Failure of Promising Investigatory Lupus Drug Prompts Discussion to Improve Clinical Trials

According to a publication from The Rheumatologist, the recent failure of a seemingly-promising lupus treatment in a phase 2 study has led to a discipline-wide discussion about new research and necessary improvements to research standards.

About Lupus

Lupus is an autoimmune disease that has an incredibly diverse array of signs and symptoms. Many of these symptoms closely resemble those of other conditions, which adds to the already significant difficulty physicians can have diagnosing the disease.

Like other autoimmune diseases, lupus is caused by a malfunctioning immune response that causes the body to mistakenly attack healthy tissues and organs as though they were foreign bodies. Researchers believe lupus can be triggered by a variety of environmental factors that are influenced by certain genetic predispositions. Sunlight, infection, and certain medications have been previously identified as just a few of the many possible lupus triggers.

Lupus seems to be more common in African and Asian-Americans, Hispanics, and women. Though rare, lupus can be fatal due to severe complications like kidney failure, anemia, and even stroke. Most people who develop lupus have completely normal life expectancies. However, there is no cure, and treatment is limited to controlling the worst of the symptoms. A more direct treatment is necessary to ensure the well-being of lupus patients — who number as many as 1.5 million in the United States alone.

Failure of Anifrolumab, TULIP-1, and the Future of Lupus Medications

TULIP-1 was a phase 2 clinical study of anifrolumab’s potential to aid lupus patients by acting on type 1 interferon receptors. This target is especially appealing to researchers because all five subtypes of interferon 1 bind to the same kind of receptor, theoretically allowing for broader-spectrum blockage of interferon 1 activity in patients.

Interferons are signalling proteins that stimulate immune response in a given cell or area. By blocking the activity of type 1 interferons, researchers hoped that the overactive immune response that drives autoimmune conditions like lupus would tamp down.

However, TULIP-1 was a bust that surprised industry experts. “There have been a lot of analyses performed to find out why [the study] failed,” Dr. Richard Furie, principal investigator on the study, said of the trial. Later, at a clinical symposium, Furie gave a talk where he drew on his experiences in the TULIP-1 study to identify what he considered to be four of the most significant problems with lupus clinical trial designs:

  1. Over-statement of lupus’ activity in extra-renal disease — in other words, the activity of lupus just isn’t as aggressive as some researching physicians presume.
  2. The inclusion of patients in numerous background therapies — patients’ participation in more than one clinical trial can make it extremely difficult for researchers to determine what treatment is working if positive endpoints are reached. It “blunts our ability to discriminate” the effects of one treatment from those of another.
  3. The biological complexity of lupus — lupus may involve activity in several biological pathways that we have yet to identify. Many factors may be in play.
  4. Better endpoints for clinical trials — in order to more effectively determine if a treatment is effectively relieving lupus, scientists need better ways of identifying what constitutes a response in patients. In other words, scientists have to develop better ways of identifying when a treatment is effective.

These challenges are easier to list than solve, but Dr. Furie believes that’s just what’s necessary to improve lupus clinical trials. Lupus has been “a real tough nut to crack,” Dr. Furie noted. “But I am optimistic about the future.”

The design of clinical trials is constantly in flux. Why is it important to consider the limitations of our observational capabilities when designing new treatments? Share your thoughts with Patient Worthy!

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