After the success – but not absolute home run – by Shire plc with its injectable kallikrein inhibitor, lanadelumab, for hereditary angioedema (HAE), investor hopes swelled for Biocryst Pharmaceuticals Inc.'s oral BCX-7353, which underwent its second interim analysis of its three-part, dose-ranging phase II APeX-1 trial in the same indication with the same mechanism of action.
Those hopes were realized, as the once-daily preventive treatment at the 125-mg dose gained a 73 percent drop in HAE attacks from baseline, with a satisfactory safety profile, and "everything is on the table" with regard to the design of the pivotal trial ahead, said Biocryst's chief medical officer, William Sheridan. Shares of the Durham, N.C.-based company (NASDAQ:BCRX) closed Thursday at $6.73, up $1.60, or 31.2 percent.
J.P. Morgan analyst Jessica Fye conceded that the pharmacokinetic profile for the 125-mg dose fell "generally within the target therapeutic range (vs. 250 mg and 350 mg which were well above the range)" but said "we will continue to watch for this in the third quarter, [when] we expect to see a total of 12 patients" evaluated. "Net-net, we view these initial results for 125 mg as encouraging with what appears to be both much-improved tolerability and efficacy within striking distance of lanadelumab's lower/monthly doses," she wrote in a report.
Dublin-based Shire this month unveiled positive top-line phase III results for lanadelumab: the 300-mg dose administered once every two weeks resulted in a statistically significant reduction in mean HAE attack frequency of 87 percent compared to placebo (p<0.001). H.C. Wainwright analyst Andrew Fein said he "had certainly expected this data to be positive in light of the robust results from the prior phase Ib, as well as the mechanism of the drug. However, the much more important takeaway, as it pertains to Biocryst, is that the results did not show that the injectable eliminated HAE attacks completely." Fein said in a report that he "had expected that such an absolute event was unlikely, given the wide spectrum of patients enrolled, and we believe BCX-7353's oral optionality would still offer upside in such a case."
Still, the prospect of a sweeping success by the Shire drug was "an understandable source of anxiety for investors" as they waited for data from part two of the APeX-1 trial, which rolled out Thursday. "We believe the [Shire trial] outcome presents a best-case scenario for Biocryst and allows investors to re-engage ahead of BCX-7353 data readout: it removes the overhang for investors anxious about the possibility of a clean wipe by lanadelumab; it validates BCX-7353 clinically, re-affirming, once again, that kallikrein inhibition works for HAE; and the significant difference between lanadelumab and placebo on injection site pain (42.9 percent vs. 29.3 percent, respectively) boosts the value proposition of an oral treatment like BCX-7353."
'WHAT THEY'VE BEEN WAITING FOR'
The latest APeX-1 analysis included data from all patients in the first and second parts of the trial, pooling results from both parts of the experiment, evaluating doses of BCX-7353 125 mg (n=7), 250 mg (n=6) and 350 mg (n=18) vs. placebo (n=20) for 28 days. The baseline attack rate was about one per week. Baseline characteristics were generally well balanced between the treatment groups, and compliance with study drug dosing was excellent (≥ 98 percent), the company said.
Included in the pre-specified per-protocol analysis were data on a total of 44 subjects with confirmed type 1 or type 2 HAE completing 28 days of treatment. The percentage reductions by treatment group in the mean rate of independently adjudicated angioedema attacks for the pre-defined effective dosing period (the second through fourth weeks) in BCX-7353-treated subjects were: 73 percent for the 125-mg dose (p=0.002); 37 percent for 250 mg (p=0.128); and 58 percent for 350 mg (p=0.001), compared to placebo. In the intent-to-treat population, corresponding reductions by treatment group were: 73 percent for 125 mg (p=0.004); 44 percent for 250 mg (p=0.090); and 45 percent for 350 mg (p=0.014), compared to placebo.
A pre-planned analysis of peripheral and abdominal attacks showed reductions in peripheral attacks of 74 percent (125 mg), 54 percent (250 mg) and 90 percent (350 mg) compared with placebo in the per-protocol analysis covering the second through fourth weeks, and reductions in abdominal attacks of 72 percent (125 mg), 10 percent (250 mg) and 8 percent (350 mg QD) compared with placebo in the period. Based on that distribution, subjects in the 250-mg and 350-mg arms probably recorded transient abdominal adverse events (AEs) as HAE attack symptoms in their diaries, whereas a consistent reduction in attacks regardless of anatomical location was observed in the 125-mg arm, Biocryst said.
The 28-day treatment was generally safe and well-tolerated, with no serious or severe AEs. Three subjects in the BCX-7353 350-mg treatment arm, two of which were previously reported, discontinued study drug before the last day. A third subject in that arm dropped out due to vomiting and abdominal cramps concurrent with menses. The most common treatment-emergent adverse events were the common cold and diarrhea. Gastrointestinal AEs previously observed in the 350-mg arm were not seen at the 125-mg dose, nor were any significant laboratory abnormalities observed in the two lower dose groups.
Steady-state BCX-7353 plasma levels and kallikrein inhibition levels in HAE subjects were similar to those seen in healthy subjects administered the same doses in a phase I study, and steady-state trough drug levels (24 hours after dosing) greatly exceeded the target therapeutic range at the 250-mg and 350-mg dose levels, while trough levels for the 125-mg dose were generally within the target range. Finishing the third part of the study will let the company figure out the right dose for phase III work.
CMO Sheridan said during a conference call with investors that the company is "cautious in making statements about something being worse or better than another thing at this stage." In any case, CEO Jon Stonehouse said Biocryst's "market research, the conversations we have with the HAE patients and the physicians who treat them, all strongly point to the fact that patients are waiting for a pill for this disease. With the information we have thus far from our APeX-1 study, we are extremely encouraged that we are on the right track to getting them what they've been waiting for.