Sunday, January 17, 2021

PIpepTolDC Starts A Phase-I Clinical Trial

The idea behind this research is to remove dendritic cells from a person with T1D, grow them out with vitamin D3 and a fragment of proinsulin (C19-A3), and then put them back into the same person they came from.  The goal of this therapy is to teach the immune system to stop attacking the beta cells.

Proinsulin is a molecule that the body makes as part of the process of making insulin.  The body makes proinsulin first, and then (near the end of the process), coverts the proinsulin to insulin.  Proinsulin is  a target of the immune system's mistaken attack on beta cells, so teaching the immune system that proinsulin is a normal part of the body might cure (or help to cure) T1D.

Dendritic cells are part of the immune system which find foreign cells and "present" them to T-cells (another part of the immune system) so that the T-cells know what to attack.  You can read more about them here: http://en.wikipedia.org/wiki/Dendritic_cells.

Although this research is unique, it combines two parts which have each been used before.  Modifying dendritic cells has been done in the past by Trucco (late 2000s)  and DiaVacs (early 2010s).  Both groups were removing dendritic cells, treating/growing them, and then putting them back, just as done here.  The difference between all these lines of research was how the cells were treated while they were being grown outside the body.

Similarly, proinsulin (C19-A3) has been a focus of research by a group at Cardiff for over 10 years.  However,  they are testing a direct injection of proinsulin, not using it to train dendritic cells outside the body, as done here.

The Study

This is a phase-I study, enrolling 7 people, all of whom will get treated.  There is no control group.  The seven patients will be adults who were diagnosed between 1 and 4 years previously, so these are not honeymooners, they have established type-1 diabetes.  Each patient will receive two doses of the expanded dentritic cells, a month apart, and then be followed for two years.

The study has a total of five primary end points.  Some of these are safety related, and others measure the effects of the treatment (ie. how it effects the immune system).  There are also nine secondary end points, which measure effectiveness and more effects in the immune system.

This study is recruiting now and they hope to finish by October 10, 2022.  They are recruiting here:

City of Hope Medical Center, Duarte, California, United States, 91010
Contact: Ryotaro Nakamura    866-444-7538    DL-TolDC@coh.org   

This study is being funded by The Wanek Family Project.

Discussion

The researchers describe this as a "vaccine" or a "reverse vaccine", but most people would not consider it a vaccine at all.  Calling it a "reverse vaccine" is closer to how most people would think of this treatment.  A classic vaccine preps the body to fight off a disease.  It teaches the body about the disease ahead of time, so the body can stage a strong battle at the first sign of infection.  This treatment does the opposite.  It teaches the body not to attack something.  In some ways, it is similar to shots people sometimes get to lessen allergies.  (Although I want to emphasize that T1D is not a classic allergy.)  But in any case, I think it is a mistake to think of this as being like a classic vaccine.

Although this is a phase-I trial, it is not the first time this treatment has been tested.  It was previously tested in Europe.  This study gave three different doses to three people each (no control group).  Safety and feasibility data was good, but no effectiveness results were seen.  You can read the journal article here:
https://www.thelancet.com/journals/landia/article/PIIS2213-8587(20)30104-2/fulltext

News: https://www.businesswire.com/news/home/20201210005914/en/City-of-Hope-Now-Enrolling-Patients-for-Phase-1-Type-1-Diabetes-Investigational-Vaccine-Trial

Clinical Trial Registry: https://www.clinicaltrials.gov/ct2/show/NCT04590872

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.

Saturday, January 9, 2021

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

Beta Cells Which Hide From The Immune System

This has not progressed to clinical trials, but it is a new approach.  There is a lot of ongoing research into creating beta cells which will generate insulin in response to blood glucose, and many people talk about these as though they were a cure.  But they aren't, at least not by themselves, and for two reasons.  First, as a foreign cell they are properly attacked by the immune system.  Second, type-1 diabetes is caused by the immune system improperly attacking beta cells.  So there are two reasons why the T1D immune system is going to attack and destroy these cells.

However, the Salk Institute has found a recipe which takes stem cells and creates functional beta cells which are invisible to the immune system.  They call them "Immune-evasive".  In theory, this could protect the cells from both kinds of immune system attack, and these cells could, by themselves, cure type-1 diabetes.

Obviously, I'm going to be very interested in the research when/if it moves to human trials.  The press release from Salk makes it clear that these cells are not even ready for human trials, yet.  They need to undergo another round of animal testing, and then they can start the 10-15 years of human trials required for approval.
 
This is exactly the kind of research where human trials are important.  They are trying to create human cells which are hidden from the human immune system, but they must work in mice to start with.  So they are working with a specific kind of mouse called a NOD/SCID mouse.  The NOD refers to mice which have autoimmune diabetes.  NOD mice are the standard mice used to research cures to T1D.  The additional "SCID" refers to mice in which it is possible to experiment with human cells, because their immune systems have been modified to allow it.  So NOD/SCID mice are quite different than NOD mice.  That is a two edged sword.  The researchers must do it, because they can't start out experimenting on people, and yet they need to create human cells.  But SCID is a big change to the mouse immune system, changing three basic types of immune cells.  So this research is not going from mice to humans, it is going from highly modified mice to humans.  For me, this is an even larger jump, so the first human results are even more important. 

 

No Results from A Phase-I Trial of Ustekinumab

In 2014 a Phase-I clinical trial started to test Ustekinumab on people with honeymoon type-1 diabetes.  They completed enrollment  on May 24, 2016, which means they should have finished gathering data by May 24, 2017 and published results by May 2018.  Successful results are usually published in less than a year after completion.  But now it is well past May 2020, and I can not find any results from the study.
  
From my point of view, this means the study was unsuccessful.

You can read my previous blogging on this treatment here:
I think there have been a total of  three studies done on Ustekinumab, but only one is still active.  That one is in the UK and expected to finish in Oct-2022.  You can read more about it here:

 

Reminder: Once Weekly Basal Insulin Under Development

This is not a cure, but I'm sure some people will find it interesting.  Novo Nordisk has finished phase-II trials on an insulin that you use once a week to cover your basal needs.  You still need to take insulin for meals, but it replaces daily (or twice a day) basal insulin injections with just one injection a week.  It is called Insulin Icodec, and still needs to go through phase-III clinical trials before it is approved for use.

Fun Web Article on the History of Clinical Trials

 
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.

Sunday, December 27, 2020

Results from a Faecal Microbiota Transplantation Phase-I Clinical Trial

Faecal Microbiota Transplantation (FMT) is a surgical procedure where stool is transferred from a healthy donor into the gastrointestinal tract (usually the colon) of the patient.  The standard use is to treat people whose gut microbiota has been decimated by antibiotic treatment or who have a runaway Clostridioides difficile infection (commonly called "C. diff").  The goal is to seed the regrowth of a healthy microbiota.  This is sometimes called "bacteriotherapy" or "fecal transplant".

Recently some researchers have thought that type 1 diabetes might be triggered or encouraged by something in the gut microbiota.  I reviewed this theory (in the context of probiotics) a year ago:
https://cureresearch4type1diabetes.blogspot.com/2019/11/is-there-any-association-between-gut.html

The DIMID1 Study

This study enrolled 20 adults with T1D during their honeymoon phase (within 6 weeks of diagnosis).  Half got transplants from healthy people, and half got transplants from themselves.  Both groups went through the same procedures, but the second group got no new microbiota.  Both groups got three procedures in the first four months, and were followed for a year.  The exact times are marked with an arrow in the charts below. The primary results were C-peptide production (which measures the body's ability to generate insulin), and the secondary results were a wide variety of immunological, microbiota, and blood sugar control measurements.

This study was funded by the AMC Hospital several Dutch organizations.  It ran from 2013 to 2017 in the Netherlands. The researchers did not report on the ethnic composition of the participants.

Results

The primary results are summarized below.  The blue lines represent the people who got the a transplant from a healthy (non-T1D) donor and the red represents people who got a transplant from themselves.  These are all people in their honeymoon phase, and you can see the "transplant from healthy" group C-peptide numbers drop (as expected from an untreated group) but the "transplant from self" group stays steady, which is better than expected.  After a year the "transplant from self" group has not gotten worse, but the "transplant from healthy" group has, and the difference is statistically significant.  The "C" results are for fasting (sometimes called "baseline") C-peptide generation, while the  "D" results are for C-peptide generated in response to eating a meal.

Copyrighted material provided for educational purposes only.

Journal article: https://gut.bmj.com/content/gutjnl/early/2020/10/25/gutjnl-2020-322630.full.pdf
Personal note: this article is very well written, and easy to read.  The authors often describe why they chose to do one thing rather than another, so it is very informative.  People who want to understand why the gut microbiota might effect T1D can read the introduction for a quick, easy to understand justification.  

Clinical trial registry: https://www.trialregister.nl/trial/3542 

Discussion

Remembering that C-peptide is a measure of the body's ability to generate insulin, people who got the "transplant from self" treatment in their honeymoon phase did not deteriorate (in terms of generated C-peptide) over the next year.  Those who got the "transplant from healthy" treatment lost their ability to generate insulin (as would be expected over the course of the honeymoon).

But, what does this mean?  Is it important?  Will it lead to a cure?  These are the open questions. When I started this blog, results like this made me optimistic.  I thought that if a treatment could preserve beta cells in early testing, then as we learned more about it, later tests might show it increased beta cells and lead to a cure.  However, that has not happened in any of the treatments which showed this result early on.  Therefore, I'm no longer so positive about them. 

My current thinking is that these results are more likely to grow into a delay or prevention rather than a cure.  In particular, if this treatment had the same effect on people who were at-risk of T1D, as this study showed for people in the honeymoon phase, then it would naturally cause a delay.  If prevention turns out to be the natural result of a long delay, then this treatment could become that as well.  All that would be required is to see the same results seen here, but in at-risk people rather than honeymooners.  Of course, we can still hope for it turning in a cure, but that is less likely.

One interesting point about this result, is that the good effect was seen in the "transplant from self" group, rather than the "transplant from healthy" group.  It seems more likely that a transplantation from someone who did not have T1D would be beneficial while moving Microbiota around within the same person would not change anything.  However, in fact, the reverse is seen.  That is an odd result (at least to me) so I'm interested in seeing where it goes, if it goes anywhere.

The researchers wanted to include 34 people in their study (17 in each group).  Unfortunately, they were not funded enough to do that, so they ended up with 20 people (10 in each group).  Luckily, their results were strong enough to show up with the smaller numbers, but that is not often true.  So this study shows the practical impact of less money for research: fewer subjects in each study, and more uncertainty in the outcomes because of that. 

Other Research

Only one other clinical trial is testing FMT right now.  It is a pilot study, enrolling 10 people:
https://www.clinicaltrials.gov/ct2/show/NCT04124211

There are several clinical trials using probiotics to try to improve a patient's T1D.  This can be viewed as an alternate treatment to FMT, both of which are based on the same "gut based T1D" theory.

 

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.

Saturday, December 12, 2020

Glucose-Sensitive Insulin (NN1845) Starts A Phase-I Clinical Trial

Glucose sensitive insulin refers to any insulin formulation which becomes more available as blood glucose levels rise, and less available as those levels drop.  You can think of these insulins as self regulating or self dosing.  A person would inject enough to last for a day or more, but the insulin would only be used by the body when glucose levels were high.  A highly sensitive insulin could eliminate the need for measuring blood glucose levels and for determining insulin doses based on food, exercise, or anything else.  That would transform T1D management to the same injection each day.  In the same way people take high blood pressure medicine each day, a T1D could take glucose sensitive insulin each day, and otherwise ignore their T1D.  If successful, this could lead to a "practical cure" even if the person still "had" T1D. 

NN1845 is a glucose sensitive insulin under development by Novo Nordisk.

The Phase-I Clinical Trial

Officially, this is one clinical trial, but it is better to think of it as two separate clinical trials under one authorization. Both parts are focused on how NN1845 will act within the body (called pharmacology) and how safe it is.  Each part is expected to gather data for 10 days, so this study can be done quickly.  A total of 78 people will be enrolled.

The first part will give healthy people (people who do not have T1D) one dose of NN1845, to measure adverse effects (bad side effects), how their blood glucose changes over time, and what happens to the NN1845.  Half the people in this group will get NN1845 and half will get a placebo.

The second part will give people with established T1D either one dose of NN1845 or one dose of  insulin degludec (Tresiba®).  Again the researchers will look for adverse effects (bad side effects), how their blood glucose changes over time, and what happens to the NN1845.

This study is recruiting at the Novo Nordisk Investigational Site in Mainz, Germany, 55116.  The only contact information provided is an American phone number:     
(+1) 866-867-7178     clinicaltrials@novonordisk.com

 
Discussion
 
One thing that I really like about this study is that it should be quick.  Each part only requires about 10 days of data collection.  This is in stark contrast to most trials I follow, which are often 1 or 2 years.  This is because NN1845 is being tested like a new insulin rather than a possible cure.  Insulins start out by being tested with one dose, and then for a few weeks, and then for longer.  But those first tests are very quick.  While people given a potential cure are generally followed for a year or two, and this is true even in the early clinical trials.  Therefore, they take a lot longer to move through the development pipeline.
 
But there are big issues here.  The first is that glucose sensitive insulin is not "fixing" someone's type-1 diabetes.  In many ways, it is closer to a pin holding together a bone.  The bone is still broken, but the pin allows the person to ignore the fact that the bone is broken.  Is that a cure?  Is it a practical cure?  I'm going to track this as a potential cure, because I think some people will consider it one.  However, not everyone will.  If you don't consider this a cure, then just ignore my coverage of it.
 
The second issue is that this insulin may not be glucose sensitive enough to be a practical cure.  If NN1845 is so sensitive that you can take it in the morning, and it will act as a background insulin all day, and react so quickly that you don't need to take extra insulin for meals, for me, that would be a practical cure.  But NN1845 may not be that sensitive or that fast acting.  Maybe it will act as a background insulin, and make it extra hard to go low, but is not sensitive enough to react to meals.  That has some advantages in terms of extra safety as a background insulin, but it is not a practical cure in my mind.  For this issue, only clinical trials will answer the question of how sensitive and how fast NN1845 is.  Therefore, I'll follow the research and see what we learn.
 
Other Glucose Sensitive Insulin Research
 
An earlier glucose sensitive insulin was known as "Smart Insulin".  That insulin was developed by Smart Cells, Inc. which was bought by Merck.  The insulin made it to Phase-I trials, but the results were not good enough to continue in clinical trials.
 
About two years ago, Novo Nordisk bought Ziylo, a company developing a glucose sensitive insulin.  However, NN1845 is not the Zilyo product.  Novo Nordisk development of the Ziylo product was in the news as recently as mid-2020, so the company is positive enough on the general idea of glucose sensitive insulins to develop two different candidates in parallel.  That is a strong commitment.

There are several other glucose sensitive insulins currently in animal testing.  Maybe a dozen over all.  I'll cover those when they move into human testing.

Thanks
 
I want to specifically thank the JDCA (Juvenile Diabetes Cure Alliance) who tracked down some important background information about NN1845, Novo Nordisk, and Ziylo, and then kindly shared what they learned with me.  You can see their other research here: http://thejdca.org/2020-reports
JDCA does not fund T1D research.  They do publish the best public information on how money flows through the T1D research process, and great overviews of the research landscape in general.

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.

Monday, November 16, 2020

Diversity, Inclusion and Equality (In T1D Research)

I think it is important that we all support the Black Lives Matter movement in whatever we do.  This posting harnesses my knowledge of type-1 diabetes research to discuss how we can overcome racism in type-1 diabetes research.
 
The first thing to understand is that there is racism in type-1 research and treatment (and the institution of medicine as a whole).  In this post, I'm going to focus on two areas:
  1. Under representation in clinical trials:  If a minority group is under represented in clinical trials, then they will be under helped by the medical progress that comes out of that research.  Clinical trials are the raw material from which medical progress emerges.  Fewer Black patients in clinical trials now results in worse outcomes in Black patients later, and this damage is done no matter why a minority group is under represented in research.

  2. Fewer doctor visits and less aggressive treatment by doctors:  The most important factor in good results from T1D treatment, is seeing your health care team often, and having a good therapeutic relationship with them.  If a patient doesn't visit, or doesn't trust their endocrinology team, then their long term health is going to suffer.  Again, it doesn't matter why someone sees an endo less often or why they have less trust.  If it happens, then it hurts. 

The Patients In Clinical Trials

I've reported on 100s of clinical trials over the last 12+ years.  They fall into two groups: the majority, which don't report the ethnic or racial makeup of the people who are enrolled, and a minority which do report, and show that Black and Hispanic patients are underrepresented.  Minority groups are enrolled as a much smaller percentage than their population percentage around the recruiting locations. 

The whole point of clinical trials is to test treatments on the same people who will eventually end up taking them.  The scientific phrase is "representative sample".   Therefore, if a study seriously under enrolls any group, that study is not medically effective in testing the treatment.  The question of why enrollment doesn't match population doesn't matter in terms of effectiveness of the study.  The study is failing its primary goal, regardless of "why". 

These are not new ideas.  In the end notes section, I discuss the 1979 Belmont Report, which laid the foundation (in the United States) of Justice as a basic requirement for human experiments.  It specifically required diversity of participation, so that everyone would benefit from medical research.  It is wrong to think that diversity requirements in clinical trials are a recent response or a modern sensitivity.  They are long standing requirements.

When I point this out, there are several defensive reactions that should be discussed.

"That doesn't really matter because human bodies react to T1D the same way, so we don't need to include Black Americans or Hispanic Americans to learn how to treat/cure them.  Diversity not really needed in clinical trials."

This is wrong for at least two reasons.  First, it is arrogant to say that T1D effects all racial and ethnic groups in the same way, to the point where we don't need to include the minority groups in studies.  Remember, this is not just saying that, so far as we know, all ethnic groups react to T1D the exact same way.  It is also saying that all future research will continue to show this, to the point where we don't even need to do the research in a way which would detect differences!  In addition to being arrogant, it is a profoundly unscientific attitude.

Second, a new drug is not just a physical treatment with possible side effects.  It is something that people will decide to use in a social context.  For example, a CGM device, which only comes in white, might be more comfortable for White people to wear.  The exact same device, but in black might have higher adoption rates by Black patients.  Testing that includes minorities might find that, but testing that doesn't include minorities will not.   Drugs have these kind of social issues as well.  A White kid may not care about taking an insulin needle to school.  However, a Black kid might need to consider the real danger of police over reaction to this exact same action (even if completely legal, and medically necessary).

"We don't discriminate when recruiting.  It's just that fewer minority patients take part in clinical trials."

This argument assumes that the only kind of discrimination is personal discrimination.  It assumes if the recruiting process is not explicitly racist, then there is no racism present at all. That is wrong because it ignores both historical racism and institutional racism.

But there is another problem here. This statement is about why there are fewer minorities in the study, and the "why" question doesn't matter in terms of effectiveness of the study.  What does matter is that large groups within the population are severely under represented.   As an example, if Hispanic patients are not enrolled in a clinical trial, the results will not be as useful to them as to the groups that were enrolled.  It is not just the results of that one study, but all future research based on that study will be less useful to the excluded group.  The question of why Hispanics (or any other minority) were under represented is helpful to fixing the problem, but it doesn't matter when measuring the size and importance of the problem. 

"We're in a White neighborhood, and there just aren't that many minorities near us."

First of all, as I've said above, it doesn't matter.  If you plan to publish a study that shows drug X has effect Y, and 90% of your participants are White, then you are really showing that drug X has effect Y in White people.  If that convention in writing titles were applied universally in scientific journal articles, the racism would be obvious.  The scientific process requires that the people you enroll represent the people you plan to treat.  There is no little footnote saying "if you work in an overwhelming White neighborhood then it's OK to test a drug on a non-representitive population". 

Also, this thinking assumes that location, as a cause of ethnic exclusion from studies, is an unsolvable act of nature.  It's not.  Researchers in a heavily White area can recruit at another site more convenient to minorities.  They can hire a shuttle, pay for transportation, hire minority recruiters, or advertise in specialty social media where minorities have a strong presence.  In short, they could spend extra effort to get a representative sampling of the whole American population.  In the past, spending less money to come out with results that were only applicable to Whites was an acceptable thing to do.  It shouldn't have been then, and it certainly isn't now.

Furthermore, the location of hospitals and clinics is often the result of systemic enduring racism, in many ways.  Rich philanthropists would build hospitals in their own neighborhoods.  Clinics and doctors would prefer to build in more wealthy areas with more people like themselves.  Even if made decades ago, these clinic location decisions skew research done today.   Of course, the existence of ethnic neighborhoods was often shaped by racism in housing, law, banking, policing, and society as a whole.

Managing Type 1 Diabetes

I don't think it is controversial to say that people with T1D have better outcomes when they see their endocrinology team more often, and have a good therapeutic relationship with that team.  A good relationship meaning that each side understands and trusts the other, etc.

Recent studies (both in ADA 2020 and previous ADA conferences) show very clearly that Black Americans with T1D visit their endo teams less often than other Americans, that their doctors suggest medical interventions less often, and that (generally) they trust their medical teams less. 

The results of these differences are less effective treatments, earlier and worse complications, and higher death rates.  Two recent studies showing worse results can be seen here, but there are dozens more:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4533245/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7207918/
The first included over 10,000 people and found racial differences even after adjusting for poverty.
The second, of 200+ people found racial differences even after adjusting for insurance coverage.

As before, there are several defensive reactions that should be discussed.
 
"That's just economics.  Black people are poorer than White people (on average) so they end up going to doctors less often for everything, not just T1D."
 
There are several ways to respond to this, but the first one that pops into my mind is: so what?  Sure relative wealth contributes to the issue, but the issue is caused by many different things, and the situation would be improved by improving any one of the causes.  The fact that poverty is part of the problem does not mean we should ignore the racist part of poverty.   We can, and should, try to fix all the problems, and if we can't or won't fix one (such as poverty), maybe that means we should try even harder to fix the others (like racism).
 
Second, this argument implies that poverty is not itself caused by racism.  Obviously, that is not true.  If there is one thing we have learned from all the recent videos of racism and of police brutality, it is that discrimination is alive and well and having a big impact in the day-to-day lives of people all over America.   We are now seeing videos where everyday people viciously discriminate against minorities by refusing them service, stopping them from walking down the street or delivering packages, calling the cops on them, assuming they are criminals, and many other forms of discrimination, including murder.  And if that is bad now, think what is was like a few decades ago!  It should be obvious to everyone that this kind of day-to-day interference in the lives of minorities is a major cause of poverty.  I don't think anyone should say "the cause is poverty not racism".  They should say "the cause is racism manifesting as poverty", or "the cause is racism and poverty".
 
Lastly, I want to repeat that many studies (including the two linked above) show bias even when poverty or insurance are taken into account.
 
"It's not the fault of the medical team, if Black patients do not see them as much as White patients."

One of the findings in this year's ADA conference was that medical professionals are less likely to recommend interventions to Black patients than to White patients.  Obviously, this has bad effects in type-1 management because it means that Black patients will (on average) have fewer tools to manage their type-1 diabetes.  But it also sends a message that seeing a doctor is less important.  After all, one of the reasons we see a doctor is to get recommendations for new equipment, so if your doctor tends not to give you those, then there is less reason to visit.  And for people who think "doctors don't do that any more" remember that habits are built in the past, so if doctors provided lower service to minorities 20 or 30 years ago, those same minorities are now deciding (as middle aged adults) to see their doctors less often or not at all.   And maybe bring their children in less often, because of their very real bad experiences from their own childhood.  Racist actions in the past cause racist results in the present via history, habit, stereotypes, "community knowledge" and in many other ways. 

Changing How I Report On Clinical Trials

I am convinced that the first step towards reducing racism in clinical trials is to measure and report on racism in clinical trials.  If a clinical trial is not including minorities, then it is contributing to racism in medicine, and if I report on the "results" of that trial without including the racial makeup of the study, then I am contributing to the racist result.
 
So, I'm going to change the way I report on clinical trials.  Starting now, for all Phase-II and later studies that I report on, I'm going to include information on the diversity of the patients enrolled in the study, and I'm going to specifically call out studies that don't report on the ethnic or racial make up of their patients at all.  I'm hoping that if science reporters in general do this, we will encourage researchers to report on the composition of their clinical trials and then actually improve that composition until it is representative of the general population where they do their research.

I don't think this is a big contribution, and I wish I could do more, but I can do this, so I will do it.  We all need to do what we can.  I'm also looking for more that I can do, so if you have suggestions in this regard, please do send them to me.

Measuring Progress To Decrease Racism

What should the racial or ethnic composition of the research population be?  I did not want to get sidetracked by this discussion above, so I'm putting it down here.  I focus mostly on studies in the US, and the participation of Black and Hispanic patients is so low that discussing what it should be often is used as a "red herring" to sidetrack the discussion.

But I think there are two good answers to this question.  One is to say that the makeup of all the studies done, taken together, should be the same as the makeup of the country as a whole.  The second is to say that the makeup of each study should be the same as the makeup of the area where the study is recruiting.  Area defined broadly.  I'm not talking about within 5 miles of the research site, but maybe 20 miles, or the entire metro area where the research site is located.   I think that both of these pieces of data should be reported on.
 
Every major funder of research (the FDA, NIH, JDRF, etc.) should report on the overall makeup of the patients in the clinical research they fund in the US.  This should be compared to the nation as a whole.  More regional funders (such as DRI, the Sansum Institute, etc.) should publish numbers and work towards matching the populations in their regions.
 
Finally, each trial should publish the makeup of their patients, and these should be compared to the recruitment area(s).  This is something that the JDRF, FDA, NIH, etc. could change immediately.  All they need to do is make a condition of funding, that the researchers publish the racial composition of their participants.  When that data is published, it will provide it's own pressure to fix the problems which cause it.
 
End Notes
 
Historical Note: In the United States, the idea that the whole population must be represented in clinical research has been well established (on paper) since the Belmont Report of the late 1970s.  This federal report is part of the chain of events which led to the Federal Policy for the Protection of Human Subjects: Nuremberg Code (1947), Helsinki Declaration (1964), Belmont Report (1979), and finally the Common Rule (1991).  It listed the three fundamental ethical principles for using any human subjects for research as:
  • Respect for persons: protecting the autonomy of all people and treating them with courtesy and respect and allowing for informed consent. Researchers must be truthful and conduct no deception;
  • Beneficence: the philosophy of "Do no harm" while maximizing benefits for the research project and minimizing risks to the research subjects; and
  • Justice: ensuring reasonable, non-exploitative, and well-considered procedures are administered fairly — the fair distribution of costs and benefits to potential research participants — and equally.

The principal of "Justice" required both that minority groups must not be targeted for potentially dangerous clinical trials, nor could they be ignored by potentially beneficial ones.   Since all clinical trials are potentially dangerous and potentially beneficial, minority groups should not be over or under represented. 

More reading: https://en.wikipedia.org/wiki/Belmont_Report and https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/read-the-belmont-report/index.html

View Point: This blog posting is very US-centric.  I'm a White American, and a software engineer working in Silicon Valley, and these set my social context.  My views on who is a minority and who is the majority doesn't cover the whole world, and the examples I use are American.  If you're reading this in most of the rest of the world, they may not make sense to you, and I'm sorry for that.  The basic messages I'm trying to get across are universal, even if the details do change in different regions. 

Personal Note: Racism's huge impact and wide effect was "brought home" for me when I was buying my house.  It had a covenant prohibiting "any non-Caucasian person" from owning it.   This covenant has been unenforceable since 1953, but is still part of the deed of the house, and there is no legal way to remove it.   These covenants used to be relatively common in California, especially for single family homes.  There are plenty of people alive today who's housing choices were limited by these racist covenants.  The banking, policing, and social impact lasted long past 1953.  More reading:
https://www.cnn.com/2020/02/15/us/racist-deeds-covenants/index.html

I will say that reading these racist housing covenants in a news article is horrible, but reading them in a document you are about to sign as part of buying a house, is even worse.  Even though they are completely unenforceable, it made me feel so dirty, so unclean, and to think of the lives they ruined.

Note on language: English is undergoing a change in how we refer to ethnic and racial groups.  Both terminology and capitalization are in a state of flux.  For this blog posting I have capitalized ethnic and racial descriptors, and used them as adjectives rather than nouns.  For example writing "White people" and not "Whites" or "whites".

Thanks to reviewers: As you might expect, this blog went through more review than is usual, and it has benefited from everyone who read it and gave me feedback.  I want to thank all the reviewers.


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.

Saturday, October 24, 2020

JDRF Funding for a Cure 2020

In the US, we are in the "Walking Season" when JDRF (Juvenile Diabetes Research Foundation) asks us to walk to raise money for a cure for type-1 diabetes. So I'd like to do my part, by reminding you all of how important JDRF is to the human trials of potential cures for T1D, which I track.

Let me give you the punch line up front: 71% of the treatments currently in human trials have been funded by JDRF. (And the number is 80% for the later phase trials!) This is a strong impact; one that any non-profit should be proud of.  Below is a list of all the treatments, grouped by phase, and separated into groups that JDRF has funded, and those JDRF has never funded.  This message is even more important this year, when JDRF's donations have dropped precipitously due to the COVID pandemic.  This year, more than previous years, it is important to continue to fund research aimed at type 1 diabetes.

In Processes To Submit For FDA Approval
Summary: currently there is 1 drug in process of being submitted to the US FDA for approval for sale, and it was funded by JDRF.
  • Teplizumab by Provention Bio (At Risk)
In the forth quarter of 2020, Provention Bio plans to submit Teplizumab for FDA approval.   This application will cover people who are "At Risk" (as described below) for T1D, and the aim will be to delay the onset of T1D by 2-3 years.

Phase-III Human Trials
Summary: currently there are 2 treatments in a phase-III clinical trials.  Both are funded by JDRF:
  • Oral Insulin (Preventative)
  • Teplizumab by Provention Bio 

Note: Teplizumab is listed separately here, because it is being tested separately for people with honeymoon type 1 diabetes.

Phase-II Human Trials
Summary: there are 21 trials in phase-II, and 17 of them have been funded by JDRF, while 4 have not. Here are the treatments that have been funded by JDRF:
  • AAT (Alpha-1 Antitrypsin) by Kamada 
  • ATG and GCSF by Haller at University of Florida (Established) 
  • Abatacept by Orban at Joslin Diabetes Center 
  • Abatacept by Skyler at University of Miami (Prevention) 
  • Aldesleukin (Proleukin) at Addenbrooke’s Hospital, Cambridge, UK 
  • Diamyd, Ibuprofen ("Advil"), and Vitamin D by Ludvigsson at Linköping University
  • Diamyd, Etanercep, and Vitamin D  by Ludvigsson at Linköping University
  • Diamyd and Vitamin D by Larsson at Lund University (Prevention)
  • Gleevec by Gitelman at UCSF 
  • Gluten Free Diet: Three Studies  (Preventative)
  • Stem Cell Educator by Zhao (Established) 
  • Tocilizumab by Greenbaum/Buckner at Benaroya Research Institute 
  • TOL-3021 by Bayhill Therapeutics 
  • TOL-3021 by Bayhill Therapeutics (Established) 
  • Umbilical Cord Blood Infusion by Haller at University of Florida 
  • Ustekinumab by University of British Columbia
  • Verapamil by Shalev/Ovalle at University of Alabama at Birmingham
Not funded by JDRF:
  • ATG and autotransplant by several research groups: Burt, Snarski, and Li 
  • Dual Stem Cell by Tan at Fuzhou General Hospital 
  • Stem Cells of Arabia (Established)
  • Vitamin D by Stephens at Nationwide Children's Hospital (Prevention)
Phase-II? Human Trials
Summary: there are 14 trials in phase-II?, and 8 of them have been funded by JDRF, while 6 have not. Here are the treatments that have been funded by JDRF:
  • Alpha Difluoromethylornithine (DFMO) by DiMeglio
  • GABA by Diamyd
  • Golimumab by Janssen
  • Golimumab by Greenbaum (Established)
  • Hydroxychloroquine by Greenbaum (At Risk)
  • Intranasal Insulin by Harrison at Melbourne Health (Prevention)
  • Iscalimab (CFZ533) by Novartis
  • Rituximab by Pescovitz at Indiana University
Not funded by JDRF:
  • Azithromycin by Forsander
  • Ladarixin by  Emanuele Bosi of Dompé Farmaceutici
  • Liraglutid (At Risk)
  • NNC0114-0006 and Liraglutide by Novo-Norsk
  • Rapamycin Vildagliptin Combo by IRCCS (Established)
  • Visbiome by Medical College of Wisconsin
Phase-I Human Trials
Summary: there are 18 trials in phase-I, and 12 of them are funded by JDRF, while 6 are not. Here is the list funded by JDRF:
  • AG019 and Teplizumab by ActoGeniX
  • Alefacept by TrialNet 
  • CGSF by Haller at University of Florida 
  • Golimumab by (At Risk)
  • MER3101 by Mercia (previously IBC-VS01 by Orban)
  • MonoPepT1De by Cardiff University
  • Mozobil by University of Alberta (Established)
  • MultiPepT1De (Multi Peptide Vaccine) by Powrie at King’s College London
  • Nasal insulin by Harrison at Melbourne Health (Prevention)
  • Tauroursodeoxycholic Acid (TUDCA) by Goland at Columbia University
  • Pro insulin peptide by Dayan at Cardiff University 
  • VC-01 by Viacyte (Established)
Not funded by JDRF:
  • AVT001 by Avotres
  • Baby Teeth Stem Cells by CAR-T Biotechnology
  • Gluten Free Diet by Carlsson at Lund University
  • Mesenchymal Stromal Cell by Carlsson at Uppsala University
  • Microvesicles (MVs) and Exosomes by Nassar at Sahel Teaching Hospital 
  • ProTrans by NextCell (Established)
Summary of all Trials
56 in total
40 funded by JDRF
So 71% of the human trials currently underway are funded (either directly or indirectly) by JDRF. Everyone who donates to JDRF should be proud of this huge impact; and everyone who works for JDRF or volunteers for it, should be doubly proud.

Just Looking at Trials on Established Type-1 Diabetics
9 of these treatments (16%) are being tested on people with established T1D.
Of these, 6 are funded by JDRF.
So 66% of the trials recruiting people with established T1D are funded by JDRF.

Compared to Last Year
In 2019 there were 56 treatments in clinical trials, in 2020 there are 56 (no change).
In 2019 there was 1 treatment in process of approval to sell, in 2020 there is 1 (no change).
In 2019 there was 2 treatment in Phase-III trials, in 2020 there are 2 (no change).
In 2019 there were 21 treatments in Phase-II trials, in 2020 there are 21 (no change).
In 2019 there were 14 treatments in Phase-II? trials, in 2020 there are 14 (no change).
In 2019 there were 18 treatments in Phase-I trials, in 2020 there are 18 (no change).
The fact that there were no changes at all from last year is discussed below.

A Little Discussion
The big break through from 2019 was that Provention Bio expected to submit Teplizumab for approval in 2020.  Their most recent press release says they are still on that schedule.  They expect to complete their application to the US FDA in the 4th quarter.  
 
This year was unusual in that the total numbers did not change.  That has never happened before.  The studies were not static, a few clinical trials were removed and a few were added, but the overall counts were remarkably consistent from 2019 to 2020.  This might be because the COVID pandemic has slowed down research, but it might also be something else, or just random chance.
 
The money that we all donate is the thing that is going to move more Phase-II studies into Phase-III studies, the Phase-I studies to Phase-II, create more Phase-I studies, and so on.  If you don't like where we are on research, donating money is the way to make it better.  And if you do like where we are, then money is the way to push these things forward into the market.  If you're worried about your money going to non-research, then you can do what I do: fill out the attached form or go to the following website and send it in with your donation: http://thejdca.org/good-giving-landing-page/  (Unfortunately I don't know how to do this for on-line donations.)


Notes on How Trials Are Grouped
 
The list above uses the following marks to show the nature of the treatments, and if one treatment is being tested in different populations, then it will be listed more than once.
Honeymoon: Most trials are done on people within the first year of diagnosis.  All the studies listed above which are not Established, At Risk, or Prevention are in this Honeymoon category.
Established: One or more trials are open to people who have had type-1 diabetes for over a year. 
At Risk: One or more trials are open to people who have 2 or more autoantibodies, but have not yet started showing symptoms of type-1 diabetes.
Prevention: This treatment is aimed at preventing type-1 diabetes, not curing it.
If a trial is not marked, then it is for people in the honeymoon (first year) of T1D.

I give an organization credit for funding a treatment if they funded it at any point in development; I don't limit it to the current trial. For example, JDRF is not funding the current trials for AAT, but they did fund earlier research into it, which helped it grow into human trials. I also include indirect funding of various kinds.  I also give credit if JDRF funds research through another organization.  For example, JDRF funds both nPOD and Immune Tolerance Network and so I give JDRF credit for clinical trials based on their work.

The Difference Between Phase-II and Phase-II? Trials
Phase-II trials are "classic" phase-II trials; they are done after a successful Phase-I trial in type-1 diabetes.  What I call Phase-II? trials are done on known safe treatments, so they don't need Phase-I trials, but have never been tested on type-1 diabetes before.  These Phase-II? trials might be Phase-II from the point of view of size and safety, but they are Phase-I in terms of effectiveness, so I'm putting them in their own category.
 
How I Count Trials for This Comparison
  • I mark the start of a research trial when the researchers start recruiting patients (and if there is any uncertainty, when the first patient is dosed). Some researchers talk about starting a trial when they submit the paper work, which is usually months earlier. 
  • For trials which use combinations of two or more different treatments, I give funding credit, if the organization in the past funded any component of a combination treatment, or if they are funding the current combined treatment. Also, I list experiments separately if they use at least one different drug. 
  • The ITN (Immune Tolerance Network) has JDRF as a major funder, so I count ITN as indirect JDRF funding. 
  • I have made no attempt to find out how much funding different organizations gave to different research. This would be next to impossible for long research programs, anyway. 
  • Funding of research is not my primary interest, so I don't spend a lot of time tracking down details in this area. I might be wrong on details. 
Some Specific Notes:
  • I only include intervention studies here, because those are the only type of study that the FDA will accept for the eventual approval of a new treatment.  
    • The PreventT1D study (Vitamin D and Omega-3s) is a "field study" so not included.
    • A Rotavirus Vaccine study which was published this year was a population based study, so also not included.
  • I've removed Dr. Faustman's BCG research from my list of potential cures, because it is no longer aimed at a cure.  For more information read this blog:
    https://cureresearch4type1diabetes.blogspot.com/2018/09/every-year-in-september-or-october-i.html and for even more details
    https://cureresearch4type1diabetes.blogspot.com/2018/07/dr-faustman-publishes-follow-on-bcg.html
  • Oral Insulin: This trial was a phase-III trial, meaning that it was large and designed to provide enough information so that, if successful, the treatment could be widely used. However, as it turned out, only part was successful, and that part was phase-II sized, so I don't think we will see widespread use based on this trial alone. You can think of this as a phase-III trial with phase-II results.
  • Serova's Cell Pouch and DRI's BioHub: These two clinical trials are both testing one piece of infrastructure which might be used later in a cure. They are testing a part of a potential cure. However, in both cases, the clinical trials being run now require immunosuppression for the rest of the patient's life, so I'm not counting them as testing a cure.
This is an update and extension to blog postings that I've made for the previous twelve years:
Please remember that my blog (and therefore this posting) covers research aimed at curing or preventing type-1 diabetes that is currently being tested in humans. There is a lot more research going on than is counted here.

Please think of this posting as being my personal "thank you" note to all the JDRF staff, volunteers, and everyone who donates money to research a cure for type-1 diabetes:
Thank You!

Finally, if you see any mistakes or oversights in this posting, please tell me! There is a lot of information packed into this small posting, and I've made mistakes in the past. 

Joshua Levy 
https://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 adult 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.

Saturday, October 3, 2020

Iscalimab (CFZ533) Starts a Phase-II? Clinical Trial

Iscalimab, also known by its "code name" of CFZ533 started a phase-II? trial last November, and is expected to finish in October 2022.  Although it has not previously been tested on T1D, it has been tested on other diseases.  A total of 11 clinical studies are either completed or currently underway, including several phase-I and phase-II trials. 

Iscalimab is being developed by XOMA and Novartis.  It blocks a specific type of immune cell, called CD40.  The drug has shown some success in clinical trials on Sjögren’s Syndrome, which is an autoimmune disease like T1D.  It has also shown some success in NOD mice (which are commonly used to test potential T1D cures), although there is some controversy about this result.
 
Iscalimab is a monoclonal antibody, which is created by cloning a single cell that attacks the cell you don't want.  You end up with a vast number of identical cells, all of which attack the cell you don't want.  By carefully choosing the starting cell, you can "target" the monoclonal antibody to attack a very specific type of immune cell.  So if a disease is caused by a specific type of bad cell, then using a monoclonal antibody to target that type of cell is a promising treatment. 

This Study

The study is enrolling 102 people into two groups.  Two thirds will get the treatment, while one third will get a placebo and be a blinded control group.  It is expected to finish in Oct-2022.  The trial is open to newly diagnosed (within 2-3 months of diagnosis) children and youth (aged 6-21). 

The primary end points are aimed at safety (adverse events, i.e. "side effects") and effectiveness as a cure (by measuring C-peptides).  There are a bunch of secondary outcomes most of which are focused on how Iscalimab moves through the body, but two are also focused on effectiveness as a cure: another C-peptide measure and a measure of people who go into partial or complete remission.
 
The study is recruiting at three different sites in Belgium (Edegem in Antwerpen, Jette in Brussel, and Montegnee).  You can contact the people running the study here:   +41613241111    novartis.email@novartis.com or clinicaltrial.enquiries@novartis.com
 

Discussion

One thing unique about this study is that the drug will be given in two different ways.  The first dose will be given "intravenously", meaning into the vein.  This generally must be done under the supervision of a medical professional.   However, after the first dose, all other doses will be given "subcutaneously", meaning under the skin.  This is how insulin is injected, and can be done by anyone at home.

This drug has already completed 5 studies in other diseases, so its safety is well understood, which is why it has skipped a phase-I trial in people with T1D and jumped directly to a phase-II study.   That is why I call this study a phase-II? study.  From a safety point of view it is a phase-II study, but from an effectiveness point of view, it is a phase-I study.
 
Iscalimab is the second T1D drug that XOMA has gotten into clinical trials.  Over 10 years ago, they started a phase-II trial into Gevokizumab (Xoma 052).  That was also a monoclonal antibody, but it targeted a different part of the immune system (called IL-1).  It was unsuccessful.




 
News (not 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 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.