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Landmark lupus approval opens door for next wave of drugs

The US FDA approval of belimumab, the first new lupus drug in 50years, highlights how genomics can contribute to drug discovery and shows that long-standing hurdles in trial design can be overcome.
The US approval of Human Genome Sciences (HGS) and GlaxoSmithKlines belimumab (Benlysta) on 9March ended a 50year drought in the introduction of new lupus drugs. The two firms have blazed a path from mRNA to medicine in 15years, and analysts are now predicting peak US sales of over US$2billion annually for the monoclonal antibody (mAb). Nevertheless, the journey from the pioneering genomicsbased discovery of belimumab to market is only the beginning in establishing the therapys full potential in systemic lupus erythematosus (SLE). This approval is an impressive drug development success, but it will take time to assess the extent of its clinical impact, says David Wofsy, Professor of Medicine at The University of California, San Francisco, USA. During an advisory panel meeting ahead of the positive US Food and Drug Administration (FDA) decision, independent experts argued that belimumabs efficacy was mild. In African Americans, in which the incidence of SLE is particularly high, the drugs efficacy remainsunclear. Moreover, despite the excitement over the landmark approval, the community still faces a lack of treatment options for this complex autoimmune disease. Hopes are high that HGSs approach will ease the way for a pipeline replete with the next wave of SLE drugs (TABLE 1), because it shows that longstanding problems in clinical trial design can be overcome. Yet everyone remains keenly aware that belimumabs route to the market will serve as a rough guide at best. Its a good first step. But thats what it is a first step, says Wofsy.
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he adds. They didnt spend the time to develop the proper assays and work through the biology. Over the next few years, while exploring BLYS and its inhibition in various disease models, the company built up a case for clinical development in SLE. Mouse models of SLE had BLYS levels tenfold above normal. Conversely, inhibition of BLYS reduced disease symptoms and improved survival in the same models. Finally, BLYS levels in 250 patients with SLE changed over time as disease activity waxed and waned2. Clinical development with belimumabbegan in 2002. Trailblazing trial design Belimumabs development hit a major holdup in its Phase II SLE trial, however, when it failed to meet the coprimary efficacy end points of improvement in the SELENASLEDAI score (which measures 24 symptoms and signs of disease activity) at week 24 and time to first flare. Investors fled while the company dug into their data for glimmers of hope. A few crucial findings saved the programme. One key realization, says Bill Freimuth, the Vice President of Clinical Research at HGS, was that 24weeks was too soon to see a significant effect. They also found that only 72% of the subjects in the trial actually had serological disease, as assessed by antiself antibody levels. A third critical step, he says, was the creation of a new endpoint. Weve recognized in the past few years that a single disease activity instrument may not be sufficient to tell you whether a patient has improved and not gotten worse, because lupus is such a multisystem disease, says Ian Bruce, Professor of Rheumatology at Manchester University, UK. HGS and its outside experts therefore decided to combine several instruments into a composite end point: the SLE responder index (SRI). They chose the SELENASLEDAI score to assess improvement, because it can only register a positive change if a sign or symptom resolves entirely and therefore provides an unambiguous index. They turned to the BILAG which was developed so that clinicians could gauge when to switch a patients drugs to assess worsening, because it registers partial improvements over 88 disease items. They also incorporated the Physicians Global Assessment visual analogue scale to measure each patients overall condition. When HGS reanalysed their Phase II data retrospectively, assessing only the subgroup of serologically active patients and using the new SRI end point, they found that 46% of patients improved with belimumab compared with 29% of patients on placebo3. GlaxoSmithKline subsequently decided to exercise a longstanding option to back further development of belimumab, and Phase III trialsbegan4. They really learned from their experiences, says David Pisetsky, Chief of Rheumatology at the Durham VA Hospital, North Carolina, USA. Others in the lupus field seem to have taken the lessons on board as well. The use of a composite end point, for instance, is widely accepted as the way forward. Pisetsky notes, however, that its specifics may still change. We are now in a phase of evolution the field will still have to decide what is the most reasonable composite to assess the disease. Investigators may opt for more sensitive instruments or for those that can better examine particular manifestations of disease. UCB is already experimenting, using a composite end point in which the roles of the BILAG and SLEDAISELENA tools are reversed, in a Phase III trial of its SLE candidate epratuzumab.

Human Genome Sciences headquarters in Maryland, USA: where the magic happened. Image courtesy of National Oceanic and Atmospheric Administration/Department of Commerce.

Genomics in action HGS was founded in the early 1990s, amid early excitement about the power and potential of genomics. At a time when many have argued that the medical value of genomics has been slow to deliver, belimumab represents a proof of principle. One of the fledgling biotechs first challenges was to find a way to make sense of the earliest deluge of sequence data. We had a system to our madness, says David Hilbert, the former Vice President of research and development (R&D) at HGS and the current Vice President of R&D at the biotech Zyngenia. HGS focused on mRNA (thereby studying only expressed genes, rather than the whole genome), selectively studied genes that encoded secreted proteins (as assessed by the mRNAs leader sequence) and used expression profiles to hone in on genes that were specifically upregulated in organs or systems of interest. In 1996, they hit upon a gene that was structurally homologous to tumour necrosis factor (TNF), a key proinflammatory cytokine. Hilbert and colleagues went to work on the genes product, and found that it induced B cell proliferation1. They named the gene, and its resultant protein, accordingly: B lymphocyte stimulator (BLYS; now officially known as TNFSF13B). Belimumab, a human mAb that binds to BLYS and thereby prevents it from activating various receptors and slows B cell proliferation, was subsequentlyborn. Looking back over the early days of the programme, Hilbert points to a critical feature of the teams success: assay development. Because the team did not know a priori what kind of activity their proteins would have, their assays had to act as wide nets that would be extremely sensitive to even weak activities, he says. I think thats where most people fell off the train with genomics drug discovery,
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This approval is an impressive drug development success, but it will take time to assess the extent of its clinical impact.
Wofsy offers a cautionary note on the composite end points. Im in the minority view, but I dont think that broad indices accurately reflect the biology of the disease, he says. Instead, he argues that more specific tools are needed to measure improvement in different subsets of patients with this complex disease. For lupus nephritis a manifestation of SLE that affects the kidney and that is not included on the belimumab label he points out that the primary end point will always have to focus on the resolution of renal disease. From his perspective, HGSs success with belimumab came down to a different aspect of the design: The main reason their Phase III trials succeeded, whereas the Phase II trial failed, is sample size, he says. Both Phase III trials of the drug enrolled over 800 patients, making them the then biggest ever SLEtrials. John Stone, Director of Clinical Rheumatology at Massachusetts General Hospital, USA, points to the importance of limiting background therapies. In previous SLE programmes, the high doses of steroids that were allowed ran the risk of masking the treatment effects of the new agent, he
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explains. In the Phase III trials of belimumab, by contrast, patient enrolment was limited to those on low levels of prednisone, and dose escalation was strictly controlled towards the end of the trial. This feature, he says, allowed the effects of the treatment agent to really shine through. The lupus community has gotten smarter in how it designs trials. I hope it continues to limit patient access to steroids towards the end of trials. As different companies explore their options, a more robust strategy for clinical SLE trials will emerge. Even Freimuth cautions against following HGSs approach too closely. Theres no golden formula for success, he says. You have to evaluate the approach for each drugs relative mechanism of action, patient population and safety issues. A pipeline of immunosuppressants With at least 20 other drugs in the pipeline, the SLE community will have lots of opportunity to optimize its approach. Some companies are hoping to improve on the antiBLYS approach. Whereas belimumab only blocks soluble BLYS, Eli Lillys mAb LY2127399 also blocks membranebound BLYS and is in Phase III trials that are due to report results in 2013. Merck KGaA, meanwhile has used a fusion protein approach with its Phase II/III SLE candidate atacicept, which combines immunoglobulin with a segment of the TNF receptor superfamily member TACI. Because TACI binds both BLYS and the related TNF superfamily cytokine APRIL, it promises an advantage over belimumab. Both LY2127399 and atacicept are probably more potent than BLYS, says Dan Wallace, Clinical Professor of Medicine in the Division of Rheumatology at CedarsSinai Medical Center, California, USA, and a clinical investigator of drugs including atacicept and epratuzumab. However, they may also be associated with more infections and toxicities we dont know yet. Another strategy that has long been investigated is Bcell depleting therapies. Table 1 | Phase IIII pipeline for systemic lupus erythematosus
Drug name
Mycophenolate mofetil Epratuzumab LY2127399 Atacicept Abatacept A-623 Forigerimod Sifalimumab Rontalizumab Belimumab (subcutaneous) Laquinimod IFN Kinoid CC-11050 CNTO 136 AMG 557 AMG 811 SBI-087 BT-063 CC-930 CDP7657 AGS-009

Lead company
Roche UCB Eli Lilly and Company Merck KGaA Bristol-Myers Squibb Anthera Pharmaceuticals Cephalon AstraZeneca Roche Human Genome Sciences Teva Pharmaceutical Neovacs Celgene Johnson & Johnson Amgen Amgen Pfizer Biotest Celgene UCB Argos Therapeutics

Phase
III III III II/III II/III IIb IIb II II II II I/II I I I I I I I I I

Target
IMPDH1 B cell receptor CD22 BLYS APRIL and BLYS T-lymphocyte activation antigens CD80 and CD86 BLYS T lymphocytes IFN IFN BLYS T lymphocytes IFN receptors PDE4 and TNF Interleukin-6 ICOSLG IFN B lymphocyte antigen CD20 Unspecified JNK CD40LG IFN

APRIL, a proliferation-inducing ligand (also known as TNFSF13); BLYS, B lymphocyte stimulator (also known as TNFSF13B); CD40LG, CD40 ligand (also known as gp39); ICOSLG, inducible T cell co-stimulator ligand (also known as B7RP1); IFN, interferon; IMPDH1, inosine-5-monophosphate dehydrogenase 1; JNK, Jun N-terminal kinase; PDE4, phosphodiesterase 4; TNF, tumour necrosis factor-.

Theres no golden formula for success. You have to evaluate the approach for each drugs relative mechanism of action, patient population and safety issues.

By lowering the number of circulating B cells, the theory is that these agents should reduce the inflammatory consequences of disease. Biogen Idec/Genentechs CD20targeting rituximab, which is already approved for the treatment of Bcell lymphomas and rheumatoid arthritis, is the exemplar of the approach. Yet despite several clinical trials of the drug in SLE and regular offlabel use, conclusive evidence of its efficacy has remained elusive. UCBs Phase III candidate mAb epratuzumab which targets CD22 on the surface of B cells is the leading variation of this approach. But, points out Wallace, there are still some questions about how it works. B cell levels only drop 30% with epratuzumab compared with 90% with rituximab, so that cant be its only mechanism of action, he says. Pivotal results for epratuzumab are due in2014. BristolMyers Squibb, meanwhile, is leading the field in the development of an agent that modulates costimulatory interactions between T cells and antigen presenting cells (APCs) involved in lymphocyte activation. The firms fusion

protein, which combines cytotoxic Tlymphocyteassociated protein 4 (CTLA4) and human immunoglobulin G, is currently in Phase II/III development. CTLA4 competes with CD28 on the surface of T cells for APCexpressed CD80 and CD86, thereby blocking T cell activation and the subsequent downstream production of inflammatory cytokines. A bit deeper down in the pipeline, several companies are also pursuing inhibitors of the interferon pathway. Lupus has been recognized in the past few years as having an interferon signature that is rather unique among inflammatory diseases, explains Stone. Im very excited about these they may be relatively specific for lupus, at least in theory. In the wake of the recent success with belimumab, optimism runs high, despite the many hurdles ahead. We have a wave of good ideas. While many of these will fail, the wave will hit, saysWofsy.
1. Moore, P. A. et al. Science 285, 260263 (1999). 2. Zhang, J. et al. J.Immunol. 166, 610 (2001). 3. Furie, R. A. et al. Arthritis Rheum. 61, 11431151 (2009). 4. Navarra, S. et al. Lancet 377, 721731 (2011).

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