Boston-based Pieris Pharmaceuticals Inc., during its March 12 earnings call, talked up gastric cancer prospect PRS-343, a 4-1BB/HER2 bispecific for HER2-positive solid tumors, which has turned up single-agent and checkpoint-combination antitumor activity. The good news included partial responses in heavily pretreated patients across multiple HER2-positive tumors, with biomarker data that suggest 4-1BB agonism on T cells in phase I dose-escalation experiments, which are continuing.

CEO Stephen Yoder said exact plans are “something that we feel is best suited for a more comprehensive update in the second quarter, which is informed by refined thinking after discussing things with our advisers and, of course, continuing to give the data time to mature.” Ingmar Bruns, senior vice president and head of clinical development, said the picture for PRS-343 has only brightened since the company presented phase I data at the Society for Immunotherapy of Cancer (SITC) meeting in National Harbor, Md., in November 2019, and during Pieris’ R&D Day the same month. The firm is “intrigued by the additional clinical benefit” seen from the monotherapy study, as well as the combo effort with Tecentriq (atezolizumab), from Basel, Switzerland-based Roche Holding AG. Tecentriq was first approved by the FDA in May 2016 for urothelial carcinoma.

Pieris also has PRS-060, an inhaled IL-4 receptor alpha antagonist for moderate to severe asthma that the firm is developing with Astrazeneca plc, of London. The drug yielded robust fractional exhaled nitric oxide, or FeNO, reduction in mild asthmatics in a phase I multiple ascending-dose study. The final cohorts are being enrolled in that trial to help inform the phase IIa experiment, likely to start in the second half of this year. Beyond that, Pieris continues to advance three of four discovery programs in its five-program respiratory collaboration with Astrazeneca, which will have the option to launch the fourth discovery program in the deal this year. The company also has some discovery-stage respiratory programs, one of which will be explained further at a medical meeting in the second half of this year.

Along with the Astrazeneca pact, Pieris has a potential $1.2 billion, three-program immuno-oncology (I-O) deal with Bothell, Wash.-based Seattle Genetics Inc., which in February 2018 brought in $30 million up front, with the promise of tiered royalties that could reach a low double-digit percentage of product sales. The companies are developing anticalin-antibody fusion proteins that combine an antibody-based tumor-targeting component with an agonistic anticalin that activates a co-stimulatory receptor to drive a T-cell response within the tumor microenvironment. That’s the strategy with PRS-343. “We think investors are keenly looking toward the next steps for the asset,” Wainwright analyst Joseph Pantginis wrote in a report, noting that the company is trying to “define the right bar in the right type of patients.” Relapsed/refractory (r/r) HER2-positive gastric cancer “remains a significant unmet medical need, mainly due to the lack of a bispecific targeted I-O approach,” he added. “To make sure we properly value PRS-343, however, we believe we need to wait for the combo trial to accrue in the second half of 2020, as well as results from the ongoing emerging therapy trials,” including one in second- and third-line r/r gastric cancer, due to report in the second half of 2020, and one in first-line disease, which just began.

Efforts with Servier still early

“As for the combo PRS-343 plus atezolizumab trial, it is hard to envision potentially lower bars,” in Pantginis’ view. Kenilworth, N.J.-based Merck & Co. Inc.’s Keytruda (pembrolizumab) was approved with an overall response rate of 13% and median overall survival of six months in third-line r/r gastric cancer with PD-L1 expression above 1%, though Keytruda failed in a second-line experiment, which points to the need for combination trials and the potential merit of PRS-343 as research goes on, he said.

PRS-343’s local action could provide benefit over single-specific antibodies, which fizzled because of systemic plus liver toxicity. Those include New York-based Bristol Myers Squibb Co.’s urelumab as well as utomilumab from Pfizer Inc., also of New York. “Considering its promising safety profile observed thus far both in the monotherapy and combo regimen and its underlying mechanism of action, we believe that the PRS-343 4-1BB targeting strategy may decouple the observed antitumor efficacy from the on-target liver toxicity by restricting the 4-1BB agonistic activity to the tumor microenvironment,” Pantginis said.

Utomilumab is also being tried in combination with Bavencio (avelumab, Pfizer Inc./EMD Serono Inc.) and others; the latter drug made headlines March 13 when Darmstadt, Germany-based Merck KGaA and Pfizer disclosed an update from the phase III Javelin study in head and neck cancer, testing Bavencio in addition to chemoradiotherapy (CRT) vs. standard-of-care CRT. The trial was halted because an independent data monitoring committee said it was unlikely to show a statistically significant improvement in the primary endpoint of progression-free survival, based on a preplanned interim analysis. A detailed analysis of the experiment was being prepared and will be shared later, Merck and Pfizer said.

More recently, Pieris provided an update on its collaboration with Les Laboratoires Servier SAS, inked in 2017. Servier has decided to focus on continued and accelerated development of the two most advanced programs, including PRS-344/S095012, and to discontinue development of the two earlier-stage programs in the deal, Pieris said. Analyst Pantginis weighed in, saying that “overall, the Pieris-Servier collaboration may continue to deliver critical milestones over the next 12 months as the two programs move forward. Due to their early nature, we are not including these two assets in our valuation, but we think these may represent upside to our investment thesis, which is now focused on the progress of lead assets, PRS-343 and PRS-060,” he wrote in a report.

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