Codiak has two engineered exosome programs in Phase I, each showing different types of engineering possibilities to deliver targeted payloads that pharmaceutical companies haven’t managed to push all the way through the clinic.
While Codiak BioSciences has begun to read out early safety data from its clinical engineered exosome programs for hard-to-reach cancer targets, it’s the next one that may truly start demonstrating the potential of extracellular vesicles (EVs) for nucleic acid therapies.
Codiak has two engineered exosome programs in Phase I, each showing different types of engineering possibilities to deliver targeted payloads that pharmaceutical companies haven’t managed to push all the way through the clinic.
The first to enter was exoIL-12, exosomes engineered with a scaffold protein to display functional interleukin 12 (IL-12) on their surfaces. IL-12 is a pro-inflammatory cytokine that can stimulate immune cells to attack cancer, but systemic delivery has been shown in clinical trials to cause dose-limiting toxicities. exoIL-12 is injected into the tumor site, and initial clinical data showed no systemic exposure to IL-12 in patients with cutaneous T cell lymphoma. Efficacy data is expected by the end of the year.
The second clinical program is also designed to be injected into the tumor microenvironment and targeted to avoid systemic exposure. But unlike exoIL-12, exoSTING has a STING agonist loaded internally, inside the exosomal lumen. The STING pathway has been of interest to drugmakers in cancer immunotherapy due to studies showing its role in activating the inflammatory response to tumors, but no STING agonist has yet reached Phase 3. Clinical data for exoSTING is not yet available.
While both programs show the potential for exosomes as targeting vehicles, the next frontier is genetic medicines. Codiak is gearing up to launch clinical trials for exoASO-STAT6, an exosome using the same scaffold to attach an antisense oligonucleotide (ASO) designed to silence STAT6, a transcription factor in tumor-associated macrophages that promotes cancer progression.
Despite decades of research and a growing list of nucleic acid-based modalities, companies have struggled to deliver on their potential for hitting new therapeutic targets, and doing so with fewer doses than a protein or antibody therapy–painting the class as stranded assets in more ways than one. Of the nearly 250 new medical entities approved by the U.S. Food and Drug Administration (FDA) since 2016, only 11 are nucleic acid therapeutics like gene therapies, ASOs, or RNA interference (RNAi). All 11 are in rare diseases, and most sourced to three biotechs: Alnylam Pharmaceuticals, Ionis Pharmaceuticals and Sarepta Therapeutics.
Roadblocks Ahead
The primary challenge is delivery. The dominant therapeutic modalities today, including monoclonal antibodies, hit cell surface or intercellular targets but typically don’t enter cells on their own. By contrast, nucleic acid therapies need to enter the cell in order to change cellular function, and existing delivery systems each have their limitations.
Sarepta’s three approved ASOs are designed to be delivered systemically without a delivery vector, and target various mutations in muscle tissue of patients with Duchenne muscular dystrophy (DMD) that effect the production of the dystrophin protein. ASOs have a stronger affinity for kidney and liver than other tissues, including muscle, which impacts the formulation of drug dosage. To broaden the potential therapeutic applications, Sarepta is looking for better delivery approaches, and announced a two-year partnership with Codiak last June to explore exosomes as targeted delivery vehicles for its ASOs, as well as its gene therapy and gene editing candidates.
Delivering to targeted tissues is also an issue for RNAi therapies. Of the three approved in the U.S. – all from Alnylam – the two most recent approvals are conjugated to N-Acetylgalactosamine (GalNAc), a unique ligand specific to the liver. The third is Onpattro (patisiran) – also liver-targeted – approved for hereditary amyloidogenic transthyretin amyloidosis, and based on an older platform that uses synthetic lipid-bound nanoparticles to deliver therapies. Lipid nanoparticles, however, can prompt an immune response leading to neutralizing antibodies against potential therapies.
Like lipid nanoparticles, gene therapies have been hampered by the immunogenicity of their delivery vectors. Adeno-associated viruses are used to deliver both gene therapies marketed in the U.S., Novartis’s Zolgensma (onasemnogene abeparvovec-xioi) and Roche’s Luxturna (voretigene neparvovec-rzyl), but some patients may have preexisting immunity to the viruses, limiting the duration of replacement gene expression.
Free Delivery
EVs (including exosomes) have just begun making waves in early clinical trials as therapeutics. They are naturally shed by cells and taken up by other cells, and at least five companies–Exopharm, United Therapeutics, Direct Biologics, Cellular Biomedicine Group, and Organicell Regenerative Medicine– have unmodified EVs derived from multiple human cell sources in the clinic for a variety of diseases.
Where they occur in nature, they effortlessly excel where other vehicles fail, delivering payloads targeted to tissues without triggering a negative immune response. At least 13 companies are developing approaches to delivering genetic medicines or other therapeutic modalities with engineered EVs.
ASO
On top of its lead programs and assets in development with Sarepta, Codiak has partnered with Jazz Pharmaceuticals to develop an exoASO targeting NRAS for cancer, and has antisense programs targeting NLRP3 n neuroinflammation and neuropathy.
siRNA
In addition to its first-generation unmodified exosomes, Exopharm is also developing a range of engineered EV technologies, including an EV carrying antiviral siRNAs and with coronavirus spike protein to target vulnerable cells. The company is also developing mesenchymal stem cell-derived EVs targeted to neural tissue, and platelet-derived EVs carrying the chemotherapeutic doxorubicin for targeted cancer delivery.
ArunaBio is developing a platform of neural cell-derived exosomes, and has AB127 in proof-of-concept testing as a carrier for short interfering RNA used in RNAi therapies. It is also exploring mRNA delivery.
mRNA
Evox Therapeutics’s lead programs are engineered exosomes delivering protein therapeutics, the company also has a nucleic acid pipeline in development, with internal assets and partnerships with Takeda and Eli Lilly & Co. to develop exosomes delivering mRNA, RNAi and ASO.
Capricor Therapeutics engineers exosomes that are derived from its lead cardiac cell therapy, which is in clinical testing for DMD and COVID-19. The company is currently developing exosomes as an mRNA vaccine for SARS-CoV-2, and evaluating them for RNA delivery and other approaches.
AgeX Therapeutics is using an engineered cell line to load telomerase mRNA into exosomes, which it is exploring for age-related degenerative diseases.
miRNA
EV Therapeutics has engineered tumor-derived EVs expressing a microRNA, mi-424i, in preclinical testing as an adjuvant for immune checkpoint blockade therapies for metastatic colorectal cancer.
Therilla Development subsidiary Tavec Pharma is developing exosomes carrying miRNAs, including miR195, for cancer.
Gene Therapy
OmniSpirant Therapeutics is developing inhaled engineered EVs for lung diseases, including a gene therapy for cystic fibrosis.
Carmine Therapeutics is developing red blood cell-derived EVs for gene therapies, and has partnered with Takeda to develop two rare disease assets.
Vaccine
Versatope Therapeutics has a vaccine platform based on recombinant outer membrane EVs developed from genetically engineered bacteria. Its lead asset is a universal influenza vaccine, with proteins from multiple strains loaded into each EV, and it also developing COVID-19 and Clostridioides difficile vaccines.
All Comers
At least two early-stage companies are developing engineered EV platforms that can carry nucleic acids but have not announced specific programs, including Mantra Bio and Vesigen Therapeutics.
Gene Editing
Outside of the Codiak-Sarepta partnership, no EV companies have disclosed gene editing programs. But academics are exploring the space, and Evox has disclosed intellectual property around CRISPR technology.
