LONDON – Evox Therapeutics Ltd. has validated its exosome drug delivery technologies in a $882 million deal with Takeda Pharmaceutical Co. Ltd., in which the partners will develop protein replacement and messengerRNA (mRNA) therapies in five rare disease indications. 

As an indicator of the potential therapeutic power of exosome delivery, the lead program in the collaboration rests on the ability of exosomes to cross the blood-brain barrier and deliver a correct copy of the NPC1 gene, to treat the inherited neurodegenerative disorder, Niemann-Pick type C.

Oxford-based Evox has been advancing the program in house and it is now in late-stage preclinical development. Another program, in an undisclosed rare disease, also is part of the deal, and in addition Takeda has the option to select three further rare disease targets.

“We are really excited to work with Takeda on this,” said Antonin de Fougerolles, CEO of Evox. “They bring a lot of expertise relevant to rare diseases. It will allow us to get these drugs into patients,” he told BioWorld.

The use of exosomes as delivery vehicles represents a novel approach to treating severe disease, said Madhu Natarajan, head of Takeda’s rare diseases drug discovery unit.” [They] offer a highly differentiated platform, with the potential to enhance tissue delivery for a variety of payloads, like mRNA and proteins,” he said.

Under the terms of the agreement, Evox is in line to receive up to $44 million in an up-front payment, near-term milestones and research funding. To reach the headline $882 million figure, all five products will need to make it to market. There also will be tiered royalties on sales.

Evox will be responsible for advancing the projects to IND-enabling studies and for manufacturing exosomes up to and including phase I. Once a program is handed over, Takeda will pay for manufacturing.

de Fougerolles said ongoing preclinical research in Niemann-Pick will be done in consultation with Takeda. “We are now looking at an in vivo model, and already have some data; we will continue to do more of that, and we have some pilot safety data in non-human primates. The goal is to continue and finish preclinical [research] and move into IND enabling studies in the next year or two.”

Exosomes are nature’s way of ferrying proteins, lipids and RNA to specific destinations around the body. Attempts to piggyback these capabilities date back two decades, but the difficulties of developing efficient processes for culturing, extracting and purifying exosomes at scale has presented a significant barrier to realizing their therapeutic potential.

Building on academic research carried out at Oxford University and the Karolinska Institute in Stockholm, Sweden, Evox has generated a substantial body of intellectual property around its GMP-grade manufacturing processes. It also has developed techniques for attaching targeting molecules to the outer surface of exosomes and loading their interiors with various types of drug cargo.

At around 50 nm to 200 nm in diameter, exosome drugs have the potential to mimic their naturally occurring counterparts in accessing cells and tissues currently out of the reach of other technologies that are used to deliver protein replacement and gene therapies.

Evox most recently raised money in a series B round of $46.1 million in September 2018 and de Fougerolles said the Takeda agreement, “significantly extends our cash runway into late 2022,” while providing the means to expand the in-house portfolio.

After licensing the Niemann-Pick product to Takeda, the lead internal program is an exosome-based treatment for the urea cycle disorder, arginosuccinic aciduria. The life-threatening metabolic disease is caused by a deficiency of arginosuccinate lyase, an enzyme that plays a key role in both the urea cycle in the liver, through which ammonia is detoxified, and in the synthesis of nitric oxide from L-arginine. An overload of ammonia leads to severe neurologic impairment in patients with the rare inherited disorder.

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

“That is advancing rapidly, and we expect to file and IND or CTA in 2021,” de Fougerolles said. “We also have a variety of other programs in rare metabolic and lysosomal storage disorders.”

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.

“These and other exploratory programs are moving forward,” de Fougerolles said. “This type of deal [with Takeda] allows us to significantly expand and build up what we are doing with our proprietary pipeline.”

Evox also has completed two other small-scale collaborations, in which pharma partners have assessed the capabilities of its exosomes. A number of other companies are lining up to put the exosome technology through its paces, de Fougerolles said.