Challenges in SLE Drug Development: The Key Hurdles
Systemic Lupus Erythematosus (SLE) is an autoimmune condition characterized by the production of pathogenic autoantibodies and tissue deposition of immune complexes. The disease is extremely heterogeneous in nature—which often leads to delays in diagnosis—although it most commonly affects the musculoskeletal and mucocutaneous systems. The disruption of normal functioning of other organs, such as the kidneys, central nervous system, and heart, is also common. The SLE treatment landscape comprises primarily nonspecific therapies such as antimalarials, corticosteroids (CSs), and off-label immunosuppressants, which are often unsuccessful in treating the patients, especially those with severe disease. Additionally, long-term treatment with these agents is generally associated with several side effects, which include infections, hepatotoxicity, osteoporosis and many others. Considering the heterogeneity of SLE in terms of underlying pathophysiological pathways, manifestations and organ/system involvement, a targeted approach to treatment seems more practical. However, to date, GlaxoSmithKline’s Benlysta—a modestly effective B-cell modulator—is the only targeted therapy officially approved for treating the condition, leaving SLE as an area of high unmet need. 1
Taking into account the unmet need, the chronic nature, high drug-treatment rates, and the high diagnosed prevalence of SLE in the major markets (United States, France, Germany, Italy, Spain, United Kingdom, and Japan), the scarcity of available treatments is not the result of pharmaceutical companies paying no attention to or being unaware of the drug development opportunities in this space. Indeed, five promising novel molecules—ustekinumab (Janssen’s Stelara), baricitinib (Eli Lilly’s Olumiant), Merck KGaA’s atacicept, AstraZeneca’s anifrolumab, and Aurinia Pharmaceuticals’ voclosporin, most of which are targeted therapies—are in late-phase development, and more than a dozen agents are in the early-phase pipeline, supporting the idea that the drug companies are trying hard to leverage this opportunity.2
An analysis of the pipeline over the past several years reveals that the major reason for the surprisingly inadequate treatment landscape in SLE is the high failure rates of drugs in development. Our analysis of the agents that failed to gain approval for the indication shows that these therapies demonstrated efficacy and safety in earlier-phase trials but failed to replicate the positive outcomes in larger late-phase trials. Some of the key drugs that have followed this pattern of failure include rituximab (Biogen/Roche/ Genentech/Chugai/Zenyaku Kogyo’s Rituxan, Roche’s MabThera), abatacept (Bristol-Myers Squibb’s Orencia), UCB’s epratuzumab, and ImmuPharma’s rigerimod. Anifrolumab may also be soon added to the list; AstraZeneca recently announced that anifrolumab, currently in Phase III for SLE (clinicaltrials.gov, TULIP I [NCT02446912] and TULIP II [NCT02446899]), failed to achieve the primary end point of the SRI-4 response rate at week 52 in the TULIP I trial.3 Interestingly, before the data from the TULIP I trial were released, the agent was stealing the limelight from other agents in the SLE pipeline. As such, the news of the TULIP I failure has astounded physicians treating the disease, who had high hopes for this agent.
Upon further analysis, we recognize that these late-phase drug development setbacks can be attributed to several factors. Among the primary issues that led to the high failure rates in SLE are the difficulty of defining the right patient population for the trial, high placebo response rates, and use of co-medications. Indeed, identifying the right population for clinical trials is challenging owing to the heterogeneous nature of SLE, potentially multiple pathophysiological pathways involved, and the lack of validated biomarker tests that could predict response to the drug. Atacicept is one such example. The drug failed to achieve its primary outcome measure in a Phase IIb study (NCT01972568) in moderate to severe SLE. However, the post-hoc analysis showed that atacicept demonstrated significant efficacy in a subgroup of patients with high disease activity (SLEDAI-2K ≥ 10) and a subgroup of serologically positive patients (those with low complement and positive for anti-dsDNA antibodies).4 Another challenge facing drug developers is that SLE patients are generally treated with multiple medications—which include powerful CSs and immunosuppressants—as an ongoing regimen. Owing to the severity of the disease, it is not possible to discontinue these therapies in patients enrolled in a clinical trial because of the risk of a flare. Therefore, the use of these medications—especially in patients newly introduced to treatment and in patients with poor adherence to treatment outside of a clinical trial—may have an impact on the trial outcome by increasing the placebo response rates. A related issue is the use of CSs in clinical trials. These powerful agents could obscure the effect of a tested add-on therapy, especially if the therapy in development is only moderately efficacious.
The companies developing novel SLE drugs try to take these issues into account when designing clinical trials, but many fail to overcome these challenges. Possible solutions include developing biomarkers that would help target the drug to the appropriate SLE subpopulation, recruiting patients who are on stable treatment regimens to reduce placebo response rates, and introducing CS tapering into the trial design to mitigate the effect of these agents on disease activity.
Although it could be hard to overcome the drug development challenges in SLE, it is not an overstatement to say that the agents that will gain approval are poised to win in the SLE arena, where only a few players currently play.
Decision Resources Group recently published its SLE market forecast for 2017-2027 in the G7, reflecting the latest developments, expert insights, and expectations for the market and refreshed the content in the Systemic Lupus Erythematosus Disease Landscape & Forecast report. For more details on this research, please contact email@example.com.
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- Systemic Lupus Erythematosus | Unmet Need | US/EU | 2018 and Systemic Lupus Erythematosus | Unmet Need | Lupus Nephritis | US/EU | 2017
- Systemic Lupus Erythematosus | Disease Landscape & Forecast | G7 | 2018
- AstraZeneca, press release, August 31, 2018
- Merrill JT, et al. Efficacy and safety of atacicept in patients with systemic lupus erythematosus: Results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled, parallel-arm, phase IIb study. Arthritis Rheumatol. 2018; 70(2):266-276.