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Novel MitoXcel™-Powered Geropeptide Platform

Our MitoXcel™ geropeptides, clinical candidates PTC-2105 and PTC-2107, 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)

Our candidate MitoXcel™ geropeptides 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.

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.

Synergy Between Semaglutide and Eos’ MitoXcel™ Geropeptides

Lead clinical candidate PTC-2105, both as monotherapy and in combination with semaglutide, yielded sustained exercise endurance gains compared to saline-treated controls 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, in animals treated with PTC-2105 monotherapy at high dose (“HD”) and treated with PTC-2105 low dose in combination with SMG.

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

Both low and high dose PTC-2105, as monotherapy and  in combination with SMG and TRZ, increases the body weight and % fat mass loss observed with GLP-1 treatment alone, and reverses the loss of lean body mass, flipping it into a gain of lean body mass.

  • PTC-2105 treatment, as monotherapy and in combination with semaglutide or tirzepatide, increases fat loss while also producing lean mass increases as early as after 5 weeks of treatment.

  • By week 5 of treatment, combination of LD 2105 plus TRZ already demonstrates an increase in lean mass, compared to LD 2105 plus SMG.

MitoXcel™ Geropeptide PTC-2105 Leads to Favorable Weight Loss Composition without Affecting Food Consumption

PTC-2105 reduces body weight, relative to saline, without affecting food consumption, in a dose-response manner. 

  • Body weight reduction is solely from fat, as evidenced by a reduction in fat mass and an increase in lean mass, as analyzed by DEXA full body composition scanner.

MitoXcel™ Geropeptide PTC-2105 Acts on Aging-Specific Targets

PTC-2105 was evaluated in young mice (20 weeks; “20W”) and in natuarally aged old mice (75 weeks; (“75W”) for effects on body weight, body composition and exercise endurance.

 

  • PTC-2105 reduces body weight by week 10 in aged mice (75 weeks old), but not young mice (20 weeks old), indicating an age-specific therapeutic response for body weight reduction.


 

 

 

 

 

 

 

 

 

  • PTC-2105 reduces fat mass and increases lean mass by week 5 in aged mice (75 weeks old), but not young mice (20 weeks old), indicating an age-specific therapeutic response for body composition changes.

 

 

 

 

 

 

 

 

 

 

  • PTC-2105 increases Rotarod latency by week 10 in aged mice (75 weeks old), but not young mice (20 weeks old), indicating an age-specific therapeutic response for functional phenotypes.