Advanced Protein Therapeutics
Our lead products are novel formulations of key cytokines, protein hormones of the immune system. These include the potent immune-stimulating cytokine Interleukin-12 (IL-12), the multi-functional cytokine Transforming Growth Factor beta (TGFβ) and the anti-inflammatory cytokine Interleukin-10 (IL-10). In addition, our products include formulations of certain small molecules that have been shown to enhance or synergize with them.
IL-12 is a powerful pro-inflammatory cytokine naturally produced by the immune system in response to infection. It is one of the most promising immune therapeutic agents with the potential to activate and educate effective cellular immune responses against tumors and pathogens. However, it has a short half-life, and can be toxic when given systemically. To solve these problems, we have created a novel biocompatible formulation of IL-12 encapsulated in a biodegradable polymer matrix in microparticulate form. These particles, which can be administered orally, via inhalation, intra-genitally or parenterally, can deliver the cytokine locally with controlled kinetics and in a tissue-specific manner. Subtle but critical formulation differences have been developed to optimize the product for either mucosal or intra-tumoral delivery.
PCX12: An in situ tumor vaccination approach against pancreatic cancer.
PCX12 is an encapsulated IL-12 formulation aimed at the treatment of pancreatic cancer, one of the deadliest forms of cancers, with a five-year survival rate of only 8.5%. It is generally resistant to chemotherapy and radiation, leaving surgical resection as one of the few successful treatments. However, this treatment is only effective for patients in the early stages of the disease, leaving patients in later stages without treatment options. TheraPYX has developed PCX12 as an in situ tumor vaccination approach where IL-12 is delivered directly into the microenvironment of an established tumor in a sustained manner. The tumor itself provides an abundant supply of fresh antigen. This strategy results in not only the rapid activation of pre-existing antitumor T-effector cells but also the development of a highly effective local as well as systemic anti-tumor immune response, which induces the complete eradication of tumors in mice, and the development of long-lived systemic anti-tumor immunity. TheraPYX has teamed up with world-class oncologists at the University of Rochester to meet the challenges of pancreatic cancer. Bringing new hope to tens of thousands of patients, PCX12 will soon be tested in combination with a novel radiation therapy called Stereotactic Body Radiation Therapy (SBRT).
How PCX12 works
Pre-clinical work shows that IL-12 produces an immune-stimulatory, antitumor response that synergistically improves upon the immune stimulatory effect produced by SBRT itself. We expect that using PCX12 along with SBRT will result in improved responses and increased survival rates for patients with pancreatic cancer, and perhaps other solid tumors as well.
The Future of PCX12
The FDA has recently awarded orphan designation to PCX12 as a treatment for pancreatic cancer, and in a pre-IND meeting, generally concurred with our development plan. We are working closely with colleagues at the University of Rochester and expect to file an IND soon that will enable a clinical trial aimed at providing critical proof of principle in patients.
GneX12: Therapeutic Vaccine against Gonorrhea
GneX12 is a biodegradable, sustained-release IL-12 formulation designed for mucosal delivery and aimed at the treatment of gonorrhea, one of the most commonly reported bacterial infections in the US with an estimated incidence of over 800,000 annual cases. Normally, the orchestration of innate and adaptive immune responses normally lead to the clearance of infections. However, many bacteria – including gonorrhea – survive by perturbing the host’s immune response and preventing the development of protective immunity. We have shown that mucosal treatment of mice with GneX12 re-educates the immune response and when given alone, allows rapid clearance of N. gonorrhoeae infection. But most importantly, when given with antibiotics, GneX12 induces protective immunity against re-infection within the host, even against divergent strains of gonorrhea, something that has never been demonstrated before in any species.
Currently, no vaccine for gonorrhea exists and treatment depends entirely on antibiotics. However, the steady development of widespread antibiotic resistance has led to serious concerns that gonorrhea could soon become untreatable. Thus, in addition to use along with antibiotics to induce long-lasting, protective immunity in conventional infections, Gnex12 could also theoretically serve as a fail-safe treatment in the face of antibiotic resistance.
As a result, TheraPYX has been awarded multiple SBIR grants amounting to over $3,500,000 to support IND enabling preclinical efficacy and pharmacology and toxicity studies related to the development of GneX12. It has been vetted through the FDA in a pre-IND meeting, and will soon move into non-human primate studies
How GneX12 works
When given with antibiotics, GneX12 essentially turns N. gonorrhoeae infections in women into live vaccines that generate protective immunity against re-infection. Treatment reverses bacterial perturbation of the immune response and induces effective antibody and cellular immune responses. Importantly, protection extends to highly divergent strains of gonorrhea. Given the immune-based mechanism of protection, GneX12 should be just as effective against antibiotic resistant strains and could serve as a fail-safe treatment should antibiotics become ineffective.
The Future of GneX12
We are working closely with colleagues at IQVIA (Formerly Quintiles and IMS Health, Inc) and expect to file an IND soon that will enable a clinical trial aimed at providing critical proof of principle in select patients. TheraPYX has also teamed up with Intravacc, the Institute for Translational Vaccinology, an experienced, not-for-profit R&D organization that optimizes vaccines, vaccine processes and vaccine technologies to develop the world’s first prophylactic intra-nasal vaccine against gonorrhea, NGoXIM, which contains GneX12, along with specialized bacterial fragments that are immunogenic but not toxic. This product is intended for use in both men and women and is currently being optimized in non-human primates.
TGFβ is a key regulatory cytokine functional at many stages of development, from embryos to adult organisms. It is involved in many cellular processes such as growth, differentiation, apoptosis, and homeostasis. An important function of TGFβ in the immune system is the induction of a population of cells called regulatory T cells (Tregs). These vital and highly specialized immune cells limit other, self-destructive immune cells that drive several diseases, including Inflammatory Bowel Disease (IBD; Crohn’s disease and colitis), Systemic Lupus Erythematosus (SLE) and Juvenile (type 1) Diabetes (T1D). We, and others, have found that the simultaneous delivery of all trans-retinoic acid (ATRA), the small molecule signaling form of vitamin A, along with TGFβ, can enhance its activity on Tregs. This powerful set of observations from many researchers over the last two decades has led to the development of our most advanced product, TreXTAM.
TreXTAM: An oral treatment for IBD, SLE, and T1D.
TreXTAM consists of two active ingredients: TGFβ encapsulated in PLA microparticles and ATRA encapsulated in poly D,L-lactide-co-glycolide (PLGA) micro-particles. TrexTAM is currently aimed at the treatment of IBD. The two most common forms of IBD are ulcerative colitis and Crohn’s disease. Nearly 1.5 million Americans suffer from a form of IBD. Despite recent progress, most IBD patients are still treated with general medications that exert a mainly anti-inflammatory or suppressive effect on the mucosal immune system. Although biologic agents such as those directed against the pro-inflammatory cytokine TNFα are generally effective, 30% of patients will not respond sufficiently, and of those who initially do respond, 50% will cease to respond within a year. In addition, these biologic agents are often not cost-effective and can lead to rare but serious side effects. There remains an urgent and unmet medical need for unique, effective treatments.
How TrexTAM Works
TrexTAM is a combinatorial product containing TGFβ and ATRA. We believe that these two active agents in TrexTAM work by synergistically inducing tolerance through the generation and stabilization of Tregs in the gut. Local sustained drug delivery to the intestinal mucosa maximizes therapeutic effects and minimizes systemic toxicity. It is important to note that ATRA is already an approved pharmaceutical. Because of this, and the strength of our preclinical proof-of-principle studies in several animal models, our team at TheraPYX has been awarded multiple SBIR grants worth over $5,000,000 to develop TrexTAM.
The Future of TrexTAM
At present, TrexTAM remains in development as an oral treatment for active Crohn’s disease. However, recent observations in rodents suggest broader applicability in true autoimmune diseases, including SLE and juvenile diabetes. Considering these exciting new discoveries, we will soon conduct a pre-IND meeting with the FDA, and based on agency recommendations, design a clinical trial for this product that will provide critical proof of principle in the most applicable indication. Importantly, recent studies in mice suggest that both PLA encapsulated TGFβ (TPX6001) and PLGA encapsulated ATRA (TPX7001) may have additional applications as stand-alone products.
IL-10, originally known as cytokine synthesis inhibitory factor, is an anti-inflammatory cytokine that regulates the activity of stimulatory immune cells and enhances the activity of suppressive ones, including Treg cells. It plays a central role in limiting host immune responses to pathogens. However, the potential of IL-10 as an immune therapy has not been realized due to an inability to reach philologically effective doses in the disease microenvironment. To solve this problem, we created IL-10NanoCap (aka FAPXIL), IL-10 encapsulated in PLA microparticles. It is like our IL-12 and TGFβ products but uses modified synthetic methods to account for the more labile structure of IL-10.
FAPXIL: An oral treatment for Familial Adenomatous Polyposis (FAP)
FAP is a rare genetic disease characterized by the development of hundreds to thousands of adenomas in the rectum and colon during the second decade of life. FAP has an incidence at birth of about 1/8,300, it manifests equally in both sexes, and affects up to 50,000 Americans making it eligible for orphan status. There is no cure. Current medical care is mainly based on endoscopic surveillance to detect the onset of polyposis. Once polyps are detected, colonoscopic resection is recommended to prevent fatal cancer, which is otherwise 100% certain. There is an urgent unmet medical need for new therapies to induce duodenal adenoma regression and delay or prevent the progression to cancer. If successful, FAPXIL may also have application in the prevention of gastrointestinal tract tumors including colorectal cancer because of this well-established association between cancer, polyposis and gut inflammation.
How FAPXIL Works
Our research in rodents shows that FAPXIL activity involves the neutralization of specific disease-promoting immune cells in the intestinal lamina propria. This approach was found to affect not only intestinal polyposis, but also the development of colon tumors via specific anti-tumor immune cells in the inflamed colon.
The Future of FAPXIL
FAPXIL is in currently in preclinical development as an oral treatment for FAP. We have demonstrated that orally administered FAPXIL ameliorated established local and systemic disease and enhanced survival in a murine model of spontaneous intestinal polyposis. This observation was highly significant as it demonstrated that the therapeutic effect of oral FAPXIL treatment extended even to distant and aggressive colonic disease. Largely because of this impressive and unexpected observation, TheraPYX was recently awarded a coveted FastTrack SBIR grant by the National Institute for Diabetes and Digestive and Kidney diseases. Among other things, the project will finalize a commercial FAPXIL formulation and establish the applicability of FAPXIL to colorectal cancer. If successful, the next steps are toxicology studies in rodents and non-human primates.
TheraPYX is focused on the development of its lead products into first-in-human proof-of-concept clinical studies. An enviable aspect of all our products is that they depend upon the local release of established drug substances with well-understood molecular and cellular targets within disease pathways. All have broad applicability across several diseases. This allows the company to be product rather than indication focused. While we remain deeply committed to advancing our lead products into the clinic, we also maintain a deep pipeline of new products. These include other non-cytokine proteins and other small molecules. For example, TheraPYX was recently awarded two small phase I SBIR grants to explore proof of principle pre-clinical studies aimed at the encapsulation of an antibody against IL-10 and epigallocatechin gallate (EGCG), a dominant member of the family of small molecule compounds abundant in fresh tea leaves. While still in very early days, these efforts represent the application of our core encapsulation technology to entirely new classes of immune therapeutics and demonstrate our company’s deep commitment to continued new product development.