Novel Lupus Drugs Continue to Shine in Extended Early Data

LONDON — Two investigational drugs for lupus with encouraging primary phase II results yielded more good news from follow-on studies, reports here indicated.

The Toll-like receptor (TLR) inhibitor enpatoran showed no diminution and perhaps some increase in efficacy for patients with cutaneous and systemic lupus with 48 weeks of additional treatment beyond the original 24 weeks, and no new safety concerns arose, according to Eric Morand, MBBS, PhD, of Monash University in Melbourne, Australia.

The other study involved the anti-B cell agent ianalumab that is being tested in systemic lupus (and a variety of other conditions). Edward Vital, MBChB, PhD, of the University of Leeds in England, reported data collected after treatment had stopped in a phase II trial and after B-cell populations had rebounded. With a median of 44 weeks of post-treatment follow-up, not only did biomarker responses continue unabated, clinical indices also showed little loss of efficacy.

Both studies were presented at the European Alliance of Associations for Rheumatology (EULAR) annual meeting. Enpatoran is a small-molecule inhibitor of TLRs 7 and 8, while ianalumab is a bifunctional biologic that promotes antibody-mediated B-cell death while also deactivating remaining B cells by inhibiting B-cell activating factor, or BAFF.

For both drugs, the phase II results were strong enough that their respective sponsors have initiated twinned phase III trials: ELOWEN-1 and ELOWEN-2 for enpatoran, and SIRIUS-SLE-1 and SIRIUS-SLE-2 for ianalumab.

Enpatoran Study

The main phase II enpatoran study, WILLOW, enrolled 454 patients in two cohorts: 100 with cutaneous lupus or systemic lupus with skin manifestations in one, and 354 with systemic lupus with or without skin activity in the other. Both were randomized to three dosages of the drug (25, 50, or 100 mg twice daily) or placebo. Cutaneous Lupus Disease Area and Severity Index-Activity (CLASI-A) scores and so-called BICLA responses were the main efficacy outcome measures.

After the primary result assessment at the end of 24 weeks, study-drug patients continued on their assigned dosages, while the placebo group switched, while still blinded, to the 100-mg dose. This portion lasted another 48 weeks. A total of 379 patients continued into this extension phase. Morand reported CLASI scores and other response criteria, but not BICLA responses specifically, for the extension.

As is often the case in placebo-to-drug crossover studies, the placebo group caught up fully to the active drug groups in terms of CLASI-A scores by the extension phase’s end. Moreover, those active drug groups showed small further declines in scores, indicating additional clinical improvement in symptoms.

CLASI50 responses, representing 50% decrease from baseline in scores and evaluated in patients with skin manifestations at baseline, remained at virtually the same levels across the active drug groups throughout the extension, at close to 80% of patients. By this measure, the original placebo group didn’t quite get to that level, but still 65% of those patients reached CLASI50 by extension week 48. The same pattern was seen with CLASI70 (70% score reduction), with response rates remaining near 60% during the extension. And in this measure, the original placebo group did catch up completely.

Morand noted that there is no agreed-upon definition of remission or low disease activity for cutaneous lupus, so they invented their own: CLASI-A of 0-3. This milestone was achieved by 52-56% of the active drug groups after the first 24 weeks of WILLOW, and by 58-63% by the end of the 48-week extension.

Only 11 patients discontinued for safety reasons during both phases, and Morand said no new safety signals were seen.

Ianalumab Study

Vital’s group went that study one better. It likewise included a primary phase (28 weeks) followed by an open-label extension (24 weeks). But in this case, the investigators continued to follow participants for as long as they could afterward. Of the 65 patients completing the extension (only two were lost from the original enrollment), 62 had additional visits over the subsequent 16 weeks, and then one more evaluation whenever it could be arranged — ranging from 20 to 186 weeks from the end of the extension (median 44 weeks).

The purpose was to see what happened after B-cell populations recovered from the treatment, which appeared highly effective. During the main and extension phases, B-cell counts declined by more than 100-fold. By week 68 — that is, 16 weeks after treatment stopped — they had recovered somewhat, to about 10% of baseline. The mean at last follow-up almost reached baseline.

Levels of immunoglobulins G and M declined less with treatment than the B-cell counts would suggest, as B cells can persist in tissues, falling by perhaps 30-50% during treatment. But interestingly, during the post-treatment follow-up, the immunoglobulins hardly rebounded at all.

That was true, too, for lupus biomarkers such as anti-double stranded DNA antibodies and complement levels, all of which remained at or near where they stood at the end of treatment.

Clinical assessment mirrored the biomarkers. So-called SRI-4 responses, the most commonly used measure of clinically significant improvement in systemic lupus, were seen in some 65% of patients at the end of treatment. At week 68, it was about the same. And by last follow-up, well over half patients who had been treated for the full 52 weeks (main plus extension) still qualified for SRI-4. Patients in the original placebo group, who were switched to open-label ianalumab for the extension and thus got only 24 weeks of active treatment, did show some fall-off, but more than 40% still had SRI-4 responses at last follow-up.

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