cinrebafusp alfa (PRS-343) / Servier, Palvella Therapeutics - LARVOL DELTA

A First-in-Human Study of Cinrebafusp Alfa, a HER2/4-1BB Bispecific Molecule, in Patients with HER2-Positive Advanced Solid Malignancies (Clin Cancer Res) - P1 | N=85 | NCT03330561 | Sponsor: Pieris Pharmaceuticals, Inc. | "Of 40 evaluable patients in the 'active dose' efficacy cohorts, five showed an antitumor response, resulting in an overall response rate of 12.5% and a disease-control rate of 52.5%. Clinical activity was observed at the 8 and 18 mg/kg dose levels, with confirmed objective response rates of 28.6% and 25.0%, respectively. Cinrebafusp alfa was safe and tolerable, with grade ≤2 infusion-related reactions being the most frequent treatment-related adverse event."

P1 data • Solid Tumor

A First-in-Human Study of cinrebafusp alfa, a HER2/4-1BB Bispecific Molecule, in Patients with HER2-Positive Advanced Solid Malignancies. (PubMed, Clin Cancer Res) - "Cinrebafusp alfa demonstrates promising activity in patients with HER2-positive malignancies who have progressed on prior HER2-targeting regimens. Its acceptable safety profile suggests it could be a treatment option for patients not responding to existing HER2-directed therapies."

Journal • Metastases • P1 data • Oncology • Solid Tumor • HER-2 • TNFRSF9

PRS-343 in Combination With Atezolizumab in HER2-Positive Solid Tumors (clinicaltrials.gov) - P1 | N=41 | Completed | Sponsor: Pieris Pharmaceuticals, Inc. | Active, not recruiting ➔ Completed | Phase classification: P1b ➔ P1

Combination therapy • Metastases • Phase classification • Trial completion • Bladder Cancer • Breast Cancer • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

PRS-343-PCS_04_16: PRS-343 in HER2-Positive Solid Tumors (clinicaltrials.gov) - P1 | N=85 | Completed | Sponsor: Pieris Pharmaceuticals, Inc. | Trial completion date: Oct 2021 ➔ Dec 2023 | Trial primary completion date: Oct 2021 ➔ Dec 2023

Metastases • Trial completion date • Trial primary completion date • Bladder Cancer • Breast Cancer • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Genito-urinary Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor

Pieris Pharmaceuticals Provides Strategic Update and Announces Restructuring (Yahoo Finance) - "AstraZeneca has now informed the Company of its decision to terminate the parties' R&D collaboration agreement and hand back elarekibep along with discontinuing the remaining discovery program...Pieris' management and board of directors have assessed several strategic options, which will include focusing on execution of new or expanded partnerships to advance its therapeutic programs, including cinrebafusp alfa (PRS-343), PRS-220 and PRS-400...Pieris will prioritize capital preservation, with cash, cash equivalents and investments totaling approximately $54.9 million as of June 30, 2023....'One track is accelerating partnering discussions of PRS-220 and PRS-400. A second focal area is diligently selecting the best possible development partner and deal structure to re-initiate clinical development of cinrebafusp alfa, our former lead immuno-oncology asset, which has shown 100% ORR in five patients in a HER2+ gastric cancer trial that was discontinued for strategic reasons."

Commercial • Licensing / partnership • Pipeline update • Asthma • Gastric Cancer • Idiopathic Pulmonary Fibrosis • Immunology • Interstitial Lung Disease • Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor

Combination of cinrebafusp alfa with ramucirumab and paclitaxel is well tolerated and elicits encouraging clinical activity in patients with HER2-positive gastric/gastroesophageal junction (GEJ) adenocarcinoma (AACR 2023) - "The combination of cinrebafusp alfa with ramucirumab and paclitaxel was safe and tolerated in the 5 patients treated. Preliminary activity of cinrebafusp alfa in combination with ramucirumab and paclitaxel demonstrated a high response rate indicating that the combination can elicit clinical responses in patients who have progressed on trastuzumab deruxtecan or checkpoint inhibitor regimens."

Clinical • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • HER-2

Pieris Pharmaceuticals Announces Presentation of Positive Clinical Data for Cinrebafusp Alpa (PRS-343) At 2023 AACR Annual Meeting (Issuer Direct) - P2 | N=80 | NCT05190445 | Sponsor: Pieris Pharmaceuticals, Inc. | "Pieris Pharmaceuticals, Inc...announced the presentation of cinrebafusp alfa (PRS-343) clinical results from the Company's study in 2L+ HER2-positive gastric cancer at the American Association for Cancer Research annual meeting being held in Orlando, Florida on April 14-19, 2023. The study's principal investigator, Dr. Geoffrey Ku, will present these encouraging results at 1:30 PM EDT on April 17, 2023, which include an unconfirmed 100% objective response rate and promising emerging durability profile in the five patients enrolled into the study before discontinuation of enrollment for strategic reasons....The combination regimen was well tolerated, and all patients experienced a partial clinical response, with three patients remaining on study as of the abstract submission cut-off date of December 19, 2022."

P2 data • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

A phase 2, multi-center, open-label study of cinrebafusp alfa (PRS-343) in combination with ramucirumab and paclitaxel in patients with HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma and in combination with tucatinib in patients with HER2 low gastric or gastroesophageal junction (GEJ) adenocarcinoma (AACR 2022) - "Background: For patients (pts) with HER2-overexpressing metastatic gastric cancer, trastuzumab + chemotherapy +/- pembrolizumab is a standard first-line option but only provides an incremental overall survival (OS) benefit vs chemotherapy. Recruitment is ongoing. Approximately 10 sites in 3 countries in US, Asia and Europe are expected to participate."

Clinical • Combination therapy • P2 data • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • CD8 • HER-2

A phase 2, multi-center, open-label study of cinrebafusp alfa (PRS-343) in patients with HER2-high and HER2-low gastric or gastroesophageal junction (GEJ) adenocarcinoma (ESMO-GI 2022) - P2 | "Background For patients (pts) with HER2-overexpressing metastatic gastric cancer, trastuzumab + chemotherapy +/- pembrolizumab is a standard first-line option but only provides an incremental overall survival (OS) benefit vs chemotherapy. Significant induction of plasma 4-1BB as well as increase of CD8+ cells was observed in on-treatment tumor biopsies at active dose levels (Piha-Paul, SITC 2020). Based on pharmacokinetics (PK), pharmacodynamics (PD) and clinical efficacy data, a phase 2 dose of 18mg/kg Q2W in C1 followed by 8mg/kg Q2W maintenance was chosen."

Clinical • P2 data • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • CD8 • HER-2

"$SGEN $PIRS given the sudden stop of PRS-343, SGEN holding a stake in Pieris and knowing the preclinical combo data were promising as well as seeing responses in the clinic" (@dhovekamp42)

Preclinical

Cinrebafusp Alfa in Combination With Ramucirumab and Paclitaxel in HER2-High Gastric or GEJ Adenocarcinoma and in Combination With Tucatinib in HER2-Low Gastric or GEJ Andenocarinoma (clinicaltrials.gov) - P2 | N=80 | Active, not recruiting | Sponsor: Pieris Pharmaceuticals, Inc. | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor

Pieris Pharmaceuticals Reports Second Quarter 2022 Financial Results and Provides Corporate Update (Issuer Direct) - "Cinrebafusp Alfa (PRS-343):...Pieris will cease further enrollment in the ongoing two-arm, multicenter, open-label phase 2 study as part of a strategic pipeline prioritization to focus its resources."

Enrollment closed • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

"$PIRS to discontinue cinrebafusp alfa (PRS-343) trial" (@BioStocks)

Anticalin®-based therapeutics: Expanding new frontiers in drug development. (PubMed, Int Rev Cell Mol Biol) - "The small size and stable structure support their development as inhalable biologics in the field of respiratory diseases as already demonstrated for PRS-060/AZD1402, an Anticalin protein currently undergoing clinical development for the treatment of asthma. Cinrebafusp alfa and PRS-344/S095012 antibody-Anticalin bispecific proteins were designed to reduce potential systemic toxicity by localizing the activity to the tumor, and are currently in clinical development in immuno-oncology. Furthermore, the ease in generating bi- and multispecifics as well as the small and stable structure prompted the investigation of Anticalin proteins for the CAR T space, opening additional potential treatment options based on Anticalin protein therapies."

Journal • Asthma • Immunology • Oncology • Pulmonary Disease • Respiratory Diseases

Pieris Pharmaceuticals Reports First Quarter 2022 Financial Results and Provides Corporate Update (Yahoo Finance) - "Cinrebafusp Alfa (PRS-343): Enrollment continues in the two-arm, multicenter, open-label phase 2 study of cinrebafusp alfa, a 4-1BB/HER2 Anticalin-based bispecific for the treatment of HER2-expressing gastric cancer....The Company is reiterating its guidance and expects to report data from this arm in 2023. The second arm of the study is evaluating the efficacy, safety, and tolerability of cinrebafusp alfa in combination with tucatinib in patients with HER2-low gastric cancer. The Company is revising its guidance and now expects to report data from this arm next year due to slower than anticipated enrollment."

Enrollment status • P2 data • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

PRS-343-PCS_04_16: PRS-343 in HER2-Positive Solid Tumors (clinicaltrials.gov) - P1; N=85; Completed; Sponsor: Pieris Pharmaceuticals, Inc.; Recruiting ➔ Completed; Trial primary completion date: May 2021 ➔ Oct 2021

Clinical • IO biomarker • Trial completion • Trial primary completion date • Bladder Cancer • Breast Cancer • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Genito-urinary Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Urothelial Cancer • HER-2 • TNFRSF9

Cinrebafusp Alfa in Combination With Ramucirumab and Paclitaxel in HER2-High Gastric or GEJ Adenocarcinoma and in Combination With Tucatinib in HER2-Low Gastric or GEJ Andenocarinoma (clinicaltrials.gov) - P2; N=80; Recruiting; Sponsor: Pieris Pharmaceuticals, Inc.

Clinical • Combination therapy • New P2 trial • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor

Pieris Pharmaceuticals Announces Dosing of First Patient in Phase 2 Gastric Cancer Trial of 4–1BB/HER2 Bispecific Cinrebafusp Alfa (Yahoo Finance) - "Pieris Pharmaceuticals, Inc....today announced that the first patient has been dosed in the phase 2 study of cinrebafusp alfa (PRS-343)...for the treatment of HER2-expressing gastric cancer. The two-arm, multicenter, open-label phase 2 study is evaluating the efficacy, safety, and tolerability of cinrebafusp alfa in combination with ramucirumab and paclitaxel in patients with HER2-high gastric cancer and in combination with tucatinib in patients with HER2-low gastric cancer."

Trial status • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

"$PIRS Q3. Cash $125M Dosing completed in part 1a of phase 2a study of PRS-060/AZD1402 Dosing to begin this quarter in phase 2 study of cinrebafusp alfa" (@BioStocks)

P2a data

Pieris Pharmaceuticals Reports Third Quarter 2021 Financial Results and Provides Corporate Update (Pieris Press Release) - "Cinrebafusp Alfa (PRS-343): Pieris plans to dose the first patient in a two-arm phase 2 study for cinrebafusp alfa, a 4-1BB/HER2 bispecific for the treatment of HER2-expressing solid tumors, in gastric cancer this quarter and reconfirms its plan to report initial data from the arm evaluating cinrebafusp alfa in combination with tucatinib in HER2-low gastric cancer next year. The Company has decided to focus enrollment on second line patients and now expects to report data from the arm evaluating cinrebafusp alfa in combination with ramucirumab and paclitaxel in HER2-high gastric cancer in 2023."

P2 data • Trial status • Gastric Cancer • Gastrointestinal Cancer • Oncology

A Phase 1 Dose Escalation Study of PRS-343, a HER2/4-1BB Bispecific Molecule, in Patients with HER2-positive Malignancies (SITC 2019) - "To date PRS-343 is, to the best of our knowledge, the first clinical-stage bispecific molecule targeting 4-1BB activation to the tumor microenvironment, with initial evidence of both safety and efficacy."

Clinical • Late-breaking abstract • P1 data • Oncology • Solid Tumor

[VIRTUAL] A phase I dose escalation study of PRS-343, a HER2/4-1BB bispecific molecule, in patients with HER2-positive malignancies (ESMO 2020) - P1 | "We will also present results of a PRS-343/atezolizumab combination trial in HER2+ solid tumors...Based on these data, a phase II trial in gastric/GEJ cancer has been planned in combination with ramucirumab and paclitaxel...Funding: Pieris Pharmaceuticals. Clinical trial identification: NCT03330561."

Clinical • P1 data • Gastric Cancer • Gastrointestinal Cancer • Gynecologic Cancers • Melanoma • Oncology • Pancreatic Cancer • Solid Tumor • CD8 • HER-2

[VIRTUAL] Clinical and biomarker activity of PRS-343, a bispecific fusion protein targeting 4-1BB and HER2, from a phase 1 study in patients with advanced solid tumors (Study PRS-343-PCS_04_16) (AACR 2021) - "The authors did not submit an updated abstract. The original abstract should be considered final."

Biomarker • Clinical • P1 data • Oncology • Solid Tumor • HER-2

Pieris Pharmaceuticals Reports Second Quarter 2021 Financial Results and Provides Corporate Update (Issuer Direct) - “Cinrebafusp Alfa (PRS-343): Pieris plans to dose the first patient in a two-arm phase 2 study for cinrebafusp alfa, a 4-1BB/HER2 bispecific for the treatment of HER2-expressing solid tumors, in gastric cancer in the coming weeks…The Company expects to report results from both study arms next year…PRS-344/S095012 and Servier Collaboration: The phase 1 study of PRS-344/S095012, a 4-1BB/PD-L1 bispecific, is expected to begin later this year.”

New P1 trial • New P2 trial • P2 data • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

"Monotx PRS-343 is well tolerated & safe up to 18 mg/kg – no safety signals, no DLT identified. Increase in CD8+ cells, NK cells & cytotoxic activity in TME. Soluble 4-1BB increases in blood indicating target engagement of 4-1BB & activation of immune cells. #AACR21 $MTEM" (@mikegoodma)

Clinical • Oncology • CD8