Lupus Foundation puzzled by negative reaction to Aurinia data

 Sandra C. Raymond

 Sandra C. Raymond

As president and CEO of The Lupus Foundation of America (LFA), a role she has held for 15 years, Sandra Raymond is an outspoken advocate for the plight of lupus patients. She has worked with the board of directors and the lupus research community to bring national attention and resources to lupus research and education. Ms. Raymond came to the LFA after serving as the founding CEO of the National Osteoporosis Foundation, beginning in 1986. She envisions great progress in lupus treatment and care over the next 10 years but recognizes the urgent need to elevate lupus on the national healthcare agenda by increasing federal and private investment in research on lupus and developing constructive public policies aimed at bringing support and services to all people affected by lupus. In this interview with BioTuesdays.com, Ms. Raymond discusses the state of the disease and results of a recent clinical study by Aurinia Pharmaceuticals (NASDAQ:AUPH; TSX:AUP).

Let’s begin with a brief description of lupus.

Lupus is a lifelong autoimmune disease that can impact any part of the body. The immune system attacks the body's own healthy tissues, leading to inflammation and organ damage. This prototypical autoimmune disease affects millions of people worldwide and causes a wide range of serious and life-threatening consequences that are challenging to bring under control because of a lack of adequate treatments. Symptoms of lupus include joint damage, skin rashes, extreme fatigue and hair loss. The disease can affect the kidneys, lungs, cardiovascular system, the brain and other vital organs. While symptoms may be mild, moderate or severe, lupus may be life-diminishing. Patients may go into remission but live with the fear of disease flares, which can occur and reoccur over their lifetimes. While there is no cure, pioneering physicians have developed treatment regimens that have greatly reduced mortality over the past few decades.

Do we know what causes lupus?

Scientists believe that genetics, hormonal factors and environmental triggers cause an imbalance in the immune system. In lupus, the immune system goes into hyper-drive and fails to distinguish the difference between viruses and bacteria and healthy normal organs and tissues.  Environmental triggers are not well understood, but research has identified several of these, including sun exposure. The sun can trigger skin rashes as well as full-blown lupus flares. An early sign of lupus may be a malar or butterfly-shaped rash across the cheeks and bridge of the nose. It is important to note that up to 15% of people who get skin rashes develop systemic disease affecting one or more organ systems. In lupus, there is a significant impact on the quality of life for those affected.

How prevalent is the disease?

The Lupus Foundation of America estimates that 1.5 million Americans and five million individuals around the world have lupus. Other U.S. estimates place the number affected from 500,000 to one million. While mortality due to lupus has been greatly reduced over the past 50 years, deaths from lupus occur daily around the world. Mortality statistics are not readily available because lupus deaths are usually related to the consequences of lupus, including end-stage renal disease, cardiovascular disease and infections. Death certificates rarely list the root cause of death as lupus. Every day at the LFA, we receive memorial donations in memory of a family member who has died after struggling with lupus.

Lupus is a lifelong autoimmune disease that can impact any part of the body. The immune system attacks the body's own healthy tissues, leading to inflammation and organ damage.

Lupus is a lifelong autoimmune disease that can impact any part of the body. The immune system attacks the body's own healthy tissues, leading to inflammation and organ damage.

How is lupus treated and do the treatments work?

Over the years, pioneering physicians have developed regimens that have greatly helped bring lupus under control. Most of these therapies are borrowed from other diseases and were never tested as treatments for lupus. Steroids and chemotherapies are used to suppress symptoms of lupus. Only one therapy, Benlysta, has been approved for the treatment of some forms of lupus, including joint problems and mouth sores. Benlysta was approved in 2011 after a more than 50-year drought. But one drug will never help all people affected by lupus. An arsenal of treatments is needed.

Steroids are widely used because they suppress a hyperactive immune system. But steroids can cause side effects that include osteoporosis, bone fractures, hair loss, weight gain and insomnia, diabetes and more. With chemotherapies, there are risks of infertility, blood and nervous system disorders, to name a few. Breast cancer patients, for example, only endure a couple courses of chemotherapy and then they’re done. But a lupus kidney disease patient could be on chemo for years. And while steroids and chemotherapy can result in disease remission for a period of time, some unknown trigger can cause disease flares often in a completely different organ system.

What’s the state of lupus research?

There are at least 30 companies investing hundreds of millions of dollars to develop new medications for lupus. It is unlikely that one drug will be sufficient since I believe lupus is a spectrum of diseases that will require a variety of treatments. But bringing lupus under control and stopping organ and tissue damage while we search for cures are our immediate goals.

What was your reaction to Aurinia’s Phase 2b trial results?

the Lupus Foundation of America is very hopeful that Aurinia’s voclosporin will be added to the arsenal of treatments available to people who have waited far too long for medicines that improve the quality of their lives

the Lupus Foundation of America is very hopeful that Aurinia’s voclosporin will be added to the arsenal of treatments available to people who have waited far too long for medicines that improve the quality of their lives

I was very excited because this was the first ever study for a medication to treat active lupus-related kidney disease, or lupus nephritis, that successfully reached its primary endpoint of demonstrating greater complete and partial remission in the presence of forced steroid taper. Lupus nephritis is one of the most serious and potentially life-threatening complications of this autoimmune disease, affecting as many as 60% of people with lupus. We are looking forward to Aurinia beginning a Phase 3 trial and we’re very hopeful that Aurinia’s voclosporin will be added to the arsenal of treatments available to people who have waited far too long for medicines that improve the quality of their lives. Frankly, I was shocked at the negative reaction of some investors who focused on the number of deaths associated with the trial. Had they looked at the scientific literature, they would have found that there were deaths in Bristol Myers-Squibb’s trial of Abatacept to treat lupus nephritis. Had they looked at the original trial of mycophenolate mofetil, which is the current standard of care in lupus nephritis, they would have found there were deaths, largely in Asia. On the other hand, Aurinia’s trial was the first ever to achieve a statistically significant primary endpoint in active lupus nephritis.

[Editor’s Note: Aurinia said in its statement on August 15 that there were 265 patients enrolled in the Phase 2b study and the overall pattern of adverse events and serious adverse events was consistent with that observed in other lupus nephritis studies. There were 13 deaths across the trial: two in the high-dose voclosporin arm, 10 in the low-dose voclosporin arm and one in the control arm, with 11 of the 13 deaths occurring in Asia. All deaths were assessed by the investigator as being unrelated to treatment in the study treatment and no dose relationship was observed for the deaths. Based on the results of the 24-week analysis, Aurinia plans to meet with the FDA in the fourth quarter this year to discuss the trial data and voclosporin’s subsequent clinical development and path to registration in lupus nephritis. Further analyses of the data are being conducted and will be released later this year. The study will continue through 48 weeks, and these data will be available for release in early 2017. Shares of Aurinia dropped 56% to $1.81 when the company released the trial results on August 15. The stock closed at $2.05 on Friday.]

What do you say to Aurinia’s doubters?

Aurinia’s positive top-line results should have been viewed by all as a big win for this medically underserved disease. Amazingly, the articles focusing on deaths failed to recognize that the trial was conducted among a group of already very seriously ill patients who had very few options. The history of this disease was overlooked, even diminished, when the results of a successful trial were misinterpreted. The truth is people around the world are dying every day from the complications of lupus.

[Editor’s Note: Many analysts remain upbeat on the company’s prospects. Joseph Schwartz of Leerink said he gained some important perspective on the death rate patterns in the AURA-LV trial from speaking with management after a conference call, “which makes us incrementally more comfortable that the FDA will view the risk/benefit of voclosporin favorably.” Ed Arce of H.C. Wainwright agreed. On the whole, while results from AURA-LV carried some noisy data and unexplained imbalances, after further analysis, “we have grown confident that voclosporin has the potential to be combined with CellCept as the new standard of care for the treatment of active lupus nephritis. This belief results from our more nuanced view that the results of AURA-LV, if confirmed or perhaps even improved upon in a Phase 3 trial, tips the scales of overall risk-benefit, which has long been the ultimate arbiter of approvability for the FDA.”]

The LFA has been leading the fight against lupus in a myriad of ways including major research initiatives, national and international awareness campaigns, fostered national legislation and much more

The LFA has been leading the fight against lupus in a myriad of ways including major research initiatives, national and international awareness campaigns, fostered national legislation and much more

What’s next for the foundation?

The LFA has been leading the fight against lupus in a myriad of ways. The organization has launched major research initiatives, national and international awareness campaigns, fostered national legislation, stimulated $100-million for research and education programs, build a national network of chapters and regional offices offering service at the local level and provides daily support for patients, their caregivers and families through a network of health educators.

Pillars in the lupus field that must be built include the need for accurate statistics on the incidence and prevalence of lupus and its associated rate of mortality. To understand the biology of the disease and firmly establish targets for new medications, we must have a much more robust lupus research effort at the NIH and in the private sector. Moreover, the FDA, working with key lupus experts, must figure out better ways to design clinical trials so they can be shorter, smaller and less expensive. One project now underway addresses the need for new but simplified endpoints in clinical trials. The foundation has developed a simplified disease activity instrument, or questionnaire, which will be tested in an upcoming Phase 2 drug study conducted by a global biopharmaceutical company. The Lupus Foundation of America stands ready to launch a global movement to achieve these goals.

[Subsequend Editor’s Note: On September 30, 2016, Aurinia announced that, in addition to voclosporin achieving its primary endpoint of Complete Remission at 24 weeks, both doses of voclosporin when added to the current standard of care of Mycophenolate Mofetil and a forced oral corticosteroid taper have met all 24-week pre-specified secondary endpoints vs the control group. These pre-specified endpoints include: Partial Remission, which is measured by a ≥50% reduction in UPCR with no concomitant use of rescue medication; time to CR and PR; reduction in Systemic Lupus Erythematosus Disease Activity Index or SLEDAI score; and reduction in UPCR over the 24-week treatment period.   Commenting on the results, Dr. William Pendergraft, a principal investigator in the study, said voclosporin has demonstrated it can nearly double the number of patients that achieve complete remission in the presence of very low corticosteroid exposure.  “Based on these data, I believe this drug has the potential to significantly improve the long-term prognosis of my patients afflicted with LN and could become an integral component of the standard of care," he added.]