The phase II win against newly diagnosed glioblastoma multiforme (GBM) with the heat-shock protein (HSP) vaccine Prophage helped shares of Agenus Inc. to a satisfying rise, and brought hope for patients in the especially virulent form of brain cancer, which usually kills within one year.

Prophage, an autologous vaccine, turned up median overall survival (OS) of about 24 months when combined with standard of care, with 33 percent of patients alive at two years and still being followed for survival, the Lexington, Mass.-based company said.

Shares of Agenus (NASDAQ:AGEN) closed Tuesday at $3.55, up 33 cents, or 10.3 percent.

"I come at things from a somewhat skeptical background in general [and tend] to look at every way we could be potentially misled," said Robert Stein, chief scientific officer. "I don't see an obvious way that this represents an anomalous result."

Vaccine-treated patients in the study had a median progression-free survival (PFS) of almost 18 months, about two to three times longer than patients treated with radiation and the alkylating agent temozolomide alone. Twenty-two percent of patients were alive and without progression at 24 months and also will be followed for survival outcomes.

"I've been doing this for a long time," Stein told BioWorld Today. "I think [the efficacy thus far] borders on the miraculous, in that patients who would undoubtedly have died of their disease are now living and not just having their deaths delayed by trivial amounts of time, but actually living long enough to die from something else. We have a pretty long tail of patients living, the longest is almost four years out, and we have a number of them two or three years out."

Researchers found that response to Prophage seemed stronger in patients with less expression of the checkpoint ligand PDL-1 on their white blood cells, which could mean Prophage will complement checkpoint modulators such as PD-1 antagonists. Stein sees "at least two on the horizon" that might lend themselves to pairing with Prophage, he said: MK-3475 (pembrolizumab) from Merck & Co. Inc., of Whitehouse Station, N.J., and nivolumab, from New York-based Bristol-Myers Squibb Co. (BMS).

"The thing to recognize [about Prophage] is that this is not a dendritic cell vaccine," Stein said. "It's a biochemical preparation that can be made in a cost-effective way, it melds seamlessly with standard of care and it doesn't bring with it side effects," all traits that led the compound nicely to combination prospects.

Merck in May completed filing its FDA biologics license application for MK-3475, seeking approval to treat melanoma patients unsuccessfully treated with Yervoy (ipilimumab, BMS), an indication for which the FDA has granted it both breakthrough designation and priority review status. The FDA assigned Merck's application an Oct. 28 PDUFA date. Merck plans to file a marketing authorization application for MK-3475 in Europe for advanced melanoma by the end of 2014. (See BioWorld Today, May 7, 2014.)

"We have our own PD-1 program, and while we might think about combinations with one of the two that are likely to be registered soon, we have different options in the future," Stein said.

Agenus (previously known as Antigenics Inc.) has "six very good checkpoint modulator programs where we're going to put the focus of our internal spend," Stein said. Deal talks have begun with regard to Prophage and GBM. "The exact design [of the next trials] would be something shaped in discussions with a potential partner," he said. The company in late April signed a deal with Merck through a subsidiary. Under the terms, Agenus will discover and optimize fully human antibodies against two undisclosed Merck checkpoint targets using the 4-Antibody Retrocyte Display platform. Merck is handling clinical development and commercialization of candidates generated under the agreement, with Agenus eligible for about $100 million in milestone payments. Agenus gained rights to the platform technology through its February acquisition of Basel, Switzerland-based 4-Antibody AG.

The GBM phase II trial includes 46 patients treated at eight centers across the U.S., treated with surgical resection, radiation and temozolomide as the standard of care along with Prophage. Specifically, median overall survival (OS), the primary endpoint of the trial, totaled 23.8 months and remains durable in patients treated with Prophage, compared to standard of care alone, where median OS was 14.6 months. PFS reached 17.8 months.

Agenus uses the HSP gp96, purified from the patients' own tumor tissues, as a way to make an individualized vaccine. After the patient undergoes surgery, the tumor is shipped frozen to Agenus. The vaccine is made in about 10 hours, after which it undergoes extensive quality testing which takes about two weeks. Turnaround time for the drug from the date of surgery is about three to four weeks, as the patient is recovering. The vaccine is given as a simple intradermal injection and bears a shelf life of up to 24 months.

H.C. Wainwright & Co. analyst Reni Benjamin greeted the data "with cautious optimism, as it serves to validate the ongoing Prophage program, but we note that a single-arm study utilizing historical controls is not ideal given patient-to-patient variability in [GBM] survival data seen to date," he wrote in a research report.

Stein acknowledged that GBM "is a terrible disease, but somewhat heterogeneous. We've made every effort that we could to make sure that our patient population is representative, not preferentially enriching for people who are have a more favorable prognosis at the outset."

With $64 million in pro forma cash and the checkpoint inhibitors bound for clinical experiments in 2016, the firm, in analyst Benjamin's view, "represents an undervalued player in the immuno-oncology space."

STIMULON RESPONSE IN HERPES

There's more to come with Prophage, undergoing a combination phase II trial against melanoma with Yervoy, begun in the first quarter of this year. Prophage is being tested also in a randomized phase II trial when combined with Avastin (bevacizumab, Roche AG) against recurrent GBM, expected to complete enrollment in the middle of next year.

Among Agenus' other programs involve the company's QS-21 Stimulon adjuvant, made of an extract from the bark of Quillaja saponaria, an evergreen tree that grows in central Chile. QS-21 Stimulon, purified from a crude extract, apparently activates T-cell-mediated and humoral immunity, having been studied in many trials during 15 years of development. The adjuvant is involved in 20 programs at Agenus, Glaxosmithkline plc (GSK) and New Brunswick, N.J.-based Johnson & Johnson.

Partner GSK, of London, rolled out some bad news last year and the year before, reporting first the failure of the phase III DERMA trial with its MAGE-A3 cancer immunotherapeutic, formulated with QS-21 Stimulon, which missed its primary endpoint of extending disease-free survival (DFS) in melanoma. Next came a fizzle in non-small-cell lung cancer, in which the phase III MAGRIT trial of GSK's immunotherapeutic, known as zastumotide, missed both the first and second co-primary endpoints. Treatment did not significantly extend DFS compared to placebo in the overall MAGE-A3-positive population or in MAGE-A3-positive patients who did not receive chemotherapy. (See BioWorld Today, March 21, 2014.)

Things were looking up for the adjuvant, though, last week, when Agenus reported phase II data from a trial with the Herpv vaccine for treating genital herpes simplex virus-2 (HSV-2). Herpv contains an HSP in complex with 32 synthetic HSV-2 peptide antigens, plus QS-21 Stimulon. Agenus found that the majority of patients showed an immune response to the HSV antigens after a series of vaccinations and a booster dose at six months. More than half developed a robust anti-HSV cytotoxic T-cell immune response, and in those patients there was a statistically significant 75 percent reduction in viral load (p < 0.001).

Details from the 80-patient trial proved especially interesting. Designed to assess efficacy 45 days after a series of three vaccinations, the study last November yielded top-line data that showed a statistically significant 15 percent reduction in viral shedding (RR = 0.85, p = 0.015), as well as a 34 percent reduction in viral load that was not statistically significant (p = 0.08). All 80 patients received booster injections six months after the first shot, and more than half came away with a cytotoxic T-cell response. Among the immune responders, viral load dropped 75 percent (p < 0.001), which works out to about 40 percent for all of the patients. A 14 percent reduction in viral shedding (RR = 0.86) for the booster follow-up was in line with primary (45-day) analysis results, which seems to promise a long-term durable response.

Competitors in HSV-2 include Cambridge, Mass.-based Genocea Biosciences Inc., which is testing its protein subunit vaccine GEN-003. Genocea on Tuesday disclosed positive top-line follow-up data from a phase I/IIa study. At 12 months after the final dose, in an analysis of an exploratory endpoint, the mean reduction in genital lesion rate was 42 percent below baseline for the best-performing 30-mcg dose group, indicating that GEN-003 may continue to provide a durable effect on genital lesions beyond the six months previously reported, the company said. GEN-003 remained safe and well tolerated. Genocea intends to explore additional dose combinations in its upcoming phase II dose-optimization study, which may identify a dose that further improves the magnitude or durability of GEN-003's effect.

Vical Inc., of San Diego, has at the phase I/II stage a Vaxfectin-formulated therapeutic HSV-2 vaccine, helped by a cationic, lipid-based formulation that enhances plasmid DNA-based vaccines as well as protein- and peptide-based ones.

Preliminary data with Vical's vaccine should arrive in the middle of next year.