DFMO Starts A Phase-II Clinical Trial (TADPOL)

Difluoromethylornithine (DFMO), also known as Eflornithine, is FDA approved since 1990 as an injection to treat African Sleeping Sickness (trypanosomiasis) and since 2000 as a cream to prevent excessive hair growth in women.  DFMO has also been approved, for clinical trial use only, as an oral solution to treat certain cancers. 

I have blogged on a previous Phase-IIº  study for this treatment here: https://cureresearch4type1diabetes.blogspot.com/2018/06/alpha-difluoromethylornithine-dfmo.html

This drug lowers polyamine synthesis in beta cells.  Polyamines are a class of chemicals used in beta cells to regulate the production of insulin.  The researchers believe that too many polyamines in beta cells that also have inflammation, is part of the process that leads to type-1 diabetes.  They hope that lowering polyamine synthesis will preserve β-cell insulin production and delay the onset of type-1 diabetes.

The New Study

This study will enroll 70 people, aged 6 to 40, who are within 100 days of T1D diagnosis.  They started in March 2023 and hope to finish in December 2027.  The study chair is Emily K Sims, and funding comes from JDRF and Cancer Prevention Pharmaceuticals.

This is a randomized, placebo controlled study.  About 2/3 of the people will get a dose of 1000mg/m2 (see dose note below) because this was the most successful dose from a previous, small study.  This is two pills per day which they will take for 6 months.  There are two primary end points: C-peptide in response to a meal and side effects.  Secondary end points include more C-peptide numbers and measurements of beta cell stress.

If this study is successful at recruiting, it could be finished much more quickly than scheduled.  They only need to gather data for a total of 12 months (6 while taking the drug, and then 6 more).  That means if they can recruit 70 people in 2 years, the study would be done in 3 years, rather than the 4 years they expect, and even faster if they can recruit 70 people in a year.

More information on the study:

https://medicine.iu.edu/research-centers/pediatrics/research/diabetes/clinical/tadpol https://finance.yahoo.com/news/first-patient-enrolled-jdrf-funded-121500059.html
Clinical Trial Registry: https://clinicaltrials.gov/ct2/show/NCT05594563 

Dose Note

This drug is dosed as mg/m2, meaning milligrams per meter squared.  The dose is based on the skin area of the person getting it.  This is the first time I've seen a drug dosed like that.  I suspect it has to do with the drug's use as a hair growth preventative.

Recruiting

They have already started recruiting in Indiana, and will soon be recruiting at the rest of these sites:

Overall Contacts:
      Maria L Spall     317-278-7034     malnicho@iu.edu    
      Operations Manager     317-278-8879     tadpol@iu.edu

Barbara Davis Center, Aurora, Colorado, United States, 80045
Contact: Lexie Chesshir    303-724-1755    lexie.chesshir@cuanschutz.edu   
     
University of Chicago, Chicago, Illinois, United States, 60637
Contact: Triniece Pearson    773-359-7556    tpearson1@medicine.bsd.uchicago.edu   
        
IU Health Riley Hospital for Children, Indianapolis, Indiana, United States, 46202
Contact: Ellie M Ryan    317-278-7037    elmryan@iu.edu   
Contact: T1D Research    317-278-8879    tadpol@iu.edu   
        
Children's Mercy Hospital, Kansas City, Kansas, United States, 64108
Contact: Heather Harding        
        
University of Michigan, Ann Arbor, Michigan, United States, 48109
Contact: Sheree Nicholson    734-232-4213    nsheree@med.umich.edu   
       
Medical College of Wisconsin, Milwaukee, Wisconsin, United States, 53226
Contact: Joanne Kramer    414-955-8486    jkramer@mcw.edu   

Discussion / Previous Study

The same researcher had previous run a Phase-I clinical trial.  the results of this were published as a poster at IDS 2023.  The key quote on results was: 

An exploratory secondary analysis showed that at the two highest dose levels, treatment with CPP-1X stabilized C-peptide areas under the curve compared to placebo.

However, when I look at the poster results (especially Fig 4A) it looks to me like the placebo group dropped over time (as expected), and the treated group stayed flat.  This does lead to a statistically significant difference at 6 months, but it is not clear to me that it will lead to a cure, treatment, or delay onset, especially when given during the honeymoon when patients are already injecting insulin.  Even if the drug stops loss of beta cells, at that point, the people are already injecting insulin, so I'm not sure it will help much.

On the other hand, for the 1000mg dose group only (the biggest dose given), there is a slight increase in C-peptide generation between 3 and 6 months.  I don't think it is statistically significant, but if we are going to cure T1D, we are going to need to increase C-peptide generation, not just hold it constant in the honeymoon phase.  These are the types of results we are going to need to see, and bigger, in the follow-on study if this line of research is to be successful.

This study also shows the problems we (as a society) face in terms of diversity in clinical trials.  The study involved 41 people.  38 were White, 1 was Black, and 2 are listed as Multiple.   None were listed as Asian, or Hispanic.  They were recruiting in Indianapolis, Buffalo, and Wauwatosa, Wisconsin, and I would think they could do better than that.

Press Release: https://www.biospace.com/article/releases/panbela-announces-poster-presentation-at-immunology-of-diabetes-society-meeting-evaluating-the-potential-of-cpp-1x-eflornithine-in-recent-onset-type-1-diabetes/
The poster itself: https://panbela.com/wp-content/uploads/2023/06/ENDO2023poster.pdf 

 More Information: https://en.wikipedia.org/wiki/Eflornithine

Discussion / Compassionate Use (Right Now)

In the past, I've often said there were two ways to get access to a drug in the USA.  Either through FDA approval for your illness, or through "off label" use if the drug is approved for a different illness.  However, since 2016, there is a third way, called "Compassionate Use".  This is authorized by the 21st Century Cures Act.  I bring it up here, because Orbus, the company developing DFMO has an official Compassionate Use policy, which you can read here:
https://www.orbustherapeutics.com/s/Orbus-Expanded-Access-Policy.pdf

It is quite limited, and completely at the discretion of the company to approve.  Patients (and their parents) can not even request Compassionate Use.  Instead, their doctors must request it.  They will need to fill out an FDA form 3926.

I'm sure there are many rules and requirements for this, but the key ones are that the drug is in active clinical development (phase-II or phase-III), and the patient must have a serious or life-threatening disease or condition. 

I expect to see more of this in the future, as companies (and even later, doctors) get more comfortable with this aspect of the 21st Century Cures Act.  I want to stress, that I'm not mentioning it here because I think this particular drug is a good candidate to ask your doctor to ask the company for Compassionate Use.  As I hope I made clear in the "Previous Study" section, the results so far are not so good that they suggest to me that pre-approval treatment with DFMO is worth the uncertainty and risk.  However, I do think it is important for everyone to understand their options before the situation comes up where they might need to use those options.

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 daughter 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.

Possible Cures for Type-1 in the News (May)

Some smaller news items from May.

A Phase-I Trial of DFMO is Fully Enrolled 

Alpha Difluoromethylornithine (DFMO) is approved for two quite different issues.  The first is to remove/prevent facial hair in women, while the second is to treat sleeping sickness.  Neither of these are related to type-1 diabetes.   However, this drug was effective in preventing diabetes in NOD mice (which are predisposed to an autoimmune diabetes, similar to human type-1 diabetes), when given to these mice before they developed T1D.  That is what motivated this trial.

This trial finished enrolling new patients in Oct-2019.  Once a trial is fully enrolled, everyone knows when it will end, or at least when they will finish gathering the required data. So in a very real sense, we can see the end of the tunnel now. This trial will collect data for 6 months, so the data should be collected by April-2020, and (hopefully) will be published soon.  However, with COVID-19, nothing is certain.  My policy is to wait two years for a publication.  In fact, my experience is that successful studies are usually published in less than a year.  So from a practical point of view: if it is not out in a year, it is not likely to be successful.

Previous Blogging: https://cureresearch4type1diabetes.blogspot.com/2018/06/alpha-difluoromethylornithine-dfmo.html
Clinical Registration: https://clinicaltrials.gov/ct2/show/NCT02384889


Unsuccessful Results for a Phase-II? Trial of GNbAC1

While this trial was underway, the treatment got a new and improved name.  It is now called Temelimab.  Do not mix this drug up with Teplizumab or Tocilizumab.  All three of these drugs are different.

GNbAC1 is a monoclonal antibody which was developed by GeNeuro SA and has completed phase-II testing for treating Multiple Sclerosis, which (like type-1) is an autoimmune disease. This phase-II? trial finished in May-2019, but unfortunately was not successful.  The key sentence in the results section was this:

Concerning exploratory endpoints, there was no difference in the levels of C‐peptide, insulin use or HbA1c between treatment groups ...

Results: https://dom-pubs.onlinelibrary.wiley.com/doi/abs/10.1111/dom.14010
Previous Blogging: https://cureresearch4type1diabetes.blogspot.com/2018/06/gnbac1-starts-phase-ii-trial.html
Clinical Registration: https://clinicaltrials.gov/ct2/show/NCT03179423

Notes on Understanding Research Conclusions

Here is the entire Conclusions section for the results of the GNbAC1 study together with how I interpret them:

Temelimab appeared safe in patients with T1D. Pharmacodynamics signals (hypoglycaemia and anti‐insulin antibodies) under temelimab were observed. Markers of β‐cell functions were not modified by treatment. These results need to be further explored in younger patients with T1D with earlier disease onset.

Although if read quickly this sounds positive, it is (in fact) reporting on a failure.  So let me break it down into what each sentence actually means:

Temelimab appeared safe in patients with T1D.

Paradoxically, this is bad news when it is the first sentence in the conclusions.  Almost all T1D studies get information on both effectiveness and safety.  Because effectiveness is the more important information, if they lead with safety results, then that means the effectiveness results were not good.  For a successful study, one that gets us closer to a cure, a sentence about safety will be farther back in the conclusion section.

Pharmacodynamics signals (hypoglycaemia and anti‐insulin antibodies) under temelimab were observed. 

These results are not critical for curing T1D, especially when you remember the key result (no difference in C‐peptide, insulin use or HbA1c).  This is just reporting on what tiny crumbs of good news they could find at the bottom of their research data.   "Signals" usually means small (ie. not statistically significant) changes.  It sounds like the patients had slightly fewer low BG episodes and slightly fewer anti-insulin antibodies.

Markers of β‐cell functions were not modified by treatment. 

This is the most important result, because beta cell function means insulin production, but this did not change.  This is what matters in terms of a future cure.

These results need to be further explored in younger patients with T1D with earlier disease onset.

Normally, calls for more research should be ignored, because any research can be followed up with more research.  It is meaningless for a researcher to call for more research, because they always do this.  However, this sentence is more negative than most, because it says that the research should be done on different people than this study, which implies that more studies on these people would not be useful.  And, to make things worse, none of the conclusions suggest that this other group of people would have better results.

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 daughter 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.

Alpha Difluoromethylornithine (DFMO) Starts A Phase-II? Trial in Honeymoon Type-1 Diabetics

This trial started recruiting in April 2015, but I missed it at that time, so I'm blogging about it now.

Alpha Difluoromethylornithine (DFMO) is approved for two quite different issues.  The first is to remove/prevent facial hair in women, while the second is to treat sleeping sickness.  Neither of these are related to type-1 diabetes.   However, this drug was effective in lowering diabetes rates in NOD mice (which are predisposed to an autoimmune diabetes, similar to human type-1 diabetes), and that is what motivated this trial.

The Trial

This trial is recruiting people 12-40 years old, who have been diagnosed with type-1 diabetes in the last 2-8 months.  People will be divided up into 4 different groups, each getting a different dose.  Within each dose group, there will be 6 people who get the treatment and 3 people who get a placebo (and will be a control group).

Primary endpoints are safety related, while other endpoints (such as C-peptide) are targeted at seeing if it works.

The researchers hope to finish gathering data in Dec 2019, so publication should be some time in 2020.  (Although the primary outcome data will be collected in Dec 2018, so there is the possibility of partial results in 2019.)

This trial is being run in three locations:

Riley Hospital for Children: Indianapolis, Indiana, United States, 46202
Contact: Stephanie Woerner, FNP    317-944-2573    sestein@iu.edu 

Women and Children's Hospital of Buffalo: Buffalo, New York, United States, 14222
Contact: Michelle Ecker, RD, CDN, CDE    716-878-7609    mecker@upa.chob.edu 
       
Children's Hospital of Wisconsin: Wauwatosa, Wisconsin, United States, 53226
Contact: Joanna Kramer, CCRC    414-955-8486    jkramer@mcw.edu 


Discussion

Although listed as a Phase-I trial, in some ways it is more like a phase-II study, which is why I've listed it as a Phase-II? study.  The question mark signifies that this drug has never been tested on people with type-1 diabetes before.  I consider it Phase-II because it is the right size (42 people) and the right purpose (testing multiple different doses) to be a Phase-II study.

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02384889
Results in mice: https://www.ncbi.nlm.nih.gov/pubmed/23846959

Personal Note

I am always surprised how much researching type-1 diabetes teaches me about other subjects.  One part of the story of DFMO is both fascinating and horrifying.  After being developed in the 1990s, it was used intravenously as a treatment for sleeping sickness.  However, in 1995 production was discontinued, because saving lives in Africa was not profitable. Various non-profits lobbied the producer (a big pharma firm) to restart production, but to no avail.  Meanwhile, researchers discovered that it "cured" facial hair in women.  The cream used to do this went into production in 2000, and has been on the market since then.   Under intense pressure from the World Health Organization and non profits, the big pharma company eventually agreed to provide the drug for free to non-profits for distribution to African sleeping sickness patients, starting in 2001.  My best guess is that the lack of drug between about 1995 and 2001 killed between 40,000 and 110,00 people (very roughly).

The key moment in making the drug available may well have been a "60 Minutes" episode.  This is an American weekly news show.  It showed patients dying of sleeping sickness, or enduring painful IV treatments, which was the best non-DFMO drug available, and then followed it up with DFMO's American TV add for removing facial hair.  The juxtaposition highlighted the money-at-the-cost-of-lives reality of the situation.

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, JDCA, or Bigfoot Biomedical news, views, policies or opinions.  In my day job, I work in software for Bigfoot Biomedical.  My daughter 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.