SITC 2019 preview – Pieris joins the quest for a better Herceptin

Any signs of efficacy with PRS-343 could help Pieris claw back some of its recent losses, but Her2 targeting is increasingly competitive.

Pieris Pharmaceuticals’ lead immuno-oncology asset, PRS-343, has so far flown under the radar. This might be about to change, with the 4-1BB and Her2-targeting bispecific set to feature in a late-breaking presentation at the Society of the Immunotherapy of Cancer conference on Friday.

The findings will be early but analysts hope to see some evidence of activity in the form of response rates. With many other companies vying to develop next-generation Her2-targeting agents, Pieris will have to hope that its different approach will sets PRS-343 apart.

Reducing toxicity?

Activating 4-1BB stimulates a T-cell response, but previous efforts to harness this mechanism have led to liver toxicity. By homing in on Her2-positive cancer cells, PRS-343 is designed to limit the immune response to the tumour microenvironment; the hope is that this will help the project avoid these side effects.

The subject of the SITC presentation is a phase I dose-escalation trial in patients with various advanced Her2-positive solid tumours including breast, gastric and bladder cancers. So far only the title has been disclosed; Pieris has said that it plans to present comprehensive pharmacokinetic, safety, tolerability and biomarker data at the meeting.

Evercore ISI analysts are also hoping to see some data on response rates, noting that Pieris has implied that “at least some” patients responded to PRS-343.

In a bigger trial, a meaningful bar to hit would be around 15% in metastatic breast cancer, in line with what Herceptin monotherapy can achieve in heavily pre-treated patients, and 20% in gastric cancer, similar to that seen with immunotherapy.

However, the upcoming data will be tricky to interpret given the small number of patients in each PRS-343 dosing group. A more realistic expectation, according to Evercore, would be to see “at least a few responses” in breast and bladder cancer patients at the high doses being tested.

Another thing to watch out for will be any signs that PRS-343 could be turning “cold” tumours “hot”, indicated by increased infiltration of cytotoxic T cells into the tumour. This could be particularly important for PRS-343’s chances as a combination therapy – a phase I trial testing the project in combination with Roche’s Tecentriq is also ongoing.

Her2 rush

Still, Pieris is far from the only company looking at Her2. The most advanced of the industry’s efforts to produce a better Herceptin is Astrazeneca and Daiichi’s antibody-drug conjugate trastuzumab deruxtecan, which is expecting a US approval decision in the second quarter.

This project is forecast to be the most valuable next-gen Her2 project, according to EvaluatePharma sellside consensus; indeed, it is currently considered the sector’s most valuable oncology R&D project by some way.

Selected mid-to-late-stage next-gen Her2-targeting projects
Project Company Description Setting & trial details 2024e sales ($m)
Filed
Trastuzumab deruxtecan/DS-8201 Astrazeneca/
Daiichi Sankyo
Anti-Her2 antibody drug conjugate Metastatic breast cancer, approval decision due in Q2 2020 2,719
Phase III
Tucatinib Seattle Genetics Her2-selective TKI  Metastatic breast cancer, Her2Climb trial reported 320
Pyrotinib Jiangsu Hengrui Medicine EGFR & Her2 dual kinase inhibitor Metastatic breast cancer, China trials ongoing inc Herceptin combo 381
Margetuximab Macrogenics Anti-Her2 Fc-optimised MAb Metastatic breast cancer, Sophia trial reported 319
TAK-788 Takeda EGFR & Her2 dual kinase inhibitor 1L NSCLC with EGFR exon 20 insertions, phase III not yet recruiting 134
Varlitinib Aslan Pharmaceuticals Pan-Her inhibitor Metastatic biliary tract cancer, data from Treetopp trial imminent 4
SYD985/trastuzumab duocarmazine Synthon Anti-Her2 MAb-duocarmycin conjugate Breast cancer, Tulip trial ongoing -
BAT8001 Bio-Thera Solutions Anti-Her2 MAb-maytansinoid conjugate Metastatic breast cancer, China trial ongoing -
Phase II 
MCLA-128/zenocutuzumab Merus Anti-Her2 & Her3 bispecific antibody NRG1 fusion cancers; focus now on pancreatic & NSCLC 320
Tesevatinib Kadmon EGFR, Her2 & VEGFR kinase inhibitor Glioblastoma 247
ZW25 Zymeworks Her2 x Her2 bispecific Gastroesophageal adenocarcinoma 89
AE37 Vaccine Generex Biotechnology Anti-Her2 vaccine TNBC in combo with Keytruda -
Neuvax/nelipepimut-s Sellas Life Science Anti-Her2 vaccine Breast cancer in combo with Herceptin -
Source: EvaluatePharma, clinicaltrials.gov.

As for the chasing pack, hopes are rising for Seattle Genetics’ tucatinib after the company recently reported a win in the Her2Climb trial; a filing in third-line Her2-positive metastatic breast cancer is slated for the first quarter of 2020.

But another Her2 hopeful, Macrogenics, might struggle to find a niche for its candidate margetuximab. The latest overall survival data from the Sophia trial failed to impress, and the project could end up being reserved for patients already treated with trastuzumab deruxtecan and tucatinib, Leerink analysts reckon.

Meanwhile, Merus has switched focus with its Her2 and Her3-targeting bispecific – it had been testing the compound in breast and colorectal cancer, but has now homed in on pancreatic and non-small cell lung cancer patients with NRG1 fusions following positive early findings in this group, which were presented at the Triple Meeting.

Zymeworks also had data at that conference, from a phase I study of its bispecific ZW25. The project is designed to bind to two different locations on Her2 with the aim of increasing potency – Zymeworks makes the bold claim that the asset could be the best-in-class Her2-targeting antibody. The group plans to put this to the test with a phase III trial slated for next year pitting ZW25 against Herceptin in first-line gastro-oesophageal adenocarcinoma.

Against this backdrop, Pieris might have its work cut out to find a niche, and the stakes are particularly high for the company after phase I data with the inhaled IL-4 antagonist PRS-060 sent its share price tumbling in September. Still, any positive signs with PRS-343 could give the beleaguered group a boost.

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