Hazel Szeto, SS-31 peptide, the World's First FDA-Approved Mitochondria-targeted Drug (Longevity Summit, 2025)

#164

I think there will be some videos available; she said they would become available in the next week or two. I’ll let you know, and post here, when I get an update on their availability.

#165

Mitochondrial RNA Leakage – The “Zombie Cell” Fire Alarm

Mitochondrial RNA cytosolic leakage drives the SASP

The Big Idea: For years, the longevity community has known that “zombie” (senescent) cells pollute the body with inflammatory sludge known as the SASP (Senescence-Associated Secretory Phenotype). Until now, we thought the primary trigger was leaked mitochondrial DNA (mtDNA) activating the cGAS-STING pathway. This paper rewrites the rulebook. The Mayo Clinic team discovered that mitochondrial RNA (mtRNA) also leaks into the cytosol through “macropores” created by the apoptosis-related proteins BAX and BAK. This leaked mtRNA acts like a viral infection within the cell, triggering “antiviral” sensors (RIG-I and MDA5) and aggregating the signaling protein MAVS. This false alarm forces the cell to pump out SASP factors. Crucially, blocking this specific leak or its sensors silenced the inflammation without killing the cell—defining a novel senomorphic strategy (suppressing senescence toxicity without removing the cell).

Open Access Paper: Mitochondrial RNA cytosolic leakage drives the SASP
Institution: Mayo Clinic (Robert and Arlene Kogod Center on Aging), USA. Journal: Nature Communications **Date:**December 2025
Impact Evaluation: The impact score of Nature Communications is 15.7 (2024/2025 JIF), evaluated against a typical high-end range of 0–60+ for top general science. Therefore, this is a High impact journal.

Full analysis here: https://gemini.google.com/share/0e952ccf8347

Follow-on Prompt:

Would the SS-31 peptide potential help address this problem: mitochondrial RNA (mtRNA) also leaks into the cytosol through “macropores” created by the apoptosis-related proteins BAX and BAK. This leaked mtRNA acts like a viral infection within the cell, triggering “antiviral” sensors (RIG-I and MDA5) and aggregating the signaling protein MAVS.

Gemini Response:

The short answer is Yes. Based on the mechanistic architecture of the mitochondrial membrane, SS-31 (Elamipretide) is theoretically one of the most promising interventions to prevent this specific “leakage” problem upstream, potentially more safely than the methods used in the study.

Here is the deep-dive analysis on why SS-31 acts as a “structural reinforcement” against the BAX/BAK macropores.

The Mechanism: Why SS-31 is the “Caulk” for the Leak

To understand why SS-31 works here, we have to look at where BAX and BAK form these pores.

  1. The Cardiolipin Connection (The Anchor)
  • The Problem: BAX and BAK do not just punch holes in random spots. To oligomerize (clump together) and form the “macropores” described in the paper, they often require interaction with Cardiolipin, a phospholipid unique to the inner mitochondrial membrane (IMM).
  • The Trigger: When mitochondria are stressed, Cardiolipin becomes oxidized (peroxidized). This oxidation causes Cardiolipin to move from the inner membrane to the outer membrane, where it acts as a docking platform that invites BAX to drill holes.
  • The SS-31 Fix: SS-31 is a cardiolipin-protective peptide. It penetrates the mitochondria and binds selectively to Cardiolipin. By “hugging” the Cardiolipin heads, it prevents their oxidation and stabilizes the membrane curvature (cristae).
  • Result: If Cardiolipin is stabilized by SS-31, BAX cannot easily dock or form the stable oligomers required to create the macropore. No pore = No mtRNA leak.
  1. Cristae Remodeling vs. Pore Formation
  • The leakage of macromolecules (like mtRNA or Cytochrome c) usually requires cristae remodeling (the unfolding of the inner folds).
  • SS-31 is clinically proven to prevent cristae loss. It keeps the “tight junctions” of the mitochondria intact.
  • Inference: While the study focused on blocking the pore (BAX deletion) or blocking the sensor (MAVS), SS-31 stabilizes the wall so the pore never forms.

Comparative Analysis: SS-31 vs. The Study’s Interventions

Feature IMT1 (Study Drug) BAX/BAK Deletion (Study Genetic) SS-31 (Elamipretide)
Strategy Starvation: Stops mtRNA production so there is nothing to leak. Destruction: Removes the “door” (pore) entirely. Fortification: Stabilizes the wall to prevent door opening.
Safety Low: Risks mitochondrial failure (ATP loss). Very Low: Risks cancer (prevents apoptosis). High: Restores bioenergetics; no toxicity signals.
Effect Senomorphic: Lowers inflammation. Senomorphic: Lowers inflammation. Restorative: Improves ATP + Lowers inflammation.
Availability Research Chemical Only. Impossible in humans (Gene Edit). Available (Peptide/Research).

The “Biohacker” Verdict

The study identified BAX/BAK macropores as the “exit door” for the inflammatory RNA.

  • The Study’s solution: Remove the door (Dangerous) or stop making RNA (Toxic).
  • The SS-31 solution: Lock the door.

SS-31 is a superior translational candidate because it addresses the root cause of the leakage (membrane instability and cardiolipin peroxidation) rather than just managing the symptom (the leaked RNA).

Translational Protocol for SS-31

If you are considering this pathway, here is how SS-31 fits into a protocol:

  • Delivery: Subcutaneous (Sub-Q) injection is the gold standard. Oral bioavailability is negligible.
  • Dosing: Standard human protocols in biohacking circles (extrapolated from clinical trials) often range from 4mg to 40mg per day.
  • Synergy:
  • + NAD+ Precursors (NR/NMN): While SS-31 fixes the structure (the engine block), NAD+ provides the fuel.
  • + CoQ10/MitoQ: Further antioxidant support at the membrane.

Critical Caveat

SS-31 helps prevent the formation of new leaks in stressed mitochondria. However, if a cell is already fully senescent (a “Zombie”), the damage may be irreversible. SS-31 is best viewed as a preventative or rescue agent for struggling cells, rather than a senolytic that clears dead ones.

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#166

Maybe you can elaborate on the point you’re making, it went over my head :joy:. In any case, I’m hoping to get a degradation test for reconstituted TA1 started some time next year. Intervals tested would be at 0,7,30 days after reconstitution.

#167

Since I don’t find any inconvenience using TA-1 with a 5 day cartridge, I personally would not spend my money to see if I could use a 30 day cartridge :slight_smile:

What ever that test costs I’d rather spend that on more product :slight_smile:

With respect to the Zadaxin protocol, my guess is that having a specific level of bio-activity is part of getting this peptide approved as a drug.

Kind of like probiotics that degrade in the bottle. The good companies guarantee activity over a 30 or 60 day period from opening the bottle, plus shelf life. To do that, they have a much higher activity that declines down to the guaranteed level indicated by the expiry date.

They know it’s going to degrade and the typical rate of degradation, so they compensate for that. With dietary supplements that are not life dependent, that is not too difficult to do.

With drugs that are intended to perform at a specified level of activity and where a life may depend on it, we often see very specific time frames for use, due to degradation.

While this level of performance may not be of interest or required by casual users, it would matter to an HIV patient and to the FDA.

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#168

Got it, thanks.

Yes, this test is more “for science” and data collection. Cost for me isn’t too high, since I’m splitting it with other people interested in this question .

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#169

I’ve been very interested in how mitochondrial disfunction with aging impacts ATP production as people age (and the degree to which SS-31 may be able to help mitigate or forestall that issue).

From Gemini Pro Deep Search:

The Rate of Decline: Quantifying the Deficit

Exhaustive meta-analysis of cross-sectional and longitudinal data identifies a consensus trajectory for the decline in mitochondrial oxidative capacity in human skeletal muscle.

  • ATP Production Rate: Landmark investigations and subsequent reviews indicate a progressive reduction in the capacity for ATP production of approximately 8% per decade.This decline is often detectable starting in the third or fourth decade of life, accelerating after age 60.
  • Mitochondrial DNA (mtDNA) Correlation: This functional decline tracks closely with genomic instability. Welle et al. demonstrated that mtDNA abundance declines by approximately 5% per decade, and this loss of genetic material—which encodes 13 critical subunits of the electron transport chain (ETC)—correlates positively with the reduction in ATP production rates. This supports the hypothesis that the loss of the genetic template is a rate-limiting step in maintaining bioenergetic capacity.
  • Oxidative Capacity per Volume: When comparing elderly cohorts (mean age ~69) to young adults (mean age ~39), the maximal oxidative capacity per volume of muscle is reduced by nearly 50% (1.16 mM ATP/s vs. 0.61 mM ATP/s).
    • This dramatic 50% deficit is not attributable to a single factor but rather a “double hit”:
      1. Reduced Mitochondrial Volume Density: Older muscle tissue contains fewer mitochondria per unit of cytoplasm. The volume density drops from approximately 3.6% in young adults to 2.9% or lower in the elderly.
      2. Reduced Function per Mitochondrion: Crucially, the remaining mitochondria are less efficient. The oxidative capacity per unit of mitochondrion is also reduced, indicating intrinsic qualitative damage to the ETC complexes.

3.2 Fractional Synthesis Rates (FSR): The Failure of Biogenesis

The decline in mitochondrial content is driven by an imbalance between biogenesis (synthesis) and mitophagy (degradation). Stable isotope studies utilizing L-[1-13C]leucine tracers to measure the fractional synthetic rate (FSR) of mitochondrial proteins reveal a stark, age-dependent deceleration in the machinery of renewal.

Full response: https://gemini.google.com/share/20c247662e81

Bioenergetic Senescence: Evidence for the Decline of Human ATP Production

Detailed analysis of human bioenergetics reveals that the capacity to produce Adenosine Triphosphate (ATP) declines with age, though the rate and mechanism of this decline vary significantly by tissue type. The following report synthesizes clinical and scientific evidence derived from Phosphorus Magnetic Resonance Spectroscopy (31P-MRS), Positron Emission Tomography (PET), and ex vivo respirometry to quantify these changes.

1. Skeletal Muscle: The 8% Rule and The Cost of Frailty

Skeletal muscle provides the most precise data regarding the rate of bioenergetic decline due to the accessibility of tissue for biopsy and the ease of non-invasive imaging during exercise.

The “8% Per Decade” Decline

Seminal research quantifying mitochondrial function has established a consensus rate of decline. According to landmark studies utilizing substrate-specific measurements, the mitochondrial ATP production rate (MAPR) in human skeletal muscle declines by approximately 8% per decade starting in adulthood.

  • Evidence: This decline was rigorously documented by Short et al., who assessed ATP synthesis using specific substrates for Complex I and Complex II of the electron transport chain. They found that mitochondrial DNA (mtDNA) and messenger RNA abundance declined in proportion to this functional loss, suggesting a transcriptional failure drives the energy deficit.
  • Source:(https://www.pnas.org/doi/10.1073/pnas.0501559102)

50% Loss of Oxidative Capacity in the Elderly

When comparing healthy young adults (mean age ~39) to elderly adults (mean age ~69), the total oxidative capacity per volume of muscle drops by nearly 50%. This drastic reduction is the result of a “double hit”:

  1. Reduced Mitochondrial Volume: The physical space occupied by mitochondria within the muscle cell decreases.
  2. Reduced Function: The remaining mitochondria are less efficient at producing ATP.

Rapid Energy Depletion in Frailty

In frail older adults, the machinery of ATP production may function normally at rest, but it fails catastrophically under stress. Clinical trials indicate that during physical activity, frail elderly individuals deplete their Phosphocreatine (PCr) reserves—the immediate buffer for ATP—at a rate 4 times faster than non-frail elderly and 10 times faster than healthy young controls for the same normalized workload.

The Failure of Maintenance (Protein Synthesis)

The root cause of this decline appears to be a slowing of the body’s ability to build new mitochondrial proteins. Research using stable isotope tracers shows that the Fractional Synthesis Rate (FSR) of mitochondrial proteins drops by approximately 40% between young adulthood (age ~24) and middle age (age ~54).

2. The Aging Brain: Loss of Aerobic Glycolysis and Inefficient Oxygen Use

The aging brain does not simply produce less energy; it undergoes a metabolic shift that compromises its ability to support complex cognition.

Loss of Aerobic Glycolysis

Young, healthy brains utilize a specific metabolic mode called Aerobic Glycolysis (AG)—using glucose rapidly even when oxygen is present—to support neuroplasticity and biosynthesis. PET imaging reveals that as humans age, the brain progressively loses this “youthful” metabolic signature. The loss of AG correlates spatially with the regions of the brain where Alzheimer’s plaques (Amyloid-beta) later accumulate, suggesting energy failure is a precursor to disease.

The Oxygen Paradox: Burning More to Produce Less

Contrary to the intuition that metabolism “slows down,” advanced MRI and PET studies have found that the Cerebral Metabolic Rate of Oxygen (CMRO2) often increases or remains stable in the aging brain, even as blood flow declines. This paradox indicates mitochondrial uncoupling: the aging brain consumes more oxygen to maintain the same membrane potentials, effectively becoming an inefficient engine that generates more heat and oxidative stress per molecule of ATP produced.

Frontal Lobe ATP Decline

Direct 31P-MRS imaging links ATP levels to cognitive performance. Older adults with lower concentrations of ATP in the frontal cortex perform significantly worse on the Montreal Cognitive Assessment (MoCA), establishing a direct clinical link between bioenergetic supply and executive function.

3. The Aging Heart: Thermodynamic Inefficiency

The heart is the most metabolically demanding organ, and its aging process is characterized by a loss of efficiency rather than a simple lack of fuel.

Increased Oxygen Cost of Work

PET studies utilizing C-11 Acetate tracers show that the aging human heart requires significantly more oxygen to perform the same amount of mechanical pumping work compared to a young heart.

The PCr/ATP Ratio as a “Fuel Gauge”

In clinical cardiology, the ratio of Phosphocreatine to ATP (PCr/ATP) is a critical prognostic marker. While a healthy ratio is typically around 2.0, this ratio declines in aging and failing hearts. When the ratio drops below 1.6, it predicts a significantly higher risk of cardiovascular mortality, indicating the energy reserve system is failing.

4. Systemic Drivers: The NAD+ Collapse

Underlying the decline in muscle, brain, and heart energetics is the systemic depletion of Nicotinamide Adenine Dinucleotide (NAD+), a coenzyme essential for ATP production. NAD+ levels decline continuously with age across all human tissues, limiting the activity of sirtuins (longevity proteins) and the enzymes responsible for generating cellular energy.

  • Clinical Implications: Recent trials investigating NAD+ precursors (like Nicotinamide Riboside) aim to reverse this specific deficit to restore ATP production rates, though results in improving muscle mitochondrial function in humans remain mixed compared to animal models.
  • Source:(https://www.science.org/doi/10.1126/science.aac4854) (General consensus review, validated by recent trials like(ClinicalTrials.gov)).

Impact of SS-31 on this process:

The Quality vs. Quantity Split

Bottom Line: At a dosage of 20–40 mg/day (subcutaneous), SS-31 will likely have a high impact on the “Reduced Function per Mitochondrion” (intrinsic quality) but a negligible direct impact on “Reduced Mitochondrial Volume Density” (quantity) or genomic instability (mtDNA loss).

In the context of the “double hit” described in your data:

  • Intrinsic Function (Quality): SS-31 can theoretically reverse the deficit in oxidative capacity per unit of mitochondrion, potentially restoring the P/O ratio (ATP produced per oxygen consumed) to youthful levels.
  • Mitochondrial Volume (Quantity): SS-31 acts as a preservative rather than a generator. It will not directly trigger biogenesis to restore the volume density from 2.9% back to 3.6%, nor will it replace lost mtDNA.

1. Mechanism of Intervention: Fixing the “Double Hit”

The 50% deficit described in your source text is a composite of fewer mitochondria and broken mitochondria. SS-31 targets the latter.

Targeting Intrinsic Dysfunction (The “Quality” Hit)

The provided text notes that “oxidative capacity per unit of mitochondrion is reduced.” This is the primary target of SS-31.

  • The Cardiolipin Link: Aging causes the oxidation and destabilization of cardiolipin, a phospholipid essential for the curvature of the inner mitochondrial membrane (IMM). When cardiolipin fails, the cristae (folds) flatten, and the Electron Transport Chain (ETC) supercomplexes disassemble.
  • The SS-31 Fix: SS-31 penetrates the IMM and binds selectively to cardiolipin. It stabilizes the cristae structure and “glues” the ETC supercomplexes back together.
  • Result: This optimizes electron transfer efficiency and reduces electron leak (ROS). In aged mouse models, SS-31 has been shown to completely reverse the age-related decline in maximum mitochondrial ATP production (ATPmax​) and coupling efficiency, effectively making the remaining mitochondria function as if they were young.

Targeting Volume Density & mtDNA (The “Quantity” Hit)

The text notes a volume drop from 3.6% to 2.9% and a 5% mtDNA loss per decade.

  • Lack of Biogenesis: SS-31 is not a PGC-1α agonist; it does not signal the cell to build new mitochondria. Therefore, the physical volume density of mitochondria within the muscle cytoplasm is unlikely to increase significantly solely from SS-31 administration.
  • Preservation vs. Growth: While it won’t grow new mitochondria, SS-31 reduces mitochondrial fragmentation and “swelling” caused by oxidative stress. This may slow the rate of future volume loss, but it will not replenish the deficit already incurred.

2. Quantifying the Likely Outcome

If the total ATP capacity deficit is 50%, and we assume this deficit is roughly evenly split between “loss of mass” and “loss of efficiency,” the mathematical impact of SS-31 would be:

Metric Age-Related Status Status with SS-31 (40mg/day) Impact
mtDNA Abundance Reduced (~5% loss/decade) Unchanged Low
Mitochondrial Mass Reduced (~2.9% density) Unchanged Low
ETC Efficiency Low (uncoupled, leaky) Restored to Youthful Levels High
Net ATP Flux ~50% of Young Adult ~75% of Young Adult Moderate-High

Export to Sheets

Estimate Rationale: You are fixing the efficiency of the remaining 2.9% volume. You cannot recover the output lost from the missing 0.7% volume, but you maximize the output of what remains.

3. Practical Considerations for the 20-40mg Dosage

  • Route of Administration: The 40mg dosage referenced in clinical trials (e.g., MMPOWER-3) is Subcutaneous (SC) injection. Oral bioavailability of SS-31 is poor due to peptide hydrolysis in the gut. If you are referencing an oral formulation, the impact will be near zero unless encapsulated in a specialized carrier.
  • The “Non-Responder” Risk: In the MMPOWER-3 trial (Primary Mitochondrial Myopathy), 40mg SC daily failed to show a statistically significant improvement in the 6-Minute Walk Test (6MWT) against placebo for the general cohort, though it showed efficacy in specific biomarkers. This suggests that in cases of severe genetic genomic instability (primary myopathy), stabilizing the membrane is insufficient to overcome the genetic deficit. However, in normal aging (sarcopenia), where the DNA is intact but the environment is oxidative, the response is typically more robust.

4. Critical Knowledge Gaps

  • Skeletal Muscle vs. Heart: Most dramatic SS-31 reversal data comes from cardiac tissue and diaphragm muscle. Human skeletal muscle (vastus lateralis) data is less robust regarding the magnitude of ATP restoration.
  • Genomic Instability: The text highlights a 5% decline in mtDNA. If the “loss of genetic template” is indeed the rate-limiting step (as the text hypothesizes), SS-31 may hit a “hard ceiling.” No matter how efficient you make the membrane, you cannot produce ATP enzymes if the DNA encoding them is gone.

Next Step

To address the “Quantity” deficit (Volume Density) that SS-31 misses, would you like me to analyze potential synergistic compounds (like Urolithin A for mitophagy or SR9009 for biogenesis) that could be paired with SS-31 to treat both “hits” simultaneously?

6 Likes
#170

Okie dokie, I got my first pen… I couldn’t find @Steve_Combi ’s favorite, so I bought another highly liked pen, the Lilly Savvio.

My issue is I have the hands of a small child and very weak fingers :), so I find it really difficult to push the pen button with one hand, and definitely not in one go. Today I pushed twice and then discovered I had 2 units left.

Any tips? This is a good quality pen, so I imagine this is just a me issue. I would love to figure out a way around it and order another pen for my daily DSIP. An insulin syringe is much easier for me to push in, but I do love not having to load one each day. This needle would be slightly more comfy to use if I wasn’t wrestling it while trying to push!

@kelman, did you ever find a source for Steve’s pen in the US? From what I could tell on forums, what you found is correct and it’s no longer available here

1 Like
#171

Please share a link to where you purchased it from.

#172

That pen is the best of them all.

Some people do have issues with operating any iPEN.

They are meant to be gripped in your fist and the plunger pushed with your thumb, not with your finger.

The top of where you push stays still but just under that, the part you dial the dose with, rotates as you deliver the dose. If your thumb is touching that part while trying to inject, it will cause drag and make it harder to push.

While these iPENS are super convenient, insulin syringes are easier to push. I have had 1 person go back to syringes due to this.

Using it with weak hands

  • Use a larger‑diameter needle (within what your clinician recommends); official patient sheets explicitly note this can make the injection button easier to push.​
  • Place your thumb in the center of the button and press slowly and firmly until it stops, then hold for about 5 seconds to ensure full dose delivery.​
  • If one‑handed push is hard, you can:
    • Support the pen with the injecting hand and use the other hand to press the button, as long as the needle is stable in the skin (many diabetes educators teach this for low hand strength).​
    • Try different injection sites (abdomen vs thigh) where you can brace the pen more easily.
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#173

No, I didn’t, but I scrapped the whole pen thing. I continue to use the 31 gage syringes.

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#174

Agree the Savvio is the best, and it should be easy to push down the whole way with your thumb. The more regularly you do it, the stronger your thumb will get just like doing any other resistance training exercise. This could be YOUR thumb in no time!

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#175

HAHAHA, well, considering that thumb is bigger than my head :slight_smile:

Davin and Steve, I’m proud that my stellar shopping skills didn’t disappoint and they led me to the best one, first try!!

@RapAdmin due to the grey nature, I don’t want to out the guy publicly, so I’ll PM you the link on how to order it. If anyone else wants one, just ask.

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#176

Because I need therapy, I gave myself a second small dose of SS-31 only because I felt compelled to have success using the pen… (patience is not my virtue) and TA DA!!!

NOW I get the fuss!!! @Steve_Combi @Davin8r it was so easy this time and the needle went in like butter!! (Instead of man handling myself with the needle while trying to press the plunger). The difference was most likely this was a tiny dose so i didn’t need to push the plunger as long/hard… but hope lives! Thank you…

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#177

Here to share an unexpected potential effect from taking SS-31. N=1

However, aprox 45 days ago, I also began red daily light light therapy sessions, so it’s hard to be 100% sure it’s from SS-31, but my hunch says it most definitely is.

I have untreated ADD, and as a result, I have a horrible memory, brain fog and no focus. I will even at times forgot words while I’m speaking and it takes me forever to do anything because I have the attention span of a toddler. It has improved 10 fold since I started my longevity journey, but there was/is still room for improvement.

Well, I’ve noticed that lately I’m getting everything done I’ve wanted to do, and so much more. I keep noticing this more and more and it finally dawned on me this is not a fluke. I can pick a topic and sit around for hours and do deep dives and see things to completion… it even took me a fraction of the time to figure out the aforementioned pens vs having to take many breaks.

With my ADD, I’ve always had times of hyper focus, but they would happen at random times, but now it’s with everything I want to figure out. Normally, I start (or plan to start) everything and then I get distracted and find it hard to get back to it.

It just dawned on me that this could be from the SS-31, so I l found this:

“supports cognitive health by reducing brain fog, enhancing focus, improving memory, and combating mental fatigue”

(it was probably clearly written at the top of the thread but I didn’t pay attention… touché!)

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#178

While I believe short periods (5-10 minutes) of light therapy is good in general, you can actually ignore the light therapy as far as memory goes since you won’t necessarily notice any substantial effect from light therapy. Been doing it for over three years now, and while I tend to think it is doing something good generally speaking there isn’t anything particular that has gotten better and I can attribute to light therapy. So, if you know/notice for sure improvement in your memory and the only two things you added/did were SS-31 and light therapy you can rest assured that at least 90% of that it is indeed the effects of SS-31. Unfortunately, I find your posting subjective (not in a negative way necessarily btw but certain things/memory are hard to measure objectively) otherwise I’d give it a try as my memory is not at its best. Therefore, I’ll have to wait (before I pull the trigger on another expensive peptide, as my experience with peptides has been abysmal at best, and I refuse to spend another penny on them unless I’m fully convinced of their effectiveness). Hopefully after another month or so has passed you’ll find that the benefits are continuing and are real, at which point I’ll give it a try.

Keep us posted. Thanks.

1 Like
#179

The nice thing is if you wait, it looks like rapadmin might be finding a much more affordable option!

For clarity, I am not sure how much this is helping my memory. It might be, but for me, it’s much more about focus/clarity and functioning as if I had a normal brain :).

I will update you if anything changes. (And yeah, I am HOPING RLT is doing some good… inside or for vanity reasons. I’ll take what I can get… worst case is I find it very relaxing as Desert Shores says.

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#180

NEEDHAM, Mass., Jan. 6, 2026 /PRNewswire/ – Stealth BioTherapeutics Inc. (the “Company” or “Stealth”), a commercial-stage biotechnology company focused on the discovery, development and commercialization of novel therapies for diseases involving mitochondrial dysfunction, today provided an update on the Company’s commercial and R&D progress and highlighted 2026 strategic priorities.

“Since receiving accelerated approval for FORZINITY in September, we’ve built a robust commercial foundation and are working closely with prescribers and payers to ensure access for eligible patients with Barth syndrome,” said Reenie McCarthy, Chief Executive Officer of Stealth BioTherapeutics. “As we continue development efforts for younger affected individuals as well as for individuals living with primary mitochondrial disease and dry AMD, we remain committed to accelerating innovation across our pipeline to address urgent unmet needs in rare and age-related diseases of mitochondrial dysfunction.”

Commercial Update:

FORZINITY is currently commercially available for eligible US patients living with BTHS, a rare, serious and life-threatening mitochondrial disease.

  • On September 19, 2025, FORZINITY (elamipretide) injection received accelerated approval from the FDA as the first treatment to improve muscle strength for children and adults weighing at least 30 kg (approximately 66 pounds) with BTHS (eligible patients).
  • FORZINITY commercial supply was available in late November 2025 and AnovoRx Specialty Pharmacy, the exclusive US specialty pharmacy, began filling prescriptions in December 2025.
  • Ahead of formal launch next quarter, early demand from prescribers for eligible US patients, including those previously receiving elamipretide through the Company’s expanded access program (EAP), has exceeded the Company’s expectations.
  • Preliminary prescriber data suggest that diagnostic code usage for BTHS, known to affect approximately 150 U.S. individuals, may meaningfully exceed U.S. patient prevalence estimates.
  • The Company has engaged with pharmacy benefit providers covering over 40% of US lives to provide education in support of access and reimbursement for FORZINITY and has launched Mito Assist™, a voluntary, patient support program, to serve as a single point of coordination throughout the treatment journey.
  • The Company welcomed key members of its sales, market access, marketing and medical affairs team to support its planned formal launch of FORZINITY in the second quarter of 2026.

Research & Development Update:

In parallel with commercial execution, the Company continues to advance its development of elamipretide and other mitochondria-targeted pipeline compounds for diseases of mitochondrial dysfunction.

  • BTHS. The Company will meet with the FDA in early 2026 to discuss a regulatory path forward for individuals living with BTHS who do not currently meet the FDA-approved weight threshold for FORZINITY. The Company is continuing to provide uninterrupted elamipretide access for those younger patients already enrolled in its EAP or for whom doctors submit new requests for emergency access. The Company is on track to initiate its FDA-required post-marketing trial to confirm clinical benefit during the first half of 2026.
  • nPMD. The Company plans to meet with the FDA in early 2026 to discuss next steps in its development efforts for patients living with PMD due to polymerase gamma and other nDNA mutations (nPMD), which the Company plans to pursue as a potential next rare disease indication for elamipretide.
  • Dry AMD. The Company’s fully-enrolled Phase 3 ReNEW clinical trial of elamipretide for dry AMD is expected to read out in late 2027. An eye drop formulation of the Company’s next-in-class clinical stage compound, bevemipretide, is in Phase 1 development for dry AMD, with Phase 2 initiation targeted by year-end 2026.
  • Pipeline. Systemic bevemipretide, has recently demonstrated neuroprotective effects in Parkinson’s disease preclinical studies supported by the Michael J Fox Foundation. The Company is evaluating next steps for development of systemic bevemipretide and other pipeline compounds for diseases of mitochondrial dysfunction.
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#181
Feature Elamipretide (1st Gen) Bevemipretide (2nd Gen)
Status FDA-approved for Barth syndrome (Sept 2025). In Phase 1/2 clinical development.
Primary Route Subcutaneous (SC) injection. Topical (eye drops) or Oral.
Potency Standard; requires higher systemic doses. Higher potency and better tissue penetration.
Brain Penetration Limited. Optimized for Blood-Brain Barrier (BBB) crossing.
Target Organs Heart, skeletal muscle, retina. Central Nervous System (CNS) and retina.

(Comparison of bevemipretide with SS-31)

2 Likes
#182

Bevemipretide (SBT-272) Molecular Architecture and Design Logic

Bevemipretide is a second-generation peptidomimetic designed to rectify the pharmacological shortcomings of its predecessor, elamipretide (SS-31). While both molecules belong to the Szeto-Schiller peptide family, bevemipretide is not a simple analog; it is a structural redesign optimized for increased lipophilicity and blood-brain barrier (BBB) penetration.

1. Core Molecular Structure

Bevemipretide is a modified tripeptide. Its design utilizes a scaffold of alternating cationic and aromatic residues to facilitate mitochondrial membrane targeting.

  • Amino Acid Sequence: D-Arg-2,6-dimethyl-L-Tyr-modified C-terminus.
  • The N-Terminus (D-Arginine): The use of the D-isomer of Arginine is a deliberate design choice to prevent degradation by common proteases, extending the molecule’s half-life in systemic circulation.
  • The Middle Residue (2,6-dimethyl-L-Tyrosine): This residue is the primary engine for mitochondrial targeting. The dimethylation of the tyrosine ring increases the molecule’s ability to partition into the lipid bilayer of the inner mitochondrial membrane (IMM).
  • The C-Terminus (3-benzyl-1,2,4-oxadiazol-5-yl): This is the most significant departure from elamipretide. Bevemipretide replaces the terminal amino acid with a heterocyclic oxadiazole ring. This modification removes a polar peptide bond, significantly increasing the drug’s “greasiness” (lipophilicity), which is the primary requirement for crossing the BBB.

2. Comparison of Design Specifications

Feature Elamipretide (SS-31) Bevemipretide (SBT-272)
Peptide Class Tetrapeptide Modified Tripeptide
Molecular Weight 639.8 g/mol 607.8 g/mol
C-Terminal Group Phenylalanine amide Benzyl-oxadiazole
LogP (Lipophilicity) Lower Higher
Primary Limitation Poor CNS penetration; injection only Designed for CNS; oral potential

3. Targeted Mechanism: The Cardiolipin Interaction

The exact molecular design is intended to facilitate a high-affinity interaction with cardiolipin, a unique phospholipid found exclusively in the inner mitochondrial membrane.

When mitochondria are stressed, cardiolipin undergoes peroxidation and migrates to the outer membrane, triggering the formation of the Mitochondrial Permeability Transition Pore (mPTP) and eventual cell death (apoptosis). Bevemipretide’s cationic (positive) charge attracts it to the anionic (negative) cardiolipin. The aromatic side chains then “anchor” the molecule, stabilizing the cristae structure and preventing the cytochrome c release that leads to neurodegeneration.

Research Sources and Technical References

  • SBT-272, a novel mitochondrial candidate for the treatment of Amyotrophic Lateral Sclerosis (ALS)

  • Date: March 2020

  • Source: Muscular Dystrophy Association (MDA) Conference Abstract

  • Note: This technical poster details the structural advantages of SBT-272 over SS-31 regarding brain-to-plasma ratios.

  • Mitochondria-targeted therapy with elamipretide and bevemipretide

  • Date: June 2024 (Updated)

  • Source: Stealth BioTherapeutics Pipeline Overview

  • Note: Direct confirmation of the clinical transition from elamipretide to bevemipretide for CNS indications.

  • Discovery of SBT-272: A Second-Generation Mitochondrial Targeting Peptide

  • Date: 2021

  • Source: American Academy of Neurology (AAN) Publication

  • Note: Provides pharmacokinetic data showing bevemipretide achieves significantly higher neuronal concentrations than first-generation peptides.

Critical Assessment & Knowledge Gaps

  • The “Oral” Claim: While the molecular design (oxadiazole substitution) is intended to allow for oral bioavailability, Stealth BioTherapeutics has faced challenges in achieving consistent human dosing via the oral route. Much of the current late-stage data still relies on specialized delivery or focused topical applications (eye drops).
  • Binding Kinetics: There is a lack of independent, peer-reviewed comparative studies (outside of company-sponsored data) that quantify the exact dissociation constant (Kd) of bevemipretide vs. elamipretide for human cardiolipin isoforms.
  • Safety Profile: High lipophilicity often correlates with off-target effects or accumulation in non-target tissues (like the liver). Long-term human safety data for bevemipretide remains a major data gap.
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#183

I’m sure this is clearly stated in the above posts, but I’ll don’t quite get it, so I’ll ask… I think this is saying SBT 272 is (sort of) a form of SS-31… meaning, it’s not just from the same company but perhaps they altered SS-31 to create it? Is it similar in concept to the way we have different GLP1s, and the different companies have improved upon the first generation?

My grandmother had ALS and my mom had PD so reading this about SBT 272 just brought a happy tear to my eye.

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