsible for the formation of clots, because individuals that don’t have that coagulation factor don’t bleed.
At the time, there was a bit of controversy as to whether Factor XII was actually a requirement for coagulation, even though it was a coagulation factor. That was literally a jaw-dropping moment for me because that suggested there was a target that we could go for. We could actually stop clotting but without inducing bleeding risk.
I returned from that conference and initiated interactions with chemists at the University of Leeds, including future LUNAC co-founder Dr Richard Foster, and applied for grant funding. Initially, we received proof of concept funds from the University of Leeds then an MRC DPFS, a BHF Special Project Grant and then a Wellcome Trust Seeding Drug Discovery Initiative Grant. We used the initial funding to help us to identify a good lead compound series.
Essentially, we had exhausted the grant funding that we could go for within the academic environment so we spun out a company and then attracted investor funds. At the same time, we also secured an Innovate UK Biomedical Catalyst Award. And that’s really where our journey began in September 2019. Securing our first external VC (venture capital) funding from the UK and US firm Epidarex was also a very significant achievement. We feel this validates our leading science and also the medical need and commercial potential of the LUNAC programme.
We’ve always had good drug discovery advisors with pharma expertise. Since our MRC DPFS, right at the beginning, we had Dr Alan Naylor, a drug discovery advisor supporting us in our monthly meetings, and later in time Dr John Dixon. Once we became LUNAC, we started building our management team and expanding our advisors further.
Q: Can you tell me a little bit more about the science? What’s so special about Factor XII?
So our target is activated Factor XII (FXIIa). Factor XII is found at the initiation point of the contact pathway of coagulation, followed by Factor XI. Downstream of these two factors, you ultimately get thrombin generation which turns fibrinogen from a soluble blood protein into an insoluble fibrin mesh that is the scaffold for the clot.
At the moment in development, there are two new anticoagulant targets that are being pursued. Most activity is focused on Factor XI, but we’re focusing on Factor XII. The general thought process is that because Factor XI is “underneath” Factor XII, if you target Factor XI you're going to target anything that Factor XII will do upstream as well, with respect to clotting. So, most people have been focusing on Factor XI because that's what they believe to be the most important target (even if patients without Factor XI exhibit mild bleeding events upon a challenge such as trauma or surgery unlike Factor XII deficiency that has no symptoms).
One of the benefits of being an academic and being part of LUNAC is that I can continue my academic research alongside. One of our exciting and recent findings, which has been published in a paper in PNAS, is that Factor XII can activate another protein called prekallikrein to become kallikrein. Kallikrein can bypass Factor XI altogether and activate another coagulation factor, Factor IX, that can also give thrombin generation. Therefore, it's not necessarily the case that if you block Factor XI, you could also block all Factor XII’s activity.
Q: Why is it better to target Factor XII than other factors targeted by currently used anticoagulants?
The current targets are involved in the processes of stemming bleeding, or haemostasis, and the formation of clots, or thrombosis. Factor XII is involved in the formation of pathological clots, but not the stemming of bleeding.
As Factor XII plays an active role in growing a pathological clot, inhibiting it means you can stem a bleed but you won't grow a pathological clot. Therefore, if you cut yourself, you will still be able to form a clot because there are other processes that can do that. By targeting activated Factor XII, there's also additional benefits in the inflammatory pathway.
Q: As an academic, how did you find the spinout process?
For me, I loved it. My parents come from humble beginnings, they came from Cyprus with no money in their pocket and they started a fish and chip shop business! My dad was always a bit entrepreneurial albeit being in a completely different industry. I always liked that business sense and have always been more commercially-minded, for an academic. I actually really enjoyed the commercial component and learning about that process.
I've always been interested in creating new relationships at conferences, for example within pharma and with clinical key opinion leaders. I attended a course at Alderley Park, as part of an accelerator programme, which I loved because it focused on what was required from the customer end of things, in my case pharma and clinicians. The Yorkshire Enterprise Fellowship Training also provided me with a business mentor (Mr Paul Thorning) for a year. So it was lovely learning more about the commercial side of research. For me, I really enjoyed the commercial component of LUNAC and I still do.
I had great support from the University of Leeds, they were fantastic in helping us get set up and it's something that I've thoroughly enjoyed. It has been a complete team effort from the outset with my LUNAC co-founder Dr Richard Foster and the great teams we have put together within the University, Contract Research Organisations, advisors and the management team. .
I have two ambitions in life: I want to actually redraw the coagulation cascade and I want to get a drug to market. So, I’m en route to potentially doing both!
Q: What were the pressures of spinning out LUNAC whilst sustaining your academic roles?
It’s a balance. In academia there are pressures to publish, and while doing drug discovery in the commercial world, you have to protect your work with patents meaning that you can’t really publish until an appropriate time. Having publications coming through on other work alongside helps to alleviate the pressure and the knowledge that what you're doing is the right thing for the University and for patients potentially in the future. I think LUNAC is helping towards changing the culture of translational medicine at the University.
Q: Congratulations on being awarded Bionow’s Startup of the Year. How did the LUNAC team react to the good news? How important is that sort of recognition for early-stage businesses like LUNAC?
It’s an acknowledgement of what we're doing so I think everyone is delighted!
Up until the Bionow Awards we've kind of kept a low profile because we were still gathering momentum and we weren't quite ready to go out there publicly. So the award came at a really good time because we're at a stage now where we're really happy to show the world what we’re doing at LUNAC.
Q: What are your ambitions for LUNAC?
We want to help patients. But the realities of the industry and funding means we are looking to partner with a large pharma company, just after we have shown clinical proof of concept at the end of a Phase IIa study. So LUNAC will raise funds to take us to that point.
Q: What one piece of advice would you give to an academic considering spinning out?
If you believe in what you're developing and you believe it's going to address unmet clinical needs, or meet needs in whatever field you're in, then just pursue it.
You might have to try a few times with funding but ultimately if it's going to be fundable then someone's going to fund it.”
Many companies fail but ultimately if you believe in it, it's worth it. Just pursue it and it is possible to achieve.
References
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