Islet Cell Transplantation Clinical Trails

In this blog I'm going to report on three different clinical trials involving transplantation.  The basic idea for all of these is to transplant beta cells into someone with T1D, and those new beta cells will produce insulin and cure the person.  As I describe below, this idea has been around for 40 years, but it has not been successful in the past because of two problems: First, the body's immune system attacks the transplanted cells because it is working properly and they are foreign cells.  Second, the body's immune system attacks the new cells because it is broken and mistakenly attacks beta cells.  Some people think there is a third problem: beta cell supply, but personally, I'm less worried about that.  These three trials all attack these problems in different ways.

VX-880

A lot of people are excited about this trial because it is generating headlines like "Vertex VX-880 Clinical Results Lead To Insulin-Independence".  This is not a lie, but it is highly misleading.  I discuss the problems with transplants which require immune suppression below (and VX-880 requires immune suppression).  However, it is important to understand that these are not recent improvements.  Transplantation trials have been getting results like this for a long time.

Another reason people are excited about this study, is because the beta cells used here are created from stem cells, and therefore there is an unlimited supply available, and a lot of control over how they are made.  Previous studies used beta cells harvested from cadavers or from pigs, each of which has its own problems of supply. 

For over 20 years islet transplantation  have led to many people not needing to inject insulin for many years (search for "Edmonton Protocol" with Google).  These are the same results seen in VX-880.  They are not seen as a cure, because of the bad effects of immune suppression drugs, which are required, and which must be taken for the rest of the person's life, and because they only work for a few years.  Typically, people do not need to inject insulin for 5 or 10 years, but then they do again.  So headlines reporting on no injecting insulin a year after a transplant are nothing new.

This trial is currently running, but I'm not covering it as a potential cure for T1D.  It requires each person to take a full suite of immune suppression drugs to support the transplant.  They will need to do this for their whole lives, even if the transplant only works for a few years.  Furthermore, the drug combinations used for transplants have significant bad long term side effects, causing health problems in their own right.

Therefore, I view transplants that require life long immune suppression to be trading one drug treatment (T1D) for another (Immune Suppression), and not a cure.  At this point, I'm not even sure which is more dangerous, more hassle, and has more side effects.  

Of course, in medicine, things change over time.  In the future immune suppression may become easier and safer and I might revisit this decision, but until then, for me transplants requiring immune suppression are not cures.  

Clinical Trial Record: https://www.clinicaltrials.gov/study/NCT04786262

VX-264 (Phase-I)

For me, VX-264 is much more interesting than VX-880, even though they both use the same cells, because it does not require life long immune suppression.  In VX-264, the islet cells are encapsulated in a special, high tech membrane.  The membrane allows nutrients and sugars in, and wastes and insulin out, but blocks immune cells.  This is possible because nutrients, sugar, waste, and insulin are all relatively small, while immune cells are relatively large.

This study will enroll 17 adults and everyone will get the treatment (no control group), so I consider this a phase-I trial.  Everyone will have established T1D for at least 5 years.

The outcomes of this trial are a little complex.  Early in the study they will focus on adverse events (side effects) for a total of 2 years after the transplants, but later they focus on C-peptides 3 months after the transplants.  The secondary endpoints include C-peptides, insulin use, and A1c numbers for 2 years after transplant.

They expect to finish in mid 2026.

If successful, this would allow islet transplantation without immune suppression, and that would be a cure for T1D. 

They are recruiting at several locations in the US and Europe.  You can contact them at medicalinfo@vrtx.com or 617-341-6777, or look in the Trial Page or the "Contacts and Locations" section of the clinical trial record, which has an interactive map of the study locations.

Trial Page: https://clinicaltrials.vrtx.com/safety-tolerability-and-efficacy-study-vx-264-participants-type-1-diabetes
DiaTribe Article: https://diatribe.org/join-type-1-diabetes-trial-testing-encapsulated-insulin-producing-cells
News Article: https://investors.vrtx.com/news-releases/news-release-details/vertex-announces-fda-clearance-investigational-new-drug
Clinical Trial Registry: https://www.clinicaltrials.gov/study/NCT05791201 

Discussion

This idea of filtering out immune cells, but letting the smaller stuff in and out of the islet has a long history.  Research had already started in the 1980s, and the earliest clinical trials were running in the 1990s.  Obviously, none of those were successful, which suggests to me that the idea is a lot easier to think of than to actually implement.  The English language idiom is "The devil is in the details."  I'm not sure how many transplantation with high tech membrane type clinical trials have been run in the last 30 years, maybe 5 or 10, but certainly none was successful, so it is a hard problem that Vertex is trying to solve.

VCTX211 (Phase-I)

The VCTX211 clinical trial is also avoiding life long immune suppression. It is being run by CRISPR Therapeutics AG, and combines technology from them with stem cells and encapsulation technology from ViaCyte (since bought by Vertex).  CRISPR is powerful gene editing technology which is too complex for me to discuss here, so I don't, but you can see a list of all the different things they hope to do with it, here: https://crisprtx.com/pipeline.

This trial uses the CRISPR gene editing technique to modify the implanted cells so they are invisible to the immune system.  Therefore, they do not trigger the natural immune system rejection of transplanted organs, nor can the autoimmune attack which triggers T1D affect them.  No long-term immune suppression drugs are required. 

ViaCyte is part of a line of companies that has been trying a transplantation cure since the 1990s, the historical line is Neocrin -> Novocell -> ViaCyte -> Vertex.  

This study will enroll 40 adults who have had T1D for 5 years or longer.  They will be followed for 1 year.  Everyone will get the treatment; there is no control group.  The primary end points include side effects and C-peptide generation.  Secondary end points include several of insulin, A1c, and side effect measurements.

They expect to finish in mid 2025.

This trial is recruiting in two locations in Canada: Edmonton and Vancouver.  You can contact them at +1-877-214-4634 or MedicalAffairs@crisprtx.com.

Clinical Trial Registry: https://www.clinicaltrials.gov/study/NCT05565248

Discussion

This study is absolutely huge, both for T1D and for every other transplantation cure in the world.  Right now, most organ transplantation is a big deal, because it requires immune suppression, which has a whole raft of problems and issues associated with it.  If CRISPR can be used to avoid that, suddenly every form of transplantation is going to become a much better, much more common cure than it was before.

The idea that using CRISPR to make stem cells that could be transplanted to anyone has been an active area of research for years now, and here is an article that covers it from 2019:
https://www.ucsf.edu/news/2019/02/413311/crispr-gene-editing-makes-stem-cells-invisible-immune-system
Although I don't believe that this research was exactly the same as what is being tested in VCTX211.

Recent news on CRISPR based treatments of sickle cell disease:
https://www.statnews.com/2023/12/08/fda-approves-casgevy-crispr-based-medicine-for-treatment-of-sickle-cell-disease/
But it is important to note that for this disease, CRISPR is not used to make the cells invisible to the immunological system.  That is why the VCTX211 clinical trial is so important. 

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 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 and CRISPR start a Phase-I Clinical Trial (VCTX210A-101)

For many years, it has been clear that one possible path to a cure is to transplant new beta cells and also in some way prevent the body from rejecting those new, transplanted cells.  Since the 1980s many different companies have tried encapsulated beta cells as a path to a cure.  The idea is that beta cells cure T1D and encapsulation means both that the person does not need to take anti-rejection drugs and that the person's autoantibodies cannot destroy the new beta cells.  Unfortunately, even after 40 years of research done by many different companies, this line of research has not been successful.

The JDRF has a good timeline of their support for stem cell therapies here:
https://www.jdrf.org/blog/2021/11/29/jdrf-timeline-stem-cell-therapies/
Note that they have funded several different research projects, and ViaCyte is just one of them. 

ViaCyte is one of these "old school" beta cell transplantation companies.  They have developed an infrastructure to grow large numbers of beta cells from stem cells.  However, recently they have partnered with a CRISPR company (called CRISPR Therapeutics).  CRISPR is a technology to edit genes.  In this case, they are editing genes in their newly grown beta cells, so that the beta cells are invisible to the patient's immune system.  The hope is that this is going to have two important effects:  First, the body will not reject the transplanted beta cells.  Second, the bodies' autoimmune attack will not be able to target the transplanted beta cells.

Obviously, either one of these effects would result in a huge step forward on the path to curing T1D, and both of them together could result in an outright cure.  This combination is what they have just started testing in a Phase-I clinical trial.

The Phase-I Clinical Trial

This is an open label (no blinding) clinical trial with 10 participants who are adults (18-65 years old) and have established T1D (diagnosed at least 5 years prior).  All 10 people will get the treatment; there is no control group.

The gene edited, stem cell derived beta cells are loaded into a device and then implanted into a person.  The person is then followed for 6 months.   The trial's end points involve safety and several scientific measures of transplant success.  The researchers will check for bad side effects, if the body is generating antibodies against the transplanted cells, and new autoantibodies related to T1D.  They will also see if the stem cells are growing properly.  However, none of the end points measure success in treating or curing T1D.  There are no measures of C-peptides (the body generating its own insulin) or lowered requirements of insulin, or improved A1c. This study is really focused on testing safety and ability to be tolerated, not effectiveness.

Because patients are only followed for 6 months, they hope to run this study from January 2022 to December 2022.  This includes the time needed to recruit the patients and the time to actually run the study on each patient.

This trial is being run in Canada, and you can get more information on participating here:
Contact: Clinical Trials     +1 (877) 214-4634     MedicalAffairs@crisprtx.com

The study locations include:

• University of Alberta,  Edmonton, Alberta, Canada
  Contact: Parastoo Dinyari    +1 (780) 407-1501    parastoo@islet.ca   
  

• University of British Columbia, Vancouver, British Columbia, Canada    
  Not yet recruiting
  

• LMC Manna, Toronto, Ontario, Canada
  Enrolling by invitation

Clinical Trial Record: https://www.clinicaltrials.gov/ct2/show/NCT05210530

Discussion and Opinions

I'm very happy that a company is testing a combination cure, which (in theory) will both generate new beta cells and prevent the autoimmune process from destroying the new beta cells.  This is something I've been hoping for for 10 years. 

Normally, I'd would be happy with the speed of this trial.  Finishing this year means we will get our first data very quickly.  However, this clinical trial is only measuring safety outcomes, not effectiveness results.   Although phase-I trials are sometimes safety only, in T1D research it is normal to include some effectiveness outcomes.  They can give an early signal of success.  Not having effectiveness measures makes the short duration and quick results of this study less important, because (at best) it can only show us the treatment is safe, and not that it actually works (much less, works well).  We might need to wait to the end of the phase-II trial to see if it works, which will be very frustrating. 

Here are two very good articles which cover this clinical trial:

• https://diatribe.org/viacyte-and-crispr-introduce-new-stem-cell-therapy-for-type-1-diabetes
  
• https://www.diabetesdaily.com/blog/potential-type-1-diabetes-milestone-the-first-trial-of-gene-edited-islet-cells-has-begun-696253

And here is the official press release:

• http://www.crisprtx.com/about-us/press-releases-and-presentations/crispr-therapeutics-and-viacyte-inc-announce-first-patient-dosed-in-phase-1-clinical-trial-of-novel-gene-edited-cell-replacement-therapy-for-treatment-of-type-1-diabetes-t1d

Some notes on names and terminology:

• ViaCyte refers to this product as PEC-QT, but CRISPR Theraputics calls it VCTX210 in the press release and VCTX210A in the clinical trial record.
• The stem cells are created using CRISPR/Cas9, which is an improved form of CRISPR gene editing.
• The clinical trial is called VCTX210A-101 by the companies running it, and has the clinical trial registration number NCT05210530.

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.

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.

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

An Encapsulated Human Islet Transplant Cure in Phase-I
For the last many years, I have thought that LCT was the only company actively doing clinical trials on an encapsulated islet cell cure for type-1 diabetes.  However, I recently found this clinical trial record: http://www.clinicaltrials.gov/ct2/show/NCT00790257


These guys are testing human encapsulated islet cells (so not pig cells, as LCT is using).  They started in November 2008 and ending in December 2013, and includes 15 people.  They're doing this one trial in two phases, the first phase is only open to people who have already had an organ transplant (which I'm sure is delaying the study, since it takes a long time to recruit people like that). They call their device a "Monolayer Cellular Device", and the work is being done in Belgium

News on Otelixizumab by Tolerx

I have two tidbits on Tolerx's Otelixizumab.  The first is from news article which was discussing the start of their DEFEND-2 clinical trial, which is a confirmatory phase-III trial.  So that is the last stage before FDA approval.  So, as the quote shows below, Tolerx is starting to look to eventual approval:

If the trial [DEFEND-2] is successful, the company plans to send the drug candidate to the U.S. Food and Drug Administration in 2012.

Obviously that is good news.  For comparison, Diamyd was talking about starting the approval process in 2011, and LCT at one time was 2011, but more recently was 2013.  To the best of my knowledge we have never started the marketing approval process for a non-insulin drug to target type-1 diabetes.  So having three possible starts in the next 3 years is great.  Although that is tempered by the fact that only one of these treatments has been tested on established diabetics, and none of them represents a cure so far.

The other piece of news is a little more technical.  Here is the key quote:

The new research findings support existing data suggesting that otelixizumab may work in patients with new-onset type 1 diabetes by blocking the function of T killer/effector cells that mistakenly attack and destroy insulin-producing beta cells, while simultaneously stimulating T regulatory cells that are thought to protect against future T killer/effector destruction. Clinical data from the recently completed DEFEND-1 Phase 3 study and the ongoing DEFEND-2 confirmatory Phase 3 study will be evaluated in light of these new findings to determine whether this dual effect of otelixizumab is consistent with results from patients who have received otelixizumab.

 Press release: http://www.prnewswire.com/news-releases/tolerx-presents-research-at-european-diabetes-meeting-and-enrolls-first-patient-in-europe-in-the-defend-2-phase-3-clinical-study-in-type-1-diabetes-103610664.html

What this means is that they believe that their experiments show that Otelixizumab works in two different ways.  First, it blocks the bad killer T-cells.  The cells that are directly attacking the pancreas.  Second it increases the actions of the regulatory T-cells, which are cells designed to control killer T-cells.  That is potentially a powerful combination (although it will be interesting to see how long it lasts).  Another interesting piece of data is how selective is it?  Attacking the bad killer T cells is one thing, but it would be even better to NOT attack the good killer T cells.  The press release implies that it is selective, (which would be great) but this is a case where we need to see the numbers, to see exactly how selective it is. 


Both Tolerx (Otelixizumab) and MacroGenics (Teplizumab) Start Separate Subcutaneous Trials
Both Tolerx and MacroGenics are starting clinical trials designed to test their respective drugs when given subcutaniously.   The current clinical trials for both drugs require an IV (drip into a blood vein).  Those can not be done at home.  However, these studies are checking to see if the respective drugs can be injected just under the skin (called Subcutaneously, or SubQ).  That is how insulin is injected.  So if these clinical trials are successful, that means people would be able to inject themselves at home, rather than go to a clinic and have a nurse do it.

These are both phase-I studies and both are still recruiting new patients.
The Teplizumab study has 71 people, and should complete in July 2012, and is honeymoon only.  You must be within 1 year of diagnosis.
The Otelixizumab study has 28 people, and should complete was supposed to finish in July 2010. This study is not limited to honeymoon diabetics, but you must have A1C numbers above 9%, you must generate a little C-peptide.  If the study shows that the drug has the same (or similar) effect when injected like just under the skin as they see with IV drips, then I would love to see how it effects long established diabetics. 

Clinical trial record: http://www.clinicaltrials.gov/ct2/show/NCT01189422 Teplizumab
Clinical trial record: http://www.clinicaltrials.gov/ct2/show/NCT00946257 Otelixizumab

Testing C-Peptides: Fasting as good as Stimulated?
A little background: When your body makes insulin, it also makes a small molecule called C-Peptide.  This is very important to diabetes research, because if a researcher sees insulin in a person's blood, there is no way to know if that insulin came from an injection or from internal production.  However, C-peptide only comes from internal insulin production.  So when someone measures if a drug helps insulin production, what they really do is measure C-peptide.  Years ago the US FDA adopted this standard, so that in order to get a new drug approved to help a diabetic produce more insulin, the drug company must show evidence that the new drug increases C-peptide levels.  (Paradoxically, measuring insulin is considered a second rate way to testing insulin production, because the type-1 diabetic might have injected more insulin for any number of reasons.)  C-peptide is the gold standard of measuring insulin production.


But there are two ways to measure C-peptide: fasting and after a meal (which is sometimes called a "challenge" or "stimulated").  The fasting one is quicker and easier to do (at least for the researchers, the patient may prefer a meal :-) )  But the meal one is considered a better measure of effectiveness.   Basically, a fasting C-peptide measure tells you how well your body creates "basil"  (ie. no food) insulin.  While the meal test tells you how well your body creates "bolus" insulin (in response to food).  The meal one is considered better, but the fasting one is easier.  


The summary of this poster session is that the results of the two different tests are linked.  So that doing a fasting test predicts what will happen for a meal test, and doing a meal test predicts what will happen for a fasting test.  If confirmed by other trials, this will make it cheaper and easier to do clinical trials in the future (especially for large numbers of people) since you will only need to do a fasting test.



Press release: http://www.sys-con.com/node/1544442


Novocell Terminates Encapsulated Islet Transplant Clinical Trial
Years ago, Novocell was developing an encapsulated islet cell transplant cure, similar to LCT, although my memory was that they were using human islet cells, not pig cells.  In any case, the research did not move forward.  They started a phase-I clinical trial in 2005, but in 2006 they stopped recruiting for it.  I think that it has been moribund ever since, but they just (April 2010) officially terminated it.


The company recently changed it's name to ViaCyte, and is working on an encapsulated islet cure called "Pro-Islet".  They are doing animal ("pre-clinical") studies, so I'm not following it as yet.  


http://www.clinicaltrials.gov/ct2/show/NCT00260234

Final End of TT-223
A few days ago, Transition Therapeutics announced the end of clinical research for TT-223:

Transition Therapeutics announced today [17 Sept 2010] that a clinical study of gastrin analogue TT-223 in combination with a Lilly proprietary GLP-1 analogue in patients with type 2 diabetes did not meet its efficacy endpoints. Given these findings, there will be no further development of TT-223.

Press release: http://www.transitiontherapeutics.com/media/news.php

My translation: Even when we mixed it with another drug, it still did not work well enough to move forward.

So that's about as dead as you can get.  (Although INGAP went through this same process and was later "reborn" by the original developers who thought it had a future even though their big pharma backers did not.  Those guys are still doing clinical trials of INGAP (renamed Exsulin) and who knows what will happen?)

A little history:
TT-223 was one of the possible cures in existence when I started tracking them on my original web status page.  They were initially funded by JDRF, but then Eli Lily took over development from Transition Therapeutics, the small company that JDRF had funded.  JDRF got it's money back at this point because their funding was no longer needed, and they then reinvested it in something else.  But Eli only continued the type-2 testing, not the type-1 testing.  So almost exactly a year ago I blogged about this, and said that TT-223 was dead as far as a cure for type-1 (at least until someone started testing it again in type-1 diabetics).  You can read that post here:
http://cureresearch4type1diabetes.blogspot.com/2009/09/two-possible-cures-go-to-boneyard.html
At that point I stopped following TT-223.  However, an alert reader continued to follow them, and so when they issued the press release above, that reader forwarded it to me.  Thanks!  You know who you are.

Rituximab in the Real World
I have previously blogged on Rituximab (sold as Rituxan):
http://cureresearch4type1diabetes.blogspot.com/search/label/Rituximab
This drug is already approved for use in the US for certain diseases, and there was a recently published article on it's safety as applied to rheumatoid arthritis, which is an autoimmune disease of the same general family as type-1 diabetes.  You can read that here:

News coverage: http://www.medpagetoday.com/Rheumatology/Arthritis/22038
Abstract: http://onlinelibrary.wiley.com/doi/10.1002/art.27555/abstract

This study was based on a registry of over a thousand French citizens who were treated with Rituximab and who were followed up for at least a year.  So this is a much bigger study than the Phase-I study for type-1 diabetics, which was less than 90 people for 1 year. 

There were two interesting results, from my point of view:

First, the overall rate of serious infection was about the same in this trial as it had been in the trials that were used to get approval for the drug in the first place.  That's good news, because those approval trials generally exclude patients who have "co-morbidities" (that is: something else wrong with them).  On the other hand, real world use include patients who have several different diseases.  (Especially rheumatoid arthritis.)  And having more than one disease raises the chance of serious infection, and that is exactly what this study was looking at.  So it is good news that the side effects were no worse for real world use as for experimental use.

Second, the serious infection rate was much higher (about 5 times as high) for people who had "low IgG levels".  So the authors of the study suggest that people getting Rituximab get tested for that before each dosing.  Other co-morbidities that were associated with a higher chance of serious infection included chronic lung disease and/or cardiac insufficiency and extraarticular involvement. (Which are not common in type-1 diabetics, and especially not young ones.)

I think this is good safety news for this drug. Both because it shows it is safe when used "as-is", but also because it provides a clear path to even higher levels of safety via a simple screening process. 

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. 
Blog: http://cureresearch4type1diabetes.blogspot.com
Web: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials