Founded in 2014 by Danish veterinary scientist Dorte X. Gram, after discovering a TRPV1 antagonist molecule whilst working for Novo Nordisk, Pila Pharma (Sweden) is working on a potential first-in-class drug candidate that has shown promising safety data and efficacy in diabetes trials. The company is now eyeing an opportunity to show efficacy on weight loss. As we all know, however, developing and driving a new drug candidate through trials and onto the market for any SME is challenging. CEO Gustav H. Gram explains why he believes the right partnerships can develop the assets and the attitudes to overcome them.
How would you summarize the difference between TRPV1 and GLP-1?
GLP-1 is a gut hormone that reduces hunger signalling and can lead to gastrointestinal side effects. TRPV1 is a sensory receptor found throughout the body in nerves and organs. It’s been extensively studied in pain and inflammation, but not in the context of metabolic dysfunction. We are pursuing the discovery made by our founder, Dorte X. Gram, who during her time working as a scientist at Novo Nordisk in their obesity pharmacology unit, discovered that inhibition of the TRPV1 receptor could be a potential new treatment of diabetes, obesity, and other related disorders.
Because we target a receptor found on nerve endings, a receptor known for its role in touch, sensation, and the regulation of pain and inflammation, patients on our drug (XEN-D0501) might feel sensations like warmth, cold, or tingling – similar to getting anaesthesia at the dentist. So the side effect profile is very different to GLP-1s. Plus, our drug is a small molecule with a simple chemical synthesis, so it can – theoretically – be mass-produced very efficiently. Whilst other major companies in the space are working on small molecule alternatives, it’s not easy. For example, the only current marketed oral formulation of a diabetes drug reportedly requires upwards of 20 times the amount of API compared to the injectable, and since it's not a small molecule, it’s a complex product to make. Currently, it's apparent that they can sell all the injectables they make, so there's little incentive to pivot. Patients do need affordable, oral, and stable solutions, however, and accessibility is key if you want to address the volume of patients.
So TRPV1 offers another option for patients?
Exactly. In five to ten years, I expect to see a wider range of solutions such as potent injectables for those needing major weight loss, and more accessible oral options for those needing smaller reductions. We generally expect the market to fragment into many smaller subcategories and subgroups of patients all needing differentiated solutions. It's an exciting prospect for us to bring something brand new to the table, but we’re taking it step by step, and trial by trial. Our drug candidate has previously been exposed to 300 subjects, so we already have safety data, which is encouraging. While investors often want to accelerate timelines, we’re being deliberately measured and we have some steps to do in order to showcase an even more comprehensive safety and efficacy profile.
Whilst we have quite a bit of diabetes and cardiovascular data, we will of course re-assess the case for the drug candidate if it doesn’t achieve meaningful weight-loss. There are still significant unmet needs in type 2 diabetes, especially as GLP-1s remain unaffordable and inaccessible for many. There’s a path forward, regardless, but whether we will play in the big leagues or the smaller, but still valuable, segments will depend on the data.
You’re looking for a partner to advance your TRPV1 inhibitor program. What specific qualities or capabilities are you hoping for?
It goes without saying that a partner would have aspirations to come in and jointly define with us the best path forward, including with the size and financial capabilities to progress the program through late stages. It would be ideal to have a partner with knowledge of TRPV1 as a target and small molecule capacity. This would lift both production and scaling of a tablet-based treatment. But we are open to discuss with any larger company looking for a differentiated solution for their portfolio of drug products for cardiovascular, renal, and metabolic conditions. I sense a great interest in our drug candidate – especially the delivery and side-effect profile, which differ from other molecules as they primarily target different gut hormones.
Financially, getting to market would take a significant toll on a small company like ours. I don’t think we’re in a position to go through the public markets, unless we have outstanding proof-of-concept results that put us on a par with the best products available, albeit with a completely different mechanism of action.
Our plan has always been to advance through proof-of-concept and then ideally partner with a larger pharmaceutical company. This would help with manufacturing, regulatory pathways, and the large-scale clinical trials needed to bring a product to market.
What are the challenges in finding a partner to move the program forward?
This is speculative, but it seems that large pharma companies are sitting on significant cash reserves and being very cautious about which drug classes they invest in. Our challenge is that we’re not targeting a traditional metabolic pathway, which means we often have to somewhat educate potential partners on how we believe the mechanism works. The best way to educate, of course, is to show compelling data.
Pharma tends to wait until a target is validated before investing, but we’re starting to see more companies express interest in this space, and in obesity in particular. GLP-1 drugs are grabbing most of the attention, but there are established companies in the space – as well as those looking to enter it – actively scouting for what else is out there. They’re looking into complementary mechanisms that could either work alone or in combination with GLP-1s or other gut hormones to improve weight loss, safety, and tolerability, especially concerning gastrointestinal side effects.
We believe we have a unique edge by targeting TRPV1 and, as far as we know, we’re the only ones working on this specific target. Still, we need to support our case with strong data – and that takes time and money.
What is the projected timeline for establishing proof of concept for weight loss with XEN-D0501?
Our next clinical study, a smaller phase IIa trial in overweight people with diabetes, should take around 12 months from when the trial commences. This is primarily a dose-escalation trial to assess the safety on higher doses and longer duration, but we have included a secondary endpoint for the assessment of body weight reduction. If we go by the industry standard of wanting phase IIb clinical data, it will likely be a few more years. However, we do anticipate and sense partnership interest at the earlier stage, but it will still require compelling weight loss data.
We of course also consider and assess whether to commence pure obesity studies. These could be pre-clinical but, given that our drug candidate has a lot of safety data, we could potentially go straight to human trials. This is of course lucrative as an oral scalable solution for weight management with a tolerable profile, which is highly sought after.
How does the mechanism of action and side effect profile compare to existing GLP-1 treatments?
By inhibiting the TRPV1 receptor, it should be possible to downregulate inflammation, inhibit hunger signalling via nervus vagus activity, and potentially promote energy expenditure. So we hope it’s not just inhibition of hunger signalling or satiety stimulation. One of the primary side effects patients observe is increased temperature. We see that as a sign of thermogenesis – and a good thing if managed well. Traditionally the drug class has had some issues with agents that pushed hyperthermia, which is of course not something we want to do. Hence why the next phase IIa study is important for us to understand and really define the therapeutic window.
We are taking big precautions in our phase IIa trials – moving forward at the right pace to assess the right tolerance level of the drug. Another observed side effect has been very mild nerve numbness and tingling. Altogether it points to a vastly different side-effect profile than GLP-1s and we don’t foresee this drug class to have any gastrointestinal safety issues.
What is your view on the future of obesity therapeutics?
I envision a landscape where both injectable and oral therapies coexist; where they’re tailored to different patient needs and accessibility levels. There is a clear opportunity for innovation here. It will not necessarily center around big weight-loss; the focus will be on quality, so leaner weight loss where it's predominantly fat mass. Achieving between five and 15 percent weight loss over a year will be far more beneficial to most patients in the addressable market, and tolerability will be increasingly important as having high discontinuation rates is not beneficial. With time, there will also be solutions purely for weight maintenance, whereby patients can spin off the more complicated and expensive solutions in favour of an easy one that enables them to stay at their desired weight without the rebound effect.
Our goal is to stay focused and realistic. There’s still a long road ahead. While the potential is thrilling, it's critical to keep expectations grounded. A lot depends on the data. If we can demonstrate efficacy, especially around weight regulation, that would be quite groundbreaking – it’s never been shown with this target before.
The founder of Pila Pharma, Dorte X. Gram, always says that her first and primary goal is to prove that she was right in her discovery, and the second is to do something good for the world. If we can do both – if we can show that this mechanism works and deliver a meaningful therapy – that would be profound. By 2030, I hope we’ll see broader acceptance of different approaches to treatment of overweight, and if we can play a role in that transformation, it would be a tremendous achievement.
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