Islet Cell Regeneration and the gene INGAP, Part 9

Date: June 12, 2002
Moderator: Kate Gilbert
Subject: Update on INGAP Research Development – Human Trials
Guest: Dr. Aaron I. Vinik, Research Director, Strelitz Diabetes Institutes, EVMS
Appearing on www.diabetesstation.com

KATE GILBERT: We are most honored to welcome to Diabetes Station this evening Dr. Aaron Vinik, Director of the Strelitz Diabetes Institutes and most recently Virginia Scientist of the Year!

Dr. Vinik plays a key role in the Strelitz Diabetes Institutes' quest to cure both Type 1 and Type 2 diabetes through regeneration of the pancreas. In the 80s, Dr. Vinik spearheaded the discovery of "ilotropin," a chemical substance that can re-awaken the potential of cells to produce insulin, and more recently INGAP (Islet Neogenesis Associated Protein), a protein inside the pancreas which is responsible for this reawakening.

In tests on animals made diabetic with streptozotocin, researchers found that a small, specialized section of the INGAP protein, called a peptide, travels straight to the pancreas, where it "wakes up" inactive adult pancreatic stem cells. Once stimulated, the formerly sleepy cells give birth to beta cells, which are responsible for manufacturing insulin. The peptide also seems to trigger the creation of companion cells in the pancreas, which begin making glucagon and other hormones needed to regulate blood sugar levels in people with both Type 1 and Type 2 diabetes.

Dr. Vinik’s work with INGAP moved into human clinical trials on December 5, 2001. 62 people with both Type 1 and Type 2 diabetes were to be recruited to participate at three medical institutes around the country: the University of Texas in San Antonio, the University of North Carolina at Chapel Hill and the MedStar Research Institute in Washington. The trial involves doctors giving these people intra-muscular injections of the INGAP peptide, once a day for 34 days.

Welcome back to Diabetes Station, Dr. Vinik!

Dr. Vinik - Could you possibly start by telling us what stage the clinical trials are at today? Have all 62 participants received their 34-day "course" of INGAP? And how many are now insulin-independent?

AARON VINIK, MD, PHD: Kate, thanks for the question. I must remind you that the studies on INGAP in humans are Phase 1/2a and the primary end-point is safety. So far, there have been no significant side effects, for which we are very grateful.

MARY: What minor side effects, if any have been noted?

AARON VINIK, MD, PHD: Minor side effects that one sees with placebo e.g. diarrhea and headache, but we do not know if this has occurred in the placebo arm or the treatment arms. None have necessitated stopping the study.

CAROLINA: Are any patients with Type 1 in the current phase of the trials?

AARON VINIK, MD, PHD: Carolina, there are about equal numbers of Type 1 and Type 2 patients in the study.
ALLISON: When will you know the results? How long before you can say whether the treatments are successful?

AARON VINIK, MD, PHD: The results of this study are emerging as we go along. With safety being our primary interest, we are monitoring closely the appearance of adverse events and so far we feel blessed to report that there have been none of consequence.

DC: I am hoping to learn the results of the Phase 1 trials, if there were any side-effects, if C-peptide levels were monitored.

AARON VINIK, MD, PHD: DC, so far there have been no side effects worthy of mention. It is a double-blind, placebo controlled study and C-peptide levels have been measured.

ALLISON: I forget, what's C-peptide?

AARON VINIK, MD, PHD: C-peptide is the connecting peptide between the A and B chains of insulin. For every molecule of insulin your pancreas makes it makes a molecule of C-peptide as it is split off from the insulin within the parent proinsulin molecule. The reason we measure C-peptide and not insulin is because there is species specificity and we can measure human production of C-peptide even if there are antibodies to insulin in the circulation or if the person is getting pig or beef insulin.

LISA MARIE: Dr. Vinik, can you tell us if any participants are producing measurable amounts of C-peptide? I understand if you cannot say.

AARON VINIK, MD, PHD: Lisa Marie, I would like to tell you if this is the case but the study is blinded so we will not have the C-peptide results until the whole cohort has completed the study. Then we will be able to break the code and see what has transpired.

DAVER: Dr Vinik, with the latest info on halting the immune process with a relatively short treatment of Anti CD-3, will you be planning on testing that therapy in conjunction with the INGAP peptide.

AARON VINIK, MD, PHD: We are very enthusiastic for the development of new, more powerful agents to suppress the autoimmune response. We anticipate that in some individuals we will need to use INGAP in combination with immunosuppressive agents but have not resolved whether CD-3 or some of the others on the horizon will be the appropriate mix.

DC: Have any of the large animal studies been published Dr. Vinik? Thanks!

AARON VINIK, MD, PHD: The large animal studies will be presented at the National Endocrine meetings in San Francisco this coming week.

ALLISON: Dr. Vinik, when will you know whether the treatments have been a success in fixing the cells?

AARON VINIK, MD, PHD: We know that the damaged cells can be fixed by replacing them with new cells based on our animal studies. Dr. Rosenberg will be presenting a paper at the National Endocrine Society meetings next week to show that this is feasible in an animal model in which the cells of the pancreas have been destroyed and there is an inflammatory cell infiltrate.

KATE GILBERT: Was INGAP trialed on animals with Type 1 Diabetes? If so, did you observe an autoimmune attack against the newly regenerated cells?

AARON VINIK, MD, PHD: INGAP has been used successfully on animal models of Type 1 diabetes.

DC: Have you had many discussions with Transition Therapeutics (waratah)? Are the approaches at all similar?

AARON VINIK, MD, PHD: We have not engaged in discussions with Transition Therapeutics.

GREGG: Are Phase 2 cohorts selected, and when will the Phase 2a begin? Thanks!

AARON VINIK, MD, PHD: Gregg, the Phase 2 cohorts have not been selected in their entirety as yet.

ED: Are there any conflicts of interest that could slow INGAP progression to market? Corporate or private.

VALERIE: What can people do to help speed up the process from human trial to a treatment that can be used to cure children who have diabetes?

AARON VINIK, MD, PHD: If everything looks good after Phase 2 then we will be dependent upon the FDA (Food & Drug Administration) to examine the information and determine whether or not INGAP can be fast-tracked.

DAVER: Dr Vinik, are any of the participants in the trial not diabetic? Thinking would be to expand the beta cells of non-diabetic relatives for living donor transplantation.

AARON VINIK, MD, PHD: Daver, that is an interesting thought indeed. We have now completed our large and small animal studies of normal animals and shown that INGAP will produce a 2-4 fold increase in the islet mass. The newly formed islets function to maintain normal homeostasis i.e. they are stimulated by glucose and in its absence are turned off. We have not entertained the notion that we could use a human as an islet bank but are working on human islets in the test tube to see if they can be expanded, or if the tendency to apoptosis when they are removed from their natural environment can be prevented, thus producing an increase in the islet yield for transplantation.

SPARK: Dr. Vinik, I was under the impression that the trials currently underway were to test single doses (Phase I) and 5 doses (Phase 2a) for safety only. Am I correct?

AARON VINIK, MD, PHD: Spark, that is correct but we have also included several other measurements to seek trends toward efficacy for the repeated dosing arm of the study.

JULIANNE: Why were diabetics with complications not selected for the first round of trials?

AARON VINIK, MD, PHD: Diabetics with complications were not selected because unlike transplantation when you are using potentially harmful drugs for the immune suppression, we are giving an agent that appears to cause no harm and hopefully only good.

KATE GILBERT: Dr Vinik ... can you explain further the success you have had in animal models of Type 1 diabetes? Did you use immune suppression to arrest the autoimmune attack we see in islet/pancreas transplantation?

AARON VINIK, MD, PHD: Our studies in animal models of Type 1 diabetes have produced some interesting results. In one model, we have not had to use immunosuppression, and with INGAP treatment, the existing inflammatory cell infiltrate appeared to dissipate. Some of the data on another model that is notorious for its immune-mediated insult and rejection appears to indicate a salutary response to the combination of immunosuppressive agents and INGAP.

ED: Where does INGAP come from?

AARON VINIK, MD, PHD: Ed, INGAP is produced within the pancreas in the acinar tissue and transported to the precursor cells to stimulate transdifferentiation into adult endocrine cells.

ED: I mean, where and how do you derive the INGAP that you use for the treatment?

AARON VINIK, MD, PHD: Sorry Ed, I misunderstood. INGAP Peptide can be synthesized in the test tube. That is why there will be no limit on its production.

CHERYL: How many people have been dropped (or voluntarily dropped out) from the study?

AARON VINIK, MD, PHD: No person has been dropped from the study as of this point in time.

MARTIN: If a person had diabetes for over 30 years, would they still have antibodies to destroy the new islet cells?

AARON VINIK, MD, PHD: Martin, that depends on the type of diabetes. In Type 2 diabetes most do not have antibodies to start. In the common or garden variety of Type 1a diabetes, there are antibodies in 95% of people that disappear with time over say 20 years. In Type 1b diabetes antibodies may persist for life. This is the type that occurs predominantly in older women with other autoimmune disorders.

SPARK: When do the blinders come off?

DC: When do you expect the entire cohort to complete the study, Dr?

AARON VINIK, MD, PHD: I think we will see the beginning of the next phase at the end of summer.

KATE GILBERT: What type of trial will the next phase be? (I love how fast you work!)

AARON VINIK, MD, PHD: The next trial will be the Phase 2 of the current study and the same centers will participate. One additional center may be involved and when we move to the next phase more centers will be needed. Approximately the same number of people are required for the second phase of these studies as were required for the first part (62).

BOB: Why is INGAP administered intramuscular instead of subcutaneous?

AARON VINIK, MD, PHD: We chose the intra-muscular route based upon animal pharmacokinetic data. We found that it was well absorbed and delivered to the pancreas when given intra-muscularly. We are continuing to study the best route of administration.

CHERYL: Is GMP currently accepting people for the studies? I have tried to get accepted at UNC, but was told they only had room for 5 subjects in Phase 1 & that they would be given "1st choice" for going into Phase 2.

AARON VINIK, MD, PHD: Cheryl, that is true but be sure to tell them of your interest should an opening occur.

KATE GILBERT: Dr Vinik - Are you collaborating with any other teams currently?

AARON VINIK, MD, PHD: Yes, we are collaborating with a number of people and Institutions. For example some of the work is being done with Dr. Rosenberg at McGill University, and we have ongoing studies with the people in Alberta, San Antonio, Chapel Hill, Washington to name a few.

BERTIE: Thank you Dr. Vinik for your time and patience with us and your INGAP studies. Nineteen years requires both patience and fortitude. We hope you continue to have more success as your studies progress. (Exciting to hear that you've seen no adverse side affects and haven't lost any human participants for any reason!) Looking forward to reading published reports on your animal studies at the Endocrinology meetings next week. Will watch my Medscape...

AARON VINIK, MD, PHD: Bertie, thanks for the kind thoughts, do go see David Taylor Fishwick’s presentation at the ADA and Drs. Rosenberg and Pittenger's at the Endo society.

ALLISON: Dr. Vinik, do you think this process will be safe in the under 18 population? I'm 16 and I am curious.

AARON VINIK, MD, PHD: I hope that this will be safe in the under 18 population. This is a very important point since neither pancreas nor islet transplantation is really feasible in this young population.

MARY: Is ilotropin a protein extracted from plastic wrap? And is this protein in any foods? if so, would you suggest diabetics consume any/more of these foods?

DC: Dr. Vinik, is wrapping in saran anything like ischemia-reperfusion?

AARON VINIK, MD, PHD: I love the questions on cellophane and saran. We believed once that there was something unique to the cellophane because a group doing these experiments in SA found that the type of saran mattered. We now have established that it is the degree of obstruction of the ductal system produce and you can use a piece of wire. Is it the same as ischemia reperfusion? Yes and no. We are not creating ischemia but are obstruction the ducts partially. We do not release the pressure and get a rebound as occurs in ischemia reperfusion.

LISA: People with Type 1 who were slim were not allowed to participate. If INGAP works, will it be open to everyone?

AARON VINIK, MD, PHD: People with Type 1 and 2 who are slim were sought for the trial but unfortunately people in the US tend not to be too slim. These people will clearly be candidates for the next phase of the work.

ANITA: How do I find out if a center near me is participating?

KATE GILBERT: Anita - there are currently only three centres. Go to www.dif.org for more details.

AARON VINIK, MD, PHD: Contact GMP companies for information on a center near you.

ROD: Is there a chance that researchers at University of Toronto will be involved in Phase II or later studies?

AARON VINIK, MD, PHD: I cannot say which center will be chosen for the next phase of the study.

KATE GILBERT: Dr Vinik - Have any of the participants in the current trial been able to reduce their insulin dose or diabetes medications?

DC: If at least one, or more importantly half of the subjects' insulin requirement dropped, I sure would like to know......

SPARK: I think we'd all like to know that DC, patience is key.

SHANA: DC, it is a double blind study, so if there were changes noted, they would have to open the study to see if the person was taking the INGAP or the placebo. They cannot do that until the study is completed.

AARON VINIK, MD, PHD: I would also be happy to see changes in insulin dosing when we know who was on which treatment arm.

KATE GILBERT: Our time is coming to an end, unfortunately. Dr. Vinik - Do you have any final thoughts for us? Perhaps you would like to share your team's goals for the next twelve months?

AARON VINIK, MD, PHD: Kate, I want to thank you for asking. While we are developing INGAP as a therapy a host of new questions arise. Research in diabetes and improving our understanding of what was needed did not stop with the discovery of insulin. Here at the Strelitz Diabetes Institutes we are commencing the next phase of our work and be sure to see Drs Pittenger and Taylor's presentations. We are asking for e.g. who is INGAP deficient? Are there genetic abnormalities in some people? Are there antibodies to INGAP? What regulates INGAP normally and what goes wrong? What are the targets for INGAP? Clearly, these are critical questions and require a great deal of support.

Our Diabetes Institutes Foundation (DIF) has been wonderful in the way they have stood behind this effort and made it possible to bring the work to this level. Sept 11th saw many changes in people’s fortunes and progress we anticipate might be hindered by this unfortunate event. We think the DIF merits further support for their valiant effort and belief in the program that has made this all feasible.

KATE GILBERT: Fine words, Dr Vinik!! We are all behind you and will be contacting the DIF http://www.dif.org to find out how we can support you personally or through lobbying to increase your support. Thank you once again for your dedication.

KATE GILBERT: Dr Vinik. It has been a great honor to have you with us tonight to share as much as you can about the INGAP study. It really is a privilege to be able to follow the progress of your work so closely. On behalf of everyone at Diabetes Station I'd like to thank you sincerely for your time and commitment, and wish you many more bouts of luck like that of the saran wrap!!!

KATE GILBERT: Please also pass on our thanks and regards to Anna Goldenberg and her team at the DIF who work tirelessly to keep us all up to date as much as possible in regard to your progress!

DAVER: Thanks for the update Dr Vinik, best of luck with these trials. Kate as usual, you were a fantastic host, thank you.

DC: Dr. Vinik, thanks for putting up with all of our curious questions, we really can't thank you enough for all your work. Peace.

AARON VINIK, MD, PHD: Good night all and thanks for the scintillating questions. Take Care AIV