Regina Berkovich, MD, PhD: The use of repository corticotropin injections, or what we used to call ACTH in medical school—adrenocorticotropic hormone—is another FDA-approved option for MS [multiple sclerosis]–relapse therapy. As I pointed out earlier, it was approved in 1978 after an extensive, multicenter study by James Rose, PhD, which actually originated here in Los Angeles. He was professor of neurology working at UCLA [University of California, Los Angeles]. He conducted the first clinical trial in multiple sclerosis that was multicenter and placebo controlled and enrolled the largest number of participants at that time. The study was started in the late 1960s, was conducted for a few years, and was reported to the scientific community in the 1970s, which eventually led to the approval of ACTH for MS relapse.
Among other things, this was the first study in which the Disability Status Scale was implemented. Many different clinical metrics in relapse evaluations that we now understand as classical actually came from that first study, which has become classic by now. The study was placebo controlled, very well conducted, multicenter, and it looked at the effects of corticotropin as compared with the placebo. It showed the faster and more robust recovery of patients experiencing MS exacerbation, as compared with the placebo.
I think that the important point for us to remember is that ACTH is not a steroid. It is a hormone, but it is not a steroid. It is a protein. If we remember the HPA [hypothalamic pituitary adrenal] axis, we recall that it is a regulatory hormone, which is at a much higher level than the cortisol. That may explain why the mechanism of action and the targets of corticotropin are much more diverse than those with the adrenal hormones, such as systemic steroids or cortisol.
From this, I would like to speak about different receptors that these particular hormones have affinity to. While we know that systemic steroids, cortisol, methylprednisolone, and prednisone have a high affinity to the glucocorticoid receptors, the ACTH—as a protein and not a steroid—has affinity to a different type of receptors, which are called melanocortin receptors. It is philosophically and physiologically expected that a higher-level regulatory hormone would have more targets than the hormone that is much lower in the whole system of the HPA. And indeed, it is so. We used to think back in medical school that ACTH activates the adrenal glands, and the adrenal glands produce cortisol. However, that seems to be only 20% of the story, or maybe even less. ACTH works on different types of receptors spread throughout the body, and different tissues and cells.
The class of melanocortin receptors represented on adrenal glands are only 1 class of 5. The other receptors are distributed through blood cells, including lymphocytes, microglia, skin, and bone tissue. Their representation is extremely widespread. I’ve just touched upon the very top tissues, but there are many.
The mechanism of engaging the anti-inflammatory effect is also different, as compared with the glucocorticoid receptors. It goes deeper into the anti-inflammatory mechanisms, and as a regulatory hormone, it is expected to have a completely different immunology of the outcomes that have been shown in some of the clinical trials.