Analysts split on what the positive, pooled-groups phase II data in pancreatic cancer might mean for Halozyme Therapeutics Inc.'s larger, ongoing phase III trial, but the company sounded upbeat in a conference call on the top-line results from HALO 202 with PEGPH20 (pegylated recombinant human hyaluronidase).

Chief Medical Officer Athena Countouriotis said it's "premature for me to speculate in regard to what [the FDA] will think of the hazard ratio [HR] trend for overall survival [OS], but obviously we're very excited by the totality of the dataset."

Jefferies analyst Eun Yang, however, was less so and said her firm "remain[s] cautious" about the phase III outcome.

San Diego-based Halozyme popped the lid on top-line results from the combined analysis of stages I and II and stage II alone of HALO 202, a randomized, multicenter experiment with lead compound PEGPH20 in combination with Abraxane (nab-paclitaxel, Celgene Corp.) and gemcitabine in stage IV pancreatic cancer. Among the findings, the overall study population showed a statistically significant increase in progression-free survival (PFS) in patients with high levels of hyaluronan (HA-high) treated with the triple combo as compared to Abraxane and gemcitabine alone.

Stage II of the study, which completed enrollment in February 2016, showed a 91 percent improvement in median PFS for HA-high patients in the PEGPH20 arm, 8.6 months compared to 4.5 months in the control arm, and achieved its primary endpoint to evaluate and demonstrate a reduction in the rate of thromboembolic events (TEs) in the PEGPH20 arm.

"The phase III is a very unique design," Countouriotis said. "It's 420 patients randomized, a double-blind placebo-controlled study, very similar to our phase II in terms of patient population, companion diagnostic, etc. There is one interim analysis where we will evaluate the final PFS data and also have the opportunity to increase the sample size based on the overall survival [OS] data. We haven't given further specifics around that powering assumption, because that could jeopardize the integrity of the study," but the stage II OS results are "encouraging" with regard to the phase III assumptions, she said.

Yang dug into the details. The phase III trial begun in March 2016 is testing the drug in 420 patients at more than 160 sites, with co-primary endpoints of PFS and OS, powered to show an HR of 0.59 on the PFS endpoint, as compared to the PFS HR of 0.48-0.63 in phase II. Halozyme "sees approval as possible on PFS data at the interim analysis (at full number of PFS events' accrual), if [outcomes are] directionally supportive in OS" and if they show a favorable risk/benefit profile, she wrote in a report. Other possibilities at the interim peek, though, include continuing to the final analysis, boosting enrollment to 570 patients for the final OS measure or stopping the trial due to futility, she said. "In metastatic pancreatic cancer, the effect size in phase III meaningfully diminishes vs. phase II from prior experience," she added.

Piper Jaffray analyst Charles Duncan took a brighter view, saying that the pooled results, "while in a small group," demonstrate cause for optimism. The adaptive interim look triggered by PFS events "should help to avoid a 'near miss' on either endpoint," he wrote in a report. Even more upbeat was J.P. Morgan's Jessica Fye, who called the phase II results "better than expected" and found that they bode well for phase III findings. While she conceded that the PFS HR observed in stage II was not as strong as in stage I, the pooled HR in high-HA patients of 0.51 (p=0.048) is better than the PFS HR that the phase III is powered to show.

"Bigger picture, expectations heading into these data were low and, in our view, today's data is supportive of a PFS benefit with the drug," she wrote in a report. "That said, with the phase III just underway, it will be some time before we get the ultimate results and along these lines we see focus in the stock at least partially shifting back to the company's Enhanze pipeline opportunities."

The Enhanze hyaluronidase-based approach temporarily degrades hyaluronan, a chain of natural sugars in the body, to help other injected drugs disperse and absorb better.

STAGE II TE BALANCE PLEASES

Countouriotis said the phase II results "consistently showed a strong efficacy signal, not only from the stage II dataset in terms of both PFS with the 91 percent improvement in the median, but also [in] OS." Questioned about the 0.63 HR, she reminded listeners that "this is a small sample size with a small number of events and, as I mentioned, any one patient can have an impact on the overall HR, but we believe it still strongly supports the ongoing phase III's design, especially when you look at the combined data," with their "very strong improvement."

Temporarily breaking down hyaluronan – which is present throughout the body – is what Halozyme's marketed, injectable version of hyaluronidase does. Hylenex is approved for better subcutaneous fluid administration to achieve hydration, as well as to increase the dispersion and absorption of other injected drugs. In subcutaneous urography, it's deployed for improving the resorption of radiopaque agents. But Hylenex acts only locally at the injection site, is quickly inactivated in the body, and does not survive in the blood. Enter pegylated PEGPH20, with an increased half-life and intravenous delivery. About 50 percent of pancreatic cancer patients bear elevated hyaluronan, and attacking it at the corridor into the tumor can reduce the pressure, open up the blood vessels and deliver more drugs into it. The chance for approval based on PFS or OS gives Halozyme a leg up in the challenging indication. (See BioWorld Today, April 9, 2015.)

Enthusiasm was already building at the American Society of Clinical Oncology meeting in Chicago in 2015, where Halozyme shared some early phase II data. The good news came despite an earlier clinical hold due to an unexpected imbalance in TEs between the treatment and control groups. The hang-up prompted Halozyme to halt the study and modify its protocol before proceeding with a second stage. (See BioWorld Today, April 7, 2014, and June 2, 2015.)

J.P. Morgan's Fye observed that the latest stage II data "show only a slight imbalance in TE events with the addition of low-molecular-weight heparin (LMWH)." Specifically, In stage II they totaled 14 percent, or 12 out of 86 patients, in the triple-combo group vs. 10 percent, or four out of 39, a "clear improvement" over stage I, which tallied 43 percent vs. 23 percent.

"On the call, the investigator viewed these rates as comparable between the arms and said they are what one would expect with LMWH prophylaxis in this patient population," she noted.

Shares of Halozyme (NASDAQ:HALO) closed Thursday at $12.61, up $1.92, or 18 percent.