On September 20, 2020 Pieris Pharmaceuticals, Inc. (NASDAQ:PIRS), a clinical-stage biotechnology company advancing novel biotherapeutics through its proprietary Anticalin technology platform for respiratory diseases, cancer, and other indications, reported a clinical data update from the phase 1 monotherapy and atezolizumab combination studies of PRS-343, a 4-1BB/HER2 bispecific for the treatment of HER2-positive solid tumors, in an oral presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Virtual Congress 2020 (Press release, Pieris Pharmaceuticals, SEP 20, 2020, View Source [SID1234565384]). PRS-343 continues to demonstrate durable clinical benefit in the active dose cohorts, including a confirmed complete response, in heavily pre-treated patients across multiple HER2-positive tumor types. Additionally, a significant expansion of CD8+ T cells in the tumor microenvironment of responders and a substantial increase of soluble 4-1BB were observed in the active dose cohorts, suggesting 4-1BB-mediated target engagement driving clinical benefit. PRS-343 also shows an acceptable safety profile at all doses and schedules tested in each clinical study. The Company reaffirms its commitment to moving PRS-343 into a phase 2 trial in second-line gastric cancer in combination with paclitaxel and ramucirumab.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"PRS-343 has shown remarkable clinical benefit in the treatment of patients who have cancers that are refractory to standard treatments. I am particularly impressed with the single-agent activity in these heavily pre-treated patients as well with as the durability of response," said Geoffrey Y. Ku, MD, Assistant Attending and Head, Esophagogastric Section, Gastrointestinal Oncology Service at Memorial Sloan Kettering and a principal investigator for the PRS-343 monotherapy trial. "I look forward to assessing the benefit of PRS-343 in combination with standard of care therapy, ramucirumab and paclitaxel, in second line HER2-positive gastric cancer."

The phase 1 first-in-human, open-label multicenter monotherapy trial has enrolled 74 patients, including 21 additional patients enrolled in higher dose cohorts (≥2.5 mg/kg) since the data presented at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 2019 Annual Meeting. Thirteen dose levels have been evaluated, 11 of which have been evaluated at a Q3W dosing schedule. The 11th dose level (8 mg/kg) has also been evaluated at a Q2W dosing schedule, including a Q2W dosing schedule in combination with obinutuzumab, and at a Q1W dosing schedule. The 12th (12 mg/kg) and 13th (18 mg/kg) dose levels have been evaluated exclusively at a Q2W dosing schedule.

The phase 1 first-in-human, open-label multicenter atezolizumab combination trial has enrolled 41 patients. Seven dose cohorts have been evaluated at a Q3W dosing schedule ranging from 0.05 mg/kg to 8 mg/kg in combination with a fixed 1200 mg dose of atezolizumab.

Primary objectives of both trials include characterizing the safety profile of PRS-343 in monotherapy or in combination with atezolizumab and identifying the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D) of PRS-343 alone and in combination with atezolizumab. Secondary objectives include assessing potential immunogenicity and pharmacodynamic effects, characterizing the pharmacokinetic profile, investigating a dosing schedule, and investigating efficacy.

As of the cut-off date of July 27, 2020, 33 patients in the monotherapy trial and 29 patients in the atezolizumab combination trial were evaluable for a response at active dose levels in the trials, which began at cohort 9 (2.5 mg/kg) in the monotherapy trial and cohort 4 (1 mg/kg) in the atezolizumab combination trial.

In the monotherapy study, one patient with stage 4 rectal adenocarcinoma achieved a confirmed complete response at the 18 mg/kg Q2W dose level and three patients achieved a partial response at the 8 mg/kg Q2W dose level.
In the atezolizumab combination trial, four patients achieved a confirmed partial response at active dose levels.
Across the active dose levels and schedules, 13 patients in the monotherapy trial and 8 patients in the atezolizumab combination trial experienced stable disease.
As of the cutoff date, treatment duration across active dose levels is over 66 weeks in the monotherapy trial and over 78 weeks in the atezolizumab combination trial for at least one patient.
Post-treatment increases in CD8+ Tumor Infiltrating Lymphocytes and blood-based s4-1BB suggest clinical benefit is linked to 4-1BB activity
Treatment-related adverse events (TRAEs) in both trials were primarily grade 1 and 2. The most common TRAEs in the monotherapy trial were infusion-related reactions. Less than 6% of TRAEs in the monotherapy trial were grade 3, and one TRAE in that trial was grade 4 (infusion-related reaction). The most common TRAEs in the atezolizumab combination trial were infusion-related reactions and vomiting. Less than 6% of TRAEs in the atezolizumab combination trial were grade 3, and there were two grade 3 or above events (grade 4 AST increase and grade 3 transaminitis that became grade 5 hepatic failure).
"The newly presented data reinforce our conviction in the significant potential of PRS-343, the only HER2-targeted adaptive immune system engager in clinical development, to improve the lives of patients with few treatment options," said Stephen S. Yoder, President and Chief Executive Officer of Pieris. "In addition to showing single-agent clinical benefit, including complete response, PRS-343 continues to show impressive durability of response. Furthermore, the biomarker data are consistent with a 4-1BB mechanism of action, validating our 4-1BB bispecific approach. We look forward to completing the in-use studies necessary for resolution of the partial hold and beginning the phase 2 trial of PRS-343 in combination with ramucirumab and paclitaxel alongside our clinical trial collaborator Eli Lilly and Company."

A copy of the presentation is available at this link.

About PRS-343:

PRS-343 is a 4-1BB/HER2 fusion protein comprising a 4-1BB-targeting Anticalin protein and a HER2-targeting antibody. The drug candidate is currently in development for the treatment of HER2-positive solid tumors. Ongoing phase 1 studies of PRS-343 include a monotherapy study and a combination study with atezolizumab. Based on encouraging initial results from both studies, which demonstrated clinical benefit and biomarker data indicative of a 4-1BB-driven mechanism of action, the Company is actively working towards completing the required in-use studies, resolving the partial hold and initiating a phase 2 study of PRS-343 in combination with ramucirumab and paclitaxel for the treatment of HER2-positive gastric cancer in a second line setting.