Though it provided what CEO Craig Thompson called "key information" to inform a second trial, Anthera Pharmaceuticals Inc.'s narrow topline phase III SOLUTION miss with recombinant pancreatic enzyme replacement therapy (PERT) Sollpura (liprotamase) in cystic fibrosis (CF) patients who have exocrine pancreatic insufficiency (EPI) sent shares of the firm (NASDAQ:ANTH) reeling 63 percent, or $1.27, to close at 74 cents.

The level of the stakes was reflected in a November research report by H.C. Wainwright analyst Andrew Fein who, ahead of the latest data readout from the Hayward, Calif.-based company, reminded Wall Street that, "in our initiation of coverage in July, we encouraged investors to value Anthera based solely on its Sollpura program in exocrine pancreatic insufficiency in CF. We elected to neglect the blisibimod program entirely, while highlighting that even a probability-discounted consideration of the Sollpura program alone justified a premium to trading levels." Blisibimod, despite sliding past an interim futility analysis in February 2015, went on to fall short of its phase III endpoint in the trial called CHABLIS-SC1, testing the selective peptibody antagonist of the B-cell activating factor cytokine against systemic lupus erythematosus. "In perspective, the company's market cap at yesterday's close post-blisibimod's miss was $90 million, while the 2015 sales of the standard-of-care porcine pancrease Creon [pancrelipase, Abbvie Inc.] were $632 million." Fein deemed Anthera's valuation "attractive" ahead of the SOLUTION results in CF. (See BioWorld Today, Nov. 11, 2016.)

EPI is characterized by low absorption of fat and other nutrients due to a reduction in digestive enzymes produced by the pancreas. SOLUTION evaluated Sollpura, a PERT with no enteric coatings, which means less pill burden compared to pig-derived PERTS. The trial enrolled 126 patients. After a three-week run-in period on Creon or Zenpep (pancrelipase, Allergan plc) to establish baseline coefficient of fat absorption (CFA), the patients were randomized to either Sollpura or Pancreaze (pancrelipase, Janssen Pharmaceuticals Inc.), with the primary endpoint set at non-inferior CFA measured when eight weeks pass. The trial just missed its main mark: that margin in the primary modified intent to treat (mITT) analysis. But researchers did find that, by additional pre-specified analyses of CFA (mITT-baseline observation carried forward and per protocol), Sollpura hit the non-inferiority goal. The study also confirmed that the ratio of the three enzymes in the drug turned up appropriate response in the coefficient of nitrogen absorption, which measures protein digestion and absorption. In a conference call with investors Wednesday, Thompson noted that SOLUTION participants were "well controlled on stable PERT therapy prior to screening, as demonstrated by a CFA of at least 80 percent. A 15 percent non-inferiority margin was specified for the study and the lower bound of the 97 percent of the confidence interval study was 16 percent, so basically [the result was] a 1 percent miss."

HIGHER STARTING DOSE NEXT TIME?

William Shanahan, chief medical officer, said the baseline characteristics of the enrolled population was well balanced and representative of a typical CF study population, with a mean age of 21.8 years, 97 percent Caucasian, and almost an even split between male and female. Sollpura was generally well tolerated compared to Pancreaze, though other symptoms related to malabsorption were generally modestly more frequent in the Sollpura arm. The overall rate of treatment-emergent adverse events was 41.5 percent for the Sollpura arm and 38.1 percent for the Pancreaze arm. "Patients' ability to increase their doses during the study were hindered by time restrictions and dose increments allowed per protocol," Shanahan pointed out, and some were prevented from increasing their dose due to the daily limit of 10,000 lipase units/kg/day based on upper dose limits for PERTs. SOLUTION, he said, provided "extremely useful insights into modifications that need to be made in the succeeding study." CEO Thompson said Anthera plans to start the new trial in the first quarter of next year, and it will "provide investigators and patients the flexibility to adjust their Sollpura dose based upon malabsorption symptoms at any time during the study, which we believe will allow patients to achieve the optimal level of fat absorption as measured by CFA." He said the new study should "only modestly delay the filing of the BLA, which we expect will occur in the first quarter of 2018, in line with the completion of required chemistry, manufacturing and controls activities." The company is discussing "potentially bringing patients in on a starting higher dose as well, but we've just received the data from the SOLUTION trial recently" and is still "putting it all together." Meanwhile, results from the extension phase of SOLUTION are due in the first quarter of next year, too.

Piper Jaffray analyst Edward Tenthoff said in a report earlier this month that his firm "remain[ed] confident" of a positive outcome from the SOLUTION experiment. "We view CFA as a low bar for success, given [that] the therapies will be administered with matched lipase doses," he wrote. Jefferies' Matthew Andrews also sounded optimistic in an alert to investors Dec. 8, saying that "we believe the phase III study has a high likelihood of success based on its non-inferiority design, a well-controlled patient population enrolled in the study [potential for less variability in efficacy], improved formulation [higher lipase dose], and weight-based dosing," in contrast to fixed dosing used by the drug's previous developer, Indianapolis-based Eli Lilly and Co. He noted that the study had passed two safety reviews by the data monitoring board. Anthera acquired Sollpura from Lilly in the summer of 2014. Terms were not disclosed at the time, but a later SEC filing showed that the transaction involved no up-front money, with Anthera obligated to make milestone payments of up to $43 million upon reaching regulatory and commercial goals.