Aravive Inc.'s chief medical officer, Gail McIntyre, told BioWorld that a "very clever mechanism" designed by researchers at Stanford University helped lead to positive data from the first 12 patients of the ongoing phase Ib part of the phase Ib/II experiment with AVB-500 against notoriously hard-to-beat ovarian cancer.
"We have to be guarded, but we're showing a threefold increase in the historical control rate, which is pretty good," McIntyre said. "If our profile holds, we should be able to combine our drug with pretty much everything out there," she added.
Wall Street provided shares of the Houston-based firm (NASDAQ:ARAV) with a sharp upward ride that peaked at $9.72 but flattened out by the end of the day, closing at $8.68, an increase of 37 cents.
The drug, fast-tracked by the FDA, is a recombinant fusion protein that neutralizes growth arrest-specific 6 (GAS6) activity by binding with high affinity, thereby inhibiting the GAS6-AXL signaling pathway. In the open-label phase Ib effort, patients with recurrent, platinum-resistant disease were enrolled into two cohorts, one investigating a combination of AVB-500 with pegylated liposomal doxorubicin (PLD) and the other testing a combination of the drug with paclitaxel (PAC). In both study groups, AVB-500 treatment led to early proof of concept with best overall response rate by investigator determined RECIST v1.1 criteria and durable response in responders. The candidate proved well-tolerated, too, with no dose-limiting toxicities.
Results were unveiled in a late-breaking oral presentation at the European Society for Medical Oncology (ESMO) Congress in Barcelona, Spain, and showed clinical benefit (partial response [PR]+stable disease [SD]) in seven out of 12 patients (58%), and PR in five out of 12 patients (42%). The mean response rate in patients treated was 50% with AVB-500+PAC, and 33% with AVB-500+PLD. Three responders had at least 60% tumor regression, and two had more than 80%. The current average treatment duration for responders is seven months, and four of five patients who responded remain on study. Two have completed their chemotherapy regimen and are receiving AVB-500 alone. Ovarian cancer afflicts more than 22,000 women each year in the U.S., with about 14,240 deaths attributed annually to the deadliest of all gynecologic malignancies. Most patients are diagnosed with advanced disease that quickly becomes resistant to chemo.
Aravive said it continues to use model-informed drug development to guide selection of higher drug doses for evaluation in phase Ib and identify the optimal drug dose for AVB-500. Preliminary data from subsequent patients enrolled in the study have yielded an exposure-response relationship which has guided the company to study higher doses of the drug in the expansion cohort (15 mg/kg and 20 mg/kg every two weeks).
Separate from the ESMO presentation, Aravive offered updated info regarding the initial 28 evaluable patients in the ongoing expansion study. Here, AVB-500 continues to be well-tolerated, with response rates correlating to drug exposure. Peak and trough levels after the first dose of AVB-500 appear to predict antitumor activity, the company said, and the relationship of peak drug level with PR and clinical benefit rate were statistically significant, with "p" values of 0.0236 and 0.0337, respectively.
In all, 72.7% of patients with peak drug level >225 mg/L (the high drug level) achieved clinical benefit compared to 17.6% with peak drug level <225 mg/L (the low drug level). At a confidence level of 0.95, the "p" value was 0.0118. The clinical benefit rate in the first 28 patients stands at 61%, with 25% PR.
As the data continue to mature, the best response rates are subject to change, Aravive noted, but a review of the baseline characteristics and demographics of the patients did not reveal any apparent differences, suggesting that the drug exposure is the primary driver of antitumor activity. The company was careful to point out that the statistical significance is marginal, given the total of 28 subjects; results should be interpreted with that in mind.
Aravive plans to report the detailed analysis when data from the first 30 patients on the current 10-mg/kg dose mature, which will happen toward the end of this year, and the data analysis will be evaluated to inform the company's regulatory strategy. If exposure-response links as they stand now are confirmed in the dose-escalation portion of the expansion study by mid-2020, Aravive intends to explore an accelerated pathway with the regulators, McIntyre said. "My experience with the FDA is that they're very keen to get therapies that show such promise out there pretty quickly."
The company is also thinking about biomarker-driven, individualized dose adjustments, and will incorporate the exposure-response information into studies in clear-cell renal cancer and renal fibrosis. AVB-500's approach is somewhat analogous to the VEGF trap strategy, McIntyre said, "but when you inhibit VEGF, you will have cardiovascular issues. The stars sort of align here. We have knockout data that say you're not going to have toxicity if you knock this out of your developing animal or even your adult animal, and then we've done the monkey tox" without any signals. "This is very specific," she said. "We're mopping up GAS6 – we're just not letting it bind to AXL and start all of this downstream activity. I've worked in oncology for a long time now, but I have not had a drug that has basically a safety margin between monkeys and oncology patients," with solid efficacy as well. "When you flood the body with AVB-500, that protein, that high-affinity AXL decoy protein, is going to win."