Q&A: Study safely increases peptide doses to treat eosinophilic esophagitis

Key takeaways:

• ‘1104 aims for long-term disease remission without immunity suppression.
• Healthy volunteers tolerated 16 mg, 32 mg and 64 mg doses.
• Future clinical trials may use these doses for superior efficacy.

Healthy volunteers taking a first-in-class peptide designed for treating eosinophilic esophagitis did not experience any clinically significant adverse safety findings at any of three evaluated doses, according to a press release.

The phase 1 multiple ascending dose clinical trial assessed the use of ‘1104 from Revolo Biotherapeutics in 24 healthy volunteers who received two doses at 16 mg, 32 mg or 64 mg or a matching placebo via IV bolus.

According to Revolo, ‘1104 is derived from mycobacterium tuberculosis chaperonin 60.1, which is a natural immune-regulatory protein that is involved in resetting the immune system.

Healio spoke with Roly Foulkes, PhD, chief scientific officer, and Jonathan Rigby, MBA, CEO, both of Revolo, to find out more about how ‘1104 may benefit patients with eosinophilic esophagitis and other autoimmune and allergic diseases.

Healio: What are the current best practices for treating EoE?

Foulkes: Currently, treatment options for EoE range from nonpharmacologic approaches, such as dietary elimination and surgical intervention to dilate the esophagus, to pharmacologic solutions, such as corticosteroids, leukotriene antagonists or immunomodulators. Only one FDA-approved biologic is available to people living with EoE. Although there has been progress made in improving available treatment options for patients, there is still a need for new treatment innovations.

Healio: What are the limitations of these practices?

Foulkes: Although dietary control is key in the management of EoE, dietary elimination often leads to suboptimal responses because identification of the specific EoE triggers is not always possible and long-term adherence to dietary therapy can be difficult.

Current pharmacological approaches also lead to suboptimal responses, given that they target the inflammatory pathway after the immune system has been activated. They also require chronic frequent dosing, which can lead to poor compliance. In addition, existing steroid therapies suppress the immune system, which can ultimately put patients at risk for developing serious infections and life-threatening side effects.

Healio: How does ‘1104 improve on these practices?

Foulkes: The goal of ‘1104 is to offer superior long-term disease remission from less frequent chronic dosing without suppression of the immune system. Compared with focusing on the reduction of eosinophil infiltration or inflammatory pathways, ‘1104 has a broader mechanistic effect to address EoE’s complex pathophysiology.

Healio: Could you summarize how ‘1104 works?

Foulkes: ‘1104 works to reset the immune system “upstream,” or before the inflammatory cascade has occurred. It binds to monocytes as they mature into dendritic cells, prompting delivery of a modified “regulatory” signal to naive immune cells. This results in the generation of activated regulatory immune cells, such as B regulatory (Bregs) and T regulatory (Tregs) cells, which are key immune cells that support immune tolerance.

These cells prevent the proliferation of T effector cells and inflammatory molecules, preventing the immune system from entering override without suppressing the immune system. Bregs are longer living than Tregs. As such, ‘1104 has the potential to lead to long-term disease remission for patients.

Healio: Could you summarize the results of previous studies of ‘1104’s efficacy?

Foulkes: In a phase 2a clinical trial, ‘1104 showed a statistically significant improvement in patient-reported dysphagia symptoms compared with placebo.

The data confirmed ‘1104’s broad mechanistic effect across a range of key immune cell types associated with EoE, the key differentiator from other therapies. Treatment with ‘1104 increased activated Bregs and Tregs in all patients while also reducing key inflammatory cells, including eosinophils and T effector cells. Treatment with ‘1104 also led to the normalization of key EoE genes, which control inflammation and tissue remodeling.

‘1104 has demonstrated safety and tolerability in four clinical studies with the administration of IV or subcutaneous clinically relevant doses. Preclinical studies have demonstrated the disease-agnostic aspect of ’1104, as it reduced cellular inflammation to a range of allergens.

Healio: How do the results of the new phase 1 study build on these studies?

Rigby: In previous studies, ‘1104 was evaluated at doses up to 8 mg. The positive safety data from the phase 1 multiple ascending dose study, which evaluated ‘1104 at the 16 mg, 32 mg and 64 mg doses, supports dosing of ‘1104 at higher doses than those administered in clinical trials to date.

Healio: Why are these results significant?

Rigby: These new results are significant as they support higher dosing of ‘1104 in future clinical studies. Revolo believes that higher doses of ‘1104 administered over a longer duration of treatment could potentially result in a superior efficacy profile for EoE patients.

Healio: What is the next step in this research?

Rigby: In the first half of 2024, Revolo plans to initiate a phase 2b clinical trial of ‘1104 in EoE at higher doses than those tested to date. Revolo also plans to initiate a phase 2a clinical trial of ‘1104 in food allergy.

Healio: Do you have any other comments about ‘1104 and its development?

Rigby: This year, we have made great clinical and preclinical progress with ‘1104 that supports its broad mechanistic effect, a key differentiator from therapies to date, and its safety profile. Data continue to demonstrate ‘1104’s disease-agnostic mechanism of action and its potential to become a platform for the treatment of several allergic diseases.

As we look toward 2024, we are excited to initiate two new clinical trials for ‘1104 in the first half of the year and continue to evaluate any additional indications for which ‘1104 could make a difference.

Reference:

• Revolo Biotherapeutics announces the completion of phase 1 multiple ascending dose clinical trial of ‘1104. https://revolobio.com/2023/09/21/revolo-biotherapeutics-announces-the-completion-of-phase-1-multiple-ascending-dose-clinical-trial-of-1104/. Published Sept. 21, 2023. Accessed Oct. 5, 2023.