Drug candidates with blockbuster potential for CNS diseases

Could you give us an overview of IRLAB’s current drug development pipeline?

Based on Nobel Prize-winning research, IRLAB has grown rapidly to become recognised and respected as a world-leader in understanding the complex neuropharmacology of CNS disorders, especially Parkinson’s disease (PD). It has a well-defined and strategically focused R&D pipeline of innovative treatments targeting various stages of Parkinson’s as they worsen over time.

The pipeline currently includes five drug candidates, all of which have the potential to revolutionise the treatment of PD. Four of the candidate drugs target the symptoms that have the greatest impact on function and quality of life for people living with Parkinson’s: dyskinesias caused by levodopa treatment, balance problems and the associated risk of falls and fall injuries, dementia, apathy and cognitive impairment. The fifth project is a potential new basic and first-line treatment that could replace levodopa.

Our lead candidate, mesdopetam, is a dopamine D3-receptor antagonist which is being developed for the treatment of levodopa-induced dyskinesias; a severe form of troublesome involuntary movements commonly occurring in people with PD. More than 30 percent of all Parkinson’s patients experience dyskinesias and millions of individuals are affected. Mesdopetam has the potential to be used as an adjunct to basic levodopa treatment in a very broad patient group.

Based on the positive efficacy and safety data generated in Phase I and II, the plan is to initiate a Phase III programme for mesdopetam. Following successful interactions at the End-of-Phase 2 meeting for mesdopetam with the US Food and Drug Administration (FDA) earlier this year we now look forward to the interactions with European drug regulatory authorities in the autumn for the start of a Phase III clinical programme.

Our Phase IIb asset, pirepemat, is being developed to improve balance and reduce falls by strengthening nerve cell signalling in the prefrontal cortex via action at 5HT7 and alpha-2 receptors. Falls are a significant consequence of Parkinson’s that may have severe complications, such as fractures, impaired mobility and reduced quality of life, and are often described as one of the most problematic symptoms for which no treatment options are currently available.

Following successful completion of Phase I and IIa studies, a Phase IIb study of pirepemat is currently being performed which aims to evaluate different doses of pirepemat in people living with PD in order to identify the optimal dose for Phase III. Top-line data from the Phase IIb study is expected at the beginning of 2025.

The third project in clinical phase, IRL757, is in Phase I and is being developed for the treatment of apathy. Apathy is prevalent in 40 to 60 percent of people being treated for Alzheimer’s disease (AD) and also has high prevalence in other neurodegenerative diseases, such as PD. Preclinical efficacy indicates that IRL757 has a unique pharmacology with the potential to reverse disruption in cortical to sub-cortical nerve signalling, a proposed mechanism underlying apathy in neurological disorders. We are very proud that the Phase I study is financed by a grant from The Michael J. Fox Foundation, the largest non-profit organisation for supporting Parkinson’s research. In addition, a research collaboration has been established with MSRD, a company within the Otsuka group of companies, which will finance the development of IRL757 through clinical Proof-of-Concept.

We also have two very promising preclinical projects where IRL942 is targeting improved cognitive function in people with Parkinson’s and other neurological disorders such as Alzheimer’s. About 12 percent of adults aged 65 years or more experience cognitive decline, which greatly affects quality of life, and it is even more common in people living with neurological disorders. In several preclinical models of impaired cognitive function, IRL942 shows a unique ability to activate frontal cortical neurotransmission, synaptic gene expression, and associated circuits, improving cognitive function.

IRL1117 is also in the preclinical phase and intended to be developed as a new generation oral treatment for the basic symptoms of Parkinson’s. If successful, it has the potential to replace levodopa as the mainstay treatment for people living with Parkinson’s with a better or equal efficacy but without the side effects of levodopa. IRL1117 is expected to be ready to move into clinical development at the end of 2024/first half 2025.

Can you elaborate on the specific characteristics and mechanisms of action that make IRL1117 a promising candidate compared to existing treatments for Parkinson’s disease (PD), like levodopa?

The most common treatment for Parkinson’s is levodopa, a substance that is converted to dopamine in the body and replaces the dopamine that can no longer be produced in the brain. The treatment often initially provides good symptom relief and those affected by the disease can live a largely normal life. The problems arise after a few years of treatment when long-term exposure to levodopa causes the amount of a certain type of dopamine receptors to increase, which creates an imbalance in the signalling of nerve cells. This incorrect dopamine signalling leads to a form of involuntary movements known as dyskinesia; this side effect is often perceived as very bothersome by both patients and relatives. While IRLAB is developing the first drug candidate, mesdopetam, for the treatment of levodopa-induced dyskinesias, the company is also developing IRL1117 as a new generation of oral treatment for the basic symptoms of PD.

IRL1117 is an orally available and potent dopamine D1 and D2 receptor agonist, like levodopa but with a different mechanism of action. In preclinical settings, IRL1117 has demonstrated rapid onset and more than 10 hours of sustained efficacy. Based on the results of these studies, IRL1117 is expected to be at least as effective as levodopa while not inducing the troublesome side effects seen with levodopa treatments. Furthermore, the goal is to develop IRL1117 as a “once daily” medication in contrast to levodopa which often must be taken many times per day with fluctuations in efficacy as a result. Our goal is to develop IRL1117 into a drug for all individuals diagnosed with Parkinson’s, which today amounts to nearly six million people across the eight largest markets globally.

How does the use of IRLAB’s research platform ISP and specialised models of PD contribute to the identification and development of these novel drug candidates?

The fact that IRLAB, despite its limited resources, has succeeded in producing so many first-in-class candidates can be explained by the company’s proprietary drug discovery and development platform, the Integrative Screening Process (ISP). ISP has significant advantages over traditional drug discovery and development because the process is based on an advanced preclinical disease model. Thanks to an extensive database and AI-based analysis methods such as machine learning, ISP provides a reliable prediction of the effect a particular substance will have on diseases and their symptoms. The model is also highly risk-reducing because it catches unwanted side effects at an early stage. According to IRLAB’s calculations, the probability that an ISP-generated drug will reach pivotal Phase III studies is almost three times higher than for a drug developed with traditional methods – 20 percent compared to seven percent.

Since the process of finding new drug candidates is based on the disease and not on a specific target molecule, a so-called drug target – which is otherwise standard in traditional drug development – the majority of IRLAB’s identified drug candidates are first-in-class molecules with a completely new mechanism of action. ISP is based on more than 25 years of pharmacological research and includes a world-unique, standardised database with data from nearly 1,500 CNS substances in all known CNS drug classes as well as a large number of substances derived from academic research.

How do you envision the future of drug discovery evolving over the next decade?

The future of drug discovery is poised for significant transformation over the next decade, driven by advancements in technology, data science, and collaborative efforts. The next decade will likely see drug discovery become faster, more precise, and more collaborative. The integration of AI, omics technologies, and global collaboration will be key drivers, but it will also require adaptive regulatory processes and a strong focus on ethical considerations to ensure these advances benefit everyone.

At IRLAB we are well prepared to meet this future. Based on ISP, we have created a documented ability to generate completely new drug candidates with blockbuster potential in the field of CNS diseases. The company has already built up a unique project portfolio focusing on improving the lives of people with Parkinson’s and their families, and the ISP platform can further broaden the project portfolio in several CNS disorders. The portfolio has reached a stage that is unparalleled in the global pharmaceutical industry and is attracting increasing attention from the medical profession, industrial players and investors. We are continuing our efforts to create maximum value for those affected by this progressive and incurable disease, for their relatives, health and social care and of course, also for the company’s shareholders.