Immune-resetting peptide gets orphan drug designation for eosinophilic esophagitis
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Key takeaways:
- Patients experienced significant improvements in dysphagia median symptom scores.
- Eosinophils and CD4+ and CD8+ cells all decreased, and regulatory T and B cells increased.
The FDA has granted an orphan drug designation to ’1104 from Revolo Biotherapeutics, a first-in-class immune-resetting peptide designed to treat eosinophilic esophagitis, according to a press release.
Revolo submitted its request to the FDA before initiating its phase 2a RVLO 121-04 study, where patients with EoE received three doses of ’1104 over 2 weeks.
There is a significant unmet need for effective treatment options for patients who have EoE, Woody Bryan, PhD, president and CEO at Revolo, told Healio.
“For many patients, early disease control is critical to avoid the thickening of the tissue of the esophagus,” Bryan continued. “This designation highlights the FDA’s recognition of ’1104’s potential to address this unmet need.”
With approximately 180,000 children and adults living with EoE in the U.S., Bryan said, Revolo is eager to move ’1104 into the next stage of development.
Current treatments for EoE include dupilumab (Dupixent; Sanofi, Regeneron), which the FDA approved for use in children aged 1 to 11 years in January, and strict elimination diets and steroid treatments that aim to decrease inflammation, Bryan said.
“Unfortunately, steroid treatments are currently off-label, can have safety concerns, and have limited long-term efficacy and safety, and must be dosed frequently,” he continued.
Also, dupilumab, which is the only biologic approved for EoE, must be dosed subcutaneously every week.
“In addition, some patients don’t respond or partly respond to currently available treatment options,” Bryan said. “Despite these available options, there remains a large unmet need for new medicines that target the disease ahead of the inflammatory cascade.”
According to Revolo, ’1104 resets the immune system “upstream,” or before the inflammatory cascade. Clinical trials have shown that ’1104 has a broad mechanistic effect across a range of immune cells associated with EoE, which differentiates it from other therapies, Bryan said.
“’1104 increases the number of regulatory B and T cells, key cells involved in immune system balance, paired with a decrease in allergic effector cells, leading to the potential to avoid chronic inflammation without suppressing the immune system,” he said.
“Given the long-living nature of B and T regulatory cells, ’1104 may result in long-term remission for patients, an aspect that we hope to evaluate in future studies with ’1104,” he continued.
During the double-blind, placebo controlled, multicenter RVLO 121-04 study, 36 adults with active EoE received repeat doses of ’1104. Revolo reported a statistically significant improvement in patient-reported dysphagia median symptom scores from baseline that were sustained for 4 weeks after the last dose, compared with placebo.
Also, there were statistically significant reductions in eosinophils and in pro-inflammatory CD4+ and CD8+ cells compared with baseline, as measured in esophageal tissue by flow cytometry, along with a statistically significant increase in T regulatory cells in esophageal tissue and B regulatory cells in the blood.
“The phase 2a trial met its primary efficacy endpoint with a reduction in the eosinophil cell counts in esophagus tissue,” Bryan said.
The study additionally found a normalization of 15 key EoE genes considered to affect tissue remodeling, eosinophil and mast cell count, inflammation, cell adhesion, and the epithelium lining, Bryan said.
Revolo further noted that results from its trials have not raised any safety concerns and that patients have shown tolerability with no serious adverse events or study drug discontinuations due to drug-related adverse events.
“Overall, the totality of the data reinforces the broad mechanism of action of ’1104 and clinical potential,” Bryan said. “Based on these initial data, we believe ‘1104 holds positive potential to have an impact on EoE treatment approaches.”
Positive results from an additional phase 2 study prompted Revolo to submit an amended request to the FDA. The company plans on initiating a phase 2B trial in adults with active eosinophilic esophagitis that will evaluate higher doses and longer durations of therapy later this year.
Perspective
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The Revolo compound represents a next-generation immunomodulator that has potential to reset the inflammatory cascade. The compound, referred to as ’1104, shows potential based on an early phase 2 study. The drug is based on extensive preclinical immunological and genetic science and holds promise for EoE and other allergic diseases. As an orally active agent, it could be quite attractive if proven to be efficacious and safe.
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