Finding a Complementary Secondary Endpoint in Lupus Clinical Trials

Finding a Complementary Secondary Endpoint in Lupus Clinical Trials January 10, 2017
By Sebastian S. Gehrke, PhD, BioSpace.com Contributor

As a notoriously difficult indication to demonstrate efficacy in randomized clinical trials (RCTs), lupus has been plagued with a plethora of late-stage failures over the past decade. Recently, the lupus research community has come together in an effort to define a universally accepted lupus low disease activity state (LLDAS)—drawing parallels to the disease activity score (DAS28) leveraged in rheumatoid arthritis.


If accepted and adopted, LLDAS will likely complement the existing systemic lupus responder index (SRI) as the preferred outcome measure in lupus trials and clinical practice, as the SRI does not represent a target state for good long-term outcomes in systemic lupus erythematosus (SLE) patients, nor does the SRI include treatment variables to define therapeutic thresholds for current standard of care (SOC).

Given that SRI is by no means an ideal approach to assessing disease activity in SLE, GlobalData believes that LLDAS used alongside SRI represents the best available approach to evaluating drug efficacy.

Historically, drug development in lupus has been haunted by high-profile failures in the clinic, primarily due to the heterogeneous nature of the SLE patient population—no two cases are alike.

GlobalData identified a multitude of additional reasons to blame for the undesirable outcome in RCTs, including an incomplete understanding of the disease, an absence of reliable instruments to measure disease activity at a given point in time (as lupus comes in unpredictable episodes of flares), and, most importantly, a lack of guidelines from regulatory agencies such as the FDA, EMA, and Japan’s PMDA. In 2011, GSK broke what had become the status quo by introducing the SRI—a composite measure that uses the SELENA-SLE Disease Activity Index (SELENA-SLEDAI), Physicians Global Assessment (PGA), and the British Isles Lupus Assessment Group index (BILAG), to quantify disease activity—to the lupus community, ultimately leading to the approval of Benlysta (belimumab).

While Benlysta initially was welcomed by the lupus community, key opinion leaders interviewed by GlobalData expressed disappointment with Benlysta’s limited efficacy in the management of SLE, meaning that to date, rheumatologists and nephrologists still rely primarily on steroids and other immunosuppressant agents that are linked to cancer and other long-term adverse events to manage disease activity in SLE patients. This lack of efficacious drugs further challenges the ability of the SRI to reflect a meaningful outcome in lupus patients.

In November 2016, at the ACR/ARHP Annual Meeting, AstraZeneca presented SRI data from a recently completed Phase IIb study showing that SLE patients who received anifrolumab were almost four times more likely to achieve an LLDAS, as defined by a SLEDAI-2K of 4 or less, absence of flares as measured by the SELENA-SLEDAI Flare Index (SFI), a PGA score of 1 or less, oral steroids of 7.5mg/day or less, and being appropriately controlled by the recommended dose of immunosuppressants. Importantly, AstraZeneca was the first company to validate LLDAS in a post hoc analysis as a meaningful outcome for SLE patients in RCTs. Furthermore, LLDAS has recently been validated in a longitudinal study across nine countries, in which researchers showed that an LLDAS translated to a reduced risk of future organ damage accrual in SLE patients, with 44 percent of SLE patients treated with SOC meeting all criteria of the LLDAS after one year of treatment.

GlobalData believes that the surprisingly low number of patients qualifying for an LLDAS is representative of the current state of the lupus treatment landscape, where half of all patients fail to see symptom relief from the current standard of care.

Experts interviewed by GlobalData share the belief that LLDAS is a meaningful addition to measure the disease activity in lupus, and in particular they welcomed the inclusion of a therapeutic threshold for steroids and immunosuppressive medications.

GlobalData sees this SOC dosing criteria as the most important addition of the LLDAS in assessing lupus disease activity, as the SRI relies on a regulated steroid tapering regime and disqualification of patients in need of rescue medications in order to achieve statistically meaningful differentiation of the treatment and placebo (SOC) trial arms.

While the SRI arose out of the need to approve Benlysta, the LLDAS arose from the lupus community’s desire to define a reachable treatment target to facilitate a treat-to-target approach in lupus, a development that GlobalData expects to represent an important shift in the clinical research landscape for SLE.

To date, the lupus pipeline has seen unprecedented R&D efforts—some experts argue there are currently more targets evaluated in lupus than there are patients suffering from this rare disease—with currently more than 60 products across all phases of clinical development.

GlobalData anticipates the majority of these products to use the SRI as primary endpoint. While physicians agree that the SRI is not the best tool to measure disease activity in lupus, they accept the need as a community to standardize clinical drug development in lupus to facilitate the arrival of new drugs to address the remaining unmet needs in lupus. Consequently, GlobalData expects the SRI to become the new standard endpoint in RCTs, but highly recommends the use of LLDAS as secondary endpoint to facilitate the clinical application of new drugs. GlobalData believes that AstraZeneca’s anifrolumab is setting the bar for future drug development efforts in lupus, where a drug must achieve statistically significant results across multiple endpoint measures in order to be considered successful.

Sebastian S. Gehrke, PhD is an analyst in the Infectious Disease team at GlobalData in London. Sebastian constructs syndicated market research reports for the pharmaceutical health care sector. Sebastian’s key areas of expertise span the fields of immunology and infectious diseases. Sebastian holds a PhD in medicinal chemistry/biochemistry, which he was awarded from the University of East Anglia during his multidisciplinary doctoral studies at King’s College London, the John Innes Centre Norwich and the University of East Anglia (UK).

Back to news