18 Mar Oral Adrenocorticotropin hormone (ACTH) in multiple sclerosis (MS)
Adrenocorticotropin hormone (ACTH 1-39) is a natural endogenous protein that shows intrinsic immunomodulation via melanocortin receptors absent corticotropism. Parenteral ACTH is a FDA approved biological agent (1978) for the treatment of MS exacerbations and for flares of other autoimmune diseases for over 40 years (RA, SLE, nephrotic syndrome). We will determine optimal oral dose(s) i.e., efficacy with immunomodulation. Immunomodulation may occur with or without absorption. If optimal biological activity occurs without absorption (melanotropic), oral ACTH may offer long term beneficial immune-modulation. On the other hand, if the optimal oral dose is absorbed, lower melanotropic doses without absorption may be useful long term. Higher doses with absorption may provide additional immune effects (corticotropic) effects during relapses or attacks.
We have shown that oral ACTH shows activity in experimental autoimmune encephalomyelitis (EAE) (app A), the animal model for multiple sclerosis (MS) and in normal volunteers in a first–in-human (FIH) trial (app B). Oral alpha-MSH (ACTH 1-13), consisting of the first 13 amino acids of ACTH, also ameliorates EAE (app C). In both mice and humans, oral ACTH can decrease pro-inflammatory cytokine secretion.
New oral therapies are needed despite the multitude of oral agents becoming available because of the toxicity from small molecules (Gilenya – cardiac 38 deaths/40,000 pts), teriflunomide (hepato-teratogenicity) and DMF (life altering diarrhea, PML, Kaposi, Nrf2 MOA – bardoxolone-like toxicities in CKD).
We will give oral doses of ACTH in MS subjects on no DMTs to establish the optimal biological dose (OBD). Thereafter, we will determine whether the immune effect is independent of absorption (melanotropic) or associated with absorption (corticotropic). In addition, we will inject identical parenteral doses of ACTH in the same subjects to determine whether oral ACTH produces similar immune effects to injected ACTH.
ACTH may inhibit Th17 directly or via Th2 cells, generate regulatory CD4+CD25+ Treg or activate antigen presenting cells (APC) that secrete anti-inflammatory cytokines.
Once we establish the optimal oral ACTH dose in MS we would perform a phase II randomized controlled trial (RCT) comparing disease modifier therapy (DMT) alone to DMT + ACTH add-on therapy in patients with relapses within the last year and measure reduced MRI activity as a primary outcome & time to first relapse as secondary outcome.
Specific Aim #1:
What is the optimal biological dose (OBD) (e.g., optimal immunomodulation) for oral ACTH?
Specific Aim #2:
Is the optimal biological dose (OBD) absorbed?
Specific Aim #3:
Does the optimal biological dose (OBD) have similar immune effects to the equivalent sq dose?
Specific Aim #4:
Does ACTH regulate T cell, macrophage and/or dendritic cells function with melano-tropism activation or with cortisol (cortico-tropism) and melano-tropism?
Adult male or female subjects with CIS or MS. Patients will be on Copaxone and be clinically stable for at least 1 month. 2. Identified patients must be age >18 years. 3. Ability to understand and the willingness to sign a written informed consent document.
staley a. brod MD
Additional Study Details
Full Study Title
Oral ACTH – Melanocortin & Corticotropin Effects in MS
Study ID: 000000000
Accepts Healthy Volunteers?
staley a. brod