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Novel MitoXcel™-Powered Geropeptide Platform

Our MitoXcel™ geropeptide clinical candidates are:

  • Eos SENOLYTIX – PTC-2105, PTC-2107, and PTC-2113
  • Perseus SENOLYTIX – PTC-2110
  • Ponce Aurora – PTC-2111 and PTC-2116 (both never been tested in animals)

Key Attributes:

  • 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 MitoXcel™ 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

  • 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-ALL in vivo tumor model.  Overall survival was similar in PTC-2110-treated compared to ponatinib-treated animals despite the significantly lower exposure to drug treatment (19 vs 4 total doses per animal per group).  MitoXcel™ Technology marks a potentially safe and effective new class of cancer therapeutics.

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.

Tissue Remodelling:  Body Composition Improvements

Loss of lean body and bone mass has been the Achille’s Heel of current GLP-1/GIP agonists

Eos’s MitoXcel™ geropeptides improve body composition, reducing % fat mass, but increasing % lean body and bone mass in a dose dependent fashion.

  • After 20 weeks of therapy with Eos’s clinical candidate, PTC-2107, in a standard dose escalation study, a strong dose response correlation with improvement in all three parameters of body composition was demonstrated

  • PTC-2107-treated animals experienced a 10.7% overall weight loss, characterized by a 35% reduction in % fat mass, a 28% increase in % lean body mass and an 8 % increase in bone mass observed at the optimal dose, 50 mg/kg SC 1X/week, selected by elimination of senescent cell dose response data (see figure above).

  • Furthermore, this improvement in body composition accelerated with time of treatment with PTC-2107.

  • Importantly, neither fat, muscle nor bone was targeted directly by our geropeptides.  The improvement in body composition occurred on its own, after addressing the aging-specific targets via the MMP in the mitochondria which, among other things, leads to elimination of senescent cells throughout the body thus reducing the inflammaging caused by the SASP.

Dramatic Synergy Between Semaglutide and Eos’ MitoXcel™ Geropeptides

PTC-2105 and PTC-2107, in combination with semaglutide, yielded 100% to 150% or greater improvements in exercise endurance when measured on the Rotarod

  • Eos’s MitoXcel™ geropeptides work synergistically with semaglutide (“SMG”), acting at the Inner Mitochondrial Membrane to increase the MMP (Δψm) that decreases with age in all living organisms.

  • In addition to its activity against GLP-1, SMG also acts at the Inner Mitochondrial Membrane to slightly increase the MMP.

  • Dramatic improvements in exercise capacity were observed, including reversal of the well-known decline seen with semaglutide treatment alone.

  • When co-administered at low dose with SMG, clinical candidate, PTC-2105, dramatically improved exercise capacity on the Rotarod device, which tests for exercise endurance, motor coordination and balance, between 100-150% or more (red circled data), an astonishing level of improvement, more than double the percent improvements seen with SMG alone.

  • These synergistic effects are lost slowly over time once stopping the SMG while maintaining low dose PTC-2105 (orange circled data), while it continues at this high level of performance unabated if the combination therapy is maintained (red circled data).

  • Studies evaluating higher doses of PTC-2105/PTC-2107 in combination with SMG are in progress

MitoXcel™ Technology increases endurance both as a monotherapy (high-dose) as well as in combination with SMG (low-dose)

PTC-2105 either alone (high-dose) or in combination with SMG (low dose) showed similar endurance gains in naturally-aged, DIO mice, after only 5 weeks of treatment.

  • At high dose, Eos’s MitoXcel™ geropeptides, acting at the Inner Mitochondrial Membrane, increase the MMP (Δψm) that decreases with age in all living organisms, increasing exercise endurance.

  • Similarly, at low dose, Eos’s MitoXcel™ geropeptides work synergistically with semaglutide (“SMG”), also acting at the Inner Mitochondrial Membrane, to increase exercise endurance to approximately the same level.

  • This improvement in exercise endurance, which can be seen within the first 5 weeks of treatment, is maintained unabated at this higher level of performance as long as treatment is continued.

Low Doses of Eos’ MitoXcel™ Geropeptides in Combination with Semaglutide (“SMG”) “Fixes the Defect” of Lean Body Mass Loss Seen with SMG and all GLP-1 Agonists

Low doses of PTC-2105 and PTC-2107, in combination with SMG, increases the body weight and % fat mass loss observed with SMG alone, and reverses the loss of lean body mass, flipping it into a gain of lean body mass.

  • PTC-2105 (low dose) in combination with GLP-1 agonists, e.g. semaglutide (“SMG”) after 16 weeks of treatment

    • Increases body weight loss by an additional 4.5% compared to SMG alone

    • Increases fat mass loss and increases lean mass gain by 9% and 4%, respectively, compared to SMG alone

  • PTC-2107 (low dose) in combination with GLP-1 agonists e.g. SMG after 16 weeks of treatment

    • Increases body weight loss by an additional 15.5% compared to SMG alone

    • Increases fat mass loss and increases lean mass gain by 18% and 5.5%, respectively, compared to SMG alone

    • Increased differential fat mass loss and lean body mass gain with low dose PTC-2105/PTC2107 in combination with SMG begins to appear and accelerate after ~ 8 weeks of therapy, the senescent cell (“SC”) – elimination threshold

  • Both combinations yield an astonishing 100 – 150% increase in exercise capacity

  • Studies evaluating higher doses of PTC-2105/PTC-2107 in combination with SMG are in progress

MitoXcel™ Geropeptides Significantly Improve Overall Survival in an Aggressive B-ALL in vivo Tumor Model

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

  • 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).

  • In the currently still ongoing study, only DTC-0141 (ponatinib)-treated animals and animals treated with PTC-2110, either as monotherapy or in combination with Venetoclax, remained alive, 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