Novel Therapeutic May Offer Complete Response for Immuno-Inflammatory Diseases
There are severely limited therapeutic options for immuno-inflammatory diseases such as acute graft vs. host disease (aGVHD), lupus and asthma. Equillium, Inc. is developing a monoclonal antibody that, with a dual mechanism of action, seems to provide complete responses. The result may attenuate aGVHD and holds potential as a durable therapy to mitigate GVHD as a treatable condition.
Equillium’s lead compound, itolizumab, is a first-in-class anti-CD6 antibody that targets the CD6-ALCAM (activated leukocyte cell adhesion molecule) pathway.
“Immune modulating drugs typically inhibit either the activity of the target or in some cases the trafficking of inflammatory cells into tissues and organs. Itolizumab does both in one mechanism, and we hope this novel therapeutic may have broad utility across a range of severe immuno-inflammatory diseases” Bruce Steel, CEO of Equillium, told BioSpace.
As research shows, “Itolizumab works upstream and selectively targets the autoreactive effector T cells while sparing regulatory T cells to promote immune tolerance that may lead to durable disease remission,” Steel explained in a presentation at the recent H.C. Wainwright Investors Conference. Consequently, immune regulation is restored without immunosuppression.
Equillium’s most advanced program is for the first-line treatment of aGVHD, for which there are only a few therapies in development. Itolizumab has received Fast Track and Orphan Drug designations for this indication.
“GVHD is, essentially, a very severe side effect of bone marrow transplantation in which the transplant rejects the body (rather than the reverse) and attacks key organs,” Steel explained. Of the 10,000 allogeneic hematopoietic stem cell transplants performed each year, between 30% and 70% of recipients develop GVHD.
“Patients have up to a 95% mortality rate if they don’t respond to steroids, which is current standard of care as there are no approved therapies for first-line treatment. We hope to address the immediate insult of aGVHD and potentially dose patients for extended periods to prevent GVHD relapse, treating this somewhat like a chronic disease,” Steel said.
A Phase Ib trial for this indication is expected to be completed in the first half of 2021.
“Our interim data from last year is driving a lot of attention,” Steel said. “It showed compelling complete response rates in the first-line setting. Most of the patients who responded had a complete response. In severely ill patients – those with grade 3 or 4 disease – standard-of-care high-dose steroid treatment has demonstrated complete response rates of up to 35%, whereas we have seen complete responses and one very good partial response of 80% in patients being treated with itolizumab in addition to steroids alone.”
Steel believes those responses will, potentially, be durable. Equillium’s partner, Biocon Limited, has “Phase III data in psoriasis showing that effects lasted an extended period of time following treatment. In aGVHD, there are early signs of durability,” he said.
Equillium is working now to determine the optimum dose and expand the cohort.
While not expected to be a cure, itolizumab may offer a significant benefit to these severely ill patients. The company plans to talk with the FDA in the coming months regarding the design of subsequent trials, with the goal of rapidly moving the program ahead with the potential to submit a biologics license application (BLA) by the end of 2024.
Equillium also has a trial underway using itolizumab to treat lupus nephritis, the most frequent and serious manifestation of systemic lupus erythematosus, which affects 100,000 patients in the U.S. Between 50% and 75% do not respond to frontline treatments.
“There is one approved treatment and nine products in development, but only one – itolizumab – that modulates the activity and trafficking of effector T cells,” Steel said.
Many of the competing therapies harness T cell approaches. While promising, they may come with toxicities and a relatively narrow therapeutic index, Steel said in a presentation. Because CD6 and ALCAM-expressing cells are elevated in lupus nephritis patients and ALCAM may be a predictive biomarker for the condition, itolizumab may be an effective therapy with a favorable safety and tolerability profile.
Today there are no therapies approved that address the full spectrum of uncontrolled asthma, which affects approximately 1.3 million patients in the United States.
Mechanistically, itolizumab holds promise to treat both Th2 and Th17 driven asthma, and CD6 and ALCAM have both been shown to be upregulated in the lungs of severe asthma patients. Equillium is conducting the Phase Ib Equip study to assess the optimal subcutaneous dose of itolizumab, as well as its safety and tolerability, pharmacokinetics and pharmacodynamics, and clinical activity.
Likely milestones for 2021 include topline data from the Phase Ib Equate trial in aGVHD in 1H2021, topline data from the final cohort from the systemic lupus erythematosus study this quarter and interim data from the lupus nephritis study during the second half of the year, as well as data from the Equip Phase Ib trial for uncontrolled asthma in the latter half of this year.
Because Equillium launched the company with a license and strategic partnership with Biocon Limited, a large Indian biopharma company that specializes in protein biologics, manufacturing does not appear to be a bottleneck.
“Biocon makes itolizumab for us at commercial scale in an FDA-regulated facility in India,” Steel said.
Biocon is the fourth largest insulin supplier in the world, and also manufacturers trastuzumab and other biologics, so can handle the rigors of commercial scale and quality biologics production.
Biocon’s prior clinical development work with itolizumab significantly de-risked Equillium’s programs.
“Itolizumab was developed for psoriasis in India (marketed as ALZUMab™). Last year Biocon completed a Phase II study for acute respiratory distress in COVID-19 patients, which led to an emergency use authorization to treat COVID-19 patients in India,” Steel said. “Biocon has generated a meaningful amount of clinical data, demonstrating itolizumab is an active immune modulating agent that has been safe and well tolerated.”
Notably, Biocon is providing itolizumab to Equillium for clinical development at their cost of goods, and for development in up to three orphan indications (including GVHD) at no cost.
“As a result, we’ve been very efficient with our capital,” Steel said. “Biocon has a vested interest in our success,” he explained, with rights to the program in India, Europe and parts of Asia, while Equillium holds the commercialization rights for the United States, Canada, Australia, and New Zealand.
With approximately $90 million on-hand at the end of Q3 2020 and a recent quarterly operating cash burn of under $6 million, Equillium has the financing to complete its current clinical trials and initiate later stage development of the program.