DUBLIN – Curevac GmbH has found another taker for its mRNA-based vaccine technology, in the shape of Boehringer Ingelheim GmbH, which is paying €35 million (US$45.4 million) up front and up to €430 million in milestones for global development rights to CV9202, a therapeutic vaccine in development for non-small-cell lung cancer (NSCLC).

The deal comes just a couple of months after Tübingen, Germany-based Curevac entered a deal with €150.5 million in attached milestones with the Sanofi Pasteur arm of Paris-based Sanofi Group on a prophylactic vaccine directed at an undisclosed pathogen. Taken together, the two alliances mark a commercial coming-of-age for a technology that has also won broad support from investors – or from one in particular, Dievini Hopp BioTech Holding GmbH & Co. KG, which put €80 million into the company two years ago. (See BioWorld Today, Sept. 18, 2012.)

Curevac's RNAactive technology consists of naked RNA molecules encoding cancer antigens, which are delivered by an intradermal injection, following which they are taken up and expressed by dendritic cells. Each vaccine comprises multiple antigens. CV9202 encodes six, including MAGE-C1, MAGE-C2, NY-ESO-1, survivin, 5T4 and MUC1. Each of them is packaged with protamine, a histone-like salmon protein that stabilizes the RNA molecule and stimulates the host immune system through Toll-like receptor 7 (TLR-7).

The molecules are not chemically modified, apart from sequence modifications that boost their stability and expression. A predecessor vaccine, CV9201, which encoded five antigens, demonstrated safety and immunogenicity in a phase I/IIa study.

"We are sure it's a transient approach – the RNA is degraded after a couple of days," Curevac CEO Ingmar Hoerr told BioWorld Today. The kinetics favor a prime-boost immunization strategy, where appropriate.

Boehringer, of Ingelheim, Germany, plans to move CV9202 into combination studies with afatinib (Gilotrif/Giotrif), its recently approved inhibitor of ErbB family kinases, and with chemotherapy. At ASCO in June, it reported data from a pooled, posthoc analysis of two phase III studies, which indicated that afatinib conferred a survival benefit of more than one year, as compared with chemotherapy, in first-line patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions (Del19). Those account for about half of all activating EGFR mutations in NSCLC, with a prevalence of about 40 percent in Asian patients and about 10 percent to 15 percent in Caucasian patients.

Its combination with CV9202 could offer responders – and those with stable disease on the drug – the possibility of long-term survival, a rare outcome when kinase inhibitors are administered as monotherapy.

"This combination is very interesting," Hoerr said. "This anchored the negotiations with Boeheringer Ingelheim."

NSCLC remains a highly challenging cancer indication. The Genentech arm of Basel, Switzerland-based Roche Holding AG had a setback in a phase III trial earlier this year, when a much-vaunted combination therapy comprising onartuzumab, a monovalent antibody targeting the Met signal pathway, and the tyrosine kinase inhibitor (TKI) Tarceva (erlotinib), failed to demonstrate a survival benefit over Tarceva alone. (See BioWorld Today, March 4, 2014.)

Roche recently gained approval in Japan for a next-generation TKI, alectinib, for treating anaplastic lymphoma kinase fusion gene-positive (ALK+) NSCLC. It has breakthrough therapy designation in the U.S. Bristol-Myers Squibb Co. and Merck & Co. Inc. are both seeking approval in lung cancer for their programmed-death 1 (PD-1) inhibitors Opdivo (nivolumab) and Keytruda (pembrolizumab), which have already gained approval in melanoma in Japan and in the U.S., respectively.

Targeting immune checkpoints is, however, "a passive approach," said Hoerr. "I think the future lies in directing the immune system to the right target."

The company has entered an alliance with the New York branch of the Ludwig Institute for Cancer Research to undertake clinical trials that will combine its mRNA-based vaccines with the institute's immune checkpoint modulators.

Curevac is keeping its GMP production process in-house, as it is a proprietary process protected by patents. It is based on a cell-free transcription system that employs DNA plasmids as templates. It will use part of the up-front payment from Boehringer to scale up its production capabilities. At present, it can produce about 150 doses per year, Hoerr said, but it aims to extend that to more than 3 million. The step-up is not as daunting as that sounds, however, because of the small amounts of mRNA used in each dose.

Curevac's lead program, CV9104, is undergoing a phase IIb trial in prostate cancer patients, which is expected to read out in around 2017. "It's powered to give us a clear overall survival outcome," Hoerr said. An interim analysis of the event-based study may be available next year.