On June 18, 2024 XBiotech (NASDAQ: XBIT) reported data from its Phase 1/Phase 2 randomized, double-blind, placebo-controlled multi-center study for advanced pancreatic cancer (Press release, XBiotech, JUN 18, 2024, View Source [SID1234644427]). Known as 1-BETTER, the study examined Natrunix (anti-interleukin-1alpha) antibody in combination with an established chemotherapy regimen (ONIVYDE (ON) + 5-Fluorouracil (5FU) + Leucovorin (LV), a regimen that is already widely used for treating pancreatic cancer but is associated with difficult toxicities and less then ideal survival outcomes. Natrunix was being evaluated as an anti-cancer agent for use in cytotoxic chemotherapy combinations where the Company believes it might potentially also improve tolerability of the chemotherapy.

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The Phase 1 portion was a dose escalation study in metastatic pancreatic cancer patients to determine if dose limiting toxicities (DLTs) occurred in combination with the ON+5FU+LV regimen in second- or third-line setting. DLTs were not expected with Natrunix and none were seen. The Natrunix dose in the Phase 2 portion was thus the highest dose used in the Phase 1 portion.

Sixty-five subjects were randomized into the Phase 2 study on a 1:1 basis to receive either Natrunix+ ON+5FU+LV (Arm1) or Placebo +ON+5FU+LV (Arm2). There were 33 subjects enrolled into Arm1 and 32 into Arm2. The Phase 2 treatment period was 24-weeks with subjects receiving therapy once every other week for a total of 12 cycles.

Subjects included in the study had confirmed metastatic, unresectable, or recurrent pancreatic adenocarcinoma of exocrine pancreas and were required to have had disease progression after one prior gemcitabine-based therapy or one FOLFIRINOX and gemcitabine containing therapy. All patients were required to have at least one measurable lesion according to Response Evaluation Criteria in Solid Tumor (RECIST v1.1).

The primary endpoint for the Phase 2 study was to assess the safety and tolerability of Natrunix when used with the ON+5FU+LV combination. Overall, there were fewer adverse events (AEs) of any kind during the 24-week treatment period for the Natrunix arm compared to placebo (297 vs 336), with markedly fewer events in specific categories of adverse events during that time. There was a 28% reduction in the number of subjects experiencing significant adverse events (SAEs) in the Natrunix arm (9 out of 33) versus placebo (12 out of 32) that occurred during the 24-week treatment period. Subjects receiving the Natrunix ON+5FU+LV regimen also had about a 33% reduction in hospitalization (80 days versus 120 days) during the 24-week treatment period compared to subjects receiving placebo + ON+5FU+LV combination.

Subjects receiving the Natrunix combination also reported a 22% reduction in fatigue (28 vs 36), 32% improved appetite (19 vs 28) and 41% reduction in pain (17 vs 29) as of the last day of the 24-week treatment period compared to subjects receiving the placebo ON+5FU+LV combination.

Severe diarrhea that can be life -threatening is a significant complication for the ON+5FU+LV regimen. There was a two-fold reduction (9% versus 19%) in the incidence of severe diarrhea during the 24-week treatment regimen for patients receiving the Natrunix + ON+5FU+LV combination compared to placebo + ON+5FU+LV.

Overall Survival (OS), one of the secondary endpoints for the Phase 2 study, was conventionally defined in as time from randomization to death. The sample size for the study included intent-to-treat analysis of 33 subjects randomized into the Natrunix + ON+5FU+LV arm versus 32 subjects in Placebo + ON+5FU+LV arm. A Kaplan-Meier Survival Curve using a product limit comparison method was performed. This data highlights the observation that no subjects in the placebo ON+5FU+LV group (n=32) survived for longer than 330 days, whereas 8 subjects in the Natrunix ON+5FU+LV arm (n=33) were still alive as of day 330. Considering the small sample size, the borderline statistically significant p-value of p = 0.096 suggests prolonged survival for subjects receiving the Natrunix regimen.

The lead investigator for the study, David J. Park, MD Medical Oncologist, Medical Director for the providence St. Jude Crosson Institute, Fullerton, CA stated "Treatment of advanced pancreatic cancer in the second and third line settings presents significant challenges in terms of toxicity as well as efficacy. To observe these trends for reduced toxicity and potential survival benefit is remarkable, particularly given the limited sample size. The potential interaction between reduced toxicity, more time on treatment and improvement in survival makes intuitive sense for clinicians who treat these patients. These findings are extremely important."

While there was a relatively small number of pancreatic cancer patients enrolled in the Phase 2 portion of the study, in the Company’s opinion, the findings show better outcomes for the Natrunix + ON+5FU+LV group as compared to the control arm. The Company believes that the reduced number of serious and adverse events, the significant reduction in hospitalization, and improved OS during the respective time periods described above for each of these metrics suggest that Natrunix could represent a breakthrough advance for the treatment of pancreatic cancer.