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Novel MitoXcel™-Powered Oncopeptide Platform

Our MitoXcel™ oncopeptides, clinical candidates PTC-2109, PTC-2110, PTC-2117 and PTC-2128, are:

  • 18- to 30-amino acids in length
  • Cross the blood brain barrier
  • Administered via SC injection over an 8-16 week course of treatment in pre-clinical models

Key findings:

  • Selective Elimination of Senescent Cells: In all organs of the body, including the brain, in a dose dependent manner
  • Reduced Systemic Inflammation: Significant decrease in SASP biomarkers
  • Tissue Remodelling to a Healthier Phenotype in Muscle and Fat: Improved body composition including a reduction in fat but an increase in lean body and bone mass
  • Improved Physical Health: Enhanced metabolism, muscle strength, and exercise endurance.
  • Cognitive Benefits: Improved memory and motor coordination.
  • Dose Response Curve Demonstrated
  • Safety Profile: Without demonstrable evidence of toxicity at up to 10X the efficacious dose after up to 16 weeks of continuous dosing.  Normal liver enzyme levels and no adverse effects observed.

Mechanism of Action:  Selectively Target the Mitochondria in Senescent, Non-Senescent Cells, and Cancer Cells

  • Completely novel, aging-specific mechanism of action
  • Two key mechanisms, both targeting the Inner Mitochondrial Membrane Potential (Δψm)
  • Validated in three species:  human (in vitro), mouse (in vivo) and C. elegans (in vivo)

Enhancement of Mitochondrial Efficiency in Aging Cells by Increasing the Δψm (Mechanism #1)

  • Enhance the efficiency of the mitochondria, increasing the proportion of potential energy in the MMP (ΔΨm) that is converted to ATP.
  • Unlike Mechanism #2, which takes 8 weeks or greater to observe, Mechanism #1 can be observed, for example in IMR90 fibroblasts in vitro, within 24 hours of exposure to our geropeptides, using a Seahorse Analysis to evaluate mitochondrial function, which shows a decrease in proton leak, an increase in ATP production and an increase in coupling efficiency.

Elimination of Senescent Cells via Mitochondrial-Mediated Apoptosis (Mechanism #2)

  • Have less capacity to maintain Mitochondrial Membrane Potential (MMP) compared with normal dividing cells.
  • Exposes them to prolonged mitochondrial transition pore opening.
  • Co-localization staining studies of Cytochrome C in mitochondria (TOM20) in proliferating and senescent IMR90 cells in vitro indicate:
    • Dose-dependent decrease in co-localization in senescent IMR90 cells treated with PTC-2105, but only at much higher concentrations in proliferating IMR90 cells
    • This indicates an increased release of Cytochrome C into the cytosol, which initiates apoptosis via the Caspase pathway in senescent cells treated with PTC-2105
  • Our data suggests that this takes at least 8 weeks or greater of therapy to observe in vivo.

Cancer Cells

  • Also have less capacity to maintain MMP compared with normal cells and are thus exposed to prolonged mPTP opening and, possibly, to minority MOMP, suggesting MMP as a selective functional target for cancer cells (via Mechanism #1)
  • MitoXcel™ peptides PTC-2107 (Eos SENOLYTIX) alone and PTC-2110 (Perseus SENOLYTIX), alone and in combination with Venetoclax, significantly improve overall survival in an aggressive B cell Acute Lymphoblastic Leukemia (“B-ALL”) in vivo tumor model, in which 750,000 TOM-1 cells, harboring both a wild type ABL1 and JAK2 V617F mutation, were injected into the tail veins of NSG mice, and treatment was begun 3 days later (log rank – saline vs PTC-2110 = 0.0034).
  • DTC-0141 (ponatinib)-treated animals and animals treated with PTC-2110, either as monotherapy or in combination with Venetoclax, remained alive at the end of study, despite the significantly lower exposure to drug treatment (24 vs 5 total doses per animal per group or almost 5X greater in the ponatinib-treated group) and the absence of any ABL1-targeted TKI therapy.
  • PTC-2110 shows activity in vitro against multiple human cancer cell lines including Ph+ B-ALL, Ph-”like” B-ALL, T-ALL, AML, lung, liver, colon, breast and bladder cancer.
  • MitoXcel™ Technology marks a potentially safe and effective new class of cancer therapeutics

Our candidate MitoXcel™ oncopeptides address both the inflammaging driving aging due to senescent cells and the reduction in mitochondrial efficiency in cells as we age, via a single, age-specific target, the ΔΨm.

 

By attacking aging via two pathways, both via a single age-specific target, the lower MMP that develops in the mitochondria as we, and all living organisms, age, MitoXcel™ Technology addresses the fundamental “causes” of both aging and cancer.

Elimination of Senescent Cells:  Dose Response

Selective elimination of senescent cells in all organs of the body, including the brain, in a dose dependent manner

Eos’s MitoXcel™ geropeptide, PTC-2107, demonstrates a dose response with respect to elimination of senescent cells, plateauing at the two 50 mg/kg doses, 1x/ and 3X/ week, indicating that 50 mg/kg 1X/week is the optimal dose since it provides the maximum effect on senescent cell elimination (~ 60% SCs eliminated) at the lowest drug exposure

  • After 20 weeks of treatment, at the 25 mg/kg SC 3X/week dose, PTC-2107-treated animals experienced a 33% reduction in senescent cells (“SCs”) compared to saline treated controls (p=0.0025) as measured by senescence-associated beta-gal % area staining.

  • At the 50 mg/kg SC 1X/week dose, PTC-2107-treated animals experienced a 60% reduction in SCs compared to saline treated controls (p<0.0001).

  • There was no further increase in the elimination of SCs at the next higher dose of 50 mg/kg SC 3X/week.

  • Therefore the optimal dose of 50 mg/kg SC 1X/week was selected.

MitoXcel™ Oncopeptides Significantly Improve Overall Survival in an Aggressive Ph+ B-ALL in vivo Tumor Model

MitoXcel™ Technology marks a potentially safe and effective new class of cancer therapeutics.

  • MitoXcel™ geropeptide PTC-2107 (Eos SENOLYTIX) alone and oncopeptide PTC-2110 (Perseus SENOLYTIX), alone and in combination with Venetoclax, significantly improve overall survival in an aggressive B cell Acute Lymphoblastic Leukemia (“B-ALL”) in vivo tumor model, in which 750,000 TOM-1 cells, harboring both a wild type ABL1 and JAK2 V617F mutation, were injected into the tail veins of NSG mice, and treatment was begun 3 days later (log rank – saline vs PTC-2110 = 0.0034).

  • In animals alive on Day 31, at End of Study, treatment with MitoXcel™ oncopeptide PTC-2110 (Perseus SENOLYTIX), alone and in combination with Venetoclax, exhibited almost complete control of tumor cells, equivalent to ponatinib-treated mice, as evidenced by flow cytometry of lung and spleen, despite the significantly lower exposure to drug treatment (24 vs 5 total doses per animal per group or almost 5X greater in the ponatinib-treated group) and the absence of any ABL1-targeted TKI therapy.

  • MitoXcel™ Technology marks a potentially safe and effective new class of cancer therapeutics