Future of oral small molecule drugs – addressing potential in multiple sclerosis

What are the main trends or recent advances in oral small molecule drug development?

Daniel Vitt (DV): A current trend in oral small molecule drug development is a shift towards creating more selective and patient-friendly drugs. Vidofludimus calcium (IMU-838), a drug developed by Immunic Therapeutics, is a prime example of this. It is highly selective and has shown an excellent safety and tolerability profile to date.

Advancements in oral small molecule drug development can be attributed to significant technological improvements, particularly in screening methodologies, including AI-driven approaches, which help identify and profile drugs more effectively. Despite the rise of newer, more complex treatment technologies, small molecules continue to play a crucial role due to their simplicity, ease of management, patient convenience and cost-effective production.

What are the biggest current challenges in developing oral small molecule drugs? What approach should the pharmaceutical industry take to address these issues?

DV: The challenges associated with the development of oral small molecule drugs are closely tied to the need for selectivity. The goal is to create a molecule that effectively targets its intended mechanism without affecting other biological pathways. In addition to selectivity, these drugs must exhibit favourable pharmaceutical properties, such as efficient metabolism, optimal exposure and ease of administration, ensuring they are both user-friendly and effective for patients.

While the pharmaceutical industry has made advancements in this area, there is concern that some companies may be shifting their focus towards emerging technologies, whose long-term value may be unclear and not cost-efficient. Despite this shift, the development of small molecules remains a highly promising avenue, especially for smaller companies in a space traditionally dominated by large pharmaceutical firms.

When compared to existing treatments, what makes Vidofludimus calcium a promising candidate for the treatment of chronic inflammatory and autoimmune diseases, such as multiple sclerosis and ulcerative colitis?

Andreas Muehler (AM): While it is challenging to compare Vidofludimus calcium across different indications such as multiple sclerosis (MS) and ulcerative colitis, there are several important commonalities. One of the key advantages of Vidofludimus calcium is its safety and tolerability profile, which is comparable to that of a placebo – something rarely seen for drugs treating chronic inflammatory or autoimmune diseases.

Typically, such treatments suppress the immune system to alleviate the damage caused by autoimmune diseases. Although effective, this approach often results in significant side effects, including increased susceptibility to viral reactivation, infections, and, in some cases, a heightened risk of cancer due to reduced immune surveillance.¹

Vidofludimus calcium targets the enzyme dihydroorotate dehydrogenase (DHODH), which plays a specific role in metabolically activated immune cells involved in autoimmune diseases, without broadly affecting the immune system as a whole.

This selectivity allows it to suppress the immune system’s harmful activity without inhibiting its ability to fight infections or cancers. Additionally, preclinical data showed that Vidofludimus calcium potently activates the neuroprotective transcription factor nuclear receptor related 1 (Nurr1), which is associated with direct neuroprotective properties and may enhance the potential benefit for patients.

In clinical trials, patients treated with Vidofludimus calcium did not show increased rates of infections or infestations compared to placebo. Furthermore, other DHODH inhibitors had previously been shown to not interfere with the immune system’s response to vaccinations, allowing patients to generate a robust antibody response.

These factors make Vidofludimus calcium a highly promising candidate for the long-term treatment of chronic inflammatory and autoimmune diseases, potentially offering both efficacy and a superior safety and tolerability profile compared to traditional immunosuppressive therapies.

Furthermore, the key consideration for Vidofludimus calcium is that the definitive proof of its efficacy and safety requires the completion of Phase III studies. We believe our currently ongoing twin Phase III trials in relapsing multiple sclerosis are relatively low risk. This is because the trials’ primary endpoint – relapse activity – is closely linked to magnetic resonance imaging (MRI) lesions in these patients, for which a statistically significant effect was already shown in our previous Phase III EMPhASIS trial in relapsing-remitting MS.

MRI lesions are caused by brain tissue damage. While not every MRI lesion leads to a relapse in disease, nearly all relapses are associated with some form of brain lesion. In clinical trials, Vidofludimus calcium has shown a greater than 75 percent reduction in MRI lesions, which correlates strongly with a reduction in relapses.²

Given these findings, we are optimistic that the reduction in MRI lesions will directly translate to fewer relapses, making these studies relatively low risk. However, the final confirmation of safety, efficacy and the overall benefit-risk profile will come with the completion of the Phase III trials, which remains the most important milestone at this stage.

Can you highlight some of the key data for Vidofludimus calcium from the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) conference? What impact could this have on the future development of small molecule drugs in the sector?

AM: We presented four abstracts at The European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2024 congress, each highlighting different aspects of Vidofludimus calcium in MS. The first, a clinical abstract, focuses on the interim analysis from our Phase II CALIPER trial in progressive MS.³

The data showed that Vidofludimus calcium noticeably reduced neurofilament light chain, a biomarker of neuronal damage, compared to placebo. This suggests that the treatment could offer an effective protection of neurons. What is particularly important is that this effect is consistent across different subgroups of patients, regardless of age or disability levels, indicating broad efficacy across all progressive multiple sclerosis subtypes.

The second abstract investigates the relationship between Epstein-Barr Virus (EBV) reactivation and fatigue in MS patients. It links the reduction of EBV reactivations with potential alleviation of MS-related fatigue, a common and debilitating symptom that currently lacks effective treatment options. We believe Vidofludimus calcium could represent a promising new symptomatic therapy for MS fatigue. This aspect is currently being investigated in all our ongoing multiple sclerosis trials.

The third abstract explores neuroprotective mechanisms related to Nurr1 activation, demonstrating how Vidofludimus calcium seems to protect neurons by reducing the activity of microglial cells and thereby improving the neurotoxic environment around nerve cells. Additionally, it appears to reduce apoptosis (programmed cell death) enhancing neuronal survival under stressful conditions.

The fourth abstract focuses on the drug’s impact on T helper cells (Th cells), which play a critical role in the activation of the immune system and can contribute to the pathology of MS. This research delves into the immunological mechanisms behind Vidofludimus calcium’s effectiveness, emphasising how the drug modulates these cells to support its overall therapeutic effect.

Collectively, these findings highlight the potential of Vidofludimus calcium to not only slow MS disease progression but also address significant symptoms such as fatigue. This data could have a profound impact on the future development of small molecule drugs within the field of neurology.⁴

What developments in oral small molecule drugs do you anticipate over the next five to 10 years?  

DV: One significant trend is the increasing emphasis on the ability of these drugs to penetrate cells. Unlike antibodies, which typically interact with cell surfaces, small molecules can enter cells, opening up new therapeutic possibilities, particularly in the central nervous system. Designing small molecules that can effectively cross the blood-brain barrier could lead to substantial advancements in treating central nervous system disorders.

The pharmaceutical industry is also shifting its focus from oncology, which has been a dominant area of research, to other widespread and impactful conditions such as inflammatory and autoimmune diseases. These areas, including neurology and inflammatory conditions, present significant unmet needs, and we expect to see a surge in the development of oral small molecules targeting these conditions.

Additionally, the success of glucagon-like peptide 1 (GLP-1) agonists has demonstrated the potential for small molecules to replicate similar effects. Developing oral small molecules with comparable benefits could improve patient adherence and reduce healthcare costs.⁵

Overall, these trends suggest a future where oral small molecules play an increasingly vital role in addressing a wide range of medical conditions, from CNS disorders to inflammatory diseases, offering new treatment options and improving patient care.

References

1. Fox RJ, Heinz Wiendl, Wolf C, et al. Safety and Dose-Response of Vidofludimus Calcium in Relapsing Multiple Sclerosis. Neurology Neuroimmunology & Neuroinflammation. 2024; 11(3).
2. Fox RJ, Heinz Wiendl, Wolf C, et al. A Double‐Blind, Randomized, Placebo‐Controlled Phase 2 Trial Evaluating The Selective Dihydroorotate Dehydrogenase Inhibitor Vidofludimus Calcium In Relapsing‐Remitting Multiple Sclerosis. Annals of Clinical and Translational Neurology. 2022; 9(7):977–87.
3. Immunic, Inc. Today Announced That Data From Its Phase 2 Emphasis Trial [Internet] Immunic Therapeutics. 2024. [cited 2024Oct]. Available from: https://imux.com/immunic-announces-publication-of-extended-data-from-phase-2-emphasis-trial-of-vidofludimus-calcium-in-relapsing-remitting-multiple-sclerosis-in-the-peer-reviewed-journal/
4. Immunic, Inc. Today Announced The Presentation Of Key Data At The 40th Congress Of The European Committee For Treatment And Research In Multiple Sclerosis (ECTRIMS) [Internet] Immunic Therapeutics. 2024. [cited 2024Oct]. Available from: https://imux.com/immunic-presents-key-vidofludimus-calcium-data-at-the-40th-congress-of-ectrims-highlighting-its-therapeutic-potential-in-multiple-sclerosis/
5. Nauck MA, Quast DR, Wefers J, Meier JJ. GLP-1 Receptor Agonists In The Treatment Of Type 2 Diabetes – State-Of-The-Art.. [Internet] Molecular Metabolism. 2021; 46(46):101102.