A Combination of Rapamycin and Trametinib Extended Maximum Lifespan by up to 35%

News
#29

There have been 17 clinical trials so far involving Trametinib, usually with other cancer therapies. Here is a full list, and links to more details:

Clinical Trials Using Trametinib

Clinical trials are research studies that involve people. The clinical trials on this list are studying trametinib. All trials on the list are NCI-supported clinical trials, which are sponsored or otherwise financially supported by NCI.

https://www.cancer.gov/research/participate/clinical-trials/intervention/trametinib

This is interesting:

Trametinib

Drug design and preclinical activity

Trametinib (GSK1120212) is a reversible allosteric inhibitor of MEK1 and MEK2 activation and kinase activity, with preclinical evidence of MAPK inhibition and growth inhibition in BRAFV600E melanoma cell lines and xenografts (23).

Clinical trials

Phase I trial.

The phase I trial commenced in 2008, and of 206 patients, 97 had metastatic melanoma with no restriction of eligibility by somatic mutations, for example BRAF mutations. Thirty-six patients had BRAF-mutant melanoma and 39 had wild-type BRAF melanoma (7 of whom had an NRAS-mutant melanoma), 6 had unknown BRAF status, and 16 patients had uveal melanoma (24, 25). Dose titration commenced at 0.125 mg, with dose-limiting toxicities observed at total daily doses of 3 mg and 4 mg, and the RP2D was 2 mg once daily. At this dose, analysis of biopsies taken early during treatment and compared with baseline samples showed that there was effective inhibition of MAPK signaling as measured by phosphorylated extracellular signal–regulated kinase (ERK; 60% reduction), effective inhibition of proliferation (Ki67 reduced by 80%), and an increase in cell-cycle inhibition (p27 increased by 170%).

The most frequent toxicities included MEK inhibitor class-like toxicities such as an acneiform rash (88%), diarrhoea, peripheral oedema, and fatigue (Table 1). In the trial of 206 patients with solid tumors, ocular toxicities occurred in 15% (n = 31) of patients, including reversible central serous retinopathy (n = 3) and rarely irreversible retinal vein occlusion (n = 1). Transient left ventricular dysfunction was noted in 8% (n = 16) of patients. Twelve percent of patients treated at 2 mg required dose reductions, most commonly due to rash.

Phase III trial (METRIC).

Toxicities were similar to those in the earlier trials, including MEK inhibitor class-like effects such as rash, diarrhoea, peripheral oedema, hypertension, and transient mild cardiac dysfunction. Chorioretinopathy was rare (<1% grade 3), and no cases of retinal vein occlusion were reported. Most toxicities were mild and did not require drug discontinuation; however, 27% of patients underwent dose reduction.

Table 1.

Summary of dabrafenib and trametinib clinical trial results

TrametinibClinicalTrialSummary.pdf (46.6 KB)

3 Likes
#30

A 2022 Phase 2/3 Clinical Trial of Trametinib, and the associated side effects recorded. Daily dosing of trametinib definitely has an ugly side effect profile. The key question is whether periodic (e.g. once weekly) dosing might greatly reduce or eliminate most of these side effect risks.

The Study used oral trametinib 2 mg once daily (trametinib group)

The toxic effects observed in patients in the trametinib group of our study were similar to previous MEK inhibitor studies in patients with other cancer types, such as melanoma. However, clinical management of adverse events can be challenging, with fatigue, skin rash, and gastrointestinal side-effects occurring most commonly, and dose reductions being necessary for many patients. For adverse events of special interest, the incidence of retinal events was 2%, and, although 8% of patients had decreased ejection fraction, they often recovered, and some patients were able to be rechallenged.

Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02175-9/fulltext#tables

2022ClinicalStudySummaryofSideEffects.pdf (56.6 KB)

3 Likes
#32

ChatGPT on other MEK inhibitors:

Please list all the drugs that are classified as MEK inhibitors

ChatGPT

MEK (Mitogen-Activated Protein Kinase Kinase) inhibitors are a class of drugs used primarily in the treatment of cancer, as they target the MEK proteins involved in the MAPK/ERK signaling pathway, which is often dysregulated in tumors. As of my last update, here are some well-known MEK inhibitors:

  1. Trametinib (Trade name: Mekinist) - Approved for the treatment of melanoma, non-small cell lung cancer (NSCLC), and certain types of thyroid cancer.
  2. Cobimetinib (Trade name: Cotellic) - Used in combination with vemurafenib for the treatment of BRAF V600 mutation-positive melanoma.
  3. Binimetinib (Trade name: Mektovi) - Approved for the treatment of BRAF V600E or V600K mutation-positive melanoma, often in combination with encorafenib.
  4. Encorafenib (Trade name: Braftovi) - Although primarily a BRAF inhibitor, it’s often used in combination with MEK inhibitors like binimetinib for better efficacy in treating melanoma.
3 Likes
#33

Some very good results (significant reduction of side effects) from intermittent dosing of trametinib:

Intermittent dosing in these examples is defined as: a five-week-on and three-week-off schedule.

In February 2016, after almost a full year of continuous daily dosing, she started a 3-week drug holiday before resuming treatment using an intermittent schedule of 5 weeks of treatment followed by a 3-week break, per 8-week cycle. This approach was associated with a considerable reduction in her fatigue and an improvement of her well-being.

Like patient 2, this patient noted considerable improvement in her sense of well-being after converting to an intermittent therapy regimen. On treatment for now 18 months (13 months on intermittent drug administration), this patient continues to tolerate dabrafenib and trametinib at full dose on the five-week-on, three-week-off schedule and has resumed work unencumbered by symptoms from her disease or from the treatment.

Both patients experienced considerably fewer adverse events and no cumulative toxicity with intermittent dosing, permitting them to resume active lifestyles largely unencumbered by the anticancer treatment.

Results: Both patients showed rapid clinical improvement upon starting the regimen. They also noted improved tolerance of treatment upon transitioning to the intermittent dosing schedule. They continue to show evidence of antitumor activity 27 and 18 months respectively from the start of treatment and 15 and 13 months respectively from the start of the first break using intermittent dosing.

Intermittent Dosing of Dabrafenib and Trametinib in Metastatic BRAFV600E Mutated Papillary Thyroid Cancer: Two Case Reports

5 Likes
#34

Here is a phase 2 clinical trial looking at intermittent dosing with trametinib:

Continuous versus intermittent BRAF and MEK inhibition in patients with BRAF-mutated melanoma: a randomized phase 2 trial

The intermittent dosing arm used the same doses during weeks 1 and 5–8 of each 8-week cycle (5 weeks on). No therapy was given during weeks 2–4 on the intermittent therapy arm (3 weeks off).

Adverse events.

All adverse events assessed as possibly, probably, and definitely related to study treatment. On the continuous therapy arm, 38 patients (36%) experienced grade 3 adverse events, and 7 (7%) experienced grade 4 events, while on the intermittent therapy arm, 31 patients (31%) experienced grade 3 adverse events, and 3 (3%) experienced grade 4 events (p=0.46 for grade 3, p=0.33 for grade 4). The most common grade 3–4 adverse event across both arms was fatigue. There was a significant difference in the incidence of grade 3 and 4 pyrexia, (6 patients on continuous dosing vs 1 patient on intermittent dosing, p<0.001).

There has been at least one additional (2024) clinical study using intermittent dosing schedules, and larger numbers of patients, for trametinib, but it is behind a paywall. If anyone can access and post it please do, as it would give us more information on the side effect reduction from continuous to intermittent dosing schedules.

3 Likes
#36

I don’t think there is any hurry… we’re all going to get some extra time from the rapamycin, and it seems some de-risking could and should be done by longevity researchers on trametinib before even periodic dosing is tested by biohackers:

5 Likes
#37

Good points. Best to avoid for now.

#38

In patients, trametinib is used for the treatment of metastatic melanomas [76] and has also been used in clinical trials for the treatment of solid tumours [77] [78]. At a dose of 2 mg trametinib once a day, the drug was well tolerated with only small side effects including skin rash, diarrhoea, fatigue and retinopathy [77]. Average peak plasma levels in patients receiving 2mg trametinib daily were between 5.5 and 7.5ng/ml [77] [78], which is significantly higher than the 0.1ng/ml in mice fed with the lifespan extending dose of 1.44mg trametinib/kg food. In a mouse model of mucosal melanoma, administering trametinib via oral gavage resulted in an average peak concentration of 23.8ng/ml [79], which is more than 200-fold the concentration required for lifespan extension. Although trametinib plasma levels might not be directly comparable between chronic feeding and acute application, these results suggest that higher trametinib doses are required for its anti-cancer effect than for lifespan extension. Consistently, tumour progression or load were not significantly changed in long-lived mice treated with trametinib. The effect of trametinib at the chosen concentration of 1.44mg/kg on lifespan and health at old age was mild, indicating that we underdosed and that the optimal dose for lifespan extension might be higher. In the pre-test, a dose of 2.88 mg/kg trametinib did not cause detrimental side effects. Thus, this can be used as a guideline for future studies to optimize the dose of trametinib for maximal lifespan extension. Additionally, it would be interesting to determine whether late-onset or intermittent feeding recapitulates the effects of continuous trametinib treatment on mouse lifespan, as this would be key to enhance adherence and feasibility of trametinib treatment in humans.

2 Likes
#39

The half-life is also long, so you can take it once a week or every two weeks without any hassle.

1 Like
#40

The half-life of trametinib is 4-5 days, almost twice as long as rapamycin. If you take rapamycin every day, you may experience a lot of side effects. But once a week, it causes almost no side effects. Couldn’t a similar situation occur for trametinib taken once every two weeks? Since no one has tried it, we naturally have no information. But I think there is an unnecessary fear about this.

3 Likes
#41

There is definitely a reasonable argument that dosing once every week or two with trametinib could have very low or minimal side effects, but it would be good for a medical group to do such a test with regular blood and functional monitoring for the more serious potential risks; retinal issues, heart issues (ejection fraction), blood pressure, kidney function, anemia, etc… It would be very hard, if not impossible, for a biohacker to be able to do this type of monitoring over a period of many weeks or months, so I really think we need to lobby a longevity research group to start a small clinical study to do this, and publish the results.

@Livin and @Vlasko , given your experience with, and knowledge about, this drug what are you opinions? How would you design a study to test its safety in a pulsed once weekly or once every two week dosing schedule?

3 Likes
#42

We could use a few human test subjects if you’re volunteering?

#43

And who’s going to pay for the trial?

#44

I’m going to write up a proposal, try to get some researcher’s to partner with, then submit a the idea to Impetus Grants. I’ll post the proposal here to get people’s feedback on it before I approach the researchers.

What I’m proposing is effectively a new phase 1 clinical study (perhaps a dozen participants or so). I’d be following this type of guideline: A Comprehensive Guide to Phase 1 Clinical Trials

It seems like a small phase 1 clinical study like this with a commercially available, FDA-approved drug, might cost something like $200K to $300K; similar to the dental rapamycin study: New Study Funded: Towards reversing periodontal disease using Rapamycin

10 Likes
#45

And, more good news on trametinib; it appears it goes off patent in 2025, so at that point it becomes very inexpensive.

Trametinib (Mekinist)
Like dabrafenib, trametinib is used against melanomas containing the activating BRAF V600E or V600K point mutation [44]. It was authorized by EMA in June 2014 and the EU patent is expected to last until July 2029. However, trametinib was authorized by FDA in May 2013 and the patent is expected to expire in September 2025, resulting in three years less market exclusivity in the US.

Source: Overview of the patent expiry of (non-)tyrosine kinase inhibitors approved for clinical use in the EU and the US - GaBI Journal

5 Likes
#46

Maybe it would be a good ITP candidate for verification?

3 Likes
#47

I don’t believe there is any evidence that low-dose Trametinib has a significant life extending effect which is the main issue for this. Would it be possible perhaps to try a low-dose Trametinib trial in the wormbot?

1 Like
#48

See the earlier post by @Cohen

I also just realized I mis-interpreted the 1.44mg/kg as per kg of weight of the mouse, whereas its actually a measure of drug in the food.

2 Likes
#49

Dosing to match mice plasma levels

  • The lifespan-extending dose of trametinib (1.44 mg/kg diet) resulted in plasma levels of ~0.1 ng/ml in mice. This is significantly lower than the 5.5-7.5 ng/ml peak levels observed in human patients receiving 2 mg daily doses for cancer treatment. [1]

  • Considering trametinib’s long elimination half-life of 3.9 to 4.8 days in humans, an appropriate starting dose for human longevity trials might be 0.25-0.5 mg taken orally once or twice weekly. This weekly dose, approximately 1/8th-1/4th of the standard 2 mg daily dose used in cancer treatment, aims to maintain plasma levels similar to those observed in the long-lived mice (around 0.1-0.2 ng/ml) while accounting for the drug’s extended presence in the body.

  • Trametinib is sold in 0.5mg tablets. A single 0.5mg tablet can be obtained for $21 in a country like Turkey. If one were to use 0.5mg weekly, the yearly cost of the drug would be $1100.

  • We can follow the same principle that Dr Blagosklonny has long proposed for Rapa: The optimal longevity dose is the highest dose without side effects.

  • As an experiment, Trametinib timing can be aligned with intermittent Rapamycin timing to maximize the “fasting-like” effects (two nutrient sensing pathways blocked simultaneously).

[1] A combination of the geroprotectors trametinib and rapamycin is more effective than either drug alone, Gkioni et al, 2024 (preprint)

Trametinib user experience (Link)

  • In 2020 I ran trametinib in 2 separate experiments. I was forced to discontinue quickly due to notable unpleasant side effects.
  • Dose: 1mg/day
  • This was based on studies showing triple combo of rapa lithium tranetinib extending life close to 50%. I had calculated 4mg/day [based on the fruit fly study] and started light to be safe. Maybe I got it wrong?? Took a few days to feel like shit.
  • What were the side effects? feeling poisoned. drained. off

(Not Mine – From another Rapamycin group. Sharing because it’s very interesting!)

9 Likes
#50

Triple Drug Combination Targeting Nutrient-Sensing Network Dramatically Extends Lifespan in Fruit Flies (2019)

This study investigated the effects of combining three drugs that target different components of the nutrient-sensing network to extend lifespan in fruit flies. The researchers tested rapamycin (an mTOR inhibitor), trametinib (a MEK inhibitor), and lithium (a GSK-3 inhibitor) individually and in combination. They found that double combinations of these drugs produced greater lifespan extension (around 30% on average) compared to any single drug alone (11% on average). Most remarkably, the triple combination of all three drugs extended median lifespan by 48%. The drug combinations did not significantly alter feeding behavior or food intake, suggesting the lifespan effects were not due to dietary restriction.

Importantly, the study also found that lithium was able to counteract some negative side effects of the other drugs. Specifically, lithium reversed the increased triglyceride levels and starvation resistance caused by rapamycin treatment. The researchers conclude that simultaneously targeting multiple nodes of the nutrient-sensing network with drug combinations may be an effective strategy to maximize longevity benefits while minimizing side effects. They suggest this “polypharmacology” approach of combining established pro-longevity drugs could potentially be developed into therapies to improve health in late life.

image
image1058×576 61.6 KB

7 Likes