A new proposed treatment for scleroderma will soon be in Phase 2 clinical trials. Corbus Pharmaceuticals, based in Norwood, Massachusetts, recently received clearance from the FDA for their investigational new drug (IND), Resunab™, indicated to treat diffuse cutaneous systemic sclerosis, the most severe form of scleroderma.
“Resunab has an interesting background story,” said Yuval Cohen, PhD, CEO and Director of Corbus Pharmaceuticals, in an exclusive interview with Scleroderma News. “It is a story of a drug developed by another company that was advanced all the way to Phase 2 clinical trials for a different indication. When it did not meet clinical expectations, it was returned to the University of Massachusetts Medical School, where Mark Tepper, PhD, Chief Scientific Officer of Corbus discovered it and realized that it had potential as a novel anti-inflammatory drug.”
Originally, a different company was pursuing Resunab as a painkiller. The synthetic small-molecule drug is a potent agonist of CB2 receptors on the surface of leukocytes (white blood cells). “To understand what Resunab is and why it was previously thought to be a painkiller, we need to understand the problem,” said Dr. Cohen. In healthy individuals, when an infection occurs in the body, the immune system springs into action (inflammatory activation). Once the infection is dealt with, the immune system returns to homeostasis (inflammation resolution). However, in the case of chronic inflammation, the body does not return to homeostasis. “The majority of chronic inflammatory diseases can be boiled down to the following,” said Dr. Cohen. “A different root cause, but the same problem of heightened inflammation. The immune system never gets the signal to shut down. That is the difference between chronic inflammation in a patient and on/off inflammation in a healthy individual.”
A major part of the on/off switch (mediated through the CB2 receptor) between pro- and anti-inflammatory conditions are signaling molecules produced by leukocytes. Arachidonic acid is metabolized by leukocytes into a multitude of eicosanoids, the primary mediators of both pro- and anti-inflammation. Eicosanoids have mirror-image roles: one for pro-inflammation and one for anti-inflammation. The switch from pro- to anti-inflammation during inflammation resolution involves both turning on anti-inflammatory molecule synthesis and turning off pro-inflammatory molecule synthesis.
A separate role for CB2 receptors involves the brain and the central nervous system (CNS). There, CB2 acts to reduce pain (analgesia). “It is an ancient system,” said Dr. Cohen. “If you were a cavewoman and got bitten by a tiger, you could not just stay in your cave. It’s eat or die. Within the CNS, CB2 receptor activation would make the pain of the bite go away, while in the peripheral system, the wound trauma would be reduced.”
Hence the original pursuit of Resunab as an analgesic. But before Resunab made it to clinical trials, the founding company never looked at one important part of the pharmacokinetics of painkillers: whether or not the drug crosses the blood-brain-barrier to affect brain cells. “In retrospect, the chemical structure of Resunab explains why it has such poor penetration into the brain,” explained Dr. Cohen. “And so, the very properties that make it an unattractive pain killer are the ones that make it such an attractive candidate for an anti-inflammatory drug.”
For scleroderma patients, this could mean fewer side effects of treatment. “Each morning, patients could potentially take a pill and reset their immune system back to normal,” said Dr. Cohen. It is important to note that Resunab attenuates, rather than suppresses, inflammation, unlike some other proposed treatments for scleroderma. “The rationale is completely different: by not jamming the immune system like [non-steroidal anti-inflammatory drugs],” explained Dr. Cohen, “we’re sneaking through the back window to say [to the immune system], ‘Everything is clear so go back to normal.'”
Having completed phase 1 clinical trials with 123 patients, Resunab has a promising track record for safety, but the upcoming trial will continue to monitor patients for adverse side effects from treatment. Primarily, the study will explore any difference in clinical outcomes, as well as any decrease in the levels of pro-inflammatory mediators and increase in the levels of anti-inflammatory mediators.
For now, the initial 36 patients to be treated will receive Resunab once or twice a day, depending on dose, for three months. They will have a one-month follow up. “It is a slowly degenerative disease that is, tragically, associated with high mortality,” said Dr. Cohen. “Realistically, we are hoping to start seeing changes in terms of slowing down the disease. We hope to see an extension of life and an improvement in quality of life.” These outcomes will be tested in future, longer studies that look at patients with advanced scleroderma. “Of course, our dream is to ultimately target the population of those recently diagnosed,” said Dr. Cohen. “If we intervene early enough, then what if we never have fibrosis by resetting the immune system on a daily basis? We might have the potential to significantly reduce or prevent the appearance of fibrosis, taking away a major component of morbidity and mortality of disease.”
As a small start-up company, Corbus will be outsourcing major functions of the clinical trial. Corbus has a strong relationship with several patient advocacy groups and is aggressively hiring a world-class clinical trial development team. Already, Drs. Cohen and Tepper have a leading scleroderma expert on their team: Chief Medical Officer Barbara White, MD.
“Part of my job and passion is to educate people,” said Dr. Cohen. “Our team is 100% committed to finding out if Resunab works in patients with scleroderma. We believe in its potential and are very enthusiastic. We are giving it our all to recruit patients and begin dosing. The more people who are aware and express interest in the study, the better. It is important to engage the scleroderma community and respect patients, or else there is no point in doing this.”