Despite decades of investigation, stem cell therapies are still facing challenges around their commercialization. The stem cell therapy market has been struggling to achieve approvals and high price tags have made it difficult to generate sales for those that do reach commercialization. Moreover, it is a challenging task to introduce foreign living cells into a system as complex as the human body.
Given these challenges, some stem cell companies have expanded their focus to include the development of exosome therapeutics. Exosomes are extracellular vesicles (EVs) of endosomal origin that range in size between 30 and 100 nanometers (nm). They are secreted by all cell types, including but not limited to stem cells.
Regenerative Benefits of Exosome Therapeutics
Some researchers now believe that the regenerative benefits of stem cell therapy are mediated, at least in part, by the exosomes that these cells secrete. These exosomes can readily be harvested from stem cells cultured within a bioreactor, purified as a drug product, and infused into a patient’s body. From this perspective, exosomes are simpler, safer, and more easily transported than whole cells. They are also less risky when compared to stem cell therapeutics because they do not require the use of whole cells.
Because exosomes are vesicles secreted by cells, they do not have the capacity to transform into malignant cells, nor do they trigger an immune response. An example is the thousands of blood transfusions that have been carried out in hospitals for decades. While a matching blood group must be chosen for transfusion, no matching is required for the trillions of exosomes present in the blood plasma.
Exosomes are much smaller than the whole cells and they can circulate easily throughout the body and reach sites that require healing. Companies have also developed robust and reliable technologies to produce pharmaceutical-grade exosomes as a type of next-generation cell-free therapeutic.
Clinical Progress with Exosome Therapeutics
In recent years, several universities and research hospitals have performed small-scale Phase I clinical trials using exosomes. So far, only a few companies such as Aegle Therapeutics, Exopharm Ltd, United Therapeutics, Avalon Globocare (NASDAQ: AVCO), Organicell, and Direct Biologics, have reached the pivotal point of transitioning exosome therapeutics into human trials.
On May 11, 2018, Aegle Therapeutics announced the FDA had cleared its first IND application to initiate an exosome clinical trial in severe second degree burn patients. The company launched a Phase 1/2a trial of its lead product AGLE-102 in late 2018, making Aegle the first extracellular vesicle (EV) company cleared by the FDA to enter clinical trials in humans. Aegle has two products under development, AGLE-102 for burn treatment and AGLE-103 for the management of epidermolysis bullosa (EB).
On 28th January 2020, Melbourne-based Exopharm announced the first dosing of its human clinical trial, becoming the first company to test the therapeutic capacity of exosomes for wound healing. Its Phase I study is testing Exopharm’s Plexaris product, a cell-free formulation of exosomes from platelets that demonstrated regenerative effect in preclinical animal studies, improving wound closure and reducing scarring.
On 26th June 2019, United Therapeutics announced approval for a Phase I trial of an exosome-based therapy against bronchopulmonary dysplasia (BDP), a condition common in preterm infants that receive assisted ventilation and supplemental oxygen. BDP is characterized by arrested lung growth and development, with health implications that can persist into adulthood.
Likewise, Organicell is developing Zofin™, an acellular biologic therapeutic derived from perinatal sources that is manufactured to retain naturally occurring exosomes. To date, Organicell has received 18 eINDs (Emergency INDs) from the U.S. FDA for Zofin™, an exosome therapeutic derived from perinatal sources. The U.S. FDA has also approved Organicell for four Phase I/II randomized, placebo-controlled trials investigating the therapeutic potential of Zofin™ for chronic obstructive pulmonary disease (COPD), osteoarthritis (OA), COVID-19, and COVID Long Haulers, as well as an Expanded Access trial which was completed and published for Mild to Moderate COVID-19.
Additionally, Direct Biologics was granted approval by the U.S. FDA to conduct a clinical trial under an Investigational New Drug (IND) application for use of its ExoFlo™ product in the treatment of COVID-19 induced ARDS. Direct Biologics appears to be the only exosome company with INDs approved for the full range of COVID-19 indications, including ARDS. Direct Biologics is currently conducting a multi-center, randomized clinical trial for the study of its ExoFlo™ extracellular vesicle product. Recently, it announced that the U.S. FDA had authorized it to to expand its ongoing Phase 3 clinical trial of ExoFlo™ to all-cause moderate-to-severe ARDS.
In other promising news, Evox Therapeutics has a pipeline of seven exosome-based therapeutic product candidates. Its drug candidates have the potential to address lysosomal storage disorders (LSDs), with a global incidence of nearly one in 5,000 births, as well as genetic diseases, including inborn errors of metabolism (IEM). The company’s technology involves the loading of drugs and tissue-targeting proteins onto the surfaces of exosomes.
Codiak BioSciences’ product pipeline includes eight candidates in various therapeutic areas. Its engEx Platform is focused on engineering exosomes to target immune-based diseases, metabolic and fibrotic disorders, neurodegenerative disorders, cancer, and rare diseases.
Intriguing, Aethlon Medical is taking a different approach—it is removing exosomes for therapeutic purposes. Aethlon has developed a therapeutic hemofiltration technology to catch and remove circulating viruses and cancer-promoting exosomes through affinity attachment. Its Hemopurifier® device is being evaluated in a FDA-approved clinical study. Aethlon also owns a majority share (80%) of Exosome Sciences, Inc., which discovers exosomal biomarkers to diagnose cancer and neurological disease progression.
Commercializing Exosome Therapeutics
Despite all of this exciting progress, no exosome therapeutic has yet reached market approval, although five exosome product candidates presently in Phase III and IV trials are positioned to gain market approval in the near future. Finally, two diagnostic tests using exosome technology, the ExoDx Prostate IntelliScore Test for prostate cancer and Guardant 360 CDx test for non-small cell lung cancer, have been approved by the US FDA and are commercially available.
Rates of exosome scientific research and clinical trials are also on the rise, suggesting a bright future for exosome therapeutics. In total, at least 118 companies worldwide are now developing a diverse range of exosome therapeutics, diagnostics, research products, and manufacturing technologies.