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

New article: https://ml-eu.globenewswire.com/Resource/Download/fc66cefd-2090-4c42-95d7-b8c3237a8092 (p18) 

Clinical trial registry: https://www.clinicaltrials.gov/ct2/show/NCT04569994

Talk: https://www.youtube.com/watch?v=E0wpg4oiDBw 

 

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.

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

Merck Cancels "Smart Insulin" (MK-2640) After Unsuccessful Phase-I Trial

This is the news everyone hoped we would not get.  After completing a phase-I trial of "Smart Insulin" (also known as MK-2640), Merck has decided not to move forward with it.  They have not published the results, but have published this: "MK-2640 was discontinued due to lack of efficacy".

News report:  http://www.pharmaceutical-journal.com/news-and-analysis/features/towards-a-smarter-insulin/20203828.article

Discussion

This was the first (and so far only) glucose responsive insulin to be tested in humans.  However, there are several "smart insulins" being tested in animals, not to mention "smart artificial cells" and "smart membrane" based technologies, all aimed at automatically regulating the amount of insulin in the blood stream.  I expect some of these to enter human trials in the next few years.  So "smart insulin" may yet be a trail blazer, even if it itself was unsuccessful.

If results from this study are ever published, I'll blog on them here.  However, there is nothing forcing Merck to publish these results if they don't want to.

Phase-II T-Rex Trial Update

Caladrius Biosciences recently announced that they had enrolled the 70th patient (out of 111) in their clinical trial of CLBS03 for T1D.  So it has taken them roughly 18 months to recruit 2/3 of the patients they need.  If they can keep up that pace, they will finish recruiting in the third quarter of 2018, and finish collecting data in the third quarter of 2019, and publish in 2020.

Previous Blogging: http://cureresearch4type1diabetes.blogspot.com/search/label/Polyclonal%20Tregs

A quick summary of this treatment is as follows: remove one specific type of T regulator cell (called "CD4(+)CD25(+)CD127(lo)") from a person with type-1 diabetes.  Grow them out so you have about 500 times more, and then put them back in the same person.  Since regulatory T cells naturally regulate the body's immune system, and the patient now has more of them, the hope is that they will prevent the autoimmune attack which causes type-1 diabetes.

They are recruiting patients in about 15 locations all over the US, so read the clinical trial registry to get a complete list and some contact information.

News Report: https://www.caladrius.com/press-release/caladrius-biosciences-announces-enrollment-of-the-70th-subject-in-the-phase-2-t-rex-clinical-trial-of-clbs03-for-type-1-diabetes/
Clinical Trial Registry: https://clinicaltrials.gov/ct2/show/NCT02691247

SIMPONI (Golimumab) Starts A Phase-I Trial In Pre-Symptomatics

Golimumab (sold as Simponi) is an immune system modulator, which has been approved in the United States and many other countries for treatment of several autoimmune diseases, so testing it on type-1 diabetes makes a lot of sense.  This is the second trial underway for this drug.  (The other one is called T1GER, and is for honeymooners.)  Simponi has already been approved to treat rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, and ankylosing spondylitis.

This study is recruiting people who have two autoimmune antibodies (but no other symptoms of type-1 diabetes). They are recruiting 30 kids (aged 6-21), and will follow them for 17 months. Each kid will get 26 weekly injections.  Half the patients will get Simponi and the other half will get a placebo.  They hope to finish this study in mid 2021.

This study is current recruiting in Linkoping University Hospital, Linkoping, Sweden, SE 58185.
Study contact: 844-434-4210 JNJ.CT@sylogent.com
They hope to start recruiting at other locations in Sweden and Finland soon.

The unusual thing about this trial is that they will not measure any effectiveness data at all.  The only data gathered will be safety and side effect data.  No C-peptide data, no A1c, or insulin usage.  That's very unusual for a type-1 diabetes study.  In my experience, even the phase-I studies gather some effectiveness data.

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT03298542
Previous Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02846545

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.

Research In The News (November)

MK-2640 ("Smart Insulin") Completes Enrollment Collection of a Phase-I Clinical Trial And Then Adds a New Part

MK-2640 is the Merck identifier for what we all know as Smart Insulin.  It is the only "self dosing" insulin currently in human trials.  The idea behind this drug is that you could inject it (maybe twice a day, maybe once a day, maybe once a week), and then it would release insulin if your BG numbers were high, and not if they were low.  It is sort of a chemical artificial pancreas.

Because there is no data from human testing (nor have I seen any animal data), there is no way for me to know if MK-2640 is going to turn into a "lantus killer" (i.e. a great basal insulin), or if it is going to turn into something much closer to an artificial pancreas.   For example, something you take once a week and not count carbs or otherwise worry about type-1 diabetes.

The First News 

On 29-June-2015 Merck updated the clinical trial record to show that they were no longer recruiting people for this trial.   Since this trial collects data for 37 days, that tells me that they finished in August. However, a different part of the record suggests they might have finished collecting data even earlier.  Yet another part of the record was updated to show an "Estimated Study Completion Date" of October 2015.  So that was all good news, and I was looking forward to them publishing results.

The Second News

Then (in September) they added a third part to what had previously been a two part clinical trial. Part three seems to be a continuation of part two (meaning they are testing in type-1 diabetics and are comparing MK-2640 to regular insulin.  They are now recruiting again (presumably for part three), and have pushed out the completion date to early 2016.  Part three will add 16 people to the test (from 58 to 74), but the testing looks pretty similar to part two.

A (Very Little) Discussion

Most of this clinical trial involves giving people MK-2640 (different groups of people getting three different doses), and then dripping sugar into them for 9 hours (7 hours in part three) and seeing what happens.  The sugar is an IV drip ("intravenous infusion"), not eaten in a meal.  In this case "what happens" means things like: side effects, BG levels, how quickly the body "clears" the drug out of the system, etc.

For me, the most important data will be how quickly MK-2640 lowers BG levels when sugar first starts hitting the bloodstream. If it lowers BG levels quickly, that means that it will work for meals (and is more of an AP replacement). However if it is slow to lower BG levels, that implies that it is more of a Basal insulin, and might replace Lantus/Levemir in the market, but not replace pumps/APs.

However, as I am an optimist, I will not forget that IV sugar is much faster acting than carbs eaten in a meal, so even if the results are so-so for IV sugar, I would expect better results from a real meal.  Of course, it could turn out exactly the opposite: the slower sugar absorption might result in slower MK-2640 reaction times.  I guess we'll have to wait for the first "real world food" tests.  I only hope it gets that far.

I interpret adding the new part three section to be all good news.  They added that after they had run the first two parts, and I don't think they would do more testing if the first parts did not look good.  (A pessimist might say that if part two was not good, they were hoping to save the trial with data from the new part.  However, I am an optimist so I think if part two was not good they would have just stopped, and since they pushed ahead, that is good news.)

Similarly, part two followed people for 9 hours, but part three only followed them for 7 hours.  Is that good news, because it means that Smart Insulin reacted quickly?  Or is it bad news because, Smart Insulin lost effectiveness after that?  There is no way to tell, until they publish.

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02269735

MultiPepT1De (Multi Peptide Vaccine) Starts A Phase I Study

This is a follow on study to one of the very first clinical trials I ever followed:
http://cureresearch4type1diabetes.blogspot.com/search/label/Peakman
That older trial injected a peptide (part of an insulin molecule) in the hopes that the immune system would learn not to auto-attack.  This new study injects a mix of peptides to provide a broader education to the immune system.  The basic idea is like injecting peanut proteins to teach the immune system not to be allergic to peanuts.

The study will enroll 24 adults, within four years of diagnosis.  There is no information available on number of injections, duration of the study, primary or secondary end points.  They are recruiting in London, England.  Contact information is:  Ms Rhanya Chaabane, Tel: 02071888472 Ext: 81932,
rhanya.chaabane@gstt.nhs.uk.

Note: This trial is registered with the United Kingdom's clinical trial registry which contains a lot less information than the United States clinical trial registry.  It is also registered with the European Union clinical trial registry, but they don't publish records for phase-I trials at all.  Therefore, I have a lot less information about this trial than other trials, which is why they are not getting a blog posting of their own.

Trial web site: http://www.multipeptide.co.uk/
Magazine article: http://www.multipeptide.co.uk/pdf/jdrf_article_on_multipeptide.pdf
Clinicial Trial Record: http://public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID=19114


Stop Following Gevokizumab (Xoma 052)

I've decided to stop following the drug Gevokizumab (which started it's research life as Xoma 052). You can see my previous coverage here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Xoma%20052

The last news I had related to this drug in type-1 diabetes was that it started a Phase-II clinical trial in 2009.  The clinical trial record was updated to "Completed" in 2014, but there is no listing for published results.  I have searched for any results, but can find none, so I'm going to assume that the phase-II trial was a failure.  (It was run by a commercial company, so there is no reason for them to publish the results, if the trial failed.)

Since that time, Xoma, the company developing Gevokizumab, has published clinical trial results for both type-2 diabetes and Behçet's disease uveitis (both failed their primary end point).

Based on all this, I'm going to remove Gevokizumab (Xoma 052) from the list of possible cures of type-1 diabetes that I follow.

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.

Smart Insulin (MK-2640) Starts Clinical Trials

This is a blog posting that I've been waiting four years to write: the start of clinical trials for "Smart Insulin".

First, some general background on "Smart Insulin". The idea here is simple: create a chemical that holds insulin and only releases that insulin when the sugar level in the surrounding region is high. You would not have to measure blood sugar levels or match insulin to food. Instead you would just take this "self-dosing" insulin compound and it would release insulin as needed based on what you ate or did not eat.

"Smart Insulin" was the name of the first strong contender in the field, which was developed by Dr. Zion first at MIT and then at Smart Cells, which was later bought by Merck.  The term is also used generically, to refer to any "self dosing" or "Glucose Responsive Insulin"  (although I'm sure Merck's trademark lawyers would not approve).  No other self dosing insulin is in human trials, but SIA-II, Ins-PBA-F, and Sensulin, are being developed, and those are just the ones that I know about.  Smart Insulin had been tested in mice when it was sold to Merck (in 2010) and so a lot people, myself included, thought it would be in clinical trials quickly.  Obviously, the "quick" part did not happen, but the clinical trial part has started.

Smart Insulin (MK-2640) Starts A Clinical Trial

But the big news is that Smart Insulin has started clinical (human) trials.  In fact, the trial started months ago, in November 2014.   I missed it, mostly because Merck changed the drug's name from "Smart Insulin" to "L-490" to "MK-2640".   The clinical trial was under the name MK-2640, and I missed it.  Luckily Mike Hoskin at DiabetesMine publicized the name change.  You should read his blog for some general background, but notice that MK-2640 (the smart insulin I discuss here) is the second part of the posting:  http://www.healthline.com/diabetesmine/more-brains-smart-insulin

The trial itself has a fairly complex design.  It's two trials combined into one.  Part 1 is a group of 7 different "panels" (dosing regimens) given to healthy people.  Part 2 is a comparison of regular insulin to MK-2640 in people who have had type-1 diabetes for at least a year.  All of this involves 58 people and is expected to be done by July 2015.  Unfortunately, I cannot tell how many people are doing what, so I don't know if each of the 58 people are doing each dosing regimen, or if the 58 people are divided up between the different doses.  Most of the data they are collecting is "pharmacokinetic" meaning they are measuring how much of the drug is available in the body at any given time.  How quickly it "washes out" of the body and so on.  They will also be looking for adverse events and also patient drop outs caused by adverse events.  For a drug like "smart insulin" where variable dosing is critical to its success, focusing on pharmacokinetics makes a lot of sense to me.

The study is recruiting in Chula Vista, California, USA. Call their toll free number: 1-888-577-8839.

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02269735
ClinicAnnouncement of Merck buying Smart Cells: http://www.merck.com/licensing/our-partnership/SmartCells-partnership.html

Discussion

My summary is simple: in a few short months, we are going to know a lot more about how "Smart Insulin" works in people, than we know now.

One very good thing about "Smart Insulin", especially when developed by a big pharma company like Merck, is that it can move through the approval process much faster than the other drugs I cover. One of the repeating themes of this blog is that it will take a cure at least 10 years to go through the FDA's approval process, and more years are likely.  That's not rocket science, it is simple math.  The FDA requires three phases, the first phase usually takes a year to recruit the patients and a year to gather the data.  The second and third phases also take a year to recruit the patients, and two years to gather the data, and then there is a year or two for marketing approval, and we are at (2+3+3+2) 10 years.  That assumes that every phase starts the moment the previous phase ends.  In real life there are often months or years of delay between each phase, so in real life these drugs take longer to get approved.

But that is for drugs aimed at curing type-1 diabetes.  For a new insulin, most studies only collect data for three months.  Also, recruiting people is much easier, both because they are adults and because they already are taking insulin, so you're just asking them to take a different insulin.  It's not as scary as something that changes your immune system.   Bottom line is that the phase-I trial is expected to be done in 8 months (recruiting and data collection).  I would expect phase-II and phase-III trials to also be sped up, as compared to cure trials.  The downside is that insulins usually have more than 4 clinical trials before approval, and usually a couple of them are longer than 3 months. But still, I would expect a quicker testing cycle for a new insulin than for a potential cure.

This is a treatment where some people are going to think of it as a cure, and others are going to think of it as a treatment.  That's not an argument I want to spend time on.  I will cover Smart Insulin (at least this first trial) because some people do consider it a cure.  If it is highly effective, then more people might consider it a cure.  Of course, if it doesn't work well or has limitations in how it can be used, then fewer people will consider it a cure.  But I'm happy to cover it for a clinical trial or two.

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.