- How do you view the potential of LoAc® to transform the treatment landscape for ADPKD?
ADPKD is a devastating disease that affects more than 12 million people worldwide. Over the past decade, there has been important progress in our understanding of the disease, with meaningful steps forward for both patients and clinicians. However, significant challenges remain. Tolerability continues to limit long-term treatment for a substantial proportion of patients, and both current and emerging approaches target only a single pathway in kidney biology, which constrains their ability to address the full complexity and variability of ADPKD. As a result, there is a clear need for therapies that are better tolerated, more comprehensive in their mechanism, and effective across the spectrum of disease.
What excites me about LoAc® is that it takes a fundamentally different approach, working directly on the engine that drives cyst growth – the abnormally high levels of cyclic AMP (cAMP) inside kidney cells – and it does so across the whole kidney. In our preclinical work we’ve seen this translate into meaningful cyst suppression and preservation of kidney function.
If that profile holds in the clinic, I think LoAc® has the potential to offer something genuinely new and to reach patients who currently have limited options. The wider pharmaceutical industry clearly shares the view that ADPKD remains an important and underserved opportunity, and that makes it all the more important that new approaches are grounded in strong, differentiated biology.
- How does the underlying biology behind LoAc® position it as a potentially differentiated approach in ADPKD?
To understand what makes LoAc® different, it helps to start with what drives the disease. In ADPKD, mutations in the PKD1 or PKD2 genes cause a small signalling molecule called cAMP, to accumulate abnormally inside kidney cells. That excess cAMP is the central signal that drives cells to divide, fluid to build up, and cysts to grow and it sits at the core of disease progression in a way that is well established and broadly agreed upon in the field.
LoAc® works with the kidney’s own biology to bring that cAMP back under control. Rather than blocking a single receptor, LoAc® compounds enhance the body’s natural capacity to break down cAMP. They do so across the compartments of the kidney that matter most for disease, including both the collecting duct and the tubular segments of the nephron, an area that current therapies do not reach.
The result is a broader, more direct impact on the cAMP that is actually driving disease. That breadth of action is what we think underpins the strong preclinical results we’ve seen, and it’s what positions LoAc® as a potentially meaningful step forward rather than a variation of existing approaches.
- What does the preclinical biology tell us about the potential impact of LoAc® on disease progression in ADPKD?
The preclinical data we’ve generated gives us real confidence in this approach. Across multiple model systems, from cells in a dish all the way through to more complex preclinical models that mirror how the disease progresses in humans, LoAc® compounds consistently suppress cyst formation and growth.
Across these models, LoAc® compounds reduced cAMP levels in kidney tissue and in urine, a direct read-out that the approach is working as intended. We see clear reductions in kidney enlargement, measured by MRI in the same way it is assessed in clinical trials, alongside meaningful improvements in markers of kidney function. What is particularly encouraging is the consistency of these findings across different model systems and different ways of measuring disease; that breadth of evidence, all pointing in the same direction, is what gives a scientist real confidence in an approach.
What I find most compelling, however, is the data from primary cells grown directly from kidney tissue donated by ADPKD patients. These are not engineered cell lines or surrogate models – they carry the actual disease biology of the individuals they came from. Seeing consistent cyst suppression across donors with different genetic mutations and disease characteristics is, to my mind, the closest you can get to human evidence before entering the clinic. It is hard to generate, hard to replicate, and when it works as clearly as it has here, it gives me genuine confidence that the biology we are targeting is real, relevant, and translatable.
- What findings have most strengthened your confidence in the biological rationale behind LoAc®?
A few things stand out. The primary cilium work was genuinely exciting. The primary cilia of kidney cells are structures that play a central role in how ADPKD pathology develops. We published our findings in EMBO Reports in collaboration with the University of Bonn showing that cAMP built up specifically inside the primary cilium is sufficient to transform normal tubules into cysts, and that the LoAc® approach directly counteracts this. That was an important piece of the puzzle, placing our target right at the structural heart of what goes wrong in ADPKD.
As mentioned, perhaps the most confidence-building work we’ve done was in primary cells derived directly from people living with ADPKD. Seeing consistent cyst suppression with LoAc® across donors with different disease severities and different underlying mutations is a very compelling signal. It becomes more so when you consider that other therapeutic approaches, including some that have failed in clinical trials, show little or no effect on the same system. That contrast speaks directly to whether our biology is real and reproducible across the diversity of patients we would ultimately want to treat.
What has ultimately strengthened my confidence most is how well everything fits together. The published cilia biology, the consistency across preclinical disease models, and the human donor tissue data all point in the same direction, and they do so through independent lines of evidence. Layered on top of that is the fact that we have a biomarker, urinary cAMP, that we can measure non-invasively and carry directly from our preclinical work into clinical trials. That gives us a way to ask, in humans, whether the drug is doing what the biology predicts it should. Having that thread running from the earliest science all the way through to the clinic is something I think is genuinely valuable.
- What aspect of Mironid’s scientific approach or innovation are you most excited about as Head of Biology?
What I find most exciting is that this is genuinely first-in-class science built on a fascinating and challenging area of biology. The discovery that long isoforms of PDE4 form dimers was a landmark piece of published science allowing subsequent work to leverage the opportunity for pharmacological modulation but translating that into a therapeutically viable approach is a different kind of problem entirely. Allosteric modulators come with their own distinct challenges, and there is something genuinely invigorating about working at that frontier, where science is hard and the answers are not always obvious.
Most drug development has focused on blocking things: blocking receptors, blocking signalling pathways. We’re doing something fundamentally different by selectively enhancing the body’s own natural mechanism for keeping cAMP in check and doing it in the places where it matters most. That precision is what makes the approach so interesting and potentially so important. ADPKD is our focus, but aberrantly high cAMP is a driver in other diseases too, and the broader potential of an approach that can address that in a targeted way is something I find genuinely compelling.
But if I’m honest about what inspires me most, it is translational medicine and patient impact. New assays, new models, new scientific insights, all of that is energising. What drives me, though, is the thread that connects the biology in the laboratory to a person living with this disease. ADPKD patients are at the forefront of our minds in everything we do, and the possibility that the work we are doing now could one day make a real difference to their lives is what makes coming to work worthwhile.