LONDON – Ethris GmbH sealed a five-year agreement with Astrazeneca plc and its Medimmune biologics subsidiary for the discovery of messenger RNA (mRNA) therapeutics for treating pulmonary diseases.

Under the terms of the deal, Ethris will receive €25 million ($29.5 million) up front and be paid to carry out research on an undisclosed number of targets in asthma, chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis.

In addition, the Munich, Germany-based company will be eligible for research and development milestone payments and sales royalties on products that make it to market.

That is far short of the $240 million up front that London-based Astrazeneca paid Moderna Therapeutics Inc. when the two agreed to work together in March 2013 to apply mRNA to cardiovascular and metabolic diseases as well as cancer. (See BioWorld Today, Mar. 22, 2013.)

However, this is the largest corporate deal signed by Ethris since its inception and will be important in helping to move its mRNA technology forward in pulmonary diseases, said CEO Carsten Rudolph.

"We have nominated targets in place, and Astrazeneca and Medimmune can nominate additional targets," Rudolph told BioWorld. "We hope to demonstrate, together with them, proof of concept of selected targets, and to have really viable candidates that can be developed into clinical programs."

He added, "This collaboration pairs our proprietary technology with the world-class expertise of Astrazeneca and Medimmune in respiratory diseases, biologics development and commercialization."

Ethris claims to have developed platform technologies that enable it to steer around the problems of immunogenicity, stability and intracellular delivery that have confounded attempts to shape mRNA constructs that can be used long term for the endogenous production of therapeutic proteins.

The company's stabilized, non-immunogenic mRNA (SNIM RNA) technology achieves this by replacing a proportion of certain native nucleotides with introduced nucleotides. "If you do it in the right ratio, you largely reduce the binding of mRNA to the immune system," said Rudolph.

The modifications simultaneously give mRNA greater stability.

In preclinical models, the chemical modification allows SNIM RNA to be administered repeatedly, leading to sustained expression of therapeutically active proteins.

In parallel, Ethris has developed polymer and liposomal formulations for intracellular delivery.

Whereas the vast majority of mRNA products in the pipeline aim to take advantage of mRNA's immunogenic properties for cancer vaccines and infectious disease treatments, Ethris aims both to replace recombinant protein therapies and to provide a safer, more effective form of gene therapy.

Although good animal evidence exists, as yet there are no human data demonstrating non-immunogenicity of SNIM RNA. "We are still in preclinical development, so we can't guarantee [non-immunogenicity]," Rudolph said. "But I'm very optimistic."

The most advanced product in the Astrazeneca/Moderna mRNA collaboration, AZD-8601, is one of very few mRNA programs in the clinic that has the aim of promoting endogenous production of a therapeutic protein.

However, AZD-8601 differs from the proposed Ethris products in consisting of naked mRNA for local administration. The product, which encodes for vascular endothelial growth factor (VEGF) A, is in a phase I trial in Germany to treat diabetic ulcers in men with type 2 diabetes.

Subjects are due to receive a single injection of AZD-8601, which, it is hoped, will initiate a strong, local and transient surge in production of VEGF A, leading to the production of new blood vessels and improved blood supply.

The deal with Astrazeneca also will allow Ethris to move forward its in-house programs in cystic fibrosis, two inherited ciliopathies with similar symptoms to cystic fibrosis and a treatment of the inherited urea cycle disorder ornithine transcarbamylase deficiency. Rudolph said the objective is to file the first investigational new drug application in 2019.

The amount of money raised by Ethris since it was spun out of Ludwig Maximilian University of Munich and the Technical University of Munich in 2009 has not been disclosed.

In addition to venture capital backing from HS Lifesciences and Orbimed, Ethris was awarded a €3.6 million government grant in 2011. Rudolph said the company, with its current programs, is funded up to 2019.