Aduro Biotech Inc. CEO Stephen Isaacs said the company suspects "more of a port issue" than anything else with the latest problem in pancreatic cancer trials with products based on the Listeria-based immunotherapy construct platform, using live, attenuated, double-deleted, or LADD, Listeria monocytogenes. "You can set up a biofilm on the port, in that if the port is accessed during the Listeria infusion – and that's what we went through in the first Listeria event – then you can get a positive draw out of the port," he said during a conference call with investors. "The question is, can the biofilm cause the symptoms that the patient is experiencing? We don't know, but we're instituting procedures to look into that question."

The FDA put a partial clinical hold on the program that bars enrollment of new patients in the phase II ECLIPSE experiment testing CRS-207, but those undergoing treatment can stay on it. The FDA's move followed notification of the agency that a blood culture sample from an indwelling port of a metastatic pancreatic cancer patient who presented with gastrointestinal symptoms tested positive for Listeria, which is suspected to be linked with CRS-207. The patient was doing well after intravenous (I.V.) antibiotics, and subsequent blood cultures tested negative for Listeria. Protocols will be revised in accordance with more feedback from regulators, Aduro said.

Only two such cases have arisen out of 350 treated with the LADD platform across indications.

Shares of the Berkeley, Calif.-based firm (NASDAQ:ADRO) closed Monday at $11.70, down 55 cents.

Late last year, Princeton, N.J.-based Advaxis Inc. was able to reach an agreement with regulators to lift the clinical hold on three compounds in its Listeria program. The agreement involved implementing risk-mitigation measures such as study protocol inclusion/exclusion criteria, post-administration antibiotic treatment and patient surveillance measures. (See BioWorld Today, Dec. 17, 2015.)

The hold for Advaxis' axalimogene filolisbac came in response to the company's submission of a safety report to the FDA involving one patient with end-stage cervical cancer who had last received the drug in early 2013. That patient underwent an accident between her first and second dose and as a result ended up with numerous in-dwelling medical implants. In July 2015, she was hospitalized, and during that stay cultured positive for Listeria monocytogenes, a finding traced back to Advaxis' therapy. The patient received a course of I.V. antibiotics and was discharged. In mid-August 2015, the patient returned to the hospital with respiratory distress caused by her metastatic disease and passed away later that day. The cause of death was found exclusively due to progression of her cervical cancer. Advaxis investigated and concluded that the positive culture for Listeria was highly likely related to the implants the patient received due to her accident between the first and second doses.

Jefferies analyst Biren Amin noted that Advaxis did not fully disclose the tweaked antibiotic regimen, but "we [suspect] it has incorporated trimethoprim/sulfamethoxazole into its trials. We suspect [the] FDA may have required an anti-infective regimen started several days after each cycle vs. after completion of all cycles, and Aduro may have to provide a similar regimen," he wrote in a research report. "Another option could be administration of a 21-day regimen after completion of all cycles. Nonetheless, it seems the trial protocols will be excluding patients with in-dwelling devices."

Meanwhile, though, Advaxis on Monday said the 12-month overall survival (OS) seen in stage two of its restarted trial was 37.5 percent. "These data are in line with the 38.5 percent reported in part one, despite minor dosing differences," Amin said. "Based on [medical] literature, the patients in both parts of this trial would've been expected to observe a 12-month OS of 25 percent vs. a 38 percent average between both stages." Stage two, he reminded investors, was interrupted by the clinical hold, so that only 24 patients were analyzed. "Previously, management planned to re-enroll stage two of this trial to generate additional data; however, based on the current data it no longer feels the need," he wrote.

Advaxis also aims to approach the EMA about moving ahead with an accelerated filing in refractory cervical cancer. Shares of Advaxis (NASDAQ:ADXS) closed Monday at $8.76, down 38 cents.

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As for Aduro, Natalie Sacks, chief medical officer, said the company's "assumption going forward is that whatever changes we make would affect all protocols using the LADD-based products," and changes would "include increased surveillance, specifically having patients come back after they've completed treatment on a regular schedule," along with altering the antibiotic regimen, though "very importantly" the changes would not be expected to affect the mechanism of action of the therapy. Aduro's CRS-207 is a live-attenuated listeria that secretes mesothelin into the cytosol of antigen presentation cells (APCs) that take up the Listeria. APCs go on to activate T cells to attack the tumor.

The latest holdup "represents another unfortunate perception knock for LADD," said Roth Capital Partners analyst Joseph Pantginis, whose confidence in the platform remains high. "We fully expect the company and FDA to institute thoughtful, modified protocols and for the programs to continue. We also believe investor confidence remains low on the interim STELLAR data expected shortly. Overall, we believe the LADD platform has been widely discounted by many investors based on our discussions. What remains unchanged, however, is the growing excitement for the STING program partnered with Novartis" AG, of Basel, Switzerland, he wrote in a report.

A phase IIb trial, STELLAR adds checkpoint inhibitor Opdivo (nivolumab, Bristol-Myers Squibb Co.) to GVAX and CRS-207. Opdivo and the other PD-1 checkpoint inhibitors haven't had much success as monotherapies to treat pancreatic cancer.

The prostate cancer vaccine GVAX, which is also combined with CRS-207 in ECLIPSE, has been tested by Cell Genesys Inc., which merged with Biosante Pharmaceuticals Inc., before it was purchased by Aduro. GVAX's overall response rate was less than optimal, but patients who responded had CD8+ T cells in their tumors, suggesting that up-regulating the immune system could enhance GVAX's activity.

In the spring of 2015, Aduro hooked up with Novartis. Their deal centers on the development and commercialization of immuno-oncology products generated from its stimulator of interferon genes (STING) targeted cyclic dinucleotide (CDN) platform technology. CDNs are small molecules naturally expressed by bacteria and immune cells that are known to activate the STING signaling pathway in immune cells. A central mediator of innate immune response, STING when stimulated induces the expression of various interferons, cytokines and T-cell recruitment factors that amplify and strengthen immune activity. (See BioWorld Today, Jan. 6, 2015.)

Under the terms of the agreement, Aduro will receive an initial up-front payment of $200 million with Novartis making a 2.7 percent equity investment in the company valued at $25 million, with a commitment for another $25 million investment that will be made at a later date.

In addition, Aduro could get up to $500 more million in milestone-based rewards. The pact covers the joint research, development and commercialization of CDN-based therapies in the field of oncology. Aduro will maintain rights to its CDN technology in all other therapeutic areas, including infectious disease and autoimmunity.

About two years ago, another pharma biggie came to the company's door when Johnson & Johnson unit Janssen Biotech Inc. committed $30 million up front, plus up to $787 million in milestones to Aduro for an exclusive global license to a lung cancer treatment based on the Listeria strategy. The deal followed Aduro's exclusive licensing of prostate cancer candidates to Janssen in May for up to $365 million. (See BioWorld Today, Oct. 17, 2014.)