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Novel MitoXcel™-Powered Geropeptide Platform

Our MitoXcel™ geropeptide lead 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 and longer 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 >40X the efficacious dose after more than 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 and Non-Senescent 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 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.

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 “cause” of  aging.

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

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.

PTC-2105 Leads to Elimination of Senescent Cells via Mechanism 2

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

PTC-2105 Leads to a Reduction in Systemic Inflammation Consistent with the Widespread Elimination of Senescent Cells

PTC-2105 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-Induced Reduction in Systemic Inflammation Leads to Tissue Remodeling

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.

PTC-2105-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 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 necropy

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.

PTC-2105 is Also Synergistic with Semaglutide via Mechanism 1

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 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 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 semaglutice (SMG) and tirzepatide (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.

PTC-2105 Improves Body Composition Outcomes in Combination with Semaglutide (“SMG”) Compared to SMG Alone, and Completely Replaces SMG by 30 Weeks of Treatment or Sooner When Used Either Alone or in Combination with SMG

In two different independently performed studies, SEL-053 (data shown below) and SEL-051 (data not shown), after ~30 weeks of treatment in naturally aged older animals, both showed that PTC-2105 provides for a greater weight loss, including a greater loss of fat and a greater gain of lean mass than treatment with SMG.

  • In the SEL-053 study, naturally aged 75-week-old mice were fed 60% HFD for 3 weeks, then switched to 45% HFD for 3 weeks (e.g. 6 weeks HFD) prior to treatment initiation, and were maintained on 45% HFD for 47 weeks of treatment (study remains ongoing)

  • Treatment groups included saline negative control, semaglutide (“SMG”) dosed SC injections, 3X/week, 0.2 mg/kg, then increased to 0.4 mg/kg after week 5 in all combination groups, PTC-2105 alone SC injections, 3X/week 25 mg/kg, and the combination of PTC-2105 at 10, 25 and 50 mg/kg with SMG.

  • PTC-2105 monotherapy surpassed body weight loss with SMG at 30 weeks of treatment

  • Animals treated with SMG experienced a rapid “rebound” weight gain back to the level of the saline control group withing 1 – 2 weeks of stopping SMG at Week 35.

  • On the contrary, animals treated with the combination of PTC-2105 and SMG experienced little rebound weight gain up to the PTC-2105 body weight level (PTC-2105 10 and 25 mg/kg plus SMG) or no rebound weight gain when SMG was stopped (PTC-2105 50 mg/kg plus SMG) at Week 35.

  • After Week 45, when PTC-2105 was also stopped, leaving all groups off of any treatment, combination groups that had been treated with PTC-2105 at 25 and 50 mg/kg experience NO REBOUND WEIGHT GAIN by Week 47.  This experiment is ongoing and animals continue to be monitored.

  • In pre-clinical mouse models, PTC-2105-treated animals, as monotherapy or in combination with SMG, lost more fat and gained more lean mass than SMG-treated monotherapy.

PTC-2105, Whether as Monotherapy or in Combination with SMG, Improves Physical Functioning Compared to SMG Treatment Alone

Olden DOME SMART cage are AI‑powered “smart lids” that convert standard mouse home cages into continuous, 24/7 multi‑parameter behavioral and health monitoring platforms—enabling high‑resolution, automated, real‑time tracking of activity, sleep, movement, food/water intake, and other digital biomarkers, which dramatically improves data quality, reduces human‑handling bias, enhances welfare, and increases reproducibility in preclinical mouse studies.

  • In the SEL-053 study, naturally aged 75-week-old mice were fed 60% HFD for 3 weeks, then switched to 45% HFD for 3 weeks (e.g. 6 weeks HFD) prior to treatment initiation, and were maintained on 45% HFD

  • Treatment groups included saline negative control, semaglutide (“SMG”) dosed SC injections, 3X/week, 0.2 mg/kg, then increased to 0.4 mg/kg after week 5 in all combination groups, PTC-2105 alone SC injections, 3X/week 25 mg/kg, and the combination of PTC-2105 at 10, 25 and 50 mg/kg with SMG.  At Week 40, all animals were moved to Olden DOME SMART cages.

  • NOTE:  SMG was stopped at Week 35 in all SMG monotherapy and combination groups, and PTC-2105 was subsequently stopped at Week 45 in all monotherapy and combination groups.

  • At Week 45, after 5 weeks of monitoring in these DOME cages, PTC-2105-treated animals, as a monotherapy and in combination with SMG (25 mg/kg PTC-2105, 1X/week), improved activity metrics such as distance traveled, average acceleration and average awake speed.  SMG-treated animals declined in all three metrics compared to controls.

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

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.