LONDON – Evox Therapeutics Ltd. sealed a $1.2 billion collaboration with Eli Lilly and Co. to apply its exosome technology to the doubly difficult task of systemically delivering RNA interference and antisense oligonucleotide drugs, to reach central nervous system targets.

This is the second big deal in under three months for Evox, which in March signed a $882 million agreement with Takeda Pharmaceutical Co. Ltd. to use its exosomes to deliver protein replacement and messenger RNA therapies in five rare diseases.

In the Lilly deal, Oxford, U.K.-based Evox will be responsible for engineering exosomes to achieve brain and CNS delivery to five unspecified neurological disease targets.

The terms include $20 million up front, research funding over three years and a $10 million investment from Lilly in exchange for a convertible bond. The rest of the $1.2 billion headline figure will be in milestone payments if all five products are approved, and will be followed by additional royalties on net sales of products that make it to market.

Evox will be responsible for exosome engineering to achieve brain/CNS targeting, drug loading and analytics. The company also will develop in vitro assays and manufacture material for in vivo preclinical studies. Candidates will be handed over to Lilly after preclinical proof-of-concept studies are completed.

The agreement will allow Evox to further assess and increase the power of its exosomes to deliver oligonucleotide payloads, at the same time as demonstrating the technology can be used to reach CNS targets, said Antonin de Fougerolles, CEO.

Antonin de Fougerolles, CEO, Evox

“CNS targeting is something we are very interested in, not only for RNAi and antisense oligonucleotides – the targeting technology could be used to deliver other payloads,” de Fougerolles said. “It was always an area where we wanted to find a partner like Lilly, with RNAi and oligonucleotide expertise,” he told BioWorld.

Exosomes are nature’s way of ferrying RNA to specific destinations around the body. In addition to developing efficient processes for culturing, extracting and purifying exosomes at scale, Evox has developed techniques for attaching targeting molecules to their outer surface and loading their interiors with various types of drug cargo.

To date, Evox has shown systemically administered exosome-loaded RNAi drugs can be delivered to the CNS in in vivo rodent models. Having Lilly as a partner and paying for the research, it will now be possible to work on further targets and move into higher animal models, said de Fougerolles.

Taken together, the deals with Lilly and Takeda will enable Evox to build its expertise in delivering different sorts of payloads, which it can then apply to its own pipeline. “The Lilly deal is completely non-overlapping on what we are doing with Takeda, as relates to indications and cargoes,” said de Fougerolles. “That is very useful in helping us advance different elements of our own programs.”

Neither the Lilly nor Takeda agreements involve broad licensing, leaving Evox plenty of scope in how it applies the resulting know-how.

De Fougerolles said the cash and research funding will be a significant boost for Evox’s in-house projects. “The way we view this, is that both deals allow us to do significant work on our proprietary programs,” de Fougerolles said. “It is going to be a springboard for internal development.”

So far, Evox’s internal research has focused largely on the delivery of protein replacement therapies and messenger RNA. “As we make sense of delivering RNAi and antisense oligonucleotides, we can use [the know-how] to target other non-neurological targets,” said de Fougerolles.

At present, the lead internal program is a treatment for the urea cycle disorder, arginosuccinic aciduria, a serious metabolic disease caused by a deficiency of arginosuccinate lyase. The enzyme plays a key role in the urea cycle in the liver, through which ammonia is detoxified. The overload of ammonia leads to severe neurologic impairment in patients with the rare inherited disorder.

In March 2019, Evox won a £1.5 million (US$1.8 million) U.K. government grant to fund preclinical development of the urea program in collaboration with researchers at University College London.

Other nondilutive funding has come from the Bill and Melinda Gates Foundation, which in December 2018 awarded Evox an undisclosed sum to work on using exosomes to deliver anti-infective drugs.

Evox most recently raised money in a series B round of $46.1 million in September 2018. De Fougerolles said the $10 million convertible bond it is issuing to Lilly “is helpful for us, as we think of what we might do in terms of future fundraising.”

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