Use of Targeted Synthetics in Rheumatic Diseases

Sergio Schwartzman, MD: The advantage of the targeted synthetics over the biologics is, number 1, the issue of not having the necessity for the extreme requirements for the development and maintenance of a biologically driven disease.

These are chemical substances, the JAK [Janus kinase inhibitors] inhibitors. Number 2, they’re oral agents. They’re much easier to administer and don’t require infusions or subcutaneous injections. Number 3, their adverse effect profile is different. One component that’s completely obviated with the targeted synthetics is that you don’t produce anti-product antibodies against the synthetics, hence you don’t have some of the diseases that we think are associated with these complications. For example, some patients who get anti-TNF [tumor necrosis factor] agents develop neurological diseases that are thought to be due to the anti-TNF agent. MS [multiple sclerosis] or MS-like disease, peripheral neuropathy, seizures, Guillain-Barré syndrome have been described.

These types of adverse effects are not seen in patients who are treated with synthetics. I think as the panorama of targeted synthetics evolves, it will not completely replace but it will live in tandem with biologics and will ultimately surpass them. So we have a lot of therapies, and I think our challenge now isn’t so much that we don’t have things to use for patients with rheumatic diseases the way that we used to 30 years ago. Our challenge now is picking which 1 to use in a given patient. There’s a huge need for a better structured approach to determining which biologic fits the right patient.

The Janus kinase inhibitors work intracellularly. Without getting into too much detail, if we think about the abnormal immune response, that’s driven by the stimulation and overexpression of cells and the cells that we think are active in the immune response. The biologics work by either blocking cytokines that we think stimulate these cells or blocking the receptors that are utilized by these cytokines to activate cells. So, this is all extracellular. Whereas the targeted synthetics, and specifically here the Janus kinase inhibitors, don’t work extracellularly—they work intracellularly. Once a cytokine binds to its receptor, it then stimulates the JAK/STAT cascade to activate the cell. What the Janus kinase inhibitors do is they block that by blocking that Janus kinase. It’s a completely different mechanism of action, hence the different drug delivery and the different safety component as well.

In terms of the Janus kinase inhibitors, we have an approved Janus kinase 1 and Janus kinase 3 inhibitor, so it blocks both of those. We have an approved Janus kinase 1, Janus kinase 2 inhibitor, which was the second Janus kinase inhibitor that was approved. Very soon, we will have a very selective Janus kinase 1 inhibitor. Whether that makes a difference in terms of the efficacy is difficult to determine in the absence of head-to-head studies. We have no head-to-head studies where 2 Janus kinase inhibitors have been pitted against each other. I should also mention that Janus kinase inhibition, although I’ve listed the predominant Janus kinases that were blocked, is not absolute. For example, the Janus kinase 1/3 inhibitor that we have approved has a very small effect on Janus kinase 2. I think that selectivity is important. It’s very hard to differentiate across the Janus kinase inhibitors without having head-to-head studies.

Transcript edited for clarity.