Leading Approaches to Extracellular Vesicles Therapies

Extracellular vesicles therapy is gaining momentum. 

Two financings – and a surprise stock bump – in three days for the some of the most advanced extracellular vesicle (EV) companies show investors are champing at the bit to see the technology unleashed.

But the range of advancing approaches shows the versatility of the science at companies like Codiak, Evox and ExoPharm as they look to capitalize on a multitude of different opportunities.

Extracellular vesicles have come a long way in recent decades, as researchers realized their role in intracellular and intraspecies communication–and not just a cellular waste disposal system. Vesicles are formed inside all sorts of eukaryotic and prokaryotic cells and, depending on the species and function, can contain proteins, lipids, RNA and DNA.

After forming, the vesicles bud from the cell membrane and can travel safely via body fluids and be taken up by target cells or organisms, transmitting specific messages and even changing phenotypic activity. Extracellular vesicles play a role in disease spread, for example sending messages within the tumor microenvironment and contributing to metastasis, and companies like Exosome Diagnostics Inc. already market disease diagnostics based on detecting their presence.

But companies are even more interested in their therapeutic potential. Research over the last decade has shown that naturally occurring Extracellular vesicles–particularly exosomes, produced in mammalian cells–play vital roles in wound healing, tissue regeneration, immune response, limiting infection and more, and engineering can make them even more versatile.

Some research suggests EVs may provide most of the therapeutic benefit seen with cell therapies, without most of the risks associated with immune response. And some can naturally penetrate a variety of tissues to deliver their cargoes, making them a potential delivery vehicle for therapeutics that need to cross the blood-brain barrier.

First in Humans

The first clinical trials for an Extracellular vesicles-based therapy were announced in 2019 for Australian company Exopharm, testing its Plexaris blood platelet-derived EVs for wound healing in up to 20 patients in a safety/tolerability cohort and a biological activity cohort.

The company’s platform is built on a ligand-based exosome affinity purification (LEAP) technology for extracting and purifying EVs, which can be used for autologous testing, as in the Plexaris trial. The company is also planning a follow-on study using for an allogeneic approach to Plexaris.

Its leadership in the naïve Extracellular vesicles therapeutic space explains why Exopharm’s stock is up 173% in the past year. The company is one of several testing the innate ability of EVs as therapies, but it isn’t stopping there.

In May 2020, the company announced preclinical data showing Plexaris EVs could be engineered to load anticancer chemotherapy doxorubicin and increase its efficacy. The company has additional engineered preclinical programs in infectious disease and neurodegeneration, and another naïve EV program for osteoarthritis.

First Data

The next company into the clinic was Cambridge-based Codiak BioSciences, which began dosing patients in clinical trials for two lead programs last fall. The company specializes in engineered exosomes, fusing naturally occurring proteins from the Extracellular vesicles surface and lumina to different targeting or therapeutic molecules.

The first program out of the gate in September was a safety trial for its exoIL-12 therapy, which displays the pro-inflammatory cytokine IL-12 on its surface. IL-12-based immunotherapies have been successful in animal models, but no known IL-12-based cancer therapy has yet reached Phase III trials.

Codiak’s reported positive initial safety data for its exoIL-12 program in healthy people in December, showing no systemic exposure due to its ability to specifically target the tumor microenvironment. The next arm of the study will test exoIL-12 in patients with early-stage cutaneous T cell lymphoma.

In October, Codiak launched a Phase I/II trial for its exoSTING program in patients with advanced/metastatic, recurrent, injectable solid tumors. These Extracellular vesicles are engineered to deliver STING from the exosomes’ lumen directly to innate immune antigen-presenting cells near tumors, targeted using PTGFRN surface proteins to prevent toxic STING leakage into circulation. Safety and preliminary efficacy data are expected by the mid-2021.

Just weeks after the trials launched, Codiak closed a $74.4 million initial public offering, and last month it closed another public offering, netting $66.4 million in gross proceeds.

Follow the Money

The day after Codiak’s latest financing, rare disease company Evox Therapeutics announced a £69.2 million ($95.4 million) Series C round it said would push several preclinical assets into human testing in 2022, including engineered exosomes delivering protein therapeutics for argininosuccinic aciduria and citrullinemia type 1 and an undisclosed modality for phenylketonuria.

Evox also announced two deals last year with Eli Lilly and Takeda worth a total of $74 million up front. In the Takeda deal, the companies will codevelop what was Evox’s lead protein therapeutics program in Niemann-Pick disease type C (NPC), plus an undisclosed rare disease program delivering either a protein or mRNA therapy. And in June, Lilly and Evox agreed to develop up to five exosome therapeutics delivering brain- and CNS-targeting antisense and RNA interference exosome therapies.

COVID-19 Opportunities

Extracellular vesicles are also taking root in the race to develop vaccines and therapies for COVID-19. Organicell Regenerative Medicine is running a Phase I/II trial for Zofin, a human amniotic fluid-derived biologic containing EVs and nanoparticles, for patients with moderate to severe acute respiratory syndrome (SARS) related to COVID-19.

In August 2020, Kimera Labs–a manufacturer of naturally derived exosomes for research purposes–filed an investigational new drug (IND) application for its XoGlo mesenchymal stem cell-derived exosomes. The company said it was planning a clinical trial for 160 patients with Acute Respiratory Distress Syndrome (ARDS) secondary to COVID-19 infection. A similar CGMP product–Direct Biologics’ human bone marrow MSC-derived Extracellular vesicles–are also in Phase II testing for COVID-19 associated ARDS.

And in November, regenerative medicine company Capricor Therapeutics launched a Phase II trial for its cardiosphere-derived cells in up to 60 COVID-19 patients with cardiac dysfunction receiving oxygen.

While not an Extracellular vesicles product, the company has previously presented data suggesting exosomes are behind the therapeutic effects of its cells and is developing them in a therapeutic program on their own. Capricor also announced positive preclinical data last year for an exosome-delivered SARS-CoV-2 mRNA vaccine and is working with the FDA on a clinical development strategy.