2016 and beyond


The quest for
a cure continues


+

2015


Anti-IFN-α agent
trial initiated


+

2011


Anti-IL6 agent
trial initiated


+

+


2010


Anti-CD22 agent
Phase 3
trial initiated

+


2009


First primary
endpoint met
in SLE

2009


SRI published
and endorsed
by FDA


+

2008


Anti-APRIL agent
Phase 3
trial initiated


+

2007


Anti-BLyS agent
Phase 3
trial begins


+

2005


Anti-CD20 agent
Phase 3
trial initiated


+

2005


FDA issues draft
trial guidance


+

2005


Role of BLyS in B
cells published in
medical journal


+

2004


First World
Lupus Day


+

+


2004


Interfering with
interferons

2003


First BLyS
antibodies made


+

+


1999


BLyS gets
its name

+


1999


Alliance for Lupus
Research founded

+


1996


Human genome
science discovery

Lupus: Two decades of
discovery, development
and innovation

2016 marks the 20th anniversary since the discovery of B lymphocyte stimulator (BLyS), an important milestone in lupus – more specifically Systemic Lupus Erythematosus (SLE) - understanding and research. Here we look back on the past 20 years at some of the other milestones and turning points in research that are helping to advance the development of medicines for those suffering from this debilitating disease. Lupus continues to affect an estimated 5 million people worldwide.

1996

Human genome
science discovery

Human Genome Sciences (HGS), a biopharmaceutical corporation, identify a human protein that stimulates B cell growth during sequencing of the human genome. Previously unknown to the scientific community, this discovery was made possible thanks to technological advances in automated DNA sequencing combined with a vision for creating new medicines from the millions of gene fragments that emerged. Little did people know that this discovery would mark the start of the biggest step forward in lupus research and treatment for decades.

Stohl W, Hilbert DM. The discovery and development of belimumab:
the anti-BlyS-lupus connection. Nat Biotechnol. 2012;30:69-77.

1999

Alliance for Lupus
Research founded

Until 1999, very little attention was paid to lupus research and financial support was lacking. This prompted Robert Wood Johnson IV - whose daughter had recently been diagnosed with the disease – to host a summit of lupus experts to discuss what could be achieved with more funding. The summit revealed major scientific opportunities for progress in lupus, leading to the formation of The Alliance for Lupus Research (ALR). Since its founding, ALR has given more money to lupus research than any non-governmental agency in the world.

Alliance for Lupus Research. Mission statement. Available at:
http://www.lupusresearch.org/about-us/mission-statement.html. Last accessed April 2016.

Alliance for Lupus Research. FAQs about Alliance for Lupus Research. Available at:
http://www.lupusresearch.org/about-us/faq.html. Last accessed April 2016.

1999

BLyS gets its name

Three years on from its discovery in 1996, Human Genome Sciences (HGS) published a paper that officially named their new protein, B lymphocyte stimulator, BLyS, also known as B cell activating factor, BAFF - based on its activating effect on B cells. As the importance of BLyS in B cell development and regulation unfolded, HGS partnered with Cambridge Antibody Technology to explore monoclonal antibodies that could block the activity of BLyS as potential therapies for diseases linked to abnormal B cell activity, such as lupus.

Stohl W, Hilbert DM. The discovery and development of belimumab:
the anti-BlyS-lupus connection. Nat Biotechnol. 2012;30:69-77.

2003

First BLyS
antibodies made

Within four years, in 2003, Cambridge Antibody Technology researchers reported that they had discovered an array of over 1000 distinct antibodies, half of which prevented binding of BLyS to its receptor. Later that year, one of these antibodies was isolated and characterised. It was named LymphoStat-B, now known as belimumab.

Edwards BM, Barash SC, Main SH, et al. The remarkable flexibility of the human antibody repertoire; isolation of over one thousand different antibodies to a single protein, BLyS. J Mol Biol. 2003;334:103-18.

Baker KP, Edwards BM, Main SH, et al. Generation and characterization of LymphoStat-B, a human monoclonal
antibody that antagonizes the bioactivities of B lymphocyte stimulator. Arthritis Rheum. 2003;48:3253-65.

2004

Interfering with interferons

In New York, another lupus discovery was unveiled. Rheumatologist Dr Mary Crow, current Physician-in-Chief and Chair of the Department of Medicine at Hospital for Special Surgery in New York, showed that genes regulated by interferon (a type of protein) are potential biomarkers for lupus flares. Dr Crow’s findings encouraged research into blocking interferon pathways as a possible treatment approach, still ongoing in trials today.

Lupus Research Institute. Innovation. Available at:
http://www.lupusresearchinstitute.org/driving-discovery/innovation. Last accessed April 2016.

2004

First World Lupus Day

As research into potential treatment pathways in lupus continued, an initiative for greater lupus recognition was born. An international committee representing lupus organisations from 13 nations met in the United Kingdom to organise the first observance of World Lupus Day. They issued a rallying call aimed at governments around the world to increase financial support for lupus research, awareness and patient services. World Lupus Day now takes place annually on 10 May.

World Lupus Day. About Us. Available at
http://www.worldlupusday.org/about-us. Last accessed May 2016.

2005

Role of BLyS in B cells
published in medical journal

In the relatively short period of time since its initial discovery, the role of BLyS in B cell differentiation, survival and activation was published in 2005. BLyS and its family of receptors became established players in B lymphocyte biology, with growing evidence about their roles in the selection, differentiation, and regulation of B cells.

Cancro MP. The BLyS/BAFF family of ligands and receptors: key targets in the therapy and understanding of autoimmunity. Ann Rheum Dis. 2006;65(Suppl.3):iii34-6.

Crowley JE, Treml LS, Stadanlick JE, Carpenter E, Cancro MP. Homeostatic niche specification among naïve and activated B cells: a growing role for the BLyS family of receptors and ligands. Semin. Immunol. 2005;17:193-9.

2005

FDA issues draft trial guidance

Despite the discovery of novel therapeutic targets, researchers faced major obstacles in developing treatments for lupus. The complexity of the disease and its varying effects on multiple organ systems created a lack of consensus on clinical trial design and endpoints. In 2005, following hearings with several hundred interested parties, the U.S. Food and Drug Administration drafted the first common guidance for lupus trial design, accelerating the development and implementation of trials to test new biologic therapies. The draft guidance was finalised five years later in 2010.

FDA. Guidance for industry: systemic lupus erythematosus — developing drugs for treatment. Draft guidance, March 2005. Available at: http://www.fda.gov/ohrms/dockets/98fr/2005d-0106-gdl0001.pdf. Last accessed April 2016.

Wallace DJ. The evolution of drug discovery in systemic lupus erythematosus.
Nat Rev Rheumatol. 2015;11:616-20.

2005

Anti-CD20 agent
Phase 3 trial initiated

Another B cell–directed therapy being evaluated for SLE during this time was an anti-CD20 agent, following successful rheumatoid arthritis trials. CD20 is a specific protein on the surface of B cells that appears early in the development of B lymphocytes (white blood cells), and helps the B cell immune response. The first Phase 3 trial in SLE began in 2006 sponsored by Genentech and although randomised controlled trials have yet to establish its benefit in the disease, research continues.

ClinicalTrials.gov. A study to evaluate the safety of rituximab retreatment in subjects with systemic lupus erythematosus (EXPLORER). Available at: https://clinicaltrials.gov/ct2/show/NCT00137969. Last accessed April 2016.

Stohl W, Hilbert DM. The discovery and development of belimumab: the anti-BlyS-lupus connection. Nat Biotechnol. 2012;30:69-77.

Postal M, Costallat LT, Appenzeller S. Biological therapy in systemic lupus erythematosus. Int J Rheumatol. 2012;2012:578641.

Lupus Foundation of America. What treatments are being studied for lupus? Available at: http://www.lupus.org/answers/entry/what-treatments-are-being-studied-for-lupus. Last accessed April 2016.

2007

Anti-BLyS agent
Phase 3 trial begins

Based on the findings of BLyS observational trials, Human Genome Sciences initiated a global international trial programme to investigate the first anti-BLyS agent, involving almost 1700 patients at 220 sites in 31 countries – the largest clinical trial of its kind in history.

Benlysta Summary of product characteristics, March 2016.

Stohl W, Hilbert DM. The discovery and development of belimumab: the anti-BlyS-lupus connection. Nat Biotechnol. 2012;30:69-77.

Navarra SV, Guzmán RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377:721-31.

Furie R, Petri M, Zamani O, et al. A Phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 2011;63:3918-30.

2008

Anti-APRIL agent
Phase 3 trial initiated

Also in 2008, the Merck Group began testing another new compound in Phase 2/3 trials for SLE. This agent blocks both BLyS and a related protein involved in the B cell immune response, called APRIL. Phase 3 trials of anti-BLyS-APRIL continue today.

ClinicalTrials.gov. Atacicept phase 2/3 in generalized systemic lupus erythematosus (APRIL-SLE). Available at: https://clinicaltrials.gov/show/NCT00624338. Last accessed April 2016.

Stohl W, Hilbert DM. The discovery and development of belimumab: the anti-BlyS-lupus connection. Nat Biotechnol. 2012;30:69-77.

2009

SRI published and
endorsed by FDA

In 2009, a new measurement for SLE disease activity - SRI (Systemic Lupus Erythematosus Responder Index) - was published. Due to its complex nature, SLE had until this point lacked a reliable and sensitive gold standard for measuring disease activity which had hampered drug development efforts. SRI is a composite endpoint measure assessing reduction in disease activity, defined as clinical improvement (SELENA-SLEDAI) with no significant worsening in any organ system (BILAG) and no worsening in overall patient condition (PGA).

Wallace DJ. The evolution of drug discovery in systemic lupus erythematosus. Nat Rev Rheumatol. 2015;11:616-20.

Thanou A, Chakravarty E, James JA, Merrill JT. Which outcome measures in SLE clinical trials best reflect medical judgment? Lupus Sci Med. 2014;1:e000005.

2009

First primary endpoint
met in SLE

In 2009, for the first time ever, a randomised controlled Phase 3 trial for an SLE treatment met its primary endpoint, setting the stage for a more hopeful future for SLE research and treatment.

Stohl W, Hilbert DM. The discovery and development of belimumab: the anti-BlyS-lupus connection. Nat Biotechnol. 2012;30:69-77.

PR Newswire. Human Genome Sciences and GlaxoSmithKline announce positive phase 3 study results for BENLYSTA™ in systemic lupus erythematosus. Press release 20 July 2009. Available at: http://www.prnewswire.com/news-releases/human-genome-sciences-and-glaxosmithkline-announce-positive-phase-3-study-results-for-benlystatm-in-systemic-lupus-erythematosus-62224887.html. Last accessed April 2016.

2010

Anti-CD22 agent
Phase 3 trial initiated

In 2010, a trial investigating the first anti-CD22 agent in SLE began, sponsored by UCB. CD22 is a protein found on the surface of mature B cells, and some immature B cells, which regulates the immune system and prevents overactivation of B cell signaling.

ClinicalTrials.gov. Study of Epratuzumab versus placebo in subjects with moderate to severe general systemic lupus erythematosus (EMBODY 1). Available at: https://clinicaltrials.gov/ct2/show/NCT01262365. Last accessed April 2016.

Hatta Y, Tsuchiya N, Matsushita M, et al. Identification of the gene variations in human CD22. Immunogenetics. 1999;49:280-6.

2011

Anti-IL6 agent
trial initiated

Interleukins were the focus of a Phase 2 SLE trial initiated by Pfizer in December 2011, with an investigational anti-IL6 agent. IL-6 is a protein involved in regulating inflammation and immune responses, and is found at abnormally high levels in the blood of lupus patients. Research into IL-6 as a therapeutic target in SLE continues.

ClinicalTrials.gov. Subcutaneous treatment in randomized subjects to evaluate safety and efficacy in generalized lupus erythematosus (BUTTERFLY). Available at: https://clinicaltrials.gov/ct2/show/NCT01405196. Last accessed April 2016.

Lupus Research Institute. Promising results of lupus clinical trials presented at American College of Rheumatology meeting. Available at: http://lupusresearchinstitute.org/lupus-news/2014/11/21/promising-results-lupus-clinical-trials-presented-american-college#sthash.8oygxxcl.dpuf. Last accessed April 2016.

2015

Anti-IFN-α agent trial initiated

In 2015, a new monoclonal antibody targeting the type I interferon (IFN) receptor was progressed into Phase 3 trials by AstraZeneca. IFN-α levels are increased in SLE patients and have been shown to correlate with disease activity and kidney damage.

ClinicalTrials.gov. Efficacy and safety of anifrolumab compared to placebo in adult subjects with active systemic lupus erythematosus. Available at: https://clinicaltrials.gov/ct2/show/NCT02446899. Last accessed April 2016.

Postal M, Costallat LT, Appenzeller S. Biological therapy in systemic lupus erythematosus. Int J Rheumatol. 2012;2012:578641.

2016

The quest for a cure continues

The complexity of lupus as a disease and the difficulty of bringing new treatments to patients is demonstrated by the number of promising late-stage compounds that have failed thus far. More than 15 biological therapies have been studied since the discovery of BLyS, targeting several pathways involved in SLE pathogenesis. Although only one agent has successfully completed its Phase 3 studies so far, the insights gained during the past two decades are bringing the lupus community closer to the development of more innovative new therapies to help improve the lives of lupus patients around the world. We have come a long way since 1996.

Wallace DJ. The evolution of drug discovery in systemic lupus erythematosus.
Nat Rev Rheumatol. 2015;11:616-20.

SPEC/BEL/0039/16 – Date of preparation May 2016

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