Results from a Phase-II Clinical Trial of Baricitinib

Baricitinib works by interfering with signaling pathways inside immune cells, to reduce inflammation and lower the immune system.  It is part of a class of drugs called Janus kinase (JAK) inhibitors.  JAK comes in two forms, JAK1 and JAK2, and Baricitinib targets both of them.

Baricitinib is not a new drug; it was first approved by the US Food and Drug Administration (FDA) in 2018.  It is taken as a once-daily oral pill and used to treat other autoimmune diseases, such as rheumatoid arthritis and alopecia areata (an autoimmune form of hair loss).  Because it has been in use for several years for other autoimmune conditions, its safety profile is well-understood.

Since the drug works on other autoimmune diseases, it seems reasonable to try it on type-1 diabetes.  Also, there has been the usual success with nonobese diabetic mice, which are commonly used to test potential type-1 diabetes cures.

This Study

This study is a phase 2, double-blind, randomized, placebo-controlled trial. A total of 91 patients were enrolled, with 60 individuals assigned to receive Baricitinib and 31 to the placebo group. Participants were honeymooners, having been diagnosed within 100 days before the start of the treatment.  They took one Baricitinib pill daily for almost a year.

The primary end point was the C-peptide level after a year. C-peptide is a substance released when the body produces insulin, serving as a reliable indicator of remaining beta-cell function. 

Secondary endpoints included several practical measures of diabetes management, average daily insulin dose,  A1c levels, and various metrics of glycemic control gathered from continuous glucose monitors. Tertiary end points included measuring things inside the immune system to see how Baricitinib affected them, especially what are called "effector memory CD8+ T cells".

The Results

The grey, placebo line shows the normal progression of T1D during the honeymoon phase.  C-peptide generation falls steadily until it hits some small residual levels, where it stays constant.  The amber, treatment line shows pretty much the opposite.  C-peptide generation goes up, but then plateaus out.  There is no doubt in my mind that this is a good outcome.  Generating more C-peptide is good, and this is not just holding constant; at the beginning it is going up.

But there are two big questions here.  First, is the difference important.  Untreated people leveled out at a level around 0.43, but treated people leveled out at about 0.65 and that is still way below healthy.  Second, this plateau was constant for the last 6 months of the study. and while the people were continuing to get Baricitinib.  This tells me that at this dose, it is not just a matter of time to get more improvement.

Discussion

To me, the obvious next question is: will a higher dose show more improvement?  This study shows improvement, but not enough to cure anyone, or even make much difference in treatment.   Would a higher dose of Baricitinib have a bigger impact?

Another follow on question is: will earlier treatment prevent T1D?  This is harder to study, and we will need to wait longer for the results.  However, any treatment which preserves beta cells might prevent T1D, if given in the pre-honeymoon phase.  And it is important to remember, this treatment did more than just preserve C-peptide production, it increased it.

The findings also support the concept that JAK inhibitors, as a class of drugs, may hold promise for treating type 1 diabetes. This could lead to further exploration of other JAK inhibitors in future clinical trials for this condition. 

One other clinical trial testing JAK inhibitors is being run now.  It is testing both abrocitnib and ritlecitinib.  It started in 2023 and they hope to finish in 2026.  It is recruiting in several sites in California, Other USA locations, Australia, and one in Canada.  You can see details here:

https://www.clinicaltrials.gov/study/NCT05743244

(click on the grey space to see a map of study locations)

For More Information

• US Clinical Trials Registry (ClinicalTrials.gov): https://clinicaltrials.gov/study/NCT04774224
• Australian New Zealand Clinical Trials Registry for BANDIT study: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=380252
• Study Web Site: https://www.trialnet.org/events-news/blog/study-finds-jak-inhibitor-baricitinib-slows-t1d

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 BreakthroughT1D or JDCA news, views, policies or opinions.  I sometimes use generative AI ("chatbots") to generate draft blogs, parts of blogs, or drafter alternate wordings for these blogs.  I always review every part of every published blog to ensure that it is saying what I want, in the tone that I want, truthfully, and accurately.  My kid has type-1 diabetes and has participated in clinical trials, which might be discussed here.  I am obese and right on the border 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!

Avotres Announces Results from a Phase-I Trial of AVT001

This blog posting reports on the results of Avotres recent phase-I clinical trial into AVT001 and the company's future plans for testing.  I reported on the start of this trial here:

https://cureresearch4type1diabetes.blogspot.com/2019/12/avotress-avt001-starts-phase-i-trial.html

AVT001 is an "autologous dendritic cell therapy" meaning that a person's own dendritic immune cells are taken out, processed in some way, and then put back.  Dendritic cells can be thought of as the immune systems "sensors".  They detect foreign invaders and then communicate that knowledge to other types of immune cells (especially T cells).

This trial flows out of some work done at Columbia University.  Researchers there found a defect in a specific type of immune cell called a HLA-E–restricted CD8+ T cells.  They believe that this defect leads to the immune system attacking the beta cells in the pancreas and causing type-1 diabetes.   The basic technique being tested here is to take out dendritic cells from the patient and treat those cells so that when they are put back into the patient, they (in turn) fix the defect in the HLA-E–restricted CD8+ T cells which leads to type-1 diabetes.

This Study and Its Results

This study involved 25 people, 16 were in the treatment group and 9 in a control group.  They were 16 years old or older, and in their honeymoon phase after diagnosis of T1D.  There were primary end points for safety and a secondary end point for C-peptides.  For me, the key results are below.  

The table below covers a year, from left to right on the bottom, and the amount of C-peptides a person generated, from zero up, on the left side.   A flat line shows success.   The body continues generating C-peptides. For the first 150 days for the treated group, C-peptide numbers do not drop at all.  This is the flat purple line. After that they did drop at about the same rate as untreated people.  This is the purple line dropping down. You can notice that the purple line and the dotted orange line (the untreated group) drop at about the same rate. The difference is that the untreated group started immeadiately, but the treated group stayed constant for at least 150 days. Since the treatment group was given three infusions, 30 days apart, the treatment last 90 days (infusions were on days 1, 30 and 60).  The treatment prevented beta cell loss for at least 90 additional days.  Safety and side effect data showed that there were no safety issues.

That's hopeful news in terms of prevention.  It suggests that giving this drug before the honeymoon phase might prevent T1D or at least delay it.   Of course, a study giving this treatment to pre-honeymooners would be needed to see if this actually happened.  Such a test would compare pre-honeymooners who got the treatment to pre-honeymooners who did not, and see how many of each group progressed to the honeymoon phase of type-1 diabetes.  If enough people are enrolled, and they are followed for long enough, such as trial could be run.   My memory is that such trials have been run lasting 2 and 5 years, and enrolling from 1 to 3 hundred people, so it is reasonable to do.

Also, it is important to remember that this treatment involves removing white blood cells from a  person's blood, treating the cells in a lab, and then intravenously infusing them back into the person with T1D.  So this is two clinic visits per treatment.

Poster: https://www.avotres.com/_files/ugd/1b81f5_edb8f657a28440638f8e32d2ec98ec4f.pdf

Journal Article: https://evidence.nejm.org/doi/abs/10.1056/EVIDoa2300238

Clinical Trial Registry: https://clinicaltrials.gov/study/NCT03895996

What Next?

From the point of view of Avotres, this was a clearly successfully phase-I/II and so are in discussions with the FDA to set up a phase-III clinical trial as the next step.  There is no advantage in speculating as to what the FDA will do.  The only thing that makes sense to do is wait a few months (or a year) and see what actually happens. 

From my point of view, this was a successful phase-I study, which showed that AVT001 might work as a T1D prevention.  If given to people before the honeymoon, it might delay or even prevent the onset of T1D.  Therefore, Avotres could turn this into a prevention/delay treatment (like Tzield®) by running three more studies (one one phase-II study and two phase-III studies as a minimum) to get approval.

In addition Avotres could try to apply AVT001 to treatment of established T1D in a different set of clinical trials, and see where that led.  

For background, the FDA generally requires one phase-I study, one phase-II study, and two phase-III studies as a minimum for approval, although there are occasional exceptions.

Company website: https://www.avotres.com/ and https://www.avotres.com/companyoverview

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 BreakthroughT1D or JDCA news, views, policies or opinions.  I sometimes use generative AI ("chatbots") to generate draft blogs, parts of blogs, or drafter alternate wordings for these blogs.  I always review every part of every published blog to ensure that it is saying what I want, in the tone that I want, truthfully, and accurately.  My kid has type-1 diabetes and has participated in clinical trials, which might be discussed here.  I am obese and right on the border 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!