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European Biopharmaceutical Review

The Chameleon Uncovered

Jacoba van der Gaag and Clare Davies at Datamonitor examine the challenges facing drug development for systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a highly heterogeneous, chronic, autoimmune disease characterised by multisystem organ involvement and a broad range of symptoms. Diagnosis is therefore a complex task, and it can often be misdiagnosed, giving it the nickname ‘the chameleon disease’.

Estimating the patient population is difficult due to the limited number of robust epidemiological studies available. The Lupus Foundation of America estimates that there are approximately 1.5 million people living with lupus in the US alone (1). However, peer-reviewed epidemiological studies suggest a much more conservative prevalence and Datamonitor estimate that there are approximately 250,000 confirmed patients in the US (2).

Although the SLE prevalent population is less than that of other autoimmune diseases, many of which are currently experiencing significant attention from the pharmaceutical industry, at approximately half the population of the multiple sclerosis market, SLE has the potential for strong sales (see Figure 1). When coupled with the significant unmet needs, this is a market with substantial commercial potential. While the corresponding current SLE market size is also comparatively smaller, it is set to increase as targeted therapies reach the market.

Current treatment frequently includes steroids and anti-malarials, including prednisone and hydroxychloroquine, which are among the very few molecules to have been officially approved. There have been no new treatments approved for any form of lupus in five decades, so there is widespread use of off-label drugs, particularly immunosuppressants. While current treatment options are considered generally effective, their significant side effects present one of the greatest unmet needs in SLE.

The improvement in the safety of treatment lies in targeted therapies. This approach is a theoretically attractive way to correct the over-activity of the immune system seen with SLE, without suppressing the entire system. There is ample evidence that specifically targeting B-cells may be an effective treatment option.

Significant challenges persist in research and development (R&D), resulting in continued unmet needs in current SLE treatment options. These challenges span across both clinical and commercial aspects, and must be both acknowledged and addressed before any progress can be made. The growing collection of once-promising drugs dropping out of development has led to significant scepticism; however, recent pipeline progress has reignited interest in the disease and suggests that a change may be on the horizon.

CLINICAL CHALLENGES

The heterogeneity of SLE creates a clinical challenge for both physicians and drug developers. The flaring nature of the disease also makes the R&D process more complicated, as it can be difficult to distinguish between the impact of a therapy in a clinical trial and a natural period of non-flare.

Additionally, with a lack of regulatory guidance for clinical development, challenges and uncertainty surrounding clinical trial design contribute to the ongoing wait for new treatment options, holding back once-promising drug candidates from reaching the market. The FDA published draft guidance in March 2005 and, as of 2010, the guidelines have yet to be published in full (3). The draft document makes it clear that the recommendations are nonbinding. However, even if the guidelines are followed precisely, the FDA can still ask for further clinical trial data.

In 2009, the European Medicines Agency (EMA) published a concept paper on the need for guidelines on the clinical investigation of medicinal products intended for the treatment of systemic and cutaneous lupus erythematosus. The agency noted the importance of clearly describing acceptable study endpoints to facilitate drug development, and the draft guidance is expected to be released for consultation in the third or fourth quarter of 2010 (4). This will help to facilitate clinical trial design, although the ongoing wait for formal regulatory guidance creates the need for companies to consult with regulatory agencies throughout the development process.

The serious nature of SLE requires that the standard of care is continued during clinical trials, meaning that immunosuppressants and steroids are generally included in both the placebo and treatment arms. As a result, new drug candidates need to show superiority, or at least a steroid-sparing effect. It can be difficult to isolate the efficacy and side effects of the drug candidate over that of the steroid or immunosuppressant in clinical trials.

Rituximab is a cautionary tale in the ongoing battle between sponsors and regulators to reach the market. Branded as Rituxan in the US and MabThera in the EU, rituximab is a chimeric monoclonal antibody (MAb) targeting CD20. It is marketed by biotech and the Big Pharma powerhouses of Biogen Idec, Genentech and Roche, for the treatment of a number of Bcell non-Hodgkin’s lymphomas as well as for rheumatoid arthritis. It reached Phase III development for lupus and has gained some popularity among rheumatologists, particularly for off-label use in patients with severe manifestations of lupus, who fail to respond to alternatives. However, once expected to be the first drug to launch for SLE in recent history, rituximab failed to meet the primary, and most secondary, endpoints in the EXPLORER trial for SLE and the LUNAR trial for lupus nephritis, and is no longer expected to gain regulatory approval (5,6). With widespread physician support and anecdotal evidence suggesting impressive efficacy, the failed EXPLORER and LUNAR trials are largely attributed to the inclusion of standards of care in clinical trial design, and in particular the concurrent use of steroids.

Mycophenolate mofetil (CellCept; Roche/ Vifor Pharma), an oral transplant rejection drug, also boasts a strong physician backing. According to Datamonitor primary research, it is used to treat approximately half of all patients with lupus nephritis, but is likely to remain off-label after failing to demonstrate superiority to cyclophosphamide – an intravenous immunosuppressant – in the ALMS trial (7,8).

With several promising drugs failing to demonstrate statistically significant efficacy in clinical trials, there is a growing sense in the lupus community that inadequate clinical trial design is contributing to drug failures. If the long list of failed trials in lupus was the result of a therapy not working in SLE, it would be acceptable, but the strong signals of efficacy given by failed treatments suggest flawed trial designs.

While issues intrinsic to SLE will be difficult to overcome, other factors could potentially be more easily addressed, and recent trials suggest that lessons are being learned and applied by drug sponsors. Numerous indices exist to classify SLE, and they are commonly misused as endpoints in clinical trials (9). The SLE disease activity index (SLEDAI) and the British Isles Lupus Assessment Group Index (BILAG) are among those most frequently employed. However, while the SLE community values these indices, they were designed for diagnostic, rather than assessment purposes, which means that their application in clinical trials is not straightforward.

While common practice has been to include a single index as a primary endpoint, as was the case in rituximab’s EXPLORER trial that focused on BILAG scores, the last few years has seen a shift in thinking, starting with the Phase III SLE programme of belimumab (Benlysta; Human Genome Sciences/ GlaxoSmithKline). The primary endpoint in that programme is a composite index, which takes into account both SLEDAI and BILAG scores, as well as the physician’s global assessment. After meeting that endpoint in both trials of the programme in 2009, belimumab is now the most advanced drug candidate for lupus indications (10). Although composite endpoints have elicited some scepticism in other healthcare markets, this way of utilising SLE indices has been designed specifically for clinical trials and has already been adopted by other companies. Last year also saw positive results for Lupuzor (IPP-201101, ImmuPharma/Cephalon) and epratuzumab (Immunomedics/UCB) in Phase IIb SLE trials whose primary endpoints were also composite indices (11,12).

COMMERCIAL CHALLENGES

While clinical hurdles have received significant attention in the lupus community, considerable commercial challenges exist as well, and the two are interrelated. Companies can only be expected to face the clinical challenges if sufficient commercial rewards are anticipated. However, the absence of recent drug approvals for lupus indications means that it is difficult to know how much the market would pay for a novel treatment. While use of off-label rituximab could provide a useful benchmark for targeted therapies making their way through the pipeline, its off-label status is likely to stifle its use, limiting it to predominantly refractory patients, and those involved in clinical trials.

The best way to size SLE market potential is through analysis of patient numbers, but, as mentioned previously, epidemiology in this area is not extensive. Based on Datamonitor primary research, patients can be split by severity, with approximately 80 per cent of patients classified as mild or moderate, and the remainder being severe. By estimating the percentage of patients of each severity that receive each drug class, and using price and dose assumptions, we calculate that in 2008 SLE sales in the US, Japan and five major EU markets totalled around $1.1 billion (see Figure 1).

Based on this method, the market can be expected to triple over the next 10 years, as relatively expensive targeted therapies gain approval and subsequent penetration in the moderate to severe SLE populations.

FUTURE PROSPECTS

Without knowing what commercial rewards await a lupus breakthrough, the notorious difficulty of clinical development could prevent investment in promising drug candidates.

However, after 50 years of increasing unmet need, there are now 13 drug candidates in ongoing late-stage (Phase II or Phase III) development (see Table 1). Seven of these are targeted biologic therapies, and each could potentially benefit from belimumab’s recent Phase III success; lessons can be learned regarding possible improvements in clinical trial design, and, pending approval, belimumab will provide insight into SLE sales potential.

Table 1: Products in late-stage development for systemic lupus erythematosus (SLE), 25th February 2010
Generic (brand) name Mechanism Originator/marketing companies Highest phase
B-cells

Belimumab (Benlysta)

Humanised B lymphocyte stimulator (BLyS) MAb Human Genome Sciences/ GlaxoSmithKlein III
Atacicept B-lymphocyte stimulator ligand inhibitor; APRIL receptor antagonist ZymoGenetics/Merck Serono II/III
Epratuzumab Humanised anti-CD22 MAb Immunomedics/UCB IIb
T cells
Abatacept (Orencia)* T cell surface glycoprotein CD 28 inhibitor Bristol-Myers Squibb II/III 
Lupuzor CD4 T cell modulator ImmuPharma/Cephalon IIb
Interferon MAb
Rontalizumab Anti-IFN alpha MAb Genentech II
Sifalimumab Anti-IFN alpha MAb MedImmune/Medarex II
Other
Apremilast PDE 4 inhibitor Celgene II
R-salbutamol sulphate Beta 2 adrenoceptor agonist Astion Pharma II
CNTO-136 Anti IL-6 MAb Centocor Ortho Biotech II
Immunomodulator
Mycophenolate mofetil (CellCept)* Inosine monophosphate dehydrogenase inhibitor Roche/Vifor Pharma II
Paquinimod Immunomodulator targeting S100A9 Active Biotech II
Gusperimus trihydrochloride Unspecified immunosuppressant Nippon Kayaku II

*ongoing development is for lupus nephritis

APRIL: a proliferation-inducing ligand, CD: cluster of differentiation, IFN: interferon, MAb: monoclonal antibody, PDE: phosphodiesterase

 

Of the late-stage pipeline products, belimumab has the strongest clinical and commercial appeal (see Figure 2). This is primarily related to the expectation that it will be first to reach the market. Three other targeted therapies also have the potential to gain approval in the next 10 years. Epratuzumab is a humanised anti- CD22 MAb in development for SLE by UCB, under license from Immunomedics. After a shaky start to late-phase development, and a return from Phase III to Phase IIb development, UCB has announced positive top-line results and is consulting with regulatory authorities regarding further development plans (12).

Atacicept is also a strong pipeline product, in development by Merck Serono under license from ZymoGenetics. The treatment prevents the binding of B-lymphocyte stimulator (BLyS) and A proliferationinducing ligand (APRIL) to B lymphocytes.

Lupuzor is a small molecule immunomodulator that modulates the signalling of CD4 T-cells linked to lupus, and which may also modulate the Tregulatory pathway, for the potential treatment of SLE. In 2008, Cephalon exercised an option to license worldwide rights to ImmuPharma’s Lupuzor, a move that significantly boosts resources for the drug’s development (13).

CONCLUSION

The persistence exhibited by a number of companies involved in lupus drug development suggests eventual success. With limited data available for these drug candidates, it is difficult to say at this stage what their clinical impact could be, but the expectation that there will be continued investment in their development highlights the commercial potential in this disease area. It remains to be seen whether or not other companies can find success based on the experience of belimumab’s development, and indeed, how large that success really is. The future will see a perceptible shift in SLE drug development and a growing understanding of the pathology of lupus helping to address the clinical challenges. After years of waiting, regulatory approval of an effective therapy to treat this highly debilitating disease may be issued soon with belimumab. With the high correlation between clinical and commercial challenges, addressing one aspect will provide insight into the other, and far from reducing the attractiveness of pipeline products, a new product launch will set the agenda for additional advances.

References

  1. Lupus Foundation of America LFA, Statistics of lupus, www.lupus.org/webmodules/webarticlesnet/templates/new_newsroomreporters.aspx?articleid=247&zoneid=60,2010
  2. Naleway A et al, Epidemiology of systemic lupus erythematosus in rural Wisconsin, Lupus 14: pp862-866, 2005
  3. FDA, Guidance for Industry Systemic Lupus Erythematosus - Developing Drugs for Treatment, www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072063.pdf, 2005
  4. European Medicines Agency (EMA), Concept paper on the need for a guideline on the clinical investigation of medicinal products intended for treatment of systemic and cutaneous lupus erythematosus, www.ema.europa.eu/pdfs/human/ewp/60404009en.pdf, 2009
  5. Genentech, Genentech and Biogen Idec Announce Top-Line Results From Phase II/III Clinical Study of Rituxan in Systemic Lupus Erythematosus, www.gene.com/gene/news/press-releases/display.do?method=detail&id=11247, 2008

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Jacoba van der Gaag
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