Artificial Pancreas Updates From ADA (July 2015)

In my opinion, artificial pancreas (AP) technology was the single most important technology of the American Diabetes Association Scientific Sessions this year.  There were many papers, posters, and presentations on artificial pancreases and related technologies (such as continuous glucose monitoring, stable glucagon, etc.)  Nothing generated more Twitter buzz.

This blog posting attempts to summarize a little of the research presented.  There was way too much for me to cover it all, and so this posting gives light coverage to the most important news.

My overall summary is that we are no longer talking about if there will be an AP.  The question is: when there will be an AP, and how many APs, and how many different types of technology they will use.  I continue to be heartened by:
(a) the progress made by AP research projects over the last few months (and years)
(b) the large number of new companies entering the field
(c) the product roadmap announced by Medtronic as they move their existing partial AP to a full AP.

The AP world is more and more driven by commercial considerations, rather than research considerations, and that is a strong signal that we are close to general availability.  (Close meaning years, but not too many of them.)

This tweet summarizes my thoughts, as well:

“Closing the loop is no longer a mystery; it’s not a puzzle. We just have to do it.” 

https://twitter.com/eliotmbrenner/status/607536971192377344

Second Bi-Hormonal Artificial Pancreas In Development

I recently found out about a second bihormonal AP  (in addition to Dr.  Ed Damiano's).  These researchers are in The Netherlands, and you can read more about it here:

http://www.inredadiabetic.nl/diabetes-product-ontwikkeling/
http://www.inredadiabetic.nl/us/history/
http://www.inredadiabetic.nl/news/

It's a little hard for me to figure out exactly where they are, and I have not found any articles in scientific journals.  However, it appears that earlier this year they ran a two day test on one person, and got quite good results.  The average BG was 125.  Based on that they are hoping to run two clinical trials (called APPEL 4 and APPEL 5) later this year.  They hope those trials will used as the basis for European "CE" approval.

Maybe a Third?

They haven't started recruiting yet, but this looks like a phase-II trial for yet a third bi-hormonal artificial pancreas.  I'll blog more fully if they start recruiting:

https://clinicaltrials.gov/ct2/show/NCT02379299

Back To Ed Damiano's Bi-Hormonal Artificial Pancreas

Not from ADA, but from another conference, comes this summary of Ed Damino's current status:
http://www.medpagetoday.com/MeetingCoverage/AACE/51551?xid=nl_mpt_DHE_2015-05-16&eun=g118127d0r

But if you want a summary in 140 characters, here it is, from
https://twitter.com/DiabetesMine/status/607298177952321537:
Damiano says #BionicPancreas showing ave BGs of 135-142, which would equate to 6.5% A1C.
[What's not to like!]

Plus there was this good news tweet:
From https://twitter.com/InsulinNation/status/607300794875002882:
Ed Damiano says there is room temperature stable glucagon that stays good for up to a year. Needs FDA approval.

Medtronic's 670G

The Medtronic 670G, as announced, will be an "all but meals" style, single hormone artificial pancreas, available in the United States in April 2017.  As far as I know it is the most powerful AP with a clear commercial delivery date.  For comparison, the 640G is already available in Europe, but does not prevent "highs," only "lows".

diaTribe interviewed a patient who has used the 670G as part of a clinical trial:
http://diatribe.org/medtronic-minimed-670g-hybrid-closed-loop-exclusive-interview-17-year-old-trial-participant

This is Medtronic's press release summary of results from a 640G study, a 670G study, and some other research they presented at ADA:
http://finance.yahoo.com/news/medtronic-accelerates-path-artificial-pancreas-140201655.html
The current plan is for the 640G to be available next year, and the 670G the year after.

This news resulted in the following tweets (and many more, of course):
https://twitter.com/DiabetesMine/status/607197166193508353
https://twitter.com/DiabetesMine/status/607198339600392192

More General AP News

The following, more cautionary tweets report on other aspects of AP research:

From https://twitter.com/InsulinNation/status/607284169622880256:
During artificial pancreas study, the AP couldn't be used 1 in 3 nights because of tech issues (sensors) or family/health issues.[But I don't know which AP this tweet is about!]

From https://twitter.com/DiabetesMine/status/607284048931770368:
CDE Laurel Messer: Still enough tech issues exist with CGM sensors to impact hoe [sic, should be "how"] closed loop is used in kids and young adults.
From https://twitter.com/InsulinNation/status/607278840193400832:
Predictive pump technology significantly reduced nighttime lows in kids in almost 1000 night study. [But again: I don't know what AP this refers to!]

The following link goes to a summary of one of the ADA sessions:
http://www.saluteh24.com/il_weblog_di_antonio/2015/06/artificial-pancreas-moving-toward-pediatric-use-2015ada-meeting-in-boston.html

Personal testimonial (with graph) of how well an AP works, but I don't know which one!  Anyone recognize the screen?
https://twitter.com/DiabeticSisters/status/607709090278699008

Bigfoot Explodes Big  (In a Good Way!)

Bigfoot is a one year old company.   They had a very successful ADA and generated a lot of "buzz", which this tweet tries to summarize.
From https://twitter.com/diaTribeNews/status/604309757093011456:
@BigfootBiomed acquires Asante pumps! Goal to enter pivotal trial of full #artificialpancreas system late 2016

A "pivotal" trial is industry-speak for a phase-III clinical trial.  What they are saying is that they hope to start phase-III trials of an AP next year.  That would put them shoulder to shoulder with Medtronic and front running bihormonal research projects.  Even if they are overly optimistic, and they actually start those tests in 2017, they are still not that far away from a commercial AP.

But even more promising (to me) is that Bigfoot feels like a tech start up, not a medical device company. It feels like Silicon Valley rather than Washington D.C.  I can't tell if that's a marketing strategy or the truth, but if you look at the founders, look at the tactics (reuse the failed carcass of another project), and the strategy: it really does look like the way things happen "out here".

When a company like that can successfully create an AP, it means that APs are technology gizmos, and not medical devices, and technology products can improve much more quickly than medical products.  I'm sure the FDA will have something to say about it, but even if Bigfoot is just a 20% step in the direction of Silicon Valley, that's going to "light a fire underneath" some medical device companies.

The following link goes to one diaTribe story, but that story has links to other stories, and you can get the whole saga of how big they've grown, how quickly, and how important that might be:
http://diatribe.org/bigfoot-biomedical-acquires-asante-snap-pump-technology

TypeZero: Yet Another New Company Focused On A Single Hormone AP 

And if that were not enough, TypeZero Technologies is yet another new company trying to create a single hormone AP "from scratch".  DiabetesMine has a summary article:
http://www.healthline.com/diabetesmine/typezero-tech-closed-loop-commercialization

This is based on AP research done at the University of Virginia which I have reported on before.

Comparison

There was some debate at ADA about which was better: single hormone artificial pancreases, or bihormonal artificial pancreases.  My first reaction to this debate was this: who cares?  Either one is so much better than what we have now, let the people who like insulin only APs develop those, and let the people who like insulin and glucagon APs develop those, and let the market decide, or maybe let the market decide that there is room for more than one AP technology.  I mean some people have cable while others have satellite, why not the same with APs?  Have we learned nothing from the death of communism?  Let the market decide, as fed by the strongest proponents of each system.

My second reaction to this debate was that it can never be resolved by research. The data we have now is pretty clear: single hormone APs result in average BG numbers about 10 points higher than dual hormone APs  (for example mid 130s vs mid 140s).  However, dual hormone APs are more complex to manufacture, more complex to operate, and involve the tiny risk of long term, very low dose glucagon (and that risk is unknown, and will remain unknown for years).  So some people are going to say dual hormone is 10 points better than single hormone, end of story.  But others will say, mucking about with refilling two reservoirs is just not worth 10 points.  And neither of these opinions is right or wrong, they are just different.  And always will be.

However, even if research cannot answer a question, it can still inform the discussion, and there have been some papers directly comparing the two systems. The following tweet is one summary, but the links to the abstracts below contain more data.

From https://twitter.com/sarhoward/status/608301471529107457:
Haidar: Both single and dual hormone artificial pancreases better than pump for BG control at night, dual better for reducing hypos

http://www.thelancet.com/journals/landia/article/PIIS2213-8587(15)00141-2/abstract
http://www.thelancet.com/journals/landia/article/PIIS2213-8587(14)70226-8/abstract


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.

Artificial Pancreas Update (May 2015)

I have decided, for 2015 at least, to do quarterly updates for Artificial Pancreas research. The area is moving forward so quickly that I think that quarterly updates are warranted.

The term "artificial pancreas" refers to using a continuous glucose monitor (CGM) to feed data to a computer, which controls an insulin pump, and in some models, a glucagon pump as well. Artificial pancreas refers to using existing technology in all these areas, but connecting them together so that a person does not need to worry about counting carbs or blood glucose levels. It is all done automatically. Most people do not consider this a cure, but I follow AP research because some people do consider it a cure.  There is no doubt that such technology would be a huge step forward in treatment, and would largely prevent "dead in bed" due to low blood glucose events.

An earlier version of this blog had the wrong dates for future Medtronic product releases.  I'm sorry about that.  This posting has the correct dates.  Thanks to Tamar Sofer-Geri for finding the mistake.

Artificial Pancreas Update for April 2015

The JDRF uses a 6 step model to describe milestones on the way to the fully featured artificial pancreas that we all want.  You can read about those milestones here: http://jdrf.org/research/treat/artificial-pancreas-project/.
So when I refer to "step 1" and "step 4" and so on in this blog, I'm referring to the steps described by JDRF.

Corporate News from Medtronic

Back in January, Medtronic made the following product announcements:

• The 640G (predictive low glucose suspend) will ship in Europe in April 2015.
• The 640G will ship in the United States in April 2016.
• The 670G will ship in the United States in April 2017.
• The 670G will ship in Europe in April 2018.

News (from Close Concerns / diaTribe): https://www.closeconcerns.com/knowledgebase/r/ce9abf26

There are three pieces of good news included in those predictions.

First, the 640G is a step 2 Artificial Pancreas, so it will predict and avoid low blood glucose events.

Second, the 670G (depending on exactly how it turns out) could be a step 3 or 4 device.  That means it will predict and avoid both low BGs and high BGs, but not cover meals automatically.

Third, it means that Medtronics believes that the FDA's previous approval delays will stop:

• There was a 2.5 year delay (from European approval to US approval) for the 530G.
• Medtronics expects a 1 year delay for the 640G.
• Medtronics expects a 1 year advantage (US before Europe) for the 670G.

I hope they are right about this!  FDA's delays in earlier AP approvals are one of the major reasons AP development has been slow, and European availability is ahead of us. If the FDA is able to fix this problem over the next few years, that is a huge piece of good news for all AP companies and ultimately, all AP users.

MD-Logic Goes Commercial

MD-Logic is one of the artificial pancreas projects which has been in phase-II clinical trials.  I previously blogged on it in Nov-2014: http://cureresearch4type1diabetes.blogspot.com/2014/11/artificial-pancreas-update.html

In the past, it has been a research project, but a company called DreaMed Diabetes was founded to commercialize it, and they recently signed an agreement with Medtronic.  According to diaTribe:
http://diatribe.org/medtronic-signs-exclusive-agreement-use-glucositter-artificial-pancreas-software-future-insulin
Medtronic plans to use this technology in their artificial pancreases after the 670G.  The 670G will be a step 4 AP (automatic except for meals), while the MD-Logic based follow on will be a step 5 AP (automatic including meals).

Also, MD-Logic's blood glucose control algorithm got a "CE" mark in Europe (which is their "approval to sell" symbol).  You can read about it here:
http://www.diabetesincontrol.com/articles/diabetes-news/17774-artificial-pancreas-software-algorithm-receives-approval-in-europe-
However, I'm not sure what that means from a practical point of view.  You cannot use an algorithm by itself.  It has to be part of a piece of software or hardware, and right now no one is selling any product which uses the algorithm.  Maybe this CE mark will speed Medtronic's approval in Europe when the time comes?

Artificial Pancreas News From Tandem (makers of t:slim)

I slogged through a Tandem analyst's call in Feburary, which you can read here:
http://seekingalpha.com/article/2946926-tandems-tndm-ceo-kim-blickenstaff-on-q4-2014-results-earnings-call-transcript?part=single

There are only a few paragraphs on AP research, and my rough translation of them is this:

Tandem is currently experimenting internally, and not on people, with both predictive low glucose suspend (step 2 AP) and predictive high glucose dosing (step 3 AP).  In the second half of 2015 they will start the paperwork to run a clinical trial testing predictive low glucose suspend.  Based on discussions with the FDA at that time, they will have  better idea of how many clinical trials will be required for approval (and therefore how long it will take).  Also they will have a better idea about testing both the predictive low suspend and high dosing at the same time, or release one and then the other.

Bihormonal AP Update from CarbDM's Diabetes Summit

I attended CarbDM's "Diabetes Summit" in Silicon Valley last month.  It was wonderful, even though I could not stay to the end.  Listening to the morning speakers was very informative, but in this blog I'm going to limit myself to discussing  Dr. Ed Damiano's talk.

Dr. Damiano is working on a bihormonal (insulin and glucagon) AP, called the "Bionic Pancreas". The key piece of information from his talk was that they will finish the current round of phase-II trials on April 27th (that's the last day of data collection).   Another round of studies is planned for the second half of 2015.  For next year, the plan is to create a device that can be sold and spend the rest of 2016 and 2017 testing it.

Dr Damiano reported on results from several clinical trials (adults and children who use the AP under different circumstances).  For all these studies, the numbers were great (in my opinion).  They averaged in the low 140s or high 130s in different trials.

There were some other interesting tidbits: the daily dose of glucagon used by people on this bihormonal AP was between 1% and 3% of the dose used in a single "rescue" injection, so a relatively small amount.   Also, the amount of insulin used by people on the AP was about the same as people in the control group.  So it's clear that the bihormonal AP is using insulin more efficiently, not just using more insulin.

CarbDM's: http://carbdm.org/
The Diabetes Summit: http://carbdm.org/summit/

International Conference on Advanced Technologies & Treatments for Diabetes (ATTD 2015) 

This was a conference held in Feburary in Europe that had dozens of papers, many of which covered artificial pancreas research, continuous glucose monitoring techniques, and related areas.

You can see all of their posters here:
http://dasterminal.com/posters/attd2015/
Abstracts for a huge number of papers are here:
http://online.liebertpub.com/doi/full/10.1089/dia.2015.1525

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.

Artificial Pancreas Update (Jan 2015)

Sound track for this blog is "Living After Midnight" by Judas Priest, but performed by The Donnas:
http://grooveshark.com/#!/s/Living+After+Midnight+Judas+Priest/3ASqUY

Research into the Artificial Pancreas (AP) continues to move forward.  The term "artificial pancreas" refers to using a continuous glucose monitor (CGM) to feed data to a computer, which controls an insulin pump, and in some models, a glucagon pump as well.  Artificial pancreas refers to using existing technology in all these areas, but connecting them together so that a person does not need to worry about counting carbs or blood glucose levels.  It is all done automatically.

Metronic Starts Selling a "Step 2" Artificial Pancreas in Australia

The JDRF uses a 6 step model to get to the fully featured artificial pancreas that we wall want.  You can read about that model here:  http://jdrf.org/research/treat/artificial-pancreas-project/

Right now, Medtronic makes the only commercially available "step 1" artificial pancreas.  However, just recently they started publicising a "step 2" artificial pancreas in Australia.  The difference is that "step 1" APs cut off insulin if you are already too low, while "step 2" cuts you off before you get too low.    This is an important improvement in functionality, but it is also an important regulatory hurdle. The model number is 640G.  I can't find any press releases, or any notice on their web site, but karri on CWD posted this link to a promotional video:
https://www.youtube.com/watch?v=wl6WDkxXjBc
There are also several "Ambassador Reviews" on the Medtronic Diabetes ANZ youtube site.
It looks like they are taking orders for the device now.  However, I can't see anything on the web site related to the 640G.  Maybe they know I'm from the USA, and can't get it?

Of course, the next issue for us Americans is FDA approval.  Medtronic's "step 1" device took 31 months after European approval, before the FDA approved it!  It will be interesting to see if the FDA repeats that fiasco or not.  There has been a lot of progress, several meetings between the FDA and patient advocates (such as DOC, diaTribe, JDRF, etc.) and now we will see if any of that matters. But the clock is ticking now, and we will know a lot more when we see how long the FDA delay of approval is.


A Direct Single Hormone vs. Dual Hormone Comparison

In the past, I've tried to compare Single Hormone AP results to Dual Hormone AP results, by comparing similar results from different studies.  However, it's much better to compare the same result in the same study, rathern than combining data from different studies.  A group of researchers at Institut de Recherches Cliniques de Montreal, Montreal, QC, Canada (and elsewhere) recently did exactly this comparison.  They directly compared a regular pump plus CGM, to an insulin only AP, to a insulin and glucagon AP.  Patients (12 years or older) were treated for 3 24 hour periods.  The trial was not blinded. Funding was from the Canadian Diabetes Association, JDRF, and Medtronic (see above for involvement). They reported the following data:

Measure	Pump + CGM	Insulin AP	Dual Hormone AP
Time spent in target range	51%	62%	63%
Hypoglycaemic events	52	13	9
Symptomatic hypoglycaemic events	12	5	0
Nocturnal hypoglycaemic events	13	0	0

Opinions

I think the clear result of this trial is that the dual hormone AP is very slightly better than the Insulin AP, and they are both noticeably better than the current standard pump and CGM.  This result is similar to previous studies.

Abstract: http://www.thelancet.com/journals/landia/article/PIIS2213-8587(14)70226-8/fulltext
Clinical Trial Registry: http://clinicaltrials.gov/ct2/show/NCT01754337

Many Articles in the January Journal of Diabetes Science and Technology

The Journal of Diabetes Science and Technology had a special issue on glucagon therapy.  There were a couple of articles on stable glucagon, which is required for a bihormonal artificial pancreas (such as Dr. Damiano is working on):

From this abstract http://dst.sagepub.com/content/9/1/8?etoc:

Data are presented that demonstrate long-term physical and chemical stability (~2 years) at 5°C, short-term stability (up to 1 month) under accelerated 37°C testing conditions, pump compatibility for up to 9 days, and adequate glucose responses in dogs and diabetic swine. These stable glucagon formulations show utility and promise for further development in artificial pancreas systems.

From this abstract http://dst.sagepub.com/content/9/1/24?etoc:

Data are presented that demonstrate physical and chemical stability under presumed storage conditions ([over] 2 years at room temperature) as well as “in use” stability and compatibility in an Insulet’s OmniPod® infusion pump. Also presented are results of a skin irritation study in a rabbit model and pharmacokinetics/pharmacodynamics data following pump administration of glucagon in a diabetic swine model.

Here is a diagram of their results.  Note that they are comparing their glucagon to standard glucagon, so their trial is successful if the same colored lines are close to each other, and they are:

Although both of these are animal trials, for this kind of test, I think results in animals are likely to mirror results in people.  They are really measuring the stability of the glucagon, and the test subject species doesn't have a big impact on that.  So my normal worries about "works in mice, fails in people" are pretty small for this kind of research.

Adding Physical Activity Measurements to Aritifical Pancreas Calculations

Also in The Journal of Diabetes Science and Technology, there is this paper:
http://dst.sagepub.com/content/9/1/80?etoc
(People in the San Francisco bay area will notice that the authors are mostly local: Drs. Stenerson, two Paynes, Ly, Wilson, and Buckingham.)

This paper attempted to use data on physical activity to improve an artificial pancreas's BG numbers. The idea is simple enough: we all know that physical activity lowers BG numbers.  If an artificial pancreas knew how active you were, could it do a better job of controlling BG numbers?   The kids in the study (average age 13), did a soccer workout ("football workout", in the rest of the world) on two separate occasions.  In one case, data from an accelerometer was used to help calculate real time insulin dosing, and in the other case, this data was not used.  BG and hypoglycemic events were measured both during the soccer, but also after it, until the next morning.  There were 18 kids in the study.

Overall BG numbers were similar in each group.  Hypoglycemia events were higher when not using the accelerometer, but the difference between groups was not statistically significant. (This is the scientific way of saying "close, but not quite".)

Discussion

From my point of view, there are a couple of ways to interpret this result:

1. One could say that the study was just too early and too small to interpret the results, and it's really more of a proof of concept of how accelerometers could be tested in the future.  The most that can be said is that more research should be done. 
2. Or, one could say that accelerometer data is not needed for an artificial pancreas, because it had no statistically significant effect here.  And this is a good thing, because it means we will not have to burden type-1 diabetics with accelerometers (in addition to pump(s) and a CGM), because the extra information they provide is not needed.
3. Or, one could say that existing algorithms and accelerometers are not good enough, and we need to develop better ones in order to take advantages of this information.
4. Or, one could sort of split the difference, and say that most people don't need accelerometer data (as also supported by the good BG numbers reported by other AP tests which don't use them). However, for serious athletes who do need this extra data, we need to develop better algorithms (or accelerometers), if we are going to successfully use this data. 
5. Or, we can view this research as answering the question "how much physical exertion is needed before an AP needs exertion data to work well?"  The idea is that, of course at some level of vigorous exercise, accelerometer data will be needed.  This trial just shows that the soccer exercises wasn't enough, and we need to do something even more vigorous until it does matter.

No matter which interpretation appeals to you, we are still very early in the testing of accelerator enhanced APs.  I'm sure there will be more clinical trials before there is any consensus on the proper way to integrate accelerator data into APs.  

Interview with Dexcom

Here is a two part interview with the CEO of Dexcom, a big CGM maker.  He talks about future development, both in terms of CGMs for APs and CGMs as a replacement for finger sticks.  I found part 2 more interesting than part 1, but here are links to both:
http://www.meddeviceonline.com/doc/how-dexcom-plans-to-eliminate-the-finger-stick-and-bring-cgm-to-the-masses-part-one-0001
http://www.meddeviceonline.com/doc/how-dexcom-plans-to-eliminate-the-finger-stick-and-bring-cgm-to-the-masses-part-two-0001

Another Summary

Here is another writer's summary of artificial pancreas progress for 2014.
http://www.medpagetoday.com/Endocrinology/GeneralEndocrinology/49342

Homebrew Artificial Pancreas

As Dave Berry used to say: I'm not making this up!

This project is being called "Hacking an Artificial Pancreas" or "DIY Artificial Pancreas", but in the tradition of Silicon Valley, I would called it "Homebrew Artificial Pancreas".  It looks like we have reached the point where people can cobble together a functional AP in their garage.

You can see pictures here (two quite different paths):
https://scottleibrand.wordpress.com/2014/12/15/how-does-a-closed-loop-artificial-pancreas-work-when-you-diy-or-diyps-closed-loop-is-working/
http://circles-of-blue.winchcombe.org/index.php/2015/01/11/wearenotwaiting-thanks-to-dexdrip-introduction/
https://twitter.com/stephenistaken

If you speak twitter: #DIYPS #WeAreNotWaiting #dexdrip

Less than $100 in parts. A little soldering (sometimes).  What could possibly go wrong?

When Steve Jobs and Steve Wozniak made the Apple I they were basically making something that they could not buy, and that's what these guys are doing.  Of course the Steves were not replacing  an organ of the body.

I want to thank Dominik for sending me this. I will never look at a Raspberry Pi the same way, again.

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.

ADA 2014: Type-1 Diabetes Cure Research, Artificial Pancreas

At the 2014 ADA Scientific Sessions, there were several reports on progress on artificial pancreas (sometimes called "closed loop").  Unfortunately, all of them were reported on a day that I was not at the convention, so the information below is mostly from the printed materials at the convention, news reports, and convention "buzz".

The "Bionic" Pancreas:
Bihormonal, Closed Loop, Artificial Pancreas Progress

This was clearly the big news of the scientific meeting.  Here is my previous coverage on this (and it includes links to DiaTribe's more complete coverage):

http://cureresearch4type1diabetes.blogspot.com/2014/04/the-bihormonal-artificial-pancreas.html

Bihormal refers to supplying both insulin and glucagon (so it can raise or lower a person's blood glucose).  Closed loop artificial pancreas refers to automatic dosing as needed with data from a CGM to a pump without human intervention.  Bionic is a marketing name used by Dr. Damiano's group at Boston University.

There were two big publications on the Bionic AP.  The first was in a scientific journal, published the month before the show, and the second was a presentation at the show.

First, I'l discuss the study published just before the show.  The basic set up was that people wore the devices for one day of calibration, and then two days of data collection.   Data was collected for four groups: adults and adolescents, and people who signaled when they were going to eat a meal, and those that didn't.  No one counted carbs or dosed in response to meals.  The signaling group just told the AP that they were about to eat a breakfast, lunch or dinner; nothing about the content.

Group	Average BG	Estimated A1c	% in range   (70-180)
Adults Before Treatment		7.3
Adults who signaled meals	132	6.2	80
Adults without meal signaling	142	6.7	70
Adolescents Before Treatment		7.9
Adolescents who signaled meals	162	7.3	68
Adolescents without meal signaling	175	7.7	60

What this means, is that for adults who did not signal when they were going to eat, they had an average BG level of 142, a likely A1c level of 6.7 (if they had done this for 3 months), and their BG levels were in range 70% of the time!  Now, that looks pretty good, but the news gets better.

Here are the results from the follow up study, done by the same researchers, and given as a scientific talk.  This study was "free range" adults who were free to roam over 3 square miles of Boston, staying in a hotel, working out at a gym, and eating mostly at restaurants, while the adolescents were attending camp.  For this study, no one signaled meals.  It included 20 adults and 32 adolescents, which makes it phase-II sized by my reckoning.

This study has only two data points that matter:

Average BG Number   (for both adults and adolescents)	Estimated A1c
138	6.4

There was slight complexity in the data.  That 138 number was the average over all five days of the test.  The researchers expected that the first day would be worse than the other four, because the unit was calibrating itself to the patient the most during that first day.  For adults, this worked out, the next four days average BG was 133 suggesting that long term use would result in an even lower number, and might even drop a few more points (over time, as the AP better learned how the person reacted to insulin, glucagon, and food).  But for adolescents, that's not what happened.  They averaged 147 over days 2-5.  Even if 147 (A1c of 6.7) is the long term number, that is still a complete success.   It is lower than the ADA standard of 7.5 for adolescents.  But it is a mystery to me why those days should average higher than the first day.

Summary of NEJM data: http://www.nejm.org/action/showImage?doi=10.1056%2FNEJMoa1314474&iid=t02

Note: information for this section came from an ADA abstract, a JCEM paper, and a NEJM abstract.   You can read the whole NEJM article here:
http://www.nejm.org/doi/full/10.1056/NEJMoa1314474#t=articleTop
JCEM abstract here:
http://www.ncbi.nlm.nih.gov/pubmed/24483160

Single Hormone vs Bihormonal Artificial Pancreas
A group from Canada gave a talk where they directly compared injected insulin, an insulin AP, and an insulin and glucagon AP.  For average BG numbers, they found that both types of APs were similar to each other (the dual pumps were only very slightly better), and that they were both significantly better than injections.  However, when they looked at low BG events, then the dual hormone APs had significantly fewer such events than single hormone APs.  This makes sense, since the dual hormone pumps can directly prevent lows by dosing glucagon.

So this Canadian trial suggests that a bihormonal AP might do a little better than a "classic" AP, but it should not do vastly better, if measured by average BG.  When I first saw that poster, I was a little dubious.  Two hormones seemed like much better technology than one.  But then I saw the results below.  One of the complexities, is how does one measure an AP?  Using average BG is easy and straightforward, but should we also measure low BG events and/or high BG events?  If you do (especially low BG events), then the dual hormone APs might look better in comparison.

The Cambridge Artificial Pancreas

With all the excitement about the bihormonal AP, it is important to remember that there are also several "classic" AP projects out there.  For example, the results from the Cambridge AP, a "classic" insulin-only AP, were almost as good as the bihormonal results.  There were something like 7 presentations on various aspects of this project, so it was very well represented.

The "24 hours a day" trial included 17 people, and ran for 16 days (8 days with AP and 8 days with regular treatment).  They also reported on a nighttime only trial, which ran for 90 days!  Again, half with AP and half with regular treatment.

It's big results that matter, from the 24 hour and day trial, are:

Average BG Number   (for both adults and adolescents)	Estimated A1c
146	6.7

MD-Logic Artificial Pancreas Project

What's better than two closed loop, artificial pancreas projects?  Three!  The MD-Logic project uses a "fuzzy logic theory algorithm" to predict insulin dosing.  The research group presented a poster, which showed that using the MD-Logic AP at night, improved BG numbers the next day.  This clinical trial included 24 people and lasted for 3 months (6 weeks using the AP, 6 weeks not, for comparison).

People who used the AP woke up about 15 points lower (on average) than people who did not use it. Looking at all the BG numbers the next day, people who used the AP the night before had an improvement of about 11 points on average.  People who did not use the AP were in range about 66% of the time, while those not using the AP were in range about 62% of the time.  (Range was 70-180).

Source is poster 949-P.

The Virginia Artificial Pancreas

This is another ongoing research project into a "classic" artificial pancreas.  In the trial reported on at ADA 2014, 13 people were tested for 42 hours: 14 hours "open loop" treatment, and 28 hours of "closed loop" treatment.  People in the trial could move about a hotel.  This same research group is planning a 2 month trial of the same AP.

Source is poster 954-P and 104-LB.

Direct Comparison

Group	Average BG Estimated A1c	Size	Adolescents?	Duration	AP Use
Boston University	138 6.4	53	Yes	5 days	24 Hours/Day
Cambridge	146 6.7	17	No	8 days	24 Hours/Day
MD-Logic		24	Yes	90 days	Night Only
Virginia	135?	13	No	2 days	24 Hours/Day

When you look at that, you might say the two hormones are better than one.  But I would not read too much into that difference.  It's not huge (8 BG points and 0.3 A1c), and remember that the single hormone solution is simpler all the way around: only one hormone to buy and load into the pump, less moving parts on the device, and so on.  (Not to mention the fact that Glucagon hasn't yet been approved for this application, although that is expected.)  Of course, the comparison is based on average BG, so might miss extra low BG events in the single hormone APs.

None of this competition bothers me in the least.  I love the idea of having four closed loop systems getting to market at about the same time with slightly different feature sets.  Having a bihormonal AP with slightly better control competing against a single hormone AP which is slightly simpler, sounds like just the sort of competitive situation that feeds progress in a capitalist economy.

Other Bits and Pieces

Poster 75-LB compared CGM data from actual BG data (measured using laboratory grade equipment) from blood pulled directly from a vein. They found that CGM data was very similar to the actual BG data, and that even when different, the differences were small. The researchers conclude that existing CGM technology is not the "weakest link" of AP technology.

Poster 747-P asked people who were testing a closed loop AP, what they thought of it. They liked it. They liked it because it provided better BG control, reassured them that nothing bad would happen while they slept, and improved BG control the next day.  Poster 110-LB contained similar information, but focused on the remote monitoring of an AP in a family situation (ie. parents remotely monitoring children).  A major conclusion of this research was that families wanted the AP/remote monitoring combo being tested; it did not need any improvements at all, it just needed to be made available.

Poster 948-P tested a closed loop system using diluted insulin compared to regular insulin, for small children (aged 4-7).  They found that diluted insulin worked a little better.  Average BG levels were the same, but time spent in range was 8% higher when diluted insulin was used.

Poster 951-P tested a closed loop system which (in addition to BG data) also used energy expenditure and galvanic skin response data.  These are two measures of energy use.  The hope was that by using energy expenditure data, they could make a better AP.  However, the data showed very little difference between using this data and not, and even this little difference was only when BG was above 250.

Summary

My summary of closed loop, artificial pancreas research is this:  We are seeing cure level control in phase-II clinical trials and for several different AP systems.  This is great news, for several reasons. First, it means they "only" need to get through phase-III trials (and marketing approval) for these APs to be sold in the US. They don't need to do better than the results they already have, just produce the same results in larger trials. Second, it means that if one falls apart, there are others which can still get marketed. Third, it means that the technology is ready. When one AP is successful, that team might just be ahead of the rest, but if four groups can do it, that means the technology is here for all.

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 Tidepool 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 (May)

This post is a collection of interesting items that have not yet made it into clinical trials, or which were unsuccessful in previous clinical trials, but are still being worked on.  These are not aimed at a cure.

Comparing Three Continuous Glucose Monitors

This is the summary of a study aimed at comparing CGMs:

The Navigator and G4 Platinum had the best overall accuracy, with an aggregate mean absolute relative difference (MARD) of all paired points of 12.3 ± 12.1% and 10.8 ± 9.9%, respectively. Both had lower MARDs of all paired points than Enlite (17.9 ± 15.8%). Very large errors (MARD > 50%) were less common with the G4 (0.5%) than with the Enlite (4.3%) while the number of very large errors with the Navigator (1.4%) was intermediate between the G4 and Enlite.

Full Study: http://dst.sagepub.com/content/early/2014/04/21/1932296814532203.full.pdf+html%20


New Treatment Option for Type-1s?

LX4211 is an experimental drug designed to cause people to pee out more sugar than normal.  It is designed to cause people to need less insulin at meals, because they can get rid of more sugar by urinating it out.

Quote from the news:

Lexicon said the drug, codenamed LX4211, reduced the total dose of insulin taken by patients at meal times by 32 percent, compared with a 6 percent reduction in patients given a placebo.

News: http://www.reuters.com/article/2014/04/14/us-lexicon-pharm-diabetesdrug-idUSBREA3D0KB20140414

Discussion
When I first heard of this I thought it was a "cheap trick" and not particularly important.  But using 32% less insulin at mealtimes (which is probably about 16% less in total), is a pretty big effect, so it is at least interesting.  I would be even more interested if it improved A1c or BG numbers, since those are directly correlated with better health.  Also, the people in the study had "poorly controlled" type-1 diabetes, but the exact level of control was not stated in the clinical trial record. So it is important to see what happens with people whose control is normal or average.

This drug has been (or is being) tested in a total of 12 clinical trials; one of which is on type-1 diabetics specifically.  The type-1 test was on 36 people.  The study says that people in it must be "willing to refrain from using carbohydrate counting to adjust insulin during the study".  I'm not sure what is going on with that, but if they require people to change their insulin dosing regime as part of the study (and especially to not count carbs), that is certainly something where details matter.

There is a diagram describing how this drug works on the company's web page (but the rest of the page is mostly about type-2):
http://www.lexgen.com/pipeline/lx4211.html


Enzyme Based Artificial Pancreas

This is another way of making an artificial pancreas that uses chemistry rather than electronics. Unfortunately, it looks to me like they are many years away from even starting human tests, and once those start, they are still many more years away from availability.  Still, it is a good idea, and the more different paths to a cure that are being worked on, the better.

News: http://phys.org/news/2014-04-mechanobiology-enzyme-micropump-autonomously-insulin.html

Bi or Tri Hormonal Artificial Pancreas
The link below is to a company trying to develop a tubeless bi or even tri hormonal artificial pancreas.  Sounds interesting, but I can't tell when the website was last updated.  One of the items is a job listing, and it contains the following two quotes:

The CoreMD and "wedges" electronic hardware designs have already been completed. You will work closely with hardware and software engineering senior management in fine-tuning and prototyping (SLA) its pumping mechanism design, making re-design suggestions to save power/space, and capturing that design in SoliWorks. You will then test the SLA and re-design it if needed.  [Which sounds pretty good.]

We are looking for volunteers willing to work "pro bono" (free of charge) [Which does not sound good at all.]

http://pancreum.com/index.html

Serova

Below is an update on Serova's Cell Pouch.  It looks like they had good results on the very early testing, and expect to spend the rest of 2014 getting more, similar data.  They are still testing with immunosuppressive drugs, and obviously, this gets a lot more interesting when they stop using those.

http://online.wsj.com/article/PR-CO-20140422-903834.html

New Delivery Mechanism

The link below reports on another "cured in mice" experiment. This was done by combining GAD-65 IL-10, and an anti-CD3.  (I'm not holding my breath on that getting into human trials; not with the problems GAD65 and anti-CD3s have already had.)  However, I was interested in the dosing method.  They modified (possibly via genetic engineering) a safe bacteria, which is commonly found in the gut, to generate two of the drugs they gave.  This sounds like a very interesting and broadly useful technique, if they can control the dosing sufficiently.

http://diabetes.diabetesjournals.org/content/early/2014/03/25/db13-1236.abstract?papetoc

INGAP Continues

INGAP is a beta cell growth hormone.  It was tested on type-1 diabetics and did not have positive results.  The news article below, which reports on a high school science project, reminds me of two things:

First, some researchers never give up.  Some of them are so committed to their discoveries, that they will continue to work on them even after there have been significant failures in clinical trials. This probably is a good thing; we want researchers who are "all in" and willing to push things as far as they can possibly go, even in the face of failure.  Those are the kind of researchers who will get the eventual cure into our hands.  However, it is important to remember just how committed they can be, when evaluating what they say.

Second, it is always shocking to me just how far technology has gone, in terms of letting younger people do more serious research.  Lab equipment has gotten easy enough to use, and cheap enough to use, so that high school students can do more serious research than they ever could before, and that has to be a good thing.

http://www.montrealgazette.com/news/Montreal+teen+awarded+diabetes+research/9757443/story.html

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 Tidepool 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.

The Bihormonal Artificial Pancreas

This posting focuses on one specific type of artificial pancreas (AP), called a bihormonal artificial pancreas, or sometimes a "bionic pancreas".  As with all artificial pancreas discussion, some people don't think these devices are a cure (they are just treatment methods), while others do consider them a cure.

Many months ago, I attended a CarbDM event, where Dr. Ed Damiano discussed recent testing of bihormonal artificial pancreas.  (CarbDM is a support group for families with type-1 diabetes, which operates in several cities in Northern California, including San Francisco, San Jose, and Sacramento.  If you live there, you should see what they're doing: http://carbdm.org/.)  Anyway, as soon as I heard the presentation, and the great results, I knew I needed to blog on it.  But there was never time, and it got pushed out, and now it's six months later.  My bad.

The good news is that diaTribe has published really good summaries of Dr. Damiano's work, so I encourage you to read their postings now, and then come back to finish reading this posting:

http://www.diatribe.org/issues/62/conference-pearls

http://diatribe.org/issues/55/test-drive

http://diatribe.org/issues/59/new-now-next/1

(Brief digression on diaTribe www.diatribe.org: It is a free news service covering diabetes (both type-1 and type-2) which was spun off from Close Concerns, which is a commercial news service covering diabetes.  DiaTribe is a great source of news, because they are covering in depth something they understand very well.  They do their own analysis, so they are not just mindlessly reprinting other people's press releases, which is common from other news sources.)

Now, back to the bihormonal artificial pancreas:  The bihormonal artificial pancreas delivered a level of control (without human intervention) good enough to be called a cure.  The estimated A1c numbers were 6.2 in one study and 6.6 in the other.  The average BG numbers were 133 and 142.   At the same time, the number of BG measures below 60 was lower when using the bihormonal artificial pancreas.  So they had better control and fewer lows.

What is a Bi-hormonal Artificial Pancreas?

Artificial Pancreas refers to a pump / continuous blood glucose monitor / computer combination that controls blood sugar automatically based on data from the monitor.  All of these are existing technologies, but used together in a new way.  It is also called the "closed loop".  Bi-hormonal refers to using both insulin and glucagon.  So a bi-hormonal AP can give both insulin and glucagon, based on blood sugar levels, to automatically keep a person's blood sugar levels in range, using existing hardware technology.

The current bi-hormonal AP is composed of a G4 CGM, two T:slim pumps, and iPhone hardware that has had the phone software removed and replaced by software to control the pumps.  The current experimental prototype sounds "clunky" in the extreme.  Basically, you are wearing two pumps and a CGM device.  There are three separate sets, etc.

Take a look at this photo (hosted on diaTribe's site), to see just how "clunky" and crowded it is:

A "classic" AP is insulin only, so it can lower blood glucose, but not raise it.  A person eats sugar to raise their BG levels, but the AP doesn't control that.  A bi-hormonal AP can both raise and lower a person's BG levels, so it can have much better control.

As I said before, the current blood glucose control, as seen in already completed clinical trials, is spectacular.  In my opinion, it is good enough for a cure right now, even if they don't improve it at all moving forward.

What's the Plan Moving Forward?

The plan is to do one large, multiple site clinical trial on adults who work in hospitals and have type-1 diabetes.  The goal of this study is to have people living their normal lives, including going to work, and using the bihormonal AP, and yet be close to medical help, for trial safety.  I think of this as being a large phase-II trial.  This trial will use the current "prototype" hardware.

Next, the researchers will develop the real hardware: the hardware they expect to sell, and use that to run two large phase-III ("pivotal") trials.

The lead researcher, Dr. Ed Damiano, is totally committed to getting this device on the market by 2017.

Discussion

So the big question is, will it be on the market by 2017?  And the answer is "no one knows".  But nobody likes that answer, so there is rampant speculation, starting right here.  In my opinion, there are several risks to the 2017 date:

• Glucagon.  A bi-hormonal pump needs glucagon which can stay in the pump for 3 days, and longer would be better.  Current glucagon is not stable for long periods of time, which is why you mix a powder with water just before injecting it.  People in the current studies had to refill their glucagon every day, so that it was fresh and active when used.  That's ok for testing, but not in real use.  There are two mitigation strategies, for this risk: First there are two companies who are trying to get FDA approval for long lasting Glucagon right now.  If either one gets approval before 2017, the problem is solved.  Second, even if this problem is not solved at all, early users will need to refill glucagon each day, which is a hassle, but can be done.
• FDA Approval.  For APs this has not been predictable.  The Medtronic Veo took 31 months, after it had been approved in Europe!  However, the phase-II trials show a level of BG control much better than existing pumps or insulin injections. I would expect the phase-III trials to be even better, and therefore there will be strong data to help the FDA grant approval.  Plus (as with the Veo) I assume that patient advocacy organizations, such as JDRF, will be willing to launch a publicity program to "help" the FDA move forward.
• Business Issues.  The bihormonal AP will need a company behind it, to become reality.  Type-1 diabetics are not going to buy a research project, and insurance will not pay for one.  So there must be a commercial company that builds, markets, and sells these things.  There are several ways this could happen: they could create a new company to build and sell a bi-hormonal artificial pancreas, or they could form a company which owns the intellectual property (patents and fabrication know-how).  That company would then either licence an existing pump manufacturer to produce bihormonal APs, or sell itself to an existing pump company, which would then own the necessary patents to make bihormonal APs. In any case there is risk, but it is the "normal" risk of commercial development, not the extra risk of scientific research.
• Engineering Issues.  This bi-hormonal pump is a integration of several different components: two pumps, two hormones, a computer algorithm, a controller, a CGM, etc.  None of this is really new technology, but the current schedule assume that putting it all together will happen quickly and without a serious issue cropping up.  But there is always the risk of one of these issues cropping up, at the worst possible time.

But Is It A Cure?

I think that each of us has to decide for themselves what is a cure, and what is not.  So I'm not going to tell you this is a cure, or this is not.  (I am going to ask that you not write me nasty emails saying I'm an shill for even talking about APs as a possible cure: just because you don't think they are a cure, doesn't mean that everyone agrees with you.  All kinds of different people read this blog.)

When I talk to people, most of them accept an implanted (internal) AP as a cure for type-1, however if you take that same functionality and carry it outside the body, then most people do not consider it a cure.

The bi-hormonal prototype (ie. the thing they are testing now) requires the user to check blood glucose only to calibrate the CGM.  It requests that the user tell it about meals, but does not require any carb counting (the user clicks a button to say breakfast, lunch, or dinner).  The user does need to refill the insulin every 3 days, and during testing, refill the glucagon every day.   However, the researchers expect long lasting glucagon to be available as part of the commercial product.

In testing done so far, about 2/3s of the meals were actually warned by the user.  In the other 1/3 of the cases, the user forgot or didn't bother.  So the numbers above include failure to warn 1/3 of the time.  The researcher estimate that if the users never warned of a meal, that their average BG numbers would rise about 10, and the average A1C would rise about 0.1.

Abstracts on papers for the bihormonal artificial pancreas:
http://www.ncbi.nlm.nih.gov/pubmed/24224750
http://www.ncbi.nlm.nih.gov/pubmed/23602044

Here is a link to diaTribe coverage long storage Glucagon:
http://diatribe.org/issues/59/new-now-next/4#!

Clinical Trial Records for these studies:
http://clinicaltrials.gov/ct2/show/NCT00811317
http://clinicaltrials.gov/ct2/show/NCT01161862
http://clinicaltrials.gov/ct2/show/NCT01762059
http://clinicaltrials.gov/ct2/show/NCT01833988

Let me leave you with a diagram showing what happened to a group of people on the bihormonal artificial pancreas.  Notice that every single person ended up with an average BG between about 100 and 150.  My slogan for this diagram is "no diabetic left behind".  Even the guy who started out averaging over 220, ended up in range:

(Note: this diagram comes from a children-with-diabetes page which is collecting tax deductable donations for this research: http://cwdfoundation.org/BionicPancreas.html.)

Other Bi-hormonal Artificial Pancreas Projects

The only other research that I know of into bihormonal APs is being done in Europe, and is called the "PCDIAB" project.  You can read about it here:
http://pcdiab.eu/
and see a related clinical trial record here:
http://clinicaltrials.gov/ct2/show/NCT01916265


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 Tidepool 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.