Dear Lupus: It’s Time for a Blockbuster Medication

Clinical development of biologic therapies and other treatments for lupus remains a serious challenge, Maria Dall’Era, M.D., reported at the American College of Rheumatology’s 2016 Winter Rheumatology Symposium in Snowmass, Colorado.

“There have been many unsuccessful late-stage trials,” said Dr. Dall’Era, a rheumatologist and director of the Lupus Clinic at the UCSF Medical Center. Challenges include which patients to include in the trials, in which phase of disease, the effects of concomitant medications, and the identification of appropriate study endpoints.

As a result, the vast majority of lupus treatments are administered off-label.

These problems are daunting but the “future is bright,” Dr. Dall’Era was quick to add, noting an unprecedented number of clinical trials for lupus.

“We’ve had difficulty with large-scale phase III – and even some phase II – trials demonstrating the efficacy of experimental agents over control agents,” she said. “We’ve seen that in several high-profile, large-scale trials for lupus treatments, where we have very promising early-phase results, when we get to phase III trials, we’re just not able to demonstrate efficacy of the experimental treatment over controls.”[[{"type":"media","view_mode":"media_crop","fid":"46527","attributes":{"alt":"Maria Dall'Era, MD","class":"media-image media-image-right","id":"media_crop_8610481529030","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"5404","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"font-size: 13.008px; line-height: 1.538em; float: right;","title":"Maria Dall'Era, MD","typeof":"foaf:Image"}}]]

At the November 2015 ACR meeting in San Francisco, for example, researchers reported that epratuzumabfailed to meet its primary study endpoints in two pivotal phase III trials, Dr. Dall’Era noted.

“Epratuzumab was very promising in stage 2 and people had high hopes for it,” she lamented.

There was excitement about tabalumab as well, until development of that agent was halted following disappointing phase III clinical trial results.

The reasons for the difficulties of late-phase trials are multifactorial.

“We don’t have that blockbuster medication that’s able to make everybody better with lupus and that works rapidly so that we can see responses in clinical trials rapidly,” she said. “But it’s hard for me to believe that all of these medications that have been studied, don’t have any efficacy in lupus.”

Instead, Dr. Dall’Era suspects that a complex set of other factors is likely at play.

“Lupus is complex to study in clinical trials; the heterogeneous effects work in different ways, and different organ systems are involved, different molecular pathways are involved in different people,” she noted. “We don’t quite understand how to pre-identify which molecular pathway is operative in a particular patient, so we can’t yet match a treatment to a patient.”

Endpoints are another challenge in SLE research.

“The optimal endpoint for use in lupus trials remains unclear.  Much work is currently occurring in this important area,” she said.

Composite endpoints like the Systemic Lupus Responder Index (SRI) have been effectively used in some clinical trials, like the belimumab trials leading to its approval for the treatment of lupus in 2011, but other, more organ-specific endpoints might be better in some contexts, Dr. Dall’Era pointed out: “Do we just study patients that have skin manifestations of lupus and look at skin-specific endpoints, for example?”

“So I think all of those factors play a role in why it’s difficult to demonstrate efficacy of new therapies in lupus,” Dr. Dall’Era concluded. “I don’t think there’s one factor – all of these factors play a role.”

Despite such challenges, Dr. Dall’Era is optimistic about the future of lupus drug development. She points to anti-interferon agents as one promising area of drug development, but is quick to caution that the field awaits large late-phase clinical trial data.

“I think that we’re heading into an era where, as in the world of cancer, we try to target different disease pathways at the same time, and perhaps in different phases of disease, as is done in cancer with induction regimens, and then long-term maintenance regimens, to see if we can target multiple pathways at once-in a way that is safe for the patients and is not overly immunosuppressive,” she explained. “Unlike cancer, we don’t cure lupus right now; patients have to be on these medications for very long periods of time. We have to be careful about opportunistic infections and even secondary malignancies.”

Rational drug design that targets multiple pathways in both the innate and the adaptive immune system “makes a lot of sense,” she added. “We are trying to understand how to do that in a safe and effective manner.”  

References:

Dall’Era M. Update on biologic therapy in SLE: the old and the new." 2016 American College of Rheumatology Winter Rheumatology Symposium presentation. January 23-29, 2016. Snowmass Village, Colorado.

Megan E. B. Clowse, Daniel J Wallace, et al. "Efficacy and Safety of Epratuzumab in Patients with Moderate-to-Severe Systemic Lupus Erythematosus: Results from Two Phase 3 Randomized, Placebo-Controlled Trials," 2015 American College of Rheumatology/ARHP annual meeting.