7:03 PM
Jan 25, 2019
 |  BioCentury  |  Product Development

Target wide, test narrow in lupus

How the lupus field can springboard from its seven late-stage misses in 2018

Editor's Note: This article was updated on Jan 31, 2019 at 1:45 PM PST

While last year’s spate of clinical misses in lupus leave the field still in search of optimal targets, the 2019 outlook isn’t all doom. Companies with shots on goal are using sharper endpoints and aiming for targets with broader effects on disease biology.

2018 failed to add positively to the record of the last 50 years, which has seen only one targeted therapy approved to treat lupus.

Seven compounds failed to meet their primary endpoints in Phase II or Phase III studies: two immunotherapies targeting interferon α (IFNα) signaling, two biologics against costimulatory ligands, a peptide that dampens autoantigen presentation to T cells and two biologics targeting receptors on B cells (see Table: “2018 Lupus Report Card”).

Those results led at least two companies to abandon targets. Bristol-Myers Squibb Co. walked away from blocking T cell costimulation in lupus, and the Ablynx unit of Sanofi jettisoned its program targeting interleukin-6 (IL-6) signaling.

But companies and KOLs who spoke to BioCentury think the jury is still out on the other MOAs with clinical failures last year, in particular blockade of IFNα signaling. The mechanism’s efficacy, they argue, may have been lost in the noise inherent in standard lupus trial designs.

After missing the primary endpoint in the Phase III TULIP 1 trial of anifrolumab, a mAb against the type I interferon receptor, AstraZeneca plc is awaiting results from TULIP 2. Full data from the trials will provide insight into whether the compound works better in a subpopulation of patients with high expression of an interferon gene signature (see “On SLE’s Trail”).

Despite mixed Phase II results from its IFNα Kinoid vaccine, which induces polyclonal antibodies against the cytokine, Neovacs S.A. hopes to hit in Phase III by using an endpoint that gets around the notoriously high placebo effect in lupus and plays to the molecule’s clinical strength: enabling patients to reduce steroid use.

“This whole endpoint discussion is only a problem if you have medicines that do not blow away the disease.”

Paul-Peter Tak, Flagship Pioneering

Other companies are reducing experimental noise by stiffening SOC requirements or focusing on a specific subset of lupus patients.

Paul-Peter Tak, a venture partner at Flagship Pioneering and former chief immunology officer at GlaxoSmithKline plc, believes that better trial designs will undoubtedly uncover more compounds with therapeutic effects.

Still, a game-changing therapy would not get lost in the noise, he said. “This whole endpoint discussion is only a problem if you have medicines that do not blow away the disease.”

Tak thinks the targets that read out last year are too narrow to have transformational effects on their own, and therapies with broader MOAs -- either built into a single agent, or achieved through combination -- are more likely to create a step change.

That’s the philosophy behind at least six ongoing Phase II or III trials slated to read out over the next three years.

Table: 2018 lupus report card

All seven Phase II and Phase III lupus studies that read out in 2018 failed to meet at least one primary endpoint. Neovacs S.A. (Euronext:ALNEV) reported IFNα-Kinoid met one of its two primary endpoints, as well as a secondary endpoint of improvement vs. placebo as assesed by LLDAS (Lupus Low Disease Activity Score). Xencor Inc. (NASDAQ:XNCR) reported obexelimab met a secondary endpoint of longer time to loss of improvement (LOI) vs. placebo. ImmuPharma plc (LSE:IMM) reported Lupuzor improved response vs. placebo as assessed by SLE Responder Index 4 (SRI-4) in a subset of patients with anti-double stranded DNA antibodies, but this subgroup analysis was not a pre-defined endpoint for the study. IFNα-Kinoid and Lupuzor have Fast Track designation in the U.S. for lupus....

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