Despite sliding past an interim futility analysis in February 2015, Anthera Pharmaceuticals Inc.'s blisibimod couldn't hit the phase III endpoint against systemic lupus erythematosus (SLE) in the trial called CHABLIS-SC1 – an "obviously disappointing" outcome that the firm's chief medical officer (CMO), William Shanahan, blamed on the high placebo response.
Hayward, Calif.-based Anthera's shares (NASDAQ:ANTH) lost 31.65 percent, or 88 cents, to close Thursday at $1.90 as Wall Street learned that the compound, a peptibody that targets B-cell activating factor (BAFF), failed to meet its primary endpoint based on the SLE Responder Index-6 (SRI-6) at 52 weeks. Forty-seven percent of patients in the blisibimod arm and 42 percent in the placebo arm met the mark, not enough to make a statistically significant difference. In a conference call with investors, the company said data analysis will continue in order to determine next steps.
"With retrospective analysis or post hoc analysis of prior trials with other agents, the SRI-6 was in the 20 percent to 30 percent range," Shanahan said. "One of the major differences was that those studies required a Safety of Estrogens in Lupus Erythematosus National Assessment [SELENA]/SLE Disease Activity Index [SLEDAI] score of 6 to get into the study while ours required a score of 10," he said. "At least one hypothesis would be that this resulted in some inflation in score at the beginning of the study, resulting in a very high placebo response rate." Although guesswork, "it's at least one plausible explanation," he added. The SRI is a composite index comprising SELENA/SLEDAI, British Isles Lupus Activity Group and Physician Global Assessment criteria. A SRI-6 response requires a decrease of at least 6 points in SELENA/SLEDAI. The magnitude of blisibimod treatment effects for other SLE Response levels (SRI-4 and SRI-8) also did not achieve statistical significance.
CHABLIS-SC1 enrolled 442 moderate to severe SLE patients with baseline SELENA/SLEDAI scores of 13.5 and average corticosteroid doses of 15.6 mg, a factor that Piper Jaffray analyst Edward Tenthoff believes "may have contributed to high placebo rates and trial failure."
Anthera continues to enroll 350 SLE patients in the phase III CHABLIS 7.5 trial, which requires reduction of background steroid therapy to 7.5 mg of prednisone or less. "Blisibimod did significantly reduce serum B-cell immune activity, immunoglobulin and complement levels, which we view as encouraging for ongoing development in IgA nephropathy with 48-week phase II BRIGHT-SC data by the end of this year," he wrote in a research report. BRIGHT-SC is testing the efficacy and safety of blisibimod compared with placebo in patients with IgA nephropathy (IgAN). Subjects aged 18-65 with biopsy-proven and persistent proteinuria > 1 g/24 hours but < 6 g/24 hours during a two- to six-week period before enrollment are randomized to receive either blisibimod (300 mg per week for eight weeks and 200 mg per week thereafter) or matching placebo over the background of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.
Anthera has more in the hopper. Next to report is the phase III SOLUTION trial testing Sollpura, a recombinant pancreatic enzyme replacement therapy (PERT) with no enteric coatings, which means less pill burden compared to pig-derived PERTS. The trial enrolled 126 cystic fibrosis (CF) patients with exocrine pancreatic insufficiency (EPI). After a three-week run-in period on Creon (pancrelipase, Abbvie Inc.) or Zenpep (pancrelipase, Allergan plc) to establish baseline coefficient of fat absorption (CFA), the patients were then randomized to either Sollpura or Pancreaze (pancrelipase, Janssen Pharmaceuticals Inc.), with the primary endpoint set at noninferior CFA measured when eight weeks pass.
"We want to own shares of Anthera ahead of top-line SOLUTION data in the fourth quarter of 2016, as we view CFA as a low bar for success given the therapies will be administered with matched lipase doses," Piper's Tenthoff said. Anthera is also conducting the open-label phase III SIMPLICITY trial with a sachet formulation of Sollpura in CF-EPI infants. The primary endpoint is CFA after seven weeks, and safety will be measured out to 24 weeks, with data expected early next year.
But the news Thursday concerned blisibimod and CHABLIS-SC1, which seemed to have a "reasonable likelihood of success" when it passed interim muster near the first of the year, noted then-CMO Colin Hislop. An independent statistician said the Hayward, Calif.-based firm's BAFF experiment should continue as planned, after an analysis examined the SRI-6 response at 24 weeks. Jefferies analyst Matthew Andrews noted that new CMO Shanahan, previously with San Diego-based Arena Pharmaceuticals Inc., "is a rheumatologist by training, which will be important for development of B-mod in lupus and IgAN." (See BioWorld Today, Feb. 11, 2015.)
The ride with blisibimod has been rocky. In 2012, the market thumped Anthera after finding out the much-anticipated phase IIb PEARL-SC study results in SLE fell short of their primary efficacy endpoint because the drug didn't work in two low-dose groups. A month later, the company released promising data from a subset of patients in the study, which triggered an uptick in the share price that let Anthera price a $33 million offering. (See BioWorld Today, June 29, 2012, and July 23, 2012.)
Jefferies' Andrews said last week that although he was "cautious on blisibimod," favorable data with that compound or Sollpura "could be transformative for Anthera and its share price." When he started coverage of Anthera in late October, he put Sollpura's chance of success at 80 percent, pointing out that it "represents the first innovation for treatment of EPI since the introduction of porcine pancreatic enzyme products (PEPs). Sollpura capsules and sachet packets offer the promise of better quality of life and improved outcomes (via higher compliance) in CF patients with EPI "by lowering pill burden to one per meal/snack vs. about 16-23 per day with porcine PEPs."
Positive data could let the company resubmit Sollpura's BLA, since the FDA has agreed that the study handles concerns pointed out in the complete response letter sent to the original developer, Indianapolis-based Eli Lilly and Co. But "don't open that bottle of Chablis just yet" regarding blisibimod, Andrews wrote, with a nod to the outcome of the PEARL-SC study.