Fibrosis research: Advances and challenges

Fibrocor Therapeutics, a developer of novel therapeutics to treat fibrosis, recently appointed Piet Wigerinck as Chief Scientific Advisor. Wigerinck has taken four drugs (Prezista, Olysio, Jyseleca and Rekambys) to market. DDW’s Megan Thomas caught up with Wigerinck to learn more about his work with small molecules for fibrosis research. MT: Your appointment comes as Fibrocor seeks to advance two drug candidates - exquisitely specific kinase inhibitor small molecules (FIB992 and FIB991) for rare indications into the clinic. Can you elaborate on the clinical timeline for these small molecules? PW: FIB992 is our lead compound. Fibrocor is on track to complete all IND-enabling work to support IND filing and initiation of clinical trials in 2024. Phase I of the clinical program will dose healthy volunteers with single ascending doses of FIB992 before proceeding to a multiple ascending dose study where the drug is administered for a two-week period. We have an excellent target engagement pharmacodynamic biomarker to guide us in determining dosages for IPF patients in a Phase II that is planned to start in 2026. Regarding FIB991, we aim to start the preclinical phase at the end of 2024 and plan to move into the clinic around the end of 2025. MT: What is the current landscape of, and key challenges in, fibrosis research? PW: The big challenge with fibrotic diseases is that they evolve slowly and are diagnosed late in the disease process. This has hindered development of drugs so that, from a therapeutic intervention point of view, fibrosis research is still in its infancy. Only a few drugs have received approval for fibrotic diseases like IPF (idiopathic pulmonary fibrosis). While these drugs slow progression of the disease, usage is limited by their side-effects. It is important to first study the drugs in patients in whom the evolution of the disease can be objectively measured by clinicians. IPF is suitable, as the lung function of untreated patients declines steadily. A second challenge is that the available lab models mainly mimic the early stages of the disease, whereas patients available for clinical trials present in more advanced stages. As different biological processes are dominant during the early and the late phases of the disease, outcomes from multiple in vitro and in vivo lab models will be better predictors of clinical success. MT: What will the development of these candidates mean for the future of fibrotic disease treatment? PW: Firstly, any new treatment should improve efficacy - thus, we expect to see increased life expectancy in patients. Patients experience severe side effects with current medications leading them to discontinue therapy. The new treatments will be much better tolerated, providing more long-term benefit from consistent sustained dosing. Fibrocor is the first company developing novel drug candidates for fibrotic diseases that stop the dominant biological processes in the advanced phase of the disease when most patients are diagnosed. Fibrocor’s goal is to start a new therapeutic approach that can be combined with existing standard of care and upcoming novel treatments. MT: What technologies are Fibrocor Therapeutics utilising to advance its drug development process? PW: Through our exclusive access to one of the world’s largest fibrosis tissue biobanks, we have correlated disease progression to gene expression data, enabling us to discover novel targets on the pathway that drives the advanced stages of fibrotic disease. The gene expression data were generated by RNAseq on biopsies stored at -78°C. The most crucial step in this process is the selection of the relevant disease markers. Depending on which disease marker is chosen, different stages of the disease will be interrogated, and different targets will emerge at the end of the target selection process. MT: Have there been any obstacles which Fibrocor has had to overcome to get these candidates ready for the clinic? PW: Our clinical candidates are small molecules with good oral bioavailability that can be conveniently administered to patients as small pills. That part of the program looks easy. The bigger challenge is to follow the small molecules in the human body. As the molecules are exquisitely selective and only inhibit a single target, we have developed dedicated assays to follow the effects of our drug candidates in various parts of the body such as the blood, urine, skin, lungs and even in the nasal cavity. These assays will guide us in determining the optimal dosing regimen for various fibrotic diseases, depending on which enzymes need to be blocked in the blood, lungs, skin etc. MT: What is the current regulatory landscape in this field? PW: Fibrocor Therapeutics focuses on rare diseases, such as IPF (idiopathic pulmonary fibrosis) and Alport Syndrome. Since they are rare, medications we develop for these diseases are eligible for an Orphan Drug Designation (ODD) from the regulatory authorities if the programs show a high degree of scientific innovation. An ODD can be obtained early during the drug development process, even before a drug candidate has been administered to patients. If the early clinical data in patients look promising, special regulatory assistance programs are available. For a disease like IPF, if a new treatment can show stabilisation of the disease rather than progression, accelerated approval based on Phase II data is a realistic possibility. These indications remain very attractive for young biotech companies, as streamlined regulatory programs can accelerate the approval date by a few years. MT: You have been a key driver of the research and development programs of four approved medicines: Prezista, Olysio, Jyseleca and Rekambys. What do you think is most important when taking a drug through this process from discovery to delivery? What lessons have you learnt which you will be applying to the development of FIB992 and FIB991? PW: When I select my projects to start development, I look at two parameters: the window of opportunity and the level of innovation for patients. The window of opportunity plays on two levels. First, it plays on the clinical/regulatory level. The development and regulatory hurdles are much easier to overcome if a new treatment is addressing a real unmet medical need. Imagine if a very smart company was to discover a new treatment for hepatitis C today, as there are already two very effective, safe, and curative oral treatments available, it is very difficult to innovate beyond the current standard of care. Consequently, there is no real urgency for that next hepatitis C treatment. So, a new treatment must address a genuine unmet medical need, otherwise there is no significant commercial window of opportunity. The second level is that of the ‘competition’ between big pharma and small biotech. To be successful, biotech companies really need to be ahead of big pharma. Once the big pharma companies join the race for a specific disease or target, the window of opportunity to be successful as an independent biotech company is already closed. Trying to compete with a big pharma company is naïve: their scientists are as smart and as dedicated as the scientists in biotech – but they have much bigger teams and capabilities. Developing new drugs is a long and difficult journey; as a small organisation, you must choose your battles carefully. The level of innovation for patients is the second key criterium. When we start the development of a new drug candidate, we have a five-to-eight-year adventure ahead of us. We assume that our competition will also be at least partially successful, so we must select drug candidates that are clearly superior to current standard of care - and are better than all drugs that have shown promising Phase II data. Starting the drug development process with the ambition to be merely as good as the competition is a clear recipe for failure. You need to set the bar higher. Biography Piet Wigerinck is a pharmacist and holds a PhD in medicinal chemistry from the KU Leuven. He has over 30 years of R&D experience in the pharmaceutical and biotechnology industry. He has been responsible for all aspects of drug discovery, preclinical research, CM&C, Phase I and Phase II clinical trials. He has a broad experience in anti-infective, autoimmune and anti-fibrotic disease research. Wigerinck is the scientific co-founder of Xinvento.