Friday, March 8, 2024

Levicure's Combination Therapy

Levicure is a startup which is currently raising money to fund a phase-II trial for a combination therapy designed to prevent or delay T1D if given during the honeymoon period.  This blog posting is reporting on the results of their retrospective phase-I clinical trial.  That trial has already been completed and is motivating them to move forward with a larger phase-II trial. 

The combination therapy used three medicines: GABA, Sitagliptin or Saxagliptin (which are dipeptidyl peptidase-4 inhibitors), and Omeprazole (a proton pump inhibitor).  All three of these drugs are available now, and all have some evidence that they will help people with diabetes.  They have all been tested (in some cases in combination with other medicines and each other).  However, I think this is the first clinical trial that has reported on these three together.

The Study

This was a retrospective study, where the researchers reviewed the medical records of people who had been treated with the three drugs.  The people were given the three drugs because their doctors thought it was the right treatment for them, not because they were enrolled in a trial.  There is no randomization process and no control group.  The trial size is determined by how many people got all three treatments in the time period the researchers looked at.

The researchers ended up with 19 people. Ten of them had received the three drugs during the first year after diagnosis (their honeymoon period).  Nine more had received the drugs after that, so they had established T1D.  The two groups were analyzed separately.

Results

The group (ten people) that started therapy during their honeymoon phase, called "early therapy" below had a statistically significant rise in C-Peptide production.  The average went from just over 200 pmol/L to just under 500.  Since the average for a person without T1D is at least 365, this is an important difference, as the change is from an abnormal result to a normal one.  (All of these are fasting numbers.) 


The group (nine people) that started the treatment more than a year after the onset of T1D did not show an improvement in their C-Peptide number, and none of them was able to stop injecting insulin.  They did show improvements in treating T1D (using less insulin, having better A1c numbers, etc.)

Company: https://www.levicure.com/
History: https://healthtransformer.co/levicure-is-developing-a-breakthrough-triple-therapy-for-type-1-diabetes-b6c521e6b2c5
Clinical Trial Report: https://www.frontiersin.org/articles/10.3389/fendo.2023.1171886/full
Animal Testing: https://www.frontiersin.org/articles/10.3389/fendo.2022.1028114/full

Discussion

LADA vs. Classic T1D

Discussion of this study needs to start out with the question: Is it a LADA study, or is it a classic T1D study, and are they different?  

The successful (early treatment) part of this study enrolled people between the ages of 17 and 58 (average age was 31 and standard deviation was 13 years), so about half of these people had LADA rather than classic type 1 diabetes.  LADA stands for Latent Autoimmune Diabetes in Adults; you can think of it as classic T1D, but diagnosed in adults.  A common cut off is 30 years old.  People under that age are said to have classic T1D and after that age, LADA.  LADA has a honeymoon, just as T1D does, but it is not the same.  It is well known to be longer and stronger.  This makes it easier for drugs that delay/extend the honeymoon to work better on LADA than on T1D.  Therefore, we don't know if the good results seen here for many people with LADA are going to be as good in people with classic T1D.

Prospective vs. Retrospective Studies

I usually report on prospective studies, which are inherently more reliable than retrospective studies, and this study was retrospective.  In this case, these researchers are already raising money for another study and that new study will be prospective, so it will provide a better signal as to the success of the treatment.  In the meantime, there is nothing to do but wait, and hope they can raise the money quickly.

Similar Studies With Semaglutide

The obvious clinical trial to compare this to is the Semaglutide study which I blogged on here:
https://cureresearch4type1diabetes.blogspot.com/2023/09/strong-results-from-pilot-study-of.html
That study was in many ways very similar, both in study design and result.  They were both retrospective studies based on clinical practice, and they both had many people off insulin for a year in the honeymoon phase.

Interestingly, Semaglutide has a similar mechanism of effect to Sitagliptin or Saxagliptin.  They all end up impacting glucagon-like peptide-1 (GLP-1).  However, Semaglutide is an injected drug while Sitagliptin and Saxagliptin (tested here) are pills. 

Availability Now

The three drugs tested here are all commonly available.  GABA is a dietary supplement, Omeprazole is sold both over the counter and by prescription.  Only the second component: Sitagliptin or Saxagliptin is a prescription drug and both have been approved for use since the late 2000s.  They each have a generally good safety profile.  If you want to have an "off label" discussion with your doctor, the exact dosing information is in the clinical trial report (link above).

 

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 participates 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.

 

Monday, January 29, 2024

Results from a Phase-IIΔ Trial of Pleconaril and Ribavirin

This clinical trial represents an attack on T1D slightly different than anything I've blogged on before.

Pleconaril and Ribavirin are both antiviral drugs.  The idea here is that viruses either cause T1D or contribute to it, and that attacking viruses during the early honeymoon period will do something good.   Maybe delay the onset, extend the honeymoon, or even allow the long term survival of more beta cells to lower long term complications of T1D.  

I want to stress that this "virus causes T1D" hypothesis is just that: a hypothesis.  It is held by some researchers, but is not the consensus cause of T1D.  However, these researchers are moving forward assuming it is true, and therefore testing a prevention technique that is likely to work if it is true.  They had previously found low grade enteroviral infection in the pancreas of people recently diagnosed with T1D, and that motivated them to run this study.  

The study participants were between 6 and 15 years old and within 3 weeks of diagnosis.  These were early honeymooners.  The drug combination was in liquid form and drunk daily for six months, and then the people were followed for an additional six months, which is reported here.  Although they reported results in October, the study will continue for two more years and so we should get more results in the future.

The key finding was "During the 12-month study period, the relative decrease in C-peptide was 11% in the Pleconaril and Ribavirin group and 24% in the placebo group" (paraphrased).  So both groups dropped, but the treated group dropped much less.  See here for more discussion of why these sorts of results do not excite me.

This study was supported by JDRF, INNODIA and others.

 

Discussion

The idea that a virus causes T1D, or triggers it, or make it worse, is widely held.  Many parents remember that their kids were sick just before or as part of their T1D diagnosis.  However, the causality part has not been proven.  Viruses may cause T1D, or they might trigger it (i.e. the person was going to get T1D anyway, and the virus just caused it to manifest now rather than next month), or it may be that early T1D symptoms are similar enough to the flu so that people get them mixed up, or it might be that after a diagnosis of T1D, parents suddenly connect it to the last illness the child had.

On the other hand, Coxsackie B viruses (a type of enterovirus) have been associated with T1D in previous population studies, and enteroviruses are known to target pancreatic islets.  There is another clinical trial which attempts to use a Coxsackie B vaccine to lower the rate of T1D, and a third using flu vaccine on people in the honeymoon phase.  So the causal part is certainly possible. 

About these anti-virals specifically, I think it is important to note that Pleconaril was never approved for use by the FDA because of side effects.  It was evaluated in the early 2000s.  Ribavirin is approved, but use in T1D would be "off label" and its label includes two black box warnings.

To me, these results seem similar to the Teplizumab in honeymooners results, although with the obvious caveat that this result is in a 100 person phase-IIΔ study, and the Teplizumab study was a 300 person phase-III study.  The Teplizumab honeymoon trial reported a difference of 0.13 pmol/ml while this study reported 0.16 pmol/ml.

But also, this study only shows preservation of beta cells (and not even complete preservation), and I usually only get excited about beta cell regrowth in the honeymoon phase.

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 participates 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.