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Novel MitoXcel™-Powered Geropeptide and Oncopeptide Platform

Our MitoXcel™ geropeptide and oncopeptide clinical candidates are:

  • Eos SENOLYTIX geropeptides – PTC-2105, PTC-2107, PTC-2113 and PTC-2118
  • Perseus SENOLYTIX oncopeptides – PTC-2109, PTC-2110, PTC-2117 and PTC-2128
  • Ponce Aurora – cosmetic geropeptides – PTC-2111 and PTC-2119
  • Ponce Aurora – rapid energy beverages/supplements geropeptides – PTC-2116 and PTC-2132

Key Attributes:

  • 18- to 30-amino acids in length
  • Cross the blood brain barrier
  • Administered via SC injection over an 8-16 week course, and longer, 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
  • Acts only on Aging- or Cancer-Specific Targets
  • Safety Profile: Without demonstrable evidence of toxicity at >40X the efficacious dose after up to 20 weeks of continuous dosing.  Normal liver enzyme levels and no adverse effects observed.

Mechanism of Action:  Selectively Target the Inner Mitochondrial Membrane Potential (Δψm) in the Mitochondria of Senescent, Non-Senescent and Cancer Cells

  • Completely novel, aging-specific mechanism of action
  • Two key mechanisms, both targeting the Inner Mitochondrial Membrane Potential (Δψm)
  • Binds cardiolipin, as well as multiple key proteins involved in the Electron Transport Chain (“ETC”), especially those in Complex III and IV
    • Cardiolipin is crucial for creating and stabilizing the mitochondrial cristae membranes and maintaining IMM architecture, enabling tight packing of respiratory chain complexes.
    • Cardiolipin directly binds to and stabilizes the entire mitochondrial respiratory supercomplex (Complexes I–III–IV megacomplex), functioning to maintain ETC assembly and structural integrity, acting as a molecular glue for oxidative phosphorylation.
    • Under stress, cardiolipin undergoes peroxidation and translocation from the IMM to the outer membrane, triggering Cytochrome C detachment from cardiolipin, the first step of apoptosis.
  • This single target leads to two distinct yet equally important mechanisms of action, Mechanism 1 and Mechanism 2
  • 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)

  • Senescent cells 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™ 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 in the PTC-2110-treated animals.
  • 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.

MitoXcel™ Geropeptides Act on Aging-Specific Targets

Eos’s MitoXcel™ geropeptide PTC-2105 was evaluated in young mice (20 weeks; “20W”) and in naturally 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.

MitoXcel™ Geropeptides Lead to Elimination of Senescent Cells via Mechanism 2

Eos’s MitoXcel™ geropeptide PTC-2105 selectively eliminates 60-80% of senescent cells in all organs of the body, including the brain, after 8 weeks or more of dosing

  • PTC-2105 (SC injections 3.3 mg/kg, 3X/week, n = 5 per cohort) was dosed in 75-week-old naturally aged mice for 8 weeks

  • Senescent cell numbers are significantly and profoundly reduced in almost all organs and tissue types as analyzed by multiple senescent cell markers (β-gal, uPAR and p16)

    • SA-β-Gal: Senescence-associated B-galactosidase, a well-established biomarker of cellular senescence

    • uPAR: Urokinase-type plasminogen activator receptor, a cell surface marker associated with senescence

    • p16: p16INK4a, a regulator of the cell cycle and a well-established biomarker of cellular senescence

MitoXcel™ Geropeptides Lead to a Reduction in Systemic Inflammation Consistent with the Widespread Elimination of Senescent Cells

Eos’s MitoXcel™ geropeptide, PTC-2105’s reduction of senescent cells, which secrete the highly inflammatory Senescence Associated Secretory Factors (“SASP”) responsible for systemic “inflammaging”, reduced plasma levels of key SASP factors after 16 weeks of treatment compared to saline negative controls

  • PTC-2105 (SC injections 3.3 mg/kg, 3X/week, n = 5 per cohort), was dosed in 75-week-old naturally aged mice for 16 weeks

  • Plasma levels of key SASP factors were reduced, including CCL11, CCL10, IL-17A, IL-22, IL-32, IL-27 compared to pre-treatment levels

  • PTC-2105 is now given SC once weekly with similar results

MitoXcel™ Geropeptides-Induced Reduction in Systemic Inflammation Leads to Tissue Remodeling

Eos’s MitoXcel™ geropeptide, PTC-2105 Leads to Muscle and Fat Remodeling Towards a Younger Phenotype

  • Naturally aged 75-week-old mice treated with PTC-2105 (PTC-2105 was dosed SC injections 3.3 mg/kg, 3X/week, n = 5 per cohort) for 16 weeks showed a reduction in intermocyte space (muscle tissue rejuvenation) and a decrease in adipocyte area (fat tissue reduction)

  • A reduction in intermyocyte space is indicative of muscle tissue regeneration. An increase in myofibril count was also observed, indicative of muscle tissue regeneration (data not shown)

  • Reduction of adipocyte area signifies loss of fat mass and white adipose tissue at a cellular level.

MitoXcel™ Geropeptides-Induced Reduction in Systemic Inflammation Leads to Body Composition Improvements, Including Loss of Fat and Increase in Lean Mass

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

  • Naturally aged 75-week-old mice treated with Eos’s MitoXcel™ geropeptide, PTC-2105 (SC injection, 3.3 mg/kg, 3X/week, n = 5 per cohort), for 15 weeks and subjected to DEXA scan showed an increase in lean mass percentage and a reduction in fat mass percentage, relative to saline-treated mice, restoring body composition and muscle mass closer to that of young mice (12-week-old)

  • The increase in lean mass percentage was confirmed by weighing the gastrocnemius muscles bilaterally at end of study necropsy

  • PTC-2105 is now given SC once weekly with similar results.

MitoXcel™ Geropeptide PTC-2107 Also Leads to Body Composition Improvements, Including Loss of Fat and Increase in Lean Mass

Because MitoXcel™ Technology is a class of peptides defined by the biophysical informational content of their amino acid sequences, Eos’s MitoXcel™ geropeptide PTC-2105, which is 18 AA in length, and Eos’s MitoXcel™ geropeptide PTC-2107, which is 30 AA in length, each with unique sequences, both demonstrate Mechanism 1 and 2 activities, because the key rules defining the MitoXcel™ class are not primarily dependent on geropeptide length.

  • Naturally aged 75-week-old mice treated with Eos’s MitoXcel™ geropeptide, PTC-2107 (SC injection, 2.5, 5, 10, 25, and 50 mg/kg, 3X/week, n = 5 per cohort), for 20 weeks and subjected to DEXA scan showed an increase in lean mass percentage and a reduction in fat mass percentage, relative to baseline, in a dose dependent manner.

  • Like a true gerotherapeutic, MitoXcel geropeptides don’t target fat or muscle to achieve a healthier improvement in body composition, they simply target the underlying causes of aging via the mitochondria.

  • Phenotypic healthspan improvements, like loss of fat and gain of muscle, along with many others that we have observed and documented, are simply the downstream effects that occur without any further intervention.

MitoXcel™ Geropeptides Lead to Favorable Weight Loss Composition without Affecting Food Consumption

Eos’s MitoXcel™ geropeptide, PTC-2105, reduces body weight, relative to saline, without affecting food consumption, in a dose-response manner. 

  • Naturally aged 75-week-old mice were treated with Eos’s MitoXcel™ geropeptide PTC-2105 dosed 1X/week, 2.5 and 25 mg/kg, n = 8-10 per cohort for 8 weeks. Mice were fed a standard diet of 10% fat, 20% protein, 70% carbohydrates (by kcal%).  Food was weighed weekly.

  • As expected, PTC-2105-treated mice lost body weight in a dose-dependent manner.

  • Aggregate food consumption showed no statistically significant decrease.

  • 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™ Technology is Also Synergistic with Semaglutide via Mechanism 1

Eos’s MitoXcel™ geropeptide 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 via Mechanism 1, in as little as 5 weeks and earlier, before Mechanism 2-induced elimination of senescent cells.

  • PTC-2105 works 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.

  • PTC-2105 is now given SC once weekly with similar results.

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 higher doses of Eos’ MitoXcel™ geropeptides, PTC-2105, 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 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. PTC-2105 is now given SC once weekly with similar results.

Competitive Landscape – Eos’s MitoXcel™ Geropeptide PTC-2105 Compares Favorably to All GLP-1s Including Retatrutide

Eos’ MitoXcel™ geropeptide, PTC-2105, both alone and in combination with GLP-1s, leads to a greater fat loss than any GLP-1 on the market or in clinical development. Furthermore, it is the only therapeutic that accompanies significant loss of fat with significant gain of lean mass.

  • PTC-2105 monotherapy (SC injection, 25 mg/kg, 3X/week) treatment of 75-week-old naturally aged DIO-fed mice for 35 weeks led to a 33% loss of fat accompanied by a 7.1% gain of lean mass, for an overall weight loss of 25.9%

  • Treatment with PTC-2105 (SC injection 25 mg/kg, 3X/week) in combination with the GLP-1, semaglutide (SMG), (SC injections, PTC-2105 50 mg/kg, 1X/week + SMG 3X/week, 0.2 mg/kg, increased dose to 0.4 mg/kg after week 5) in 75-week-old naturally aged DIO-fed mice for 35 weeks led to a 66% loss of fat accompanied by a 7.4% gain of lean mass, for an overall weight loss of 58.6%

  • These results are best-in-class with respect to both overall weight loss and the quality of the resulting body composition as measured by DEXA scans in PTC-2105-treated animals compared to reported results for GLP-1s

  • Patients on Retatutride have a reported 32% total weight loss, comprised of a 22% loss of fat and a 10% loss of muscle at 48 weeks (Ph2, 12 mg once weekly). PTC-2105 monotherapy (SC injection, 25 mg/kg, 3X/week) treatment of 75-week-old naturally aged DIO-fed mice for 35 weeks led to a 33% loss of fat, accompanied by a 7.1% gain of lean mass, for an overall weight loss of 25.9%. PTC-2105 is now given SC once weekly with similar results.

MitoXcel™ Oncopeptides 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™ 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 in the PTC-2110-treated animals.

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

MitoXcel™ Geropeptide PTC-2105 Demonstrates Broad Effects Indicative of a Gerotherapeutic

PTC-2105 significantly reduces death due to late radiation (“γ-IR “) toxicity compared to saline-treated γ-IR-controls

  • As expected from a true gerotherapeutic, we have also observed unexpected yet important beneficial effects of these peptides in other biological circumstances

  • One such unexpected observation has been the protection of mice undergoing γ-IR from the lethal late radiation toxicity seen in Balb/c mice

  • In preparation for an experiment (SEL-026 study), in order to accelerate senescent cell creation in young mice, we performed low dose gamma radiation (γ-IR , 5 Gy split over 9 doses) on 26 week old Balb/c mice

  • This protocol has reliably led to increased senescent cell burden about 8 weeks after initiating γ-IR in C57Bl/6 mice.  However, Balb/c mice turned out to be more sensitive to γ-IR than C57Bl/6 mice, and 37.5% of irradiated mice died of Acute Radiation Syndrome (ARS) approximately 1 week after the conclusion of irradiation treatment, from acute bone marrow failure.

  • About 50 γ-IR survived and were treated with either PTC-2105 or saline as negative control.

  • About 3 to 6 months later, these mice began to exhibit toxicity  (e.g. weight loss) and death due to the effects of Late Radiation-Induced Toxicity (e.g. cardiac and GI toxicity, tumors).

  • We unexpectedly observed protective effects from weight loss and death due to late radiation-induced toxicity in mice treated with our lead clinical gerotherapeutic peptide, PTC-2105 compared to saline treated γ-IR-treated controls (p=0.05)

  • Radiation therapy, often used to treat cancer, generates Reactive Oxygen Species (ROS), which can damage the DNA of both cancerous and healthy cells. This damage can lead to cell death, which is beneficial for targeting tumors but can also harm normal tissues, resulting in toxicity.

  • PTC-2105 targets the MMP, reducing ROS, and thereby potentially reducing early and later toxicity due to γ-IR.