Encellin Starts a Phase-I Trial of ENC-201-CED (Encapsulated Beta Cells)

The company Encellin has started a Phase-I clinical trial to test ENC-201-CED an encapsulated beta cell product.

Encapsulated Beta Cells In General

Encapsulated beta cells are implanted devices.  The encapsulation allows blood sugar in, and insulin out, but does not allow the body's immune system to attack the beta cells. It also allows nutrients in and waste products out. This allows the beta cells to naturally grow and to react to the body's sugar by generating insulin which goes into the body's blood system. Meanwhile, the body's autoimmune attack cannot target these beta cells, and you don't need to take any immunosuppressive drugs (as you would for a normal beta cell transplantation).  The cells inside the encapsulation can come from different sources, depending on the company creating the product.

Encapsulated beta cells seem like a straight forward cure for type-1 diabetes, but companies have been working on them since the 1990s, without creating a cure.  There appear to be several difficult problems to solve, especially getting oxygen to the new cells.   Bottom line is this: while encapsulated beta cells sound like a "just needs engineering" cure for type-1 diabetes, decades of work has not led to a cure yet, so it is obviously harder than it looks.

I have blogged at least 10 times over the last 15+ years on different encapsulated beta cell approaches:

https://cureresearch4type1diabetes.blogspot.com/search/label/Encapsulated%20Transplant

This Study

This study will recruit 10 people between 18 and 70 years old.  Everyone will get the treatment.  There is no control group.  Everyone will be followed for about 4 months.  This is strictly a safety/tolerability test.  They are measuring adverse effects and how well the implant takes.  They are not measuring effectiveness.  Even in the secondary outcome measures there are no tests for A1c, Blood glucose, C-Peptide, or time in range.

The study started in March 2024 and they hope to finish in December 2025 and publish by July 2026.

Other than that, their clinical trial registry is very sparse, and I cannot find any information on the trial on the web site of the hospital which is actually running it.  Therefore, I don't know the exact requirements to participate in the study, how many operations are required, what sort of immune suppression is being used (if any), or how man encapsulated beta cells (or devices) will be implanted.

Contact Information:

Study Contact: Phone: +1-650-434-0987  Email: info@encellin.com

Study Contact Backup: resCON Research  Email: info@resconresearch.ca

They are recruiting at one site:

McGill University Health Centre Montréal, Quebec, Canada, H4A 3J1

Contact: Lin Jawhar

Principal Investigator: Steve Paraskevas, MD

Clinical Trial: https://www.clinicaltrials.gov/study/NCT06408311

Discussion

I usually don't comment on company funding because I have found that it doesn't matter who funds research.  Sometimes big name companies fund failures and people I've never heard of fund successful research.  However, I will say that Encellin is mostly funded by Khosla Ventures, which is a big name in Silicon Valley venture capital.  Also, Encellin was incubated by Y-Combinator, which is a big name "factory" of Silicon Valley start ups.  These guys would be Silicon Valley royalty, if Silicon Valley had royalty.

Company's Web Site: https://www.encellin.com/

History

About 7 years ago, there was a lot of excitement about research done at Tejal Desai's lab at UCSF.  Several people asked me about it and at least one person lobbied for me to write a blog on it.  There was widespread hope that this research would lead to a cure in a few years.  There was widespread belief that it would lead to clinical trials sooner than that.

I didn't blog on it because my policy is to wait until recruiting has started on a clinical trial (a test done on people).  Seven years ago, all we had was very optimistic press releases.  But now, finally, this clinical trial is the follow on to Tejal Desai's work all those years ago.  They have started a clinical trial on this technology and so I'm blogging on it.

Remember this when you are frustrated because some research that you heard very positive things about never seemed to go anywhere.  First, a lot of very positive sounding research never does go anywhere.  That is the normal nature of research.  Second, even when it does, it takes many years.  The successful out come still takes many years.

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 kid has type-1 diabetes and has participated 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 (September)

Unsuccessful Phase-I Clinical Trial of Beta-O2's Encapsulated Beta Cells 

Encapsulated beta cells are implanted devices.  The encapsulation coating allows blood sugar in, and insulin out, but does not allow the body's immune system to attack the beta cells. It also allows nutrients in and waste products out. This allows the beta cells to naturally grow and to react to the body's sugar by generating insulin which goes into the body's blood system. Meanwhile, the body's autoimmune attack cannot target these beta cells, and you don't need to take any immunosuppressive drugs (as you would for a normal beta cell transplantation).  I previously blogged about this trial here:
https://cureresearch4type1diabetes.blogspot.com/2014/11/beta-o2-starts-phase-i-trial-and-update.html

Unfortunately, they published unsuccessful results last year.  To quote their abstract:

Implantation of the βAir device was safe and successfully prevented immunization and rejection of the transplanted tissue. However, although beta cells survived in the device, only minute levels of circulating C-peptide were observed with no impact on metabolic control. 

Encapsulated beta cells have been an active area of research for over 20 years.  Currently ViaCyte and Sernova are both active in clinical trials in this area, and there are other contenders testing in animals.

Abstract: https://www.ncbi.nlm.nih.gov/pubmed/29288549
Full Paper: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055594/
Clinical Trial Record: https://www.clinicaltrials.gov/ct2/show/NCT02064309

The Phase-II? Clinical Trial of Ladarixin Is Fully Enrolled

Ladarixin targets two specific immune system chemicals: IL-8a and IL-8b. The idea behind this trial is that suppressing this part of the immune system will stop the autoimmune attack which causes type-1 diabetes.  I previously blogged about this study here:
https://cureresearch4type1diabetes.blogspot.com/2016/08/ladarixin-starts-phase-ii-clinical-trial.html

This study finished recruiting in June-2018, and they now expect to complete in Oct-2019.
Clinical Trial Record: https://www.clinicaltrials.gov/ct2/show/NCT02814838

Fully enrolled is an important milestone for two reasons.  First, because it is now possible to predict when they will finish collecting data.  Second, because much of the uncertainty that surrounds clinical trials, is involved with recruiting participants.  It is often unclear how hard it will be to recruit people, and how long it will take.  But that this point, all that uncertainty is behind the researchers.  From now on, it is just gather data, then analyze data, and then publish data.  Researchers have a lot more control over those later stages, then over recruiting people in the first place.

Coffee In Pilot Clinical Trial To Improve Renal Function

I will not be following this trial, because it is aimed at long term complications of T1D, not a cure.  But it sounded like so much fun, I'm mentioning it here.  Apparently caffeine changes renal (kidney) function in some unique ways which are not duplicated by other drugs.  The researchers think that a coffee in the morning might improve kidney function in a way that helps people with T1D.

They are testing this in teenagers (12-21 years old).  It is a 10 person, open label, no control group trial, which is enrolling by invitation only.  You need to already be participating in a different trial (called "CASPER") to get invited.  They drink Starbucks® cold brew every morning for 6 days.  Kidney function will be tested on the 7th day.  No word on the Peet's® version.

Clinical Trial Registry: https://clinicaltrials.gov/ct2/show/NCT03878277

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.

Dropping Four Research Programs

Every year in September or October I write a blog posting which summarizes all research being done in humans, aimed at curing type-1 diabetes.  That blog is going to be published in 2-4 weeks.   While putting that blog together I have found several research projects which I should not cover any more, and I'm listed those here, with a brief note on why they are no longer of interest.

I understand that this posting is a downer, and I'm sorry for that, but it is important to know what studies are no longer looking promising, and why.  Research naturally gets a lot of press when there is good news, but it's important to keep track of the bad news, and the "no news is bad news" situations as well.

Dendritic Cell Therapy  (DV-100) by DiaVacs
This trial was supposed to start in 2013, but never did.  The company is working on a follow on product, DV-200, and when that starts clinical trials I will follow it.  But since there has been a five year break between DV-100 and DV-200, I'm going to wait until a trial actually starts before restarting coverage.

BCG by Faustman at Harvard
This research is being removed for two reasons:

• Her phase-II trial is not using C-peptide data as either a primary or secondary outcome.  C-peptide is the standard measure for progress to a cure, so not having it as a primary or even secondary outcome means this research is no longer "aimed a curing type-1 diabetes".  (I will continue to follow it, and especially any C-peptide data that comes out, but unless C-peptides are a primary or secondary outcome, it is not cure focused for me.)
• The phase-I trial extended results show that Dr. Faustman's original theory (the TNF theory) of how BCG might cure type-1 diabetes is wrong.  The paper said specifically that the theory did not explain the results seen, and presented a new theory.  However the new theory is based on how the body digests carbs (not regenerating beta cells), and therefore is not a cure focused theory.  (Indeed, several type-2 diabetes treatments are based on similar theories).  So even if this theory is correct, the result would be treatment, not cure.

Obviously, this research group is continuing to talk about curing type-1 diabetes, but one the rules of my blog is "Actions speak louder than words" and if the clinical trial is not focused on C-peptide data, I don't think they are focused on a cure, no matter what is said.

Rilonacept by White at University of Texas

This group published their phase-I results in June 2018, but they were unsuccessful: "Rilonacept treatment for 6 months is well-tolerated in individuals with T1D of recent onset, but is unlikely to be efficacious as a single agent in preserving beta cell function."  So I don't expect any follow up work.

The Sydney Project (Encapsulated Stem Cells)
I can not find any recent references to this project.  The closest I can find is an encapsulated stem cell project being funded by the Australian Foundation for Diabetes Research.  It is doing animal research right now, so not 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, JDCA, or Bigfoot Biomedical news, views, policies or opinions. In my day job, I work in software for Bigfoot Biomedical. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Diabecell Research Closes Out (With Comments on Encapsulation In General)

Diabecell is an encapsulated pig beta cell treatment aimed at curing type-1 diabetes.  This research started in the 1990s, and was part of a group of encapsulated stem cell cures which were developed at the same time by different companies/research groups.  Most of the others ended in the late 1990s and early 2000s, but LCT continued and is still operating today.  I've blogged many times on this research: https://cureresearch4type1diabetes.blogspot.com/search/label/LCT

The last two running studies on Diabecell were marked as "completed" in October 2017.  The most recent clinical trial started in 2011, and published some results in 2016, but they were not strong.  Since it has been two years since their last results, and they have not started a new trial in that time, and also because the results of their trials have been lack-luster for years before that, I'm going to drop them from active coverage here.

Discussion

This should serve as a cautionary tale for all encapsulated beta cell cure research.  There were at least 4 companies trying to cure type-1 diabetes this way in the 1990s, and it looks like all of those were unsuccessful.  There was another crop of these in the 2000s, and most of those have been unsuccessful as well.  (Although Viacyte, founded in 1999 as Novocell, is still in active development and may yet cure type-1 diabetes.)  More recently, in the 2010s there has been another batch of start ups in this area (Dr. Melton's Semma Therapeutics, Beta-O2 Technologies, etc.), and also an even larger batch of new academic research (such as recently reported at Cornell, UCSF, etc.)

I'm positive about all this research. I'm positive about all research aimed at curing type-1 diabetes. I hope it all works. I hope any of it works (because it only takes one cure). However, I do think it is important not to get to overly excited about encapsulated beta cell research (even as it sounds straight forward), because it's obviously more complex than it sounds.

Especially, it is clear to me that the hard part is the encapsulation part, not the beta cell part.  The pig beta cells used by LCT generate the insulin that people with type-1 diabetes injected for decades (from the 1920s to the 1970s).  Those cells work just fine, so LCT's problems are encapsulation.  Other companies have used human beta cells from cadavers.  Those cells worked just fine for their previous owners, which reinforces my belief that the breakthrough that makes encapsulated beta cells successful is going to be on the encapsulation side, not the beta cell sourcing side.

Recent Clinical Trial Records:
https://clinicaltrials.gov/ct2/show/NCT01736228
https://clinicaltrials.gov/ct2/show/NCT01739829
https://clinicaltrials.gov/ct2/show/NCT00940173

Academic encapsulation research in the news:
http://news.cornell.edu/stories/2018/01/removable-implant-may-control-type-1-diabetes
https://www.ucsf.edu/news/2017/10/408731/innovative-type-1-diabetes-approach-licensed-encellin


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.

ViaCyte Clinical Trial News: VC-01 is Fully Enrolled, VC-02 Starts

This blog posting covers two important pieces of news from ViaCyte.

ViaCyte's Phase-II Trial of VC-01 is Not Recruiting
(But What does that mean?)

I missed this news, when it was announced back in May 2017, but ViaCyte's Phase-II clinical trial of VC-01 is not recruiting more people.  I'm not sure if this is a "pause" between their phase-I group and their phase-II group, or if they have finished recruiting all people for both groups.  That's important because they are gathering effectiveness data for six months.  So whatever group they finished recruiting in May, they should have effectiveness data in November.  Effectiveness data for 15 people would be good, but from the full 65 people would be even better.  Since this trial is not blinded (and has no control group), they could publish their data as soon as they have it, if they want to.

Also, they are gathering safety data for two years, so that same group will finish gathering safety data in May 2019.  The same "15 people is good 65 people is better" and "with no control group, they can publish if they wish" applies to this safety data as well.

Clinical Trial Registery: https://clinicaltrials.gov/ct2/show/NCT02239354

Differences Between ViaCyte's VC-01 and VC-02 Treatments

ViaCyte has started a clinical trial for their VC-02 stem cell implantation product, but as this treatment is not a cure (by my definition of "cure"), I will not be following it.  Don't mix up VC-02 with their earlier VC-01 product.  VC-01 is a potential cure, and I will follow it moving forward.

I found this confusing: why would a company test a non-cure after they had a cure already in the pipeline, and ahead of the non-cure?  Why even bother with the non-cure?

While VC-01 and VC-02 are encapsulated stem cells, the nature of the encapsulation is completely different.  VC-01 uses a "strong" encapsulation which prevents the body's immune system from attacking the new cells. This prevents both the normal rejection (ie. the foreign organ reaction), and type-1 rejection (ie. the malfunctioning autoantibody reaction) from attacking the new cells.  Therefore, VC-01 does not require anti-rejection drugs.  VC-02 uses a "weak" encapsulation which holds the stem cells together and in one place, and encourages new blood vessels to integrate into the encapsulation, but provides no immune protection.  People getting VC-02 will need to take anti-rejection drugs [d1].

Both VC-01 and VC-02 have the same cells inside.  They both start with ViaCyte's PEC-01 cells. These are created by harvesting human embryonic stem cells from a long-existing culture and treating them so they differentiate into pancreatic cells.  The cells that are inside the devices are these pancreatic cells.   (There are no "raw" stem cells in the device.)  This process is described on ViaCyte's web site here:
http://viacyte.com/technology/stem-cell-engineering/

The obvious question is, why would any person with type-1 diabetes choose to be in the VC-02 trial, if they could be in the VC-01 trial?  The immunosuppression required by VC-02 has known bad side effects, and there are known risks in taking those drugs for decades.

First is that the VC-01 trial is not recruiting right now.  So if you want an encapsulated ViaCyte stem cell treatment right now, VC-02 is your only option.  I don't know if the VC-01 trial is completely enrolled, or if it will open up again, to gather a second group of patients.

Second is this: The ViaCyte team believes that the reason some implanted beta cells work and some fail is "vascularization".  Vascularization is the body's ability to grow blood vessels into the new beta cells so that they can get oxygen, remove waste products, and generally integrate with the host person.   ViaCyte believes that the encapsulation used in VC-01 will allow this vascularization and therefore be successful.   However, they also believe that VC-02 will have even better vascularization, and therefore an even higher chance of success.  So if someone currently has type-1 diabetes, they may choose to have VC-02 because it has a higher chance of success (even if this is a trade off against a known higher risk from the treatment).

The VC-02 Study

Although there is only one official clinical trial of VC-02, there are two patient groups within this trial (which they call "cohorts"), and these cohorts are really separate phase-I and phase-II trials. It's just that one clinical trial registry covers both. The first cohort will be 15 patients, all of whom will get a low dose version of the treatment. The second cohort will be 40 patients, all of whom will get a higher dose version of the treatment. There is no control group. They expect to finish the second cohort in Dec 2020.

They are collecting their primary safety data at 4 months post transplant, and primary effectiveness data (C-peptide data) at 6 months post transplant.

They are recruiting at two sites:

• University of California San Diego, San Diego, California, United States, 92121
  Contact: Study Coordinator    1-844-317-STEM (7836)    alphastemcellclinic@ucsd.edu
• University of Minnesota Recruiting, Minneapolis, Minnesota, United States, 55455
  Contact: Study Coordinator    612-626-4993    kreel001@umn.edu

Clinical Trial Registry: https://clinicaltrials.gov/ct2/show/NCT03163511
ViaCyte's FAQs: http://viacyte.com/clinical/faqs/

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 (March)

ViaCyte Starts A Three Year Follow-up Safety Study in Subjects Previously Implanted With VC-01™
This clinical trial is studying people who were part of ViaCyte's clinical trial of VC-01™, an encapsulated beta cell cure.  Once the device is removed at the end of the study, the patients can enroll in this follow on study which tracks them for three additional years, looking for adverse effects.

ViaCyte is a commercial company testing an encapsulated beta cell cure.  You can read my previous blogging about them here: http://cureresearch4type1diabetes.blogspot.com/search/label/ViaCyte
They are in the middle of a large Phase-I study, which could finish as early as 2020.

Clinical record: https://clinicaltrials.gov/ct2/show/NCT02939118

Discussion

I'm hopeful that this means that one person has finished the ViaCyte protocol, which is motivating them to start this follow on.  The other option is that they are just planning ahead.  Since there is no control group, the interim data could be published, if ViaCyte wanted.

Two Phase-I Studies Start with Umbilical Cord Treg Cells 
These two studies have a lot in common, so I'm going to discuss them together: first, their similarities, then their differences. Here are the similarities:

• They are both run by the same researcher (Dr. Zhiguang Zhou) at the same hospital (Second Xiangya Hospital of Central South University).
• They recruit at the same place: Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China, 410011
  Contact: Zhiguang Zhou, MD/PhD    86-731-85292154    zhouzg@hotmail.com
• They have already started recruiting 40 people, and expect to finish in 2019.
• These trials are open to people who have been diagnosed within 3 years and are between 6 and 60 years old.
• Each has a primary end point which is safety related, and secondary endpoints which are effectiveness related and include C-peptide, A1c, insulin usage, etc.
• Both studies will work with stem cells which have been harvested from umbilical blood, separated into components, and had the T-reg cells "grown out" for two weeks.  These enriched T-reg cells will be infused into patients.  T-reg cells are regulatory cells which are part of the immune system, and work by controlling other immune cells so that those other cells don't attack beta cells.

The first study is Safety Study and Therapeutic Effects of Umbilical Cord Blood Treg on Autoimmune Diabetes: This study will have two groups, one will get the treatment, and one will be a control group and will not get the treatment.

Clinical trial registry: https://clinicaltrials.gov/ct2/show/NCT02932826

The second study is Safety and Efficacy of Umbilical Cord Blood Regulatory T Cells Plus Liraglutide on Autoimmune Diabetes: This study has four groups.  One will get the treatment and also Liraglutide, another just the treatment, a third just Liraglutide, and a fourth will be a control group.  Liraglutide (sold as Victoza) is similar to exenatide (Byetta), which is a common type-2 medication, but is also sometimes used on type-1.  Victoza is a weekly injection. 

Clinical trial registry: https://clinicaltrials.gov/ct2/show/NCT03011021

Discussion

The researchers are not clear on why they are using Liraglutide, but site its "various benefits for beta cells". They expect it will increase the effectiveness of the new T-regs, possibly by encouraging beta cell growth.

JDCA's Update on Dr. Faustman's Research

An update on Dr. Faustman's BCG research by the JDCA (Juvenile Diabetes Cure Alliance) is here:
http://eepurl.com/cHrGqX

My key takeaway points are:
* The Phase-II trial should finish in 2023.
* They have enrolled 125 out of the 150 they need.
* An 8 year follow up from their Phase-I trial should be published by the end of 2017.

(Remember, I am a fellow of the JDCA and we regularly discuss various research programs, including this one.)
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.

Beta-O2 Starts a Phase-I Trial (and an update on encapsulated beta cells generally)

Introduction to Encapsulated Beta Cells

Encapsulated beta cells are implanted devices.  The encapsulation coating allows blood sugar in, and insulin out, but does not allow the body's immune system to attack the beta cells. It also allows nutrients in and waste products out. This allows the beta cells to naturally grow and to react to the body's sugar by generating insulin which goes into the body's blood system. Meanwhile, the body's autoimmune attack cannot target these beta cells, and you don't need to take any immunosuppressive drugs (as you would for a normal beta cell transplantation).  The cells inside the coating are human beta cells, and different companies get their beta cells from different sources.

Beta-O2 Starts a Phase-I Clinical Trial

Beta-O2 is starting a phase-I clinical trial of their "ßAir Bio-Artificial Pancreas" (encapsulated beta cell) device as a possible cure for type-1 diabetes.  The devices itself is similar to other encapsulated beta cell devices (ie. Diabcell by LCT, Encaptra by ViaCyte, etc.) with one important difference: the device is injected with oxygen once a day.  This is a manual step performed by the patient.  The company claims it will take about 2 minutes, and provides pictures of the device used, which looks like a needle attached to tubing.  You can read about the device here: http://beta-o2.com/living-with-sair/

The clinical trial is pretty standard for a phase-I trial: 8 people will use the device for 6 months, and be followed for an additional 6 months.  They will test for safety and effectiveness (C-peptides, Insulin usage, and A1c numbers), and hope to finish in March 2016.

The clinical trial is being run by the Uppsala University Hospital.  Contact information is: Per-Ola Carlsson, MD, PhD  Phone number:  +46 18 4714425  Email:  Per-Ola.Carlsson@mcb.uu.se.  This trial is for adults with long established (5 years or more) type-1 diabetes.  One unusual requirement for this trial is that patients must start out using 1 unit of insulin per day per kilo of weight (or less).

The clinical trial is expected to cost about US$ 1 million, with JDRF paying for half.

Press release: http://www.fiercemedicaldevices.com/press-releases/first-patient-successfully-implanted-safetyefficacy-study-beta-o2s-air-bio
Clinical Trial Record: http://clinicaltrials.gov/ct2/show/NCT02064309

Other Encapsulated Beta Cells Research Underway

Interest in encapsulated beta cells seems to be cyclical.  When my daughter was first diagnosed, about 10 years ago, encapsulated beta cell devices were a strong area of research.  But one by one, most of the devices failed.  We then went through several years with only one company (LCT) in human trials.  Now, however, interest appears to be picking up with a new generation of human trials underway.  Here is a quick summary of the encapsulated beta cell devices that I know of:

Beta-O2: Just started a phase-I clinical trial.
Viacyte: Just started a phase-I clinical trial.
LCT: Has been doing phase-II trials for several years, but has not made any forward progress (in terms of better results), in years.
Hospital St. Luc research project: Completed (?) a phase-I trial, but not sure about any progress recently.
AZ-VUB: In phase-I, but I don't know any details.
DRI Biohub: Started clinical trials for infrastructure for such a device, but still using immunosuppression.
Sernova: Started clinical trials for infrastructure for such a device, but still using immunosuppression.
Islet Sheet Project: In animal testing.
Harvard Project: In animal testing (?).
Chicago Diabetes Project: Still using immunosuppression.
Nuvilex: Starting animal testing soon.

In my opinion, these are a lot of different research groups, all focused on the same type of cure.  For me, that's good news, because it suggests that many people believe this technology is ready to lead to a cure.  And that makes me optimistic.  Unfortunately, previous "waves" of encapsulated beta cell devices did not lead to a cure, so that makes me nervous.

Background Information

http://en.wikipedia.org/wiki/Cell_encapsulation
https://www.landesbioscience.com/pdf/HunkelerPDF.pdf

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.

VC-01 by ViaCyte Starts a Phase-I Clinical Trial

Some people are horrified at the idea of curing diseases by using embryonic stem cells.  If you are one of those people, stop reading now!  This posting is all about curing type-1 diabetes using human embryonic stem cells.  In the future, you should skip over all my blog postings with the tag VC-01 or ViaCyte.

ViaCyte (previously known as Novocell) has started a phase-I clinical trial for their encapsulated beta cell product, which is called VC-01.  This device is designed to cure type-1 diabetes.  The encapsulation coating allows blood sugar in, and insulin out, but does not allow the body's immune system to attack the beta cells. It also allows nutrients in and waste products out. This allows the beta cells to naturally grow and to react to the body's sugar by generating insulin which goes into the body's blood system. Meanwhile, the body's autoimmune attack can not target these beta cells, and you don't need to take any immunosuppressive drugs (as you would for a normal beta cell transplantation).  The cells inside the coating are human beta cells, grown from human embryonic stem cells.   Here is the company's official diagram:

This Trial

This trial will enroll 40 adults who have had type-1 diabetes for over 3 years.  There is no control group, but some people will get two implants while others will get 4 or 6 implants.  C-peptide will be measured after 6 months, and safety issues will be tracked for 2 years.  They hope to finish in August 2017.

Patients are being recruited now in San Diego, California, USA, and they plan to add more locations in the future.

Clinical Trial Record: http://clinicaltrials.gov/ct2/show/NCT02239354
ViaCyte Page: http://viacyte.com/products/vc-01-diabetes-therapy/
Twitter Traffic: https://twitter.com/hashtag/viacyte

Discussion and Opinions

Encapsulated beta cells seem like a straight forward cure for type-1 diabetes, but companies have been working on them since the 1990s, without creating a cure.  There appear to be several difficult problems to solve, especially getting oxygen to the new cells.   Bottom line is this: while encapsulated beta cells sound like a "just needs engineering" cure for type-1 diabetes, decades of work has not led to a cure yet, so it is obviously harder than it looks.

Finally, ViaCyte is very well funded.  In the last few months, they have gotten over $16 million from CIRM, $20 million from Johnson and Johnson, $5 million in venture capital, and half a million from JDRF.

Similar Work

LCT's Diabcell is similar to ViaCyte's VC-01, in that they are both encapsulated beta cell devices. They do use different encapsulation coatings, and Diabcell uses pig beta cells, while VC-01 uses beta cells grown from human embryonic stem cells.  LCT has been tested in people for over 6 years, and is currently in phase-II trials.  (At one time it had approval to be sold in Russia, but it never was sold there.) There is also a device being tested at the University Clinical Hospital Saint-Luc in Belgium, which uses human beta cells (from cadavers) and a different encapsulation coating. 

Several organizations are doing animal tests on various encapsulated beta cell devices.  These include Cerco Medical, Beta-O2, DRI, and several more.

Finally, several organizations are doing human tests on beta cell devices which are not (yet) encapsulated, but they hope to encapsulate in the future.  DRI is doing work like this, as is Serova.  If beta cells are not encapsulated, then you must take immunosuppressives for the rest of your life, so I don't consider those a cure, yet. However, if they then progress to the point where immunosuppressives are not needed, then they would be a cure.

Terminology Note

Some of the news coverage refers to VC-01 as an "artificial pancreas", however I only use that term for electro-mechanical devices.  I use the term "encapsulated beta cells" for devices like VC-01.  You might also hear people refer to it as a "bioartificial pancreas".

If you care about the stem cell production method, here is the company's diagram:

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.

Successful Case Study of New Encapsulated Islet Cell Device

Research topics ebb and flow over time.  I remember when my daughter was first diagnosed 10 year ago (was it really that long ago?) that encapsulated beta cell research was all the rage.  Then it seemed to die off, just leaving Living Cell Technology (LCT) in the field.  Now it seems to be heating up again.

Successful Case Study of New Encapsulated Islet Cell Device

Background

Encapsulated  beta cells are one potential cure for type-1 diabetes.  Beta cells are wrapped in a protective coating and are put in a person.  The coating allows blood sugar in, and insulin out, but does not allow the body's immune system to attack the beta cells. It also allows nutrients in and waste products out. This allows the beta cells to naturally grow and to react to the body's sugar by generating insulin which goes into the body's blood system. Meanwhile, the body's autoimmune attack can not target these beta cells, and you don't need to take any immunosuppression drugs (as you would for a normal beta cell transplantation).

Encapsulation research started in people in the 1990s.  The current leaders in the field are LCT, in phase-II human trials, and University clinical Hospital Saint-Luc and The Sydney Project who have both done phase-I trials.  Plus there is Sernova, the Islet Sheet Project, Viacyte (and probably several more) in animal research.

This Study

These researchers (who I will call "the Dresden group") have published a case study.  A case study report on a single person, so it's not a clinical trial.   For this person, they implanted some human beta cells (from a cadaver) encapsulated using their own alginate technology [d1], and added an oxygen infuser (which had to be reloaded every day) [d2].  The researchers implanted 2k cells / kg, which is about 1/5 of what they expect to need to cure someone.  It is very common in phase-I trials to give a very small amount of whatever you are testing, in order to check for safety.  They monitored insulin usage, and measured C-peptide levels every three months.  After 10 months, they removed the capsule and ran some tests on it.

Results

C-peptides in Response to Carbs
One way to test the effectiveness of this device, is to give the patient some sugar, and see if they generate insulin (by measuring C-peptide levels) in response to that sugar.  These researchers tested the patient once every three months, and the data is shown in the graph below:

Notice that all three response lines are pretty much the same [d3].  That is very positive news, because it means that the implanted beta cells worked just as well after 9 months as after 3 months. Previous encapsulated beta cell treatments have degraded over time, and the results after 9 months would be noticeably worse than after 3 months.

Insulin Usage Before and After
Prior to implantation, this patient used about 52 units of insulin per day.  After the implantation he used 43 units.  That's a drop of 17%.  For the first human trial, with a dose much smaller than expected for a cure, that's a very promising result.  It is especially interesting that by transplanting about 1/5 as many cells as they expect to need, the patient required almost 1/5th less insulin.  That might be coincidence, or it might foreshadow more good news to come.

Fasting C-peptides
These measured about 0.04 nmol/L on average.  The MedScape normal range (ie. non-diabetics) is about 0.26-1.03 nmol/L, so these guys were well below normal.  But again, for a first case study, with a small dose of islets, this has promise.

Moving Forward

This research needs to move forward in three ways, and hopefully they can move forward in all at the same time.  First, they need to run an actual clinical trial (ie. get more people treated).  Case studies just don't attract the same attention as clinical trials, nor should they.  One important next step for this research program is to implant this in 6-20 people and see what happens.  The second step is to implant more beta cells, and the third is to find a better way to supply oxygen to the cells.

For this case study, they implanted about 2k/kg cells.  They believe that about 10k/kg cells will need to be implanted to cure type-1 diabetes.  If you look at the insulin requirements for the patient, they dropped just below 20% after implantation.  So the next big question is, if you give more beta cells, do they generate more insulin, in proportion?  If so, that is very important.

Discussion

These researchers are using human cadaver beta cells and a proprietary alginate encapsulation technology, but of which have been done before by others.  However, they are also doing something unique, which is oxygenating the cells.  They hope that providing extra oxygen will make the cells work better and survive longer.  The trade off is that the oxygen generation system requires daily maintenance.

The obvious research to compare this to is LCT's "Diabcell".  In LCT's most recent clinical trial (a Phase-II trial), they implanted  a total of 10k/kg cells in 4 patients and 20k/kg cells in 4 patients.  The higher dose group saw a 20% drop in insulin usage. LCT did not report on the durability of this result.  So we don't know if they continued to use 20% less for months, or if the effect went away relatively quickly.  So the most recent LCT results and the Dresden results are very similar, except that these researchers reported on durability and the LCT researchers have not, and the Dresden team used far fewer cells.

In addition to the possibility of being a cure by itself (especially if the oxygen supply issue can be solved), this research is also important for what it tells us about encapsulated beta cell longevity in general.  If bigger trials show the same durability (that the cells continue to work for a long period of time), that strongly suggests that the problem that causes encapsulated beta cells to die over time is a lack of oxygen.  So that means that everyone trying to create encapsulated beta cell cures will know to concentrate on the oxygen supply.  Although this might not be new news to researchers: I remember  David King (Islet Sheet developer) talking about the importance of oxygen supply years ago.

News articles: http://health.usnews.com/health-news/news/articles/2013/10/28/scientists-report-transplant-advance-for-type-1-diabetes
http://idw-online.de/pages/de/news558740
General link on encapsulation: http://en.wikipedia.org/wiki/Cell_encapsulation

Extra Discussion

[d1] Alginate is a general term that covers all (or almost all) of the recent encapsulation techniques.

[d2] One important question is: how long is the oxygen generator used?  The paper makes it sound like it was used for the whole 10 months that the device was in use.  However, one of the researchers was quoted as follows:

For that reason, the current version of the device had an oxygen port on the outside of the body attached via tubing that had to be refilled daily by the patient for as long as a month or two, Block explained.

Source: http://health.usnews.com/health-news/news/articles/2013/10/28/scientists-report-transplant-advance-for-type-1-diabetes
and that implies the oxygen generated is only needed for a short time.  Since the generator needs to be refilled each day, and that is a hassle, this duration is important.  I did ask the researchers how long the oxygen generated was used for, but had not heard back at the time I finished this posting.

[d3] Different people view this data differently.  I tend to see them as all being about the same, but at least one person (Celsus, on islet.org) thinks that the 3 month is stronger, because it ends stronger.  However, when I look at the whole graph, I think they are all similar.  The official way to make the comparison is AUC "area under the curve", and I don't think the researchers did that math.

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.

Encapulsated Beta Cells and Sernova

This blog contains two parts.  The first is a general update on encapsulated beta cells as a possible cure for type-1 diabetes, and the second is some background and an update specifically on Sernova corporation's work on encapsulated beta cells.

General Update on Encapsulated Beta Cells
The basic idea, is that you take working beta cells and wrap them in some kind of barrier (called "encapsulation"). It must allow nutrients and sugar to flow into the beta cells, and insulin to flow out of the beta cells, but must stop the body's immune cells from getting to the beta cells.  So it must not be a complete (impermeable) barrier, but a "smart" or partial barrier.  The beta cells generate insulin in response to blood sugar.  Because they are encapsulated, the body's own immune system can not attack them.  This means both that the body's broken autoimmune attack does not kill off these beta cells, but it also means that the body's natural attack on any transplanted organ doesn't happen either.  These are both good things.

For more background, the Dec-2011 Countdown (a JDRF Publication) has a good article on Encapsulation: http://countdown.jdrf.org/Features.aspx?id=8589934725
Obviously, it focuses on JDRF's work, but it also contains a lot of the history, complexities and past problems of using encapsulated beta cells to cure type-1.  The discussion of past problems is important.  Many people seem to assume that since encapsulation sounds like a good and simple idea, it is a good idea and simple to implement.  However, different researchers have been working on this idea for over 20 years, and a cure has not been forthcoming.  So obviously, it is not as simple as it sounds.

Below I discuss status for all the encapsulated beta cell projects that I know of.  The basic summary is that one commerical company and two academic teams are in clinical trials now:  LCT is in phase-II trials and the others are phase-I, by my standards.  Sernova hopes to start clinical trials this year, but not on encapsulation directly, and the rest are in animals trials.

Status of LCT http://www.lctglobal.com/
LCT has completed a phase-I clinical trials in Russia, and has one ongoing in New Zealand.  They have also started a third clinical trial in Argentina.  At one time, they were hoping to have commercial availability in Russia in 2011, but that did not happen.  Results in people have been mixed.  A small number of people have been cured for short periods of time, and most people see improvement in their  BG control.

Status of AZ-VUB  http://clinicaltrials.gov/ct2/show/NCT01379729
This is academic research with human beta cells.
A 10 person trial, started in 2011 ends in 2013, but then patients will be followed until 2018.

Status of Université Catholique de Louvain http://www.clinicaltrials.gov/ct2/show/NCT00790257
A 15 person trial, started in 2008 and running until 2013.

Status of Sernova http://www.sernova.com/s/Home.asp
I discuss this more below, but Sernova hopes to start phase-I clinical trials in the first half of 2012 [d1].
They have already completed large animal trials.
Recent Interview: http://aheadoftheherd.com/Newsletter/2012/Ahead-Of-The-Herd-With-Sernova.html

Status of Cerco   http://www.hanumanmedical.com/  http://www.hanumanmedicalfoundation.org/type-1-diabetes-research.html
These guys are doing large animal studies now, and hope to start human trials in 2013 [d1].

Status of ViaCyte  www.­viacyte.­com
These guys are using putting embryonic stem cells into their encapsulation, which is different than the other research teams listed here, who are mostly using pig cells.  These guys have cured mice and are doing animal safety studies now, and hope to start clinical trials in 2013 [d1].
Interview: http://www.diabetesmine.com/2012/01/whats-up-with-diabetes-stem-cell-research-firm-viacyte.html

Status of Nuvilex    Cured In Mice! Nuvilex
These guys are "cured in mice".  We'll need to see what happens in people.

Background on Sernova

Sernova has a long and interesting history, which I summarize here:

It has been known for a long time, that the body's immune system does not have complete coverage within the body.  For example, the immune system is not good at attacking viral infections in the eye (for example)[d2].  One of the things that the body's immune system does not attack is your own sperm cells (or egg cells).  If you think about it, these two cells have a different genetic makeup then your body, and they might be identified as foreign invaders and attacked by the immune system.  However, this does not happen.   For sperm cells, the body has special cells, called Sertoli cells, that  are located next to the sperm cells and prevent the immune system from attacking them. [d3]

So, long ago (about 15 years) and far away (Mexico) a transplant surgeon named Rafael A Valdes-Gonzalez decided to implant into people a mixture of Sertoli cells and beta cells from pigs.  The Sertoli cells would protect the transplanted beta cells from the body's immune system. (See [d4] for discussion on pig cells, and [d5] for discussion on ethical apprvoals.)  Dr. Valdes-Gonzalez thought he was on the track to a cure, and published some promissing results [r1], but others were not so sure [r2].  Also, the standards for exotransplantation were still being created, and no where near as well formed as now.  So there was some controversy [r3].

So, when it was time to start a larger, more carefully controlled clinical trial, to resolve the doubts about the effectiveness of the treatment, the local trial review board did not give it's approval.  They pointed out that the current standard was that animal studies (preferably large animal studies) should be done prior to human studies (to assure a basic level of safety and a reasonable chance of success).  These studies had never been done.  Dr. Valdes-Gonzalez  was a transplant surgeon who was not focused on running animal trials.  As far as I know, the Mexican project has not made a lot of forward progress since then.  However, at one time around 2004, they were "open for business" at about US $35k for the operation[r4].  I don't know what the current status is.

Obviously, a lot of people were unhappy about the lack of forward progress.  One of these people was Dr. White, a Canadian researcher.   He decided to develop the Sertoli+Beta cell treatment, starting from animal trials, and worked with Sernova corporation to do so.

Sernova is working on two related projects.  The first is a pouch system which holds transplanted cells together in one place (but does not encapsulate them, there is no barrier involved).  The second is the Sertolin(tm) system, which is designed to use Sertoli cells to prevent an immune attack on the transplated cells.

Here is a quote from their web page:

Sernova, is developing two novel closely integrated proprietary platform technologies. The first is the Cell Pouch System™, a scalable device providing a natural "organ-like" environment for therapeutic cells such as insulin producing islets for diabetics and the second is Sertolin™, a cell-based technology providing an immune-privileged environment for donor cells, reducing or eliminating the need for anti-rejection drugs.

Also, their home page includes two video presentations and a power point presentation which describe what they are trying to do.

Sernova has announced that they hope to start phase-I trials for their Cell Pouch System in the first half of 2012[d1], so that is great news.  But it is limited news.  By itself, this provides no immune barrier, so it's not even part of an eventual no-rejection drug cure.  Is just a step in that direction.  Sernova has said that they are hopeful that if the pouch is successful, it means that in the future only local immune suppressive drugs would be needed.  Because the beta cells would be limited to one specific place, immune suppressive drugs would only be needed right there, also.  Since local immune suppression is safer and has less side effects than whole body immune suppression, but there's no way to know if the difference will matter.

Extra Discussion

[d1] When I use the phrase "hope to start clinical trials in ..." that means that the company or organization has said that publicly.  It does not mean it will happen; nor does it mean that I think it will happen.  Researchers in general have a strong tenancy to think they will start human trials much sooner than they actually do.

[d2] and some researchers at DRI are experimenting with transplanting cells into the eye, specifically to take advantage of this, but no human trials as yet.

[d3] After reading this, you might ask yourself, why bother with transplanting the beta cells at all?  Why not just put Sertoli cells right next to existing beta cells, and then they would protect the beta cells from the autoimmune attack.  People are working on that:
http://t1dcuredinmice.blogspot.com/2009/10/sertoli-cells-by-fallarino-at.html
but it has not progressed to human trials, yet.

[d4] The insulin generated by pig cells does work in humans.  For decades, humans injected pig and cow insulins as standard treatment.  It is only in the last 40 years or so that we have used human insulin from genetically engineered bacteria.  Prior to that, it was all animal origin insulin.

[d5] I've read several different accounts of the ethical approvals that this research had, and what it needed.  My belief is that it did have the proper approvals from the proper authorities at the time that it started, although some have claimed that the ethical approvals were lax.

References

Here are a link to PubMed references for all of Dr. Valdes-Gonzalez's work:
http://www.ncbi.nlm.nih.gov/pubmed?term=%22Valdes-Gonzalez%20R%22%5BAuthor%5D

[r1] The good results:
Three year follow up: http://axacell.com/uploaded/Publication%20Three%20-yers%20May%202007.pdf
Four year follow up:  http://www.eje.org/content/153/3/419.full.pdf+html
Long term follow up: http://www.ncbi.nlm.nih.gov/pubmed/20964645

[r2] I doubt this is a complete list of the doubters:
http://www.eje.org/content/154/6/917.full

[r3] This is not a complete list on the controversy, but enough to get you started:
http://www.ualberta.ca/~dcl3/Ref_2007-Aug-17/islet%20transplantation/islet_xenotransplantation_are+we+ready+for+clinical+trials.pdf
http://www.nature.com/nature/journal/v419/n6902/full/419005b.html
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)09285-1/fulltext
http://www.lancet.com/journals/lancet/article/PIIS0140-6736(02)09287-5/fulltext

[r4] http://eprints.qut.edu.au/3449/1/3449.pdf

Finally.....

I found this on the JDRF's "For Scientists" web site about encapsulation in general:
http://www.jdrf.org/files/General_Files/For_Scientists/MS2011/FY12_Encapsulation_Consortium_RFA_11.16.11.pdf


Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
My Blog: http://cureresearch4type1diabetes.blogspot.com
Mouse blog: http://t1dcuredinmice.blogspot.com/

LCT To Start Phase-I Human Trial in New Zealand

LCT has (finally) gotten government approval to start a phase-I human trial of their DiabeCell product. This is an encapsulated pig pancreas treatment for type-1 diabetes. The New Zealand government has promised this approval months ago, after years of dragging their feet, and now has finally made good on it's commitment. However one important limitation has been put on the trial: only so-called "brittle" type-1 diabetics can be enrolled.

Although LCT is downplaying the importance of this limitation, it has the potential to delay the end of the trial still further. Previously, almost any type-1 diabetic could take part in the trial, so it was easy to find patients to participate. But now, only "brittle" type-1s can participate and that will doubtless cause delays in recruiting participants. "Brittle" diabetics are those diabetics who's BG can drop very quickly. These are the guys who can pass out while driving, or regularly end up in the hospital after collapsing.

Limiting the study to brittle diabetics should make for better results, because these guys have the worst control, and therefore should see the biggest improvements. So from that point of view, it is a good thing. However, it will also slow the trial and delay completion, which is not good.

I view limiting the study to brittle diabetics as 100% political ass-covering (please excuse the language). I think the New Zealand minister of health had delayed so long, that he simply could not just say "yes", because he could have (and should have) done that months ago. So by forcing a change -- any change -- he can claim that the delay was for a good reason. But it's a pointless restriction, and totally unjustified. Pancreatic transplants, which have huge side effects are limited to brittle diabetics, but these encapsulated transplants have basically no side effects, when compared with whole organ transplants. Putting the same restrictions on the patients for one as for the other is really a farce.

LCT has previously started a phase-I human trial in Russia, and so far, 7 people have been treated as part of that study. Some have been treated more than once, and data has been publicized. Some patients in that study were insulin free for a period of a few weeks. I felt the overall results suggested that the treatment did work, but that the implants stopped working just a few months after they were implanted. Others were a lot more excited about these results than I was.

I can not find a USA Clinical Trial record for this work (probably because it is being done in New Zealand), and the information I've read in the press about the experiment make it sound like a repeat of the Russian human trial. Eight patients, for example. Hopefully they will at least use larger doses, so they can learn something new that way.

While getting permission to run this trial is a step forward, I'm not exactly sure how it leads to general availability of the treatment. It is the second phase-I study started, but no phase-II study is planned (that I know of). In the past LCT had talked about a phase-II study in Denver, but when the economy got into trouble a few months ago, they stopped talking about that, and laid off at least one of the key people involved in it. So overall, I'm happy to see them do another study, but I'm also waiting for some information on how they plan to get from phase-I trials (which they have done and are doing) to general availability of the treatment.

Joshua Levy