A recombinant version of alpha-fetoprotein (AFP), MM-093, may one day provide a safe treatment alternative for rheumatoid arthritis (RA) and possibly other autoimmune diseases.
Under development by Merrimack Pharmaceutical Inc of Cambridge, Massachusetts, MM-093 is now entering a Phase II trial in RA and plans are underway to conduct future clinical trials in psoriasis, multiple sclerosis, inflammatory bowel disease, and other autoimmune diseases. Preliminary in vitro and animal experiments suggest that MM-093 prevents inflammatory cells from migrating to sites where an initial immune response is underway. It is purified from the milk of transgenic goats carrying the AFP gene. "People are cautiously optimistic about the new agent," co-investigator Aryeh Fischer, MD, staff physician in the division of rheumatology at the National Jewish Medical and Research Center in Denver, Colorado, tells CIAOMed. "The idea behind it - that it is not an immunosuppressant and is a natural protein that the body makes - are all really exciting, but there is no compelling human data at this point," he says.
The newly initiated randomized, double blind, placebo-controlled study is slated to enroll 240 patients at 40 centers throughout the US. Each patient will receive a placebo or one of three doses of MM-093. Treatment will continue for 24 weeks and patients will be assessed during a 4-week evaluation period using the ACR criteria for RA improvement. While more research is needed to clarify dosing and administration issues, "we will use weekly subcutaneous injection at this point," Dr. Fischer says.
Stand-alone versus adjunct?
In the upcoming trial, the new agent will be used concomitantly with methotrexate (MTX). "Let's say this goes well and we show efficacy, we may have people on a combination who stop MTX, and at that point postulate whether it could work alone," Dr. Fisher says.
"Many of the existing RA treatments have immunosuppressive properties and the thought is that human AFP does not," he says. The hope, he explains, is that the new agent will not have some of the drug-related toxicities seen with existing therapeutic options. For example, "tumor necrosis factor-alpha inhibitors all have significant immunosuppressant properties, and lymphoma is a risk, so they require strict blood monitoring," Dr. Fischer points out.
Pregnancy-induced RA remission questions may be answered
The new study will also answer the outstanding question of why women with RA tend to go into remission during their third trimester. Although it is normally present at a level of 50 to 80 ng/mL of serum, approximately 10,000 times as much is present in the maternal circulation during the later stages of pregnancy. "AFP has been shown to have immunomodulating properties in animals, so the idea that it may be causing remission in pregnant women is everyone's best guess," Dr. Fischer explains.
In November 2003, a Phase I study found MM-093 to be safe and well-tolerated in healthy volunteers. Results from a recently completed Phase IIa safety and tolerability study at Kings College Hospital in London are pending.
References:
- Fetal protein being tested as rheumatoid arthritis treatment [press release]. Denver: National Jewish Medical and Research Center; June 2, 2005.
- Merrimack Pharmaceutical initiates enrollment in a Phase 2 study of MM-093 in patients with rheumatoid arthritis [press release]. Cambridge: Merrimack Pharmaceutical Inc; March 3, 2005.