CARMIEL, Israel—Protalix BioTherapeutics Inc., a biopharmaceutical company focused on developing and commercializing recombinant therapeutic proteins based on its proprietary ProCellEx protein expression system, started August off with encouraging clinical results for one of its lead drug candidates. In a Phase 1 trial of PRX-106, an orally administered plant cell-expressed recombinant anti-tumor necrosis factor (TNF) fusion protein, the compound showed biological activity in the gut as well as a favorable safety and tolerability profile.
The Phase 1 trial was a randomized, parallel-design, open-label study evaluating the safety and pharmacokinetics of PRX-106 in healthy volunteers. Study participants received doses of the compound equivalent to either 2 mg, 8 mg or 16 mg TNF receptor-Fc fusion protein orally, once a day for five consecutive days. The study employed fluorescence-activated cell sorting analysis using different antibodies for surface markers, which showed that all three dosages of PRX-106 promoted the induction of various subsets of T cells. Regulatory T cell activation showing biological activity in the gut was also noted.
“The results demonstrated in the Phase 1 trial are very exciting and encouraging. As T regulatory cells have a central role in the immune system, PRX-106 has the potential to be an effective agent for numerous immune-mediated indications,” commented Prof. Yaron Ilan of the Gastroenterology and Liver Units, director of the Department of Medicine of the Hebrew University-Hadassah Medical Center in Jerusalem.
These results follow positive preclinical data as well. In preclinical studies, PRX-106 was shown to relieve immune-mediated hepatitis and reduce interferon gamma levels in a mouse model of concanavalin A immune-mediated hepatitis. Oral administration of the compound also reduced immune-mediated colitis in a mouse model, promoting serum levels of anti-inflammatory IL-10 and regulatory T cells. In preclinical studies of PRX-106, specifically intravenous administration of the anti-TNF, in-vitro studies showed that “purified PRX-106 administered intravenously binds to TNF alpha, thereby inhibiting it from binding to cellular TNF receptors and preventing its downstream effects, such as TNF-induced apoptosis, in a dose-dependent manner. In a proof-of-concept in-vivo study using a well-established preclinical arthritis model, anti-TNF (IV), when injected in mice, significantly improved clinical arthritis parameters, including joint inflammation, swelling and tissue degradation.”
The TNF gene, as noted on the Genetics Home Reference page of the U.S. National Library of Medicine, “encodes a multifunctional proinflammatory cytokine that belongs to the tumor necrosis factor (TNF) superfamily.” The TNF cytokine plays a role in a variety of biological processes, including “cell proliferation, differentiation, apoptosis, lipid metabolism and coagulation,” and “has been implicated in a variety of diseases, including autoimmune diseases, insulin resistance and cancer.”
ProCellEx takes a rather unique approach to drug development. As noted on Protalix’s website, the system “uses advanced genetic engineering and plant (carrot and tobacco) cell culture technology instead of the traditional mammalian- or yeast-based systems, enabling the production of a wide range of complex, proprietary and biologically equivalent human proteins to address a variety of diseases … The closed system provides stable, optimized conditions, with manufacturing capabilities for the entire range of proteins, including antibodies, complex enzymes and plant-derived pharmaceuticals.”
“One of the major advantages of Protalix products is that the plant cells actually serve as a natural capsule; they protect the protein while delivered orally from being degraded in the stomach, so we don’t need to purify and then formulate the protein … the plant cells are very unique; they have a cell wall on top of the cell membrane that protects it from the stomach,” says Dr. Einat Almon, senior vice president of product development at Protalix.
Protalix is currently determining which indication to pursue with PRX-106, and expects to make a decision soon and begin a proof-of-concept trial near the end of the year. Given that the molecule binds TNF and can regulate the immune system through the gut to some extent, Almon says the compound has potential in immune-mediated indications such as irritable bowel disease, Crohn’s disease, colitis and some others.
“I think there is a major effort in the industry for orally delivered proteins, and there is very limited success,” Almon tells DDNews. “The Phase 1 clearly indicates that the protein stayed active and did some induction of the immune system, which was observed by upregulation of regulatory cells, meaning that the protein was delivered, stayed active and did what we thought it would do, so this is very, very encouraging for us. There is a major unmet clinical need of being able to deliver drugs orally, and it looks like using the plant cells, a natural capsule, actually does the job.”