Taking Aim at a New Target

Image courtesy Easy Vectors

When the AARDA (American Autoimmune Related Disease Association) posted a link yesterday to the clinical trials results of a drug with potential use in the treatment of autoimmune diseases, I was intrigued.

A new drug in the autoimmune world? Interesting, I thought.

The drug, ADP334, is manufactured and currently undergoing clinical trials by Arena Pharmaceuticals:

"Lymphocyte lowering at the level demonstrated in this trial has been shown to correlate with clinical efficacy in Phase 2 and Phase 3 trials of other S1P1 modulators in multiple sclerosis, psoriasis and ulcerative colitis," said William R. Shanahan, M.D., Arena's Senior Vice President and Chief Medical Officer. "The results of this trial support investigation of the efficacy and safety of APD334 in patients with autoimmune diseases." 

The randomized, double-blind, placebo-controlled Phase 1b clinical trial evaluated the safety, tolerability, pharmacodynamics and pharmacokinetics of multiple-ascending doses of APD334. In five different dosing cohorts, a total of 50 healthy volunteers received APD334 and 10 received placebo for 21 days. 

"Based on these impressive results, we plan to expedite APD334 into Phase 2 clinical trials for ulcerative colitis and Crohn's disease," said Jack Lief, Arena's President and Chief Executive Officer.

Of course, once this news was released to the press, shares of this company's publicly traded stock soared in value, hence the 1/7/15 Yahoo Finance article quoted above.

I wondered what made this drug different from other currently prescribed drugs that affect the immune system such as Azathioprine (Imuran), Mycophenolate mofetil (Cellcept), Cyclosporine (Neoral, Sandimmune, Gengraf), Methotrexate (Rheumatrex), Leflunomide (Arava), Cyclophosphamide (Cytoxan), and rituximab (Rituxan) to name just a few.

And then I read this:

APD334 is a potent and selective, orally available investigational drug candidate that targets the S1P1 receptor. Discovered by Arena, APD334 has therapeutic potential in autoimmune diseases. S1P1 receptors have been demonstrated to be involved in the modulation of several biological responses, including lymphocyte trafficking from lymph nodes to the peripheral blood. By isolating lymphocytes in lymph nodes, fewer immune cells are available in the circulating blood to effect tissue damage.

In other words, drugs in this new class target a different lymphocyte receptor than other drugs in the treatment of autoimmune disease. To understand this all a bit better, it's helpful to know what a lymphocyte receptor is and why it's so important for these drugs to target them. Here's an excellent explanation courtesy of NobelPrize.org:

White blood cells called lymphocytes originate in the bone marrow but migrate to parts of the lymphatic system such as the lymph nodes, spleen, and thymus. There are two main types of lymphatic cells, T cells and B cells. The lymphatic system also involves a transportation system - lymph vessels - for transportation and storage of lymphocyte cells within the body. The lymphatic system feeds cells into the body and filters out dead cells and invading organisms such as bacteria. 

On the surface of each lymphatic cell are receptors that enable them to recognize foreign substances. These receptors are very specialized - each can match only one specific antigen. 

To understand the receptors, think of a hand that can only grab one specific item. Imagine that your hands could only pick up apples. You would be a true apple-picking champion - but you wouldn't be able to pick up anything else. 

In your body, each single receptor equals a hand in search of its "apple." The lymphocyte cells travel through your body until they find an antigen of the right size and shape to match their specific receptors. It might seem limiting that the receptors of each lymphocyte cell can only match one specific type of antigen, but the body makes up for this by producing so many different lymphocyte cells that the immune system can recognize nearly all invaders.

So more specifically, what is an S1P1 receptor?

There are five different sphingosine 1-phosphate receptors on lymphocytes. This drug targets the first: S(sphingosine)1P(phosphate)1. These receptors are important because they control lymphocytic exit from lymph nodes and their recirculation into the blood, resulting in less of these autoimmune active lymphocytes in the circulating blood stream. Read more here.

Arena's drug is not the first to target this type of receptor. Oral fingolimod, (Gilenya) manufactured by Novartis is currently being used to treat MS. You can read more about one of the drug studies leading to it's manufacture and use here. Like all drugs that modify immune mechanisms, Gilenya is not without significant risk, one being a slowing of the heart rate or alteration of the normal electrical pattern in the heart.

The absence of apparent cardiac effects in this early study of Arena Pharmaceutical's new drug is impressive:

There were no clinically significant safety findings with respect to heart rate or rhythm or pulmonary function, and no clinically significant elevations in liver enzyme tests.

 I'm looking forward to seeing how this drug stands up in additional trials, since the development of new tools to treat autoimmune disease is vitally important.

Stay tuned, people. This should be interesting.