Ceraxa’s Mechanism of Action
Direct Cytotoxic Killing of Cancer Cells
Pendrea’s lead product, Ceraxa, contains ceramide, a naturally occurring anti-cancer compound found in normal human cells. While the role of ceramide in mediating anti-cancer activity has been known for several decades, utilization has been hampered by an inability to transport it into cancer cells. This problem has now been solved through use of Pendrea’s proprietary delivery platform.
Ceraxa is a fully synthetic, PEGylated nano-liposomal formulation that enables the systemic administration of the active pharmaceutical ingredient, C6-ceramide. Ceraxa is a highly stable formulation that induces anticancer activity via activation of phosphatase 2A, which inhibits STAT3 phosphorylation resulting in down-regulation of pro-survival and pro-mitogenic signaling in cancer cells. Ceraxa also decreases tumor micro-vascularization, inhibits glycolysis and disrupts tumor-induced immunotolerance.
Unlike normal cells, cancer cells have depleted levels of ceramide which is associated with increased resistance to chemotherapy. Restoring ceramide levels within tumor cells leads to increased cancer cell death through a number of mechanisms including induction of apoptosis, restoring sensitivity to chemotherapeutic agents, reduction of immunotolerance and activation of cancer fighting CD8 T cells.
Ceraxa’s physical properties result in a long half-life in humans (>24 hours), allowing significant accumulation of C6-ceramide in cancer calls. Once inside the cell, C-6 ceramide is converted to the active anti-cancer metabolites C16 and C18-ceramide. Preclinical efficacy of Ceraxa has been demonstrated in numerous in vitro and in vivo models of human cancers including hepatocellular carcinoma (HCC), breast cancer, pancreatic cancer, melanoma and several types of leukemia.
Ceraxa’s mechanism of action for the direct cytotoxic killing of cancer cells is depicted in the diagram below.
Ceraxa activates protein phosphatase 2a which inhibits transcriptional factor STAT3 which in turn down-regulates multiple kinases including Survivin, XIAP, MCL-1, ERK, AKT, Glycolytic enzymes, EMT transcription factor (SNAI2) thereby decreasing both drug-resistance and metastatic potential of cancer cells.
Activation of the Cellular Immune System (Immuno-Oncology)
Ceraxa’s dual mechanism of action includes several means by which it resuscitates and/or activates the immune system to kill cancer cells:
Ceraxa changes the phenotype of Tumor Associated Macrophages from the pro-cancerous M2 phenotype, which cause inflammation and a failure of T-cells to recognize tumors, to the anti-cancerous M1 phenotype. This allows T-cells to “see” the tumor resulting in resuscitation of T-cell activity and immune system mediated killing of tumor cells.
Ceraxa down regulates PD-1 on T-cells which increases the ability of T-cells to “see” and kill the tumor. By down regulating PD-1, Ceraxa also increases the efficacy of antibody-based checkpoint inhibitors such as Keytruda and Opdivo that target PD-1.
Ceraxa can be used with Tissue Specific Antigens to increase the immunotherapeutic response. It can also be used as adjunct to chimeric antigen receptor T cells (Car-T) to increase Car-T efficacy
The mechanism for the M2 to M1 Tumor Associated Macrophage (TAM) switch and the resultant increase in T-cells is depicted in the diagram below:
In the tumor microenvironment, Ceraxa changes tumor-associated macrophages from the pro-cancerous M2 phenotype to the anti-cancerous M1 phenotype, which reverses immunotolerance and reactivates T-effector-cell response to kill the tumor
Lack of Toxicity (Cancer Cell Selectivity)
Importantly, Ceraxa has been shown to be essentially free of the toxic side effects normally associated with anti-neoplastic agents. Because normal cells naturally contain high levels of ceramide, Ceraxa has no impact on normal, healthy cells. In fact, the downstream biochemical target(s) for Ceraxa are not activated in healthy cells. Thus, Ceraxa’s inhibition of glycolysis, which is a common source of energy for cancer cells but not for normal cells, is why Ceraxa selectively kills cancer cells without affecting normal healthy cells. That Ceraxa is selectively cytotoxic to cancer cells can be seen by the very high IC50 of Ceraxa in non-cancerous cells. As a result, while Ceraxa is highly lethal to cancer cells, it leaves healthy cells unharmed.
Results with Ceraxa
Ceraxa is active as a monotherapy
The results for Ceraxa as a monotherapy include tumor regression and extension of survival in multiple cancer types. The graphic below shows the effect of Ceraxa monotherapy in HCC. Note that the action of Ceraxa continues even after therapy has stopped (right hand graph; treatment is stopped at 48 days, mice survive for 265 days).
The graphics above show the effect of Ceraxa in immunocompetent HCC animal models resulting in regression of tumor growth and a 4X reduction in tumor size versus controls In the model on the left. An 85% increase in survival is shown in the model on the right.
Ceramide, an endogenous bioactive sphingolipid, has been identified as a secondary messenger in cellular signaling cascades regulating metabolism, senescence and death. Ceramide is generated naturally within cells via hydrolysis of sphingomyelin or via de novo synthesis from palmitic acid. Levels of ceramide are increased within cells in response to inducers of cellular stress including cytotoxic receptor systems, environmental stresses, and various chemotherapeutics. However, ceramide is ultimately depleted during chemotherapy resulting in a reduction or cessation of chemotherapeutic efficacy.
Ceraxa has been shown in a number of studies to restore and enhance the ability of standard chemotherapeutics to kill cancer cells. As such, Ceraxa has demonstrated synergistic efficacy with multiple standard chemotherapeutics including sorafenib (for HCC), gemcitabine (for pancreatic cancer), and low dose cytarabine (AraC) with Venetoclax (for AML). Patients whose cancers are refractory to treatment, or have relapsed while on frontline standard of care therapies, need this restoration of effectiveness.
The ability to restore activity to standard of care chemotherapeutics cannot be accomplished in any other way. The mechanism is depicted in the diagram below.
Ceramide is a natural anticancer agent in the body that is depleted during chemotherapy. By replacing the depleted levels of ceramide exogenously with Ceraxa, Pendrea is able to restore the activity of standard of care therapeutics.
The graphics below show some of the results Pendrea has achieved with restoring and/or improving the efficacy of chemotherapeutics. The first graphic shows the effect of Ceraxa plus Gemcitabine versus Gemcitabine alone in a pancreatic cancer model. The graphic also describes the mechanism for reversal of resistance by the tumor cells to Gemcitabine.
Ceraxa plus Gemcitabine reverses the resistance of pancreatic cancer cells to Gemcitabine resulting in a 3X reduction in tumor volume versus either Ceraxa or Gemcitabine alone.
In another example, the panel in the graphic below shows the combination of Ceraxa and Vinblastine achieves 67% disease free survival in Acute Myeloid Leukemia (AML), while mice treated with Ceraxa or Vinblastine alone all die. Vinblastine is not currently used for treatment of AML due to toxicity, but this remarkable result achieved with a low dose of Vinblastine may change that. The use of a 2nd generation Ceraxa Plus formulation with Vinblastine encapsulated within Ceraxa may make its use for the treatment of AML even more likely since the encapsulation of Vinblastine promises to reduce its toxicity while also increasing its efficacy.
The graphic above shows the effect of Vinblastine plus Ceraxa on Acute Myeloid Leukemia (AML) in an animal model. The combined therapy of Ceraxa plus Vinblastine results in 67% disease free survival, while animals treated with Ceraxa or Vinblastine alone all die.
Pendrea is collaborating with the University of Virginia and Memorial Sloan Kettering on the development and clinical testing of Ceraxa therapy for AML.
Ceraxa is an effective immunotherapeutic agent as its dual mechanism of direct cytotoxic killing and immune system activation is always present. Key Immuno-Oncology aspects of Ceraxa include:
It directly resurrects the immune system via the M2 to M1 macrophage switch
It down regulates PD-1 resulting in increased T-cell activity and increased efficacy for PD-1 checkpoint inhibitors
It Increases the activity of T effector cells which are repressed in cancer
It dramatically Improves CAR-T and Checkpoint Inhibitor performance
Unlike most chemotherapies, Ceraxa does not harm immune system
It is a platform that can co-deliver immuno-oncology compounds
While Ceraxa monotherapy is a very good inducer of immuno-oncology activity, as the HCC graphic above shows, Ceraxa plus adjunctive immunotherapy is even better. The bottom line in the graphic below shows that Ceraxa plus CarT therapy (Ceraxa +TCR + IM) is extremely effective at reducing tumor size, whereas controls result in substantial tumor growth. Ceraxa in combination with Tissue Specific Antigens (Ceraxa + IM) is also impressive resulting in almost no tumor growth.
Tumor size is reduced from 0.5 mm3 to approximately 0.2 mm3 for Ceraxa + CarT. Controls, including CarT without Ceraxa, resulted in tumor growth from 2.3 mm3 to 2.5 mm3.
TCR = T-cell Receptor engineering; IM = immunotherapy with tissue specific antigens