Why: We know that leriglitazone/MIN-102 is effective at slowing the progression of AMN and greatly reducing the risk of cerebral involvement, but unless I'm missing something, it's not available to me here in the US currently. But its prodrug, pioglitazone, is, and given that leriglitazone is one of the 2 major metabolites of pioglitazone, I'm willing to give it a try.
How: It's a diabetes medication, and diabetes is the most common condition for endocrinologists to treat. Last night, I emailed my endocrine doctor a request to prescribe it, along with AMN-related reasons and what I plan to do to reduce its risk, he's willing to try pioglitazone, and I picked up a starting dose of 15 mg/day from the pharmacy today.
Risks:
- Like leriglitazone, pioglitazone causes edema, and can cause heart problems. I walk on my treadmill everyday (using the handlebars to regain my balance every few steps) and wear compression socks, but I wasn't a part of the MIN-102 AMN trial, so I have no firsthand experience to know what I can do about the level of edema that it will cause.
- Like leriglitazone, pioglitazone can cause weight gain beyond the water weight from edema. For 3 months now, I have been taking the diabetes medication metformin, in case its upregulation of ABCD2 ends up being helpful for AMN (and for its other benefits, like decreasing long COVID risk, decreasing cancer risk, and slowing aging). But metformin is also effective for weight loss (and is frequently coupled with pioglitazone in diabetic patients anyway), so maybe it offers some degree of protection against weight gain, too
- Pioglitazone increases risk of bladder cancer, there was a $2.4 billion settlement over it in 2015. But most people who take pioglitazone have type 2 diabetes, which significantly increases risk of bladder cancer, and because I don't have diabetes, my starting risk of bladder cancer is lower than the average pioglitazone patient. I'm eating 2 lemons a day and will starting drinking more water and eating broccoli, all things that reduce bladder cancer risk.
- Pioglitazone can cause hepatotoxicity/liver toxicity, and in some cases, liver failure. I take 1000 mg NAC, 300 mg alpha-lipoic acid ER, and 100 IU Vitamin E 3 times per day, all of which can have a positive impact on liver health (especially NAC, which is a treatment for hepatotoxicity). I also don't drink alcohol, a major risk factor for hepatotoxicity, so hopefully liver problems don't happen.
The primary marker I'll be looking at to know if it's doing anything is my serum neurofilament light chain levels (nature.com/articles/s41467-... ), which measures rate of neuroaxonal damage, and it goes up as AMN or ALD patients age (and goes way up with cerebral involvement). I'm 34, 7 years from AMN onset and my sNfL is already at 22.6 pg/mL, but maybe pioglitazone will slow down its increase a little.
So, I've started taking pioglitazone. Given that virtually all of us have endocrine doctors, maybe pioglitazone is accessible to any of us who don't have existing contraindications like heart problems, liver problems, or bladder problems. I'm especially curious how any former leriglitazone patients, who Minoryx has cut off, fare on pioglitazone.
Needless to say, once leriglitazone becomes FDA-approved, I manage to get in vivo gene therapy, or I end up with cerebral involvement and get HPSCT, I won't be taking pioglitazone anymore.
If it turns out I tolerate 15 mg pioglitazone well, I might go up to 30 mg in a month or two.
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tetris
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I asked my doctor about these issues in the past, but she was not willing to prescribe pioglitazone to me. But I agree with you that at some level pioglitazone might be considered a poor-man's leriglitazone, since most of a dose of pioglitazone is converted into leriglitazone inside the body. One thing to keep in mind is that you're taking a much smaller dose compared to the Minoryx studies. I believe those study participants are taking somewhere in the range of 100-150 mg of leriglitazone per day. Pioglitazone is only approved for up to 45 mg per day, so you will be getting the a much smaller dose that what they are studying in the Minoryx clinical trials.
> I asked my doctor about these issues in the past, but she was not willing to prescribe pioglitazone to me.
I was careful to acknowledge the bladder/liver/edema risks and include the precautions I planned to take, but yeah your mileage may vary depending on your endocrinologist. I briefly had a different endo before this one who, while having good intentions, micromanaged my medications (refusing to prescribe 100mg emergency solu-cortef because they thought that was too high of an amount) and tried to mastermind my treatment without leaving the decisions to me. That prompted me to switch to my current endo, who offers advice when I ask, but also takes a step back and let me guide my own treatment (within reason of course: he obviously won't agree to anything that would cause harm to me). I'm probably very fortunate to have an endo who is willing to go along with my shenanigans (when prescribing metformin, he said "I doubt this will help in the way you're hoping it will. Anyway, I sent a prescription to your pharmacy").
> But I agree with you that at some level pioglitazone might be considered a poor-man's leriglitazone, since most of a dose of pioglitazone is converted into leriglitazone inside the body.
Pretty much: If I'm reading Eckland and Danhof's "Clinical pharmacokinetics of pioglitazone" correctly (find it on LibGen or DM me), virtually the only pharmacologically-active metabolites of pioglitazone is leriglitazone (which the literature refers to as metabolite "M-IV"), but M-IV only accounts for about 43% (based on series A of Table 1) of the metabolites of pioglitazone. So 45 mg pioglitazone only gets you about 19 mg leriglitazone.
Pioglitazone's only other main pharmacologically-active metabolite, M-III, is metabolized from M-IV (same as MIN-102/leriglitazone) and not directly from pioglitazone, so you're not getting some other pharmacologically-active drug that you wouldn't be getting anyway by taking leriglitazone directly. From "Clinical pharmacokinetics of pioglitazone":
> Pioglitazone is rapidly absorbed after oral administration (81%-94%) and reaches peak concentration in approximately 2.5 hours in patients with type 2 diabetes.It is extensively metabolised in the liver, and most is excreted as inactive metabolites in the faeces. Although the parent compound, pioglitazone, has a half-life of approximately 9 hours, its chief active metabolites, M-III and M-IV, have half-lives of approximately 26-30 hours.
M-II is also technically pharmacologically active, but its total effect is not significant:
> M-II is found in relatively low concentrations in man (about 10% of M-III metabolite) and does not significantly contribute to total active compounds.
> One thing to keep in mind is that you're taking a much smaller dose compared to the Minoryx studies. I believe those study participants are taking somewhere in the range of 100-150 mg of leriglitazone per day. Pioglitazone is only approved for up to 45 mg per day, so you will be getting the a much smaller dose that what they are studying in the Minoryx clinical trials.
Based on the above, one could theoretically just take enough pioglitazone to achieve the same effect as 100 mg-150 mg leriglitazone, without side effects that would not be experienced anyway under leriglitazone. But since pioglitazone is only 43% efficiency for getting leriglitazone, one would theoretically need to take 233 mg pioglitazone to achieve the same effect as 100 mg leriglitazone, which would not be safe. So, not very efficient (and taking over 45 mg of pioglitazone is not safe or realistic).
But maybe 45 mg pioglitazone will be helpful anyway, assuming I progressively increase that far without my labs looking abnormal
Table 1 and Figure 1 from Eckland and Danhof, 2000
> Beware, I was speaking to a friend (who happens to be a doctor), as far as he was concerned, these drugs lower your blood sugar.
I met with my endocrinologist last week and asked about this. He said that pioglitazone does not decrease your blood glucose, it just increases your insulin sensitivity. Same for metformin. If you are diabetic or if your blood glucose is too high, that increased insulin sensitivity will result in lowering your blood glucose, but usually not for non-diabetic patients.
But yeah, that is why the leriglitazone/MIN-102 trials (clinicaltrials.gov/study/NC... ) explicitly exclude patients with diabetes (and pioglitazone has the exact same active drug as leriglitazone). Anyone with a history of congestive heart failure should also avoid pioglitazone.
About 4 weeks in, I have a little less energy and exercise less frequently, but besides that, everything is fine, I'm still thinking clearly at and outside of day job. There's no increased leg swelling/edema yet.
My labs from a few days ago look normal, and today is my 5th day at 30 mg pioglitazone (the equivalent of 12.9 mg leriglitazone). My paraplegia is still getting worse, part of my right shin is numb now that didn't used to be, and that's supposed to be my good leg.
> Started with 10 and then they bumped me down to 9.
According to pubmed.ncbi.nlm.nih.gov/366... , the ADVANCE trial monitored patients' plasma concentrations of leriglitazone and adjusted it, targeting a plasma concentration of 200 μg·h/mL.
> 150 mg starting dose; between baseline and week 12, doses were increased or decreased to achieve plasma concentrations of 200 μg·h/mL [SD 20%]
The dosage required to reach a plasma concentration of 200 μg·h/mL varies a bit. wilburlois15 reported taking 12 mL after previously having been increased to 17 mL (healthunlocked.com/amneasie... ), so it might take a little effort to find the correct dosage, once I get nearer to the equivalent pioglitazone dosage of 150 mg leriglitazone.
Based on the serum Cmax values in Table 1 (healthunlocked.com/amneasie... ), 150mg leriglitazone / (639 ng/mL leriglitazone / 1482 ng/mL pioglitazone ) ≈ 347.9 mg pioglitazone (and the leriglitazone/pioglitazone ratio seems about the same for blood plasma as it is for serum). I'll ask to have my leriglitazone plasma concentration measured (a "pioglitazone M-IV plasma level") if I get to 345 mg pioglitazone (about 129.3 mg leriglitazone).
Do you make any blood tests yo control your treatment? I noticed you mentioned Nfl, do you make this test regularly? Do you make VLCFA control test? If Metformin may lower VLCFA it worths to check it. I'm also considering taking Metformin
> Do you make any blood tests yo control your treatment?
I am periodically taking a basic metabolic panel, to screen for heart and bladder health. A member of the ADVANCE trial told me that they were periodically given an EKG test during the trial, also to verify that heart health has not declined, and I plan to periodically request an EKG for that reason, as well.
> I noticed you mentioned Nfl, do you make this test regularly?
Although NFL is an informative test, it is a lagging indicator by about 2 months. I'm planning to have it tested again in January, but because I only started pioglitazone in mid-November, I don't expect pioglitazone to have affected NFL much by that point. I plan to check NFL every 3 months.
> Do you make VLCFA control test? If Metformin may lower VLCFA it worths to check it.
Lowering VLCFAs alone is not enough for a treatment to be efficacious for adrenoleukodystrophy. Otherwise, thyroid agonists would be helpful, because like metformin, they cross the blood-brain barrier, upregulate ABCD2, and decrease VLCFA levels, but they don't seem so helpful for slowing the progression of AMN or ALD, as I understand it.
My ALD expert neurogeneticist told me that he didn't think that ABCD2 upregulation was efficacious at my appointment with him a couple months ago, saying that ABCD2 upregulation affects different cell types than are needed for ALD/AMN treatment (see healthunlocked.com/amneasie... ). A past ALD expert neurogeneticist has also been dismissive about thyroid agonists to me in the past.
But yeah, I'm still taking metformin in case it still helps a tiny bit, because it decreases long COVID risk, and because it decreases appetite, which pioglitazone and leriglitazone increase.
> I'm also considering taking Metformin
As long as your kidneys are healthy and you aren't deficient of any B vitamins, it probably won't hurt. But because metformin can cause vitamin B12 deficiency (academic.oup.com/jcem/artic... ), vitamin B9 deficiency (pmc.ncbi.nlm.nih.gov/articl... ), vitamin B6 deficiency (diabetes.acponline.org/arch... ), and vitamin B1 deficiency (pubmed.ncbi.nlm.nih.gov/265... ) by making your body absorb B vitamins less effectively, I take a vitamin B complex supplement to help avoid risks associated with the combination of taking metformin and deficiencies of those vitamins, like lactic acidosis or anemia.
Thanks for reply. I'm disappointed that Dr. Eichler not considering ABCD2 regulators a potential treatment for ALD/AMN, I always thought that they may become a cure
In his talk at the 2024 ALD Connect Annual Meeting and Patient Learning Academy a couple months ago, he expanded a bit on the importance of cell types in ALD/AMN. At 23:24 in the recording (youtu.be/jYr78FnT--M?t=23m2... ):
> So, ABCD1 expression, however, is very cell type-specific, and we have to think about that, and recognize that in some cells, there's much higher ABCD1 than in other cells, and in disease states, this may change, whether you have cerebral ALD or you have spinal cord disease, and in what cells ABCD1 is expressed seems critical to me for precise editing and precise targeting.
He gives some examples of cell types in the brain with high ABCD1 immediately after that from this paper that he coauthored: onlinelibrary.wiley.com/doi...
I was extremely disappointed when he told me, because I asked him about ABCD2 upregulation immediately after he told me that I am not a candidate for the SwanBio/Spur Therapeutics gene therapy trial, due to my brain MRI revealing possible previous cerebral involvement that would have started, then healed. But I'm also very glad that he was direct and honest with me so that I didn't spend time chasing a treatment that would not prevent cerebral involvement.
On a lighter note, the PPARγ (peroxisome proliferator-activated receptor gamma) agonist leriglitazone is very effective at slowing the progression of AMN, of lowering the risk of cerebral involvement, and of halting cerebral involvement that has already started. If you have not seen it, I would strongly encourage you to watch Minoryx's update on leriglitazone at the 2024 ALDC Annual Meeting this last November (youtu.be/3KprqY2g48k?list=P... ). It was a major reason that I actively sought out pioglitazone: I started researching pioglitazone immediately after watching it live and requested a pioglitazone prescription from my doctor less than a week later.
Finding an endocrinologist willing to prescribe pioglitazone could be challenging, but for the result of having a small amount of protection against cerebral involvement, it could be worth it for AMN patients who don't have contraindications like congestive heart failure.
I just want to let you know I’ve been taking Lerigltizone since the advance study July 2018 I’m taking it on compassionate use now and I take 5.5ml per day. I have a brain lesion and it’s remained stable also it reduces my pain and muscle spasms.
> I’m taking it on compassionate use now and I take 5.5ml per day.
5.5 mL is 82.5 mg of leriglitazone, a lower amount than patients usually seem to take. I see you mentioned in August 2020 that you started the MIN-102 extension study at 10 mL (healthunlocked.com/amneasie... ). When did your dosage change to 5.5 mL, and do you know why it did?
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Women with cerebral ALD/AMN? Male adult transplant ?
Developing Addison's in 40s
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