TIXIMED Starts a Phase 1 Study of TIX100

TIX100 is a protein which inhibits the action of TIXNP (thioredoxin-interacting protein).  It is being developed by the TIXIMED company.  TXNIP is elevated in pancreatic islets of people with type-1 diabetes and causes beta cell death and dysfunction.  The hope is that inhibiting that protein will protect beta cells and therefore delay or prevent T1D.

Anath Shalev, a researcher at the University of Alabama, Birmingham is leading this research effort, first at UAB and now also at TIXIMED.  She first identified TXNIP in 2002 in human islets exposed to high glucose and then later showed that it played a role in glucose toxicity and diabetic beta cell loss.  Research has shown that inhibiting TXNIP protects beta cells and promotes beta cell health and function.

Recently she has run clinical trials for Verapamil, which lowers TXNIP and is already approved in the USA for the treatment of high blood pressure, migraines, and heart problems.  I have blogged several times on those studies, but especially the results from a phase-II trial here:

https://cureresearch4type1diabetes.blogspot.com/2023/03/results-from-phase-ii-verapamil-study.html

I also listed it as a drug to watch in 2024:

https://cureresearch4type1diabetes.blogspot.com/2024/01/what-to-watch-in-2024.html

because there is another phase-II study ongoing in Europe, but it is now scheduled to finish in 2025 or 2026.

TIX100 is an oral medicine, and a "small molecule", but I have not found any other public information on what it actually is.  It has been tested in animals for T1D, T2D, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).  For example: 
https://diabetesjournals.org/diabetes/article/72/Supplement_1/97-OR/150782/97-OR-Antidiabetic-TIX100-Improves-NAFLD-NASH-in

This Study

This is a blinded dosing study done in healthy people.  They are recruiting 35 people, none of whom have T1D, and giving them 6 different doses ranging from none to 200 mg of TIX100.   The goal is to make sure all potential doses are safe.  

This is a single dose study, follow up is after one week, and they expect to be done by May.  Because the end points are all safety and side effect related, we will not know anything about efficiency (if it actually works against T1D), but "the trip of 1000 miles starts with a single step".  Good results here will presumably enable an efficiency focused phase-II study.

The good things about this study are that it is quick and easy to participate in.  They are recruiting in one location:

Chula Vista, California, United States, 91911

ProSciento, Inc.  619-427-1300   hello@myproscientostudy.com

Corporate Web Page: https://tiximed.com/

Corporate Interview: https://www.youtube.com/watch?v=sezKoZi7lJU

To see a longer history of research into curing type-1 diabetes by targeting TIXNP, you can read this article: https://www.news-medical.net/news/20240731/FDA-clears-UAB-startups-TIX100-for-clinical-trials.aspx

Clinical Trial Registry: https://www.clinicaltrials.gov/study/NCT06800729

Joshua Levy

http://cureresearch4type1diabetes.blogspot.com

publicjoshualevy at gmail dot com

All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My kid has type-1 diabetes and has participated in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog!

Combination of Harmine and GLP-1RA Completes Phase-I Clinical Trial (In Healthy People)

This is the most fun I have had writing a blog in a long time.  It is not often I can blog about psychedelics and curing type-1 diabetes at the same time!  I hope it is as fun for you to read as it is for me to write.  Do not skip the "Discussion" section.

These researchers are testing Harmine as part of a long term project, which started by doing a quick screen of many chemicals, which identified Harmine as a possible way to help the body grow more beta cells.  This screening process involved cell cultures (i.e. biology not computer simulation). They then tested it in mice, and found strong beta cell growth.  They cured the mice of diabetes, but those mice did not have autoimmune diabetes.  Their pancreases were destroyed with a toxin to give them diabetes.  A different research group cured mice who were overfed into diabetes. These are both positive results, but neither involved autoimmune diabetes.

You can read about the mice research here:

https://www.genengnews.com/topics/translational-medicine/glp1-and-harmine-therapy-reverses-diabetes-in-mice-by-regenerating-beta-cells/

https://www.science.org/doi/10.1126/scitranslmed.adg3456

https://pubmed.ncbi.nlm.nih.gov/37629550/

This blog reports on their first test in people, but they did not have T1D.  The researchers hope to move on to people with T1D in the future.

  

The Study

This study is unusual in that it enrolled people without T1D ("healthy people", in medical terminology) and only looked for bad side effects ("adverse effects") in the medicine and not effectiveness.  Almost all T1D studies that I've blogged about over more than 10 years, even the earliest phase-I trials enroll people with T1D and have end points that cover both safety and effectiveness.  But not this study.

This is an open-label, no control group, dose escalation study which enrolled 27 people.   Each person goes through the following doses: 100 mg, 200 mg, 300 mg, 500 mg, 700 mg, 900 mg and 1200 mg, stopping when they experience side effects.  The researchers are trying to find the largest does that has minimal side effects.

The results are summarized like this:  Harmine HCl can be orally administered to healthy participants in doses <2.7 mg/kg with minimal or no adverse effects. Doses >2.7 mg/kg are associated with vomiting, drowsiness, and limited psychoactivity.   So a 50kg person (110 lb.) can have a dose of 135 mg with minimal adverse effects, and a 91kg / 200 lb. person can go up to 270 mg.

This is good news, because it opens the way for clinical trials on people who have T1D, and tells the researchers what is the maximum dose they can use without bad side effects.

Article: https://www.genengnews.com/topics/translational-medicine/glp1-and-harmine-therapy-reverses-diabetes-in-mice-by-regenerating-beta-cells/

Article: https://reports.mountsinai.org/article/endo2022-_3_beta-cell-harmine

JDRF's history with this research: https://www.breakthrought1d.org/minnesotadakotas/clinical-trials-and-disease-modifying-therapies/

Resulting Journal Article: https://pmc.ncbi.nlm.nih.gov/articles/PMC11549898/

Clinical Trial: https://www.clinicaltrials.gov/study/NCT05526430

Discussion

Dose Comparison to Mice Work

The important finding of this clinical trial is that doses less than 2.7 mg/kg are safe and well tolerated.  ("well tolerated" being medical jargon for "In our judgement, the side effects of this treatment are small enough so that people would be willing to get them in order to also get the benefits of the treatment".)  For comparison, two previous research projects targeted curing T2D in mice with 30 mg/kg and targeted T1D mice with 3 mg/kg.  Together, this trial in people with T1D and the previous trial in mice suggests that the 3 mg/kg is a "sweet spot" dose: high enough to work and low enough to avoid bad side effects.

However, there was another difference.  People in this study were given Harmine in a single pill, but the previous mice study gave Harmine using a subcutaneous pump (like an insulin pump) and continually dosed throughout the day.  For comparison, the T2D mice were given 30 mg/kg daily with an injection.  So if we compare the people to the T1D mice, they got a similar dose, but the people got it once in a pill and the mice got it infused daily for months.  Since pills are generally easier to take than injections, this is good news, if pills are as effective as injections.

Obviously, an important target of future research is going to be if pills are an effective way of delivering this medicine, or if a continuously dosing pump is required.

T1D Mice results: https://www.science.org/doi/10.1126/scitranslmed.adg3456

T2D mice: https://www.mdpi.com/2075-1729/13/8/1693

Psychedelics

Harmine is found in several species of plants (esp. wild Rue) and animals (esp. butterflies), but it is famous as a component of Ayahuasca, a South American psychoactive folk medicine and religious sacrament.

It is being tested for psychiatric uses (suicide prevention, treating depression, PTSD, etc.) in several clinical trials, some of which have completed and some of which are ongoing.  

My favorite quote is from one of the researchers: 

no psychoactive properties have been identified in animal studies at the doses we are employing, but animals can’t tell you if they’re hallucinating

Obviously, this is why they are carefully doing a phase-I trial on healthy humans, looking specifically for psychedelic adverse effects.  I suspect it is also the reason the study was done at the Depression and Anxiety Center at Mount Sinai Hospital in New York city.  They have more experience with this kind of clinical trial.

I'm sure the association of Harmine with Ayahuasca is going to cause some regulatory complications, even after this study shows that it is not psychoactive at the doses they are giving.  The American DEA has a long history of aggressively opposing any potential medical use associated with psychoactive drugs.  

Wikipedia article on Harmine: https://en.wikipedia.org/wiki/Harmine

Wikipedia article on Ayahuasca: https://en.wikipedia.org/wiki/Ayahuasca

What Next?

In my mind, the obvious next step is to run a phase-I or phase-II trial on people who actually have T1D, but that is not the direction these researchers are going in.  As described below they are looking for a patentable drug (which they hope will be even more effective).

And then there is the issue of bringing these discoveries to people with diabetes. Because harmine is a natural product, it can’t be patented. “If you can’t patent it, no drug company is going to make it because clinical trials are expensive,” he notes.

So, going forward, the team has turned its efforts toward other new small molecule compounds they have designed and synthesized, along with computer modeling. “Some of these are as good as harmine, and several are substantially better. Mount Sinai has patented these, and we’re now working to move them along via Mount Sinai’s Innovation Partners Program,” Dr. Stewart says.

These two paragraphs come from this article:

https://reports.mountsinai.org/article/endo2025-beta-cell-research

Joshua Levy

http://cureresearch4type1diabetes.blogspot.com

publicjoshualevy at gmail dot com

All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My kid has type-1 diabetes and has participated in clinical trials, which might be discussed here.  I am obese and right on the boarder of T2D and therefore may be taking drugs for those conditions.  My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog!