Jun. 30, 2011

Path to Progress

By Heather Boerner

Lisa Williams, 41, of Riverdale, GA, talks about her lupus experience in terms that would be familiar to any war veteran: She’s taking an arsenal of medications. She has collateral damage in her joints from the high level of steroids she uses to control flares. And joint pain is a battle she fights every day.

So it should be no surprise that the recent approval of Benlysta® (belimumab) by the U.S. Food and Drug Administration (FDA) is, to her, the equivalent of bringing out the big guns. After all, the drug—developed by Human Genome Sciences (HGS) and co-marketed with GlaxoSmithKline—is the first to be approved for lupus in more than half a century, and the first designed specifically to treat lupus since the disease was discovered. This is serious firepower, Williams says.

To Williams, and many other people with lupus, Benlysta’s approval is a powerful addition to what often feels like a war of attrition, where the dearth of drug approvals makes people with the disease think they have been forgotten.

“We want the whole ‘Dr. House’ team of people working on us,” says Williams, referring to the TV doctor who sleuths out solutions to maddeningly difficult-to-diagnose conditions. “What this approval means to me is hope. It’s not just that Benlysta has been approved, but that it opens up the door for more lupus drugs in the future.”

There has never been a medication specifically for lupus before. Standard-of-care treatment for lupus has always consisted of medications developed for other conditions: chemotherapies for cancer; organ transplant rejection drugs; anti-inflammatories; immunosuppressives; corticosteroids; and more. And while these drugs can be effective in -suppressing the overactive immune system and repressing flares in some people, they also can cause serious side effects, including an increased risk for certain cancers; high blood pressure; increased likelihood of infections; liver damage; osteoporosis; drastic changes in mood; and infertility.

Williams, for instance, has had both hips and one shoulder replaced as a result of the prednisone (a corticosteroid) she takes for lupus flares. The other shoulder needs to be replaced, but she’s holding out as long as possible. A new medication that could interrupt the disease process instead of temporarily improving the symptoms could free her from having to take bone-depleting steroids.

Long Time Coming

The path to Benlysta—and the crop of new medications now in development—has been a long time in coming. It wasn’t until about a decade ago that researchers started examining lupus in earnest, first with clinical trials testing the effectiveness of DHEA, a naturally occurring hormone. But those trials were ultimately unsuccessful.

The mapping of the human genome opened another door, revealing new targets for drug companies to study. The Lupus Foundation of America (LFA) and the National Institutes of Health both funded genetics and related research. The race, it seemed, was on.

But once the research community had potential drugs for lupus in development, they hit another wall—several, in fact. According to a groundbreaking report from The Lewin Group, commissioned by the LFA and released in 2009, the barriers to drug development in lupus fall into five main categories:

1. The biology of the disease

2. Selection of clinical trial participants

3. Selection of clinical endpoints

4. Lack of validated instruments and tools designed for use in a lupus clinical trial

5. The role of background medications (See “The Lewin Group Initiative” sidebar, below.)

Because of these complicating factors, clinical trials were unable to show that the lupus drug products under investigation were more effective than the standard-of-care medications currently in use—one of the FDA requirements for drug approval.

There could be 300 difficult decisions to make when designing a study, says Gary S. Gilkeson, M.D., professor of medicine/microbiology and immunology at the Medical University of South Carolina at Charleston. One wrong choice, and it’s possible the study results could be negative.

“It’s hard when the trials keep failing,” says Susan Manzi, M.D., director of the Lupus Center for Excellence at West Penn Allegheny Health System in Pittsburgh and an investigator in one of the Benlysta trials. “I don’t think we ever thought there wasn’t a drug for lupus that could work. It was more a matter of how to prove it and how long it would take. It was frustrating to see other rheumatological and autoimmune diseases so far ahead in the drug approval arena while we were struggling to provide treatment options for our lupus patients.”

Light at the End of the Tunnel

In 1996, researchers at HGS, in Rockville, MD, discovered a human protein target called the B cell lymphocyte stimulator inhibitor, or BLyS-inhibitor, that prevented B cells from creating antibodies that attack tissue, as they do in people with lupus. Benlysta is in a new class of drugs that target the immune system through B cells.

In an effort to accurately study the potential therapy, however, the company knew it needed to create a new approach. HGS researchers used a retrospective analysis of data from Benlysta’s Phase 2 clinical trial to create a patient responder index that proved crucial in the two subsequent Phase 3 Benlysta trials. They also required study participants to meet specific criteria, took into account all the ways a person with lupus could improve, and examined whether the drug improved outcomes in some areas without worsening outcomes in others.

You can find Benlysta prescribing information at hgsi.com/images/Benlysta/pdf/benlysta_medguide.pdf. Patients and providers can receive services and support at 877-4-BENLYSTA. The companies also created a Web site for the lupus community to come together to share stories at usinlupus.com.

Drugs on the Horizon

Other pharmaceutical and biotechnology companies are moving in the same direction as HGS, in hopes that they, too, will be able to show the efficacy of their investigational lupus drugs. (See “The Research & Development Pipeline.”)

More new medications for symptoms of lupus that Benlysta isn’t designed to address could follow in as few as two to five years, according to Gilkeson.

“Benlysta isn’t the be-all and end-all, though it is important,” he says. “There are at least three other drugs in Phase 3 clinical trials that I’d put at a two- to three-year timeframe. And there are a number of other drugs a little further down the pipeline, in the five-year timeframe. That’s the exciting part; we’ll have a number of drugs that do a number of things. Benlysta is the gateway through which they can march.”

A Community Celebrates

Though she wasn’t a candidate for Benlysta because the drug is not approved for those with lupus nephritis, Williams still made the trek from her home in Georgia to Washington, DC, in November 2010 to testify in front of the FDA’s Arthritis Drugs Advisory Committee, which was holding an open meeting on the approval of Benlysta for lupus. Williams says she went because the LFA support group she leads is full of people who could benefit from the drug.

“It makes my heart hurt to think of others struggling the way I have,” Williams says. “I don’t want them to have to go through what I’ve had to go through with the side effects from current treatments.”

While, at this time, Benlysta isn’t approved for children and teens, that’s not stopping people in that part of the lupus community from celebrating, too. The overwhelming response is one of relief that the medical community hasn’t forgotten about them. “It’s long overdue,” says Elizabeth Gallagher, whose 17-year-old daughter, Aiden, has had active central nervous system lupus for seven years.

“Even though Aiden has been treated very aggressively with the treatments available, we have been unable to get her into remission or prevent lupus from affecting other vital organs. Lupus needs this attention.”

Hope for Clinical Trials

HGS’s success is giving hope to a medical community that is pleased to see Benlysta’s approval spark other companies to get involved, Manzi says. She also hopes more people with lupus will be willing to participate in clinical trials. “Getting a new drug to market is a combined effort between patients, doctors, and industry,” she says. “We don’t want to wait so long for the next success story. We have to move these new agents forward, and that’s going to take a lot
of teamwork.”

Janice Fitzgibbon, 54, admits that participating in a clinical trial was a turning point for her. Fitzgibbon, who lives in McLean, VA, and has mild lupus, remembers being ushered into the infusion area of her medical clinic and breaking down in tears. Participating in the trial was yet more proof that she really had the disease—she’d only been diagnosed the year before—but it also ultimately empowered her.

For the past two years, Fitzgibbon has been taking part in the Phase 3 clinical trial of Benlysta. In this type of drug trial, during the first year neither the researchers nor the participants know who is receiving the drug and who is receiving inactive placebo. It wasn’t until her husband pointed out that she wasn’t calling him at work at 4 in the afternoon, begging him to come home to relieve her of parenting duties for her two teenagers, that it dawned on Fitzgibbon that she wasn’t as fatigued. She started accepting dinner invitations again. She was carrying her own grocery bags. She was off prednisone, which had prompted insomnia and suicidal thoughts after a particularly large dose.

For the past year, she knows she has been receiving Benlysta. As she has made healthful strides, this self-described type-A personality has also regained some sense of control. “I felt so out of control having this disease; I couldn’t anticipate whether I’d feel better or worse,” she says. “But being part of a clinical trial was something I could do. I’d recommend it to anyone.”

For the Gallaghers, Williams, Fitzgibbon, and the entire lupus community, this is a historic year. As LFA President and CEO Sandra C. Raymond said upon hearing of Benlysta’s approval, “Today marks the beginning of a new era of improved diagnosis, prevention, and treatment for the disease.”

The Research & Development Pipeline

There are more than a dozen pharmaceutical and biotechnology companies working to develop medications to help people with lupus. Among them are UCB; Eli Lilly and Company; Cephalon, Inc.; and EMD Serono, Inc. The drugs listed below are not approved by the U.S. Food and Drug Administration for lupus.

Investigational Lupus Drugs in Phase 3 Clinical Trials

Epratuzumab – UCB

Epratuzumab, a compound being developed by UCB and licensed from Immunomedics, is a humanized monoclonal antibody targeting the CD22 receptor and is being evaluated for the treatment of moderate to severe lupus. In a Phase 2, 12-week dose-finding study in people with predominantly high or severe lupus disease activity, differences were seen in responder rates between the tested epratuzumab dose groups and the placebo group. Most individuals showed reduced symptoms or absence of active disease within specific body systems after treatment with epratuzumab, compared with those taking placebo. Larger clinical trials are the next step. For more information, go to clinicaltrials.gov and search for “NCT01262365.” For information about UCB, visit ucb.com.

Anti-BAFF Antibody (LY2127399) – Eli Lilly and Company

The anti-BAFF antibody, being developed by Eli Lilly and Company, is a human immunoglobulin G subclass 4 (IgG4) monoclonal antibody. It has full neutralizing activity against both soluble and membrane-bound B cell activating factor, known as BAFF, which has been shown to be elevated in people with lupus. LY2127399 is currently being evaluated in Phase 3 clinical trials for the treatment of lupus. For more information, go to clinicaltrials.gov and search for “NCT01196091” and “NCT01205438.” For information about Eli Lilly and Company, visit lilly.com.

Investigational Lupus Drug in Phase 2/3 Clinical Trial

Atacicept – EMD Serono, Inc.

Atacicept (ah-TAC-ee-cept) is a recombinant, fully human fusion protein that inhibits both BLyS and APRIL, two B-cell survival factors. EMD Serono is investigating the use of atacicept to treat patients with lupus (SLE) in a Phase 2/3 clinical trial. The trial’s primary outcome measure will compare the number of SLE flares in the atacicept-treated versus the placebo-treated groups during a 52-week treatment period. Additionally, EMD Serono is conducting a Phase 1b clinical trial in lupus nephritis, which is currently enrolling. For more information regarding these trials, please go to clinicaltrials.gov and search for “NCT00624338” and “NCT01369628.” For information about EMD Serono, visit emdserono.com.

Investigational Lupus Drug in Phase 2 Clinical Trial

Lupuzor (CEP-33457) – Cephalon, Inc.

Cephalon is investigating the use of Lupuzor, which is believed to act as a peptide (portion of a protein) immunomodulator targeted at altering the way specific white blood cells in the immune system respond to the body. The primary outcome measure will compare the safety and efficacy of a 200 mcg monthly injection of investigational therapy plus standard of care against placebo plus standard of care. For more information, go to clinicaltrials.gov and search for “NCT01240694.” For information about Cephalon, visit cephalon.com.

The Lewin Group Initiative

In 2009 the Lupus Foundation of America (LFA) commissioned a nine-month study by the health policy research organization The Lewin Group to address barriers to lupus drug development. The report, “Overcoming Barriers to Drug Development in Lupus,” outlines obstacles to lupus drug development and provides recommendations for overcoming them.

The LFA immediately began implementing the report’s recommendations. To date, the LFA has:

  • Launched the LFA Collective Data Analysis Initiative that compares clinical trial designs and results.
  • Developed the Lupus Foundation of America Flare Definition (LFA-Flare) that allows lupus disease flares to be integrated into the clinical trial design.
  • Initiated a comprehensive national epidemiological study of people with lupus and related syndromes.
  • Created the LFA POINT Program, an online program that trains clinical investigators on the use of disease activity measures and other tools.
  • Co-sponsored a meeting with the National Institutes of Health on moving science from the lab to the bedside.
  • Developed a Research Registry for people with lupus interested in clinical trial participation.
  • Begun working with the Food and Drug Administration, other federal -agencies, and industry leaders to plan a scientific meeting on lupus biomarkers.

To access the full report, go to lupus.org/lewin.

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