ViaCyte on the Rise: First Diabetes Trial Data & Acquires BetaLogics IP

Clinical research on Type I Diabetes is one of the most exciting and promising areas of stem cells and regenerative medicine for human disease.

Two of the coolest companies out there in this arena have been ViaCyte and BetaLogics (owned by J&J). For more on ViaCyte see my interview with President and CEO Paul Laikind from 2015.

VC-01 post-implant final

VC-01 post-implant

Today brings great news for ViaCyte on two fronts. Incidentally, this gives me a correct prediction on my Top 20 stem cell predictions for 2016.

First, it has acquired the assets and IP of BetaLogics, bringing together two of the best biotechs to use stem cells to fight Diabetes. This is a very exciting move and will strengthen ViaCyte. The terms of the deal were not released. This is also good news for Diabetes patients as this seems likely to give ViaCyte a big boost. ViaCyte’s press release quoted Laikind:

“For more than a decade BetaLogics and ViaCyte have been independently working toward a stem cell‐derived therapy for diabetes. By combining the intellectual property and other assets of BetaLogics with ViaCyte, we will further strengthen our advanced program focused on

insulin‐dependent diabetes and solidify our leadership in the field,” said Paul Laikind, PhD, President and CEO of ViaCyte. “We look forward to delivering effective new treatments for this difficult disease.”

Second, ViaCyte has had some notable success in producing the first data in its Phase 1/Phase 2 clinical trial called STEP ONE (Safety, Tolerability, and Efficacy of VC‐01 Combination Product in Type One Diabetes). From the company on this development:

  • “The data show that pancreatic progenitor cells (PEC-01) within VC-01 can engraft, vascularize, and differentiate into pancreatic beta islet cells (insulin-producing cells) 12 weeks after implantation.
  • This is an important milestone in the development of a “functional cure” for type 1 diabetes.  And an important milestone for the industry — the clinical trial is supported by JDRF and CIRM (California Institute for Regenerative Medicine)
  • The goal is for the PEC-01 cells in VC-01 to mature and secrete insulin and other regulatory factors in response to blood glucose levels.  “

Together these events solidify ViaCyte’s leadership in the area of stem cell-based treatments for Diabetes.

Review of Biotech/Translational Talks #ISSCR2015: StemCells Inc, Semma, ViaCyte, & Le Blanc

By Heather Main

The path to the clinic is a slow and arduous activity, frustrating not only to the researcher and patient, but investors. Successful clinical translation of technologies requires a balance of science, streamlined translation and funding. To develop fantastic science and then realise the most important components cannot be adapted to the clinical environment is as disastrous as having a great product but no cash to get it past the post. The fruitful interaction of researchers, companies and clinics will save a lot of pain in streamlining technologies to patients. Thus, it was nice to see an ISSCR 2015 plenary session on stem cell therapies including companies StemCells, Inc. and ViaCyte, Inc. The topics were a good spread of autologous and allogeneic cell sources as well as therapies directed at inflammation and immune reactions versus integrative cell replacement technologies.stemcellsinc-logo

StemCells, Inc. presented progress in clinical trials with allogeneic neural stem cells in brain, spinal cord and eye disorders. As is the reality for companies giving talks some data and beautiful pictures is not disclosed. Though there were no revolutionary data sets on efficacy, what was clear was that grafts could persist 1.5 years post removal of immunosuppression (this was determined with HLA-mismatch begging the development of a Shinya Yamanaka style allogeneic HLA cell bank). It should not be a surprise that there were no amazing efficacy leaps in these first trials. There would be a lot of luck in getting the right cell, the right dose and the right transplantation method in the first go. Even the development of reliable measures of graft behaviour and efficacy will take time to develop and standardise.

Semma TherapeuticsDoug Melton was clear to state that they “haven’t (just) done an academic study”. That while they are not yet in the clinic and even though they present a more classical academic study, showing a complex defined differentiation and detailed functional analyses, that they recognise the importance of not just talking the talk but walking the walk. Doug presented their in-vitro beta-cell body technology that show functional characteristics equivalent to, if not better than, cadaveric islets. They were able to upscale this technology and are now on the prowl for encapsulation technologies to move into the clinical space, which will happen through their new start-up Semma Therapeutics.

ViaCyte New LogoIt’s always nice to hear an Aussie accent ;), giving additional benefits to listening to Alan Robins present the progress of ViaCyte in clinical trials of their pancreatic progenitor and encapsulation technologies. Following on from Doug, Alan made a couple of comments to assure the audience that there was a lot of vigorous science behind their technology, the curse of not being able to disclose and thus somewhat unfairly being seen as less careful. The ViaCyte technology is based on the major phase of expansion in pluripotent cells followed by mass differentiation and subsequent encapsulation. Interestingly in their pre-clinical animals studies the grafts were able to regulate insulin levels at the standard human blood concentrations, indicating not only functionality but also species specific functionality.

Katarina Le BlancKatarina Le Blanc presented her work on MSCs for GVHD, diabetes and vocal cord scarring. Somewhat disappointingly I heard the comments of someone leaving this talk with the all too common disregard that MSC technologies are inferior to pluripotent technologies rather than recognising them as complementary technologies. Katarina showed epithelial cell death and inflammatory markers were reduced with maximal effect at 3 weeks after IV injection for GVHD, even though they also prove that IV infused cells have mostly disappeared already at 3 days post infusion. She also showed that while coagulation and complement cascades are activated in response to IV infusion of MSCs blood clotting is not a common occurrence. The risk of clotting was cell number, dose and passage number dependent, which is a little scary when many autologous therapy clinics do not standardise the cell number they IV inject.

It’s great to see both academics and companies being recognised as the drivers of cellular therapies. Working in a stem cell company myself, I was surprised 2 years in a row to see talks from academics about skeletal muscle differentiation protocols that do not come close to our technology. It’s somewhat understandable that when it is not possible to disclose a lot of details of your research, the companies are often not taken seriously and are relegated to paid presentations during the lunch break. It is fantastic however, to see positive movement in reputable exposure for the companies attempting to drive research to patients.

New biotech Semma Therapeutics joins ViaCyte & Betalogics in stem cell Diabetes arena

Semma Therapeutics

Semma’s technology director Felicia Pagliuca, with CEO Robert Millman. Boston Globe Picture

A new biotech startup, Semma Therapeutics, announced that it seeks to fight diabetes via translating technology from the lab of Doug Melton at Harvard to the clinic.

Another major player in cell therapy-based arena for Diabetes is most likely good news for patients.

Quoted in the Boston Globe, there is a good deal of enthusiasm about the potential of this kind of therapeutic approach:

“This would be a huge breakthrough,” said Dr. George L. King, a Harvard Medical School professor and research director at Joslin Diabetes Center. “It could cure diabetes.”

Semma TherapeuticsSemma will have to compete with ViaCyte and Betalogics, which could prove challenging given, for example, that ViaCyte already has an ongoing FDA-approved clinical trial. Still Semma has raised more than $40 million, which is a good start, and this capital came from some known bio-investment players:

“Sensing a business opportunity at the juncture of stem cells and diabetes, venture firms MPM Capital, Fidelity Biosciences of Cambridge, and Arch Venture Partners of Chicago are teaming with Minneapolis-based medical technology giant Medtronic plc to back Semma in the company’s first round of financing.”

Two of the leaders of Semma are former Melton lab postdoc Felicia Pagliuca, and CEO Robert Millman. Pagliuca was first author on a high-profile Melton lab paper in Cell published just about half a year ago and post-pub reviewed on this blog.

The Semma website has more information.

Why the name Semma?

I’m not sure.

There is a SEMMA acronym in high-tech:

Sample, Explore, Modify, Model, Assess.

It’ll be exciting to see how Semma performs and more broadly how cell therapy-based approaches to Diabetes evolve. I view Semma coming on the scene as a positive.

ViaCyte CEO Paul Laikind Interview: Trial Update, Melton’s Concerns, & Future

Paul LaikindIt’s been exciting to watch the recent developments in using stem cells as the basis for treatments for Type I Diabetes. One of the major players in this arena is the privately-held company, ViaCyte.

In this post, I interview ViaCyte President and CEO, Paul Laikind. The topics include their VC-01 product, the Encaptra device, an update on their clinical trial, the healthy competition with Doug Melton, and future perspectives.

  1. Can you give an update on the VC-01 clinical trial?

Answer: We’ve enrolled four patients in the trial as of last week. The first cohort is receiving a sub-therapeutic dose with the focus on safety and tolerance. We are also including sentinels. Enrollment is currently limited to adults (age 18-55), male or female (of non-child bearing potential). They must be C-peptide negative and thus have essentially no ability to produce insulin. We are seeking to enroll patients with a stable presentation.

  1. Is there a target date for full enrollment of 40 patients?

Answer: We will most likely have six patients in the first cohort (met by mid this year) and then another 36 in the second cohort (filled sometime in 2016). Patient numbers could change though. While it is difficult to predict this early in the study, based on current projections, we expect that an initial evaluation of efficacy could occur in mid to late 2016 However, patients will continue with the implanted device for two years.

  1. Can you tell me more about the details of the trial?

Answer: It’s a dose-escalation trial. The first cohort is sub-therapeutic and these patients will have two Encaptra-250 (EN250) “dose ranging” implants. The second cohort will have an increased dose where we seek to achieve efficacy. For the second cohort we estimate patients will have four to six dose ranging units implanted. Looking to the future for the predicted actual commercial product, it will have a larger capacity with three to four times as many cells as in one current EN250. With the commercial product, the goal is to treat patients with only one or two units implanted.EN20 EN250 Quarter w labels white

  1. The sentinels are a novel approach to monitoring and data collection. How do these work and what is their make up?

Answer: The sentinels are called EN20s. They are a smaller size, about the size of a dime versus EN250, which is about half the size of a business card. During the trial, the EN20s will be withdrawn periodically from patients and analyzed histologically. The sentinels are a tremendous tool for maximizing the potential of the product. With them, we can monitor progress, troubleshoot issues, examine different surgical techniques, location, etc. The sentinels were met with enthusiasm by regulators.

  1. What are the product placement options?

Answer: There are several product placement options. We are currently focusing on placement in the lower back. The reason for that placement is that while the device can withstand the impact of a 60 mph baseball (based on cadaver testing), a needle could go right through it, so we want to put it where patients don’t typically inject insulin.

  1. What about the function of the capsule?

Answer: The theory is that the capsule will protect the cells from the patient’s immune system and thus avoid the need for immunosuppression. We are testing that in this trial. It prevents cells going in or out, but allows for proteins and smaller molecules to traverse the semipermeable membrane.

  1. Doug Melton has been quoted as being “worried” that ViaCyte technology won’t work (e.g. http://www.technologyreview.com/featuredstory/535036/a-pancreas-in-a-capsule/). He raised concerns more specifically about the Encaptra capsule, for example, functionally becoming fibrotic and mentioned worries about your cells being immature and taking a long time to mature. Any response on capsule and cells? He also has suggested that his beta cells will be a better option.

Answer: Dr. Melton’s work on the beta cell is very interesting. As to the cells, we made the choice to use the pancreatic progenitor cells. An important consideration is that when you first put in cells, they are in a hypoxic environment. Beta cells are sensitive to low oxygen levels, which can negatively affect their survival and function. Beta cells typically exist in a mature highly vascularized organ. The pancreatic progenitor cells that we use undergo an organogenesis-like process, more similar to how they behave in nature, and thus we believe they should be better able to handle low oxygen. They also are believed to release angiogenic and other factors to promote vascularization.VC-01 post-implant final

In regards to the capsule, we do expect there to be a foreign body reaction in patients after implantation, which will generate a fibrotic capsule. In fact, we see a thin fibrotic capsule around the device in mice. But in the mouse model this capsule around the device is very well vascularized. The vasculature is right up against the device membrane on the outside, allowing for oxygen and nutrient diffusion to the cells inside.

  1. How do you view the time to maturation issue?

Answer: We do not feel the maturation time of two to three months for our cells in vivo is a concern. For example, the comment has been made by some that by implanting a more mature beta cell you avoid a delay. We question that. One, while the in vitro beta cells that have been described in recent publications are relatively more mature, they are still not actually fully mature differentiated beta cells. Two, maybe more important is the issue that, more generally, grafts take time. If you put in a product made with beta cells that’s not vascularized, it will likely take time to become effective, assuming it survives the implant. Furthermore, in talking with patients, if you’ve been living with this disease your whole life, a couple months is a relatively negligible amount of time to have to wait for function.

  1. Another issue raised has been that progenitor cells produce mixed cell populations. Thoughts?

Answer: We do put in cells that are designed to form the mixed cell population of the islet with multiple hormones produced. We view that as an upside. By producing something more like a full islet we have a potentially more effective way to treat the disease. For example, glucagon-producing alpha cells can be dysfunctional in type 1 diabetes as well, and we believe these can help prevent dangerous hypoglycemic episodes. Yes, this may impact the total cell numbers needed to produce blood sugar control, but based on our calculations it is within the capacity of our approach. Of course, that remains to be demonstrated in the clinical study.

  1. What about BetaLogics?

Answer: With both Dr. Melton and BetaLogics, we view it as healthy competition. Type 1 diabetes is a disease for which we need to find a better treatment and ideally a cure. There’s room in this area for multiple efforts and we aren’t especially concerned with competition. Yet we do feel we are ahead of others and we have substantial intellectual property that they will need to navigate (~50 patents issued in the United States, and a couple hundred pending patent applications, including international). At ViaCyte we view the real competition as the biology rather than with the efforts of others as we seek to cure this devastating disease.

  1. What has been the role of CIRM and JDRF funding?

Answer: I can’t say enough about how important their support has been for the company. It has played a crucial role. We are focused on development of a transformative treatment for type 1 diabetes with stem cells. The valley of death is a real challenge to biotechs, and there is a very difficult financing environment for early stage, unproven technologies. CIRM and JDRF providing capital and in effect their endorsement has been crucial.

  1. What about the partnership with J&J?

Answer: J&J has had an interest in this sector for some time. They became investors in the company via J&J Development Corporation. They’ve been strong investors for some time, and this last year we did a transaction with them that brought in $20 million. They have the right of first refusal. Overall, I view this as a long-standing and productive association.

  1. What about projecting price or costs during the commercialization phase?

Answer: Should it be approved, the price will be partly dependent on how effective the product is. If animal data directly translate to humans (which admittedly doesn’t always happen) and there’s a functional cure where patients no longer have to use insulin, or have a reduction in insulin use, and do not have to constantly do blood tests, etc., then that would translate to savings for the healthcare system and influence how the product is priced. We also see value in how we are able to improve the quality of life for patients. If our product is able to reduce the drastic highs and lows that are so life threatening, we believe that could be very significant for patients as well.

  1. Where do you see ViaCyte in 5 years?

Answer: Obviously, at this stage, predictions are very speculative. Five years from now we hope that we will have seen success with the VC-01 product and be moving to the market. Ideally it will have proven to be a major new approach for managing type 1 diabetes and possibly a functional cure. In addition, success with the VC-01 product will validate our two platform technologies, each with strong IP. The first is directed differentiation of embryonic stem cells to a target cell (e.g. pancreatic progenitor cells) in a regulatory compliant, reproducible, and scalable manner.

The second platform is the Encaptra delivery device. We foresee multiple applications derived from these platform technologies. In summary, five years from now we hope to have made progress with the VC-01 product and have a pipeline of other new products. These could involve a variety of cell types but for the time being I’d say 95% of our efforts remain focused on the VC-01 product.

The Betatrophin Blues

All the recent high-profile papers that are having troubles are bumming me out.

The latest example is the “Betatrophin” Diabetes paper from Harvard last year.

Yesterday it was called into major doubt by a new Cell paper from a group led by Jesper Gromada at Regeneron.

The authors of the original 2013 Betatrophin paper–Doug Melton’s team at Harvard– indicated in their own accompanying, somber perspectives piece also in yesterday’s issue of Cell that they agree that their 2013 report was largely incorrect. This unfortunate turn of events is based on both the new Regeneron paper and the Melton lab’s own follow up work.

Rewind back to 2013 when the Betatrophin finding first came out and it was hard not to get into the story at that point given how it was being portrayed. A Harvard press release made little doubt that this was a seminal discovery for Diabetes research:

The hormone, called betatrophin, causes mice to produce insulin-secreting pancreatic beta cells up to thirty times the normal rate…it could eventually mean that instead of taking insulin injections three times a day, you might take an injection of this hormone once a week or once a month, or in the best case maybe even once a year.

The 2013 paper itself was also very bold with statements such as:

Thus, betatrophin treatment could augment or replace insulin injections by increasing the number of endogenous insulin-producing cells in diabetics.

Betatrophin

They raised expectations sky high.

I blogged about that apparent blockbuster finding here back then in 2013 and I definitely was excited about it given how it sounded. Now there’s a major letdown. The new paper’s title alone pretty much says it all:

ANGPTL8/Betatrophin Does Not Control Pancreatic Beta Cell Expansion

You can see the graphical abstract from this paper at left in which the authors report that Betatrophin, which now should probably go by the more objective name ANGPTL8, does not substantially impact beta cell growth, but rather seems to have a notable role in mouse triglyceride metabolism. ANGPTL8 is probably a very interesting molecule, but it is not what it seemed to be.

In the perspectives piece, the Betatrophin authors say that boosting their N of mice has led their main conclusion to come into doubt:

In Yi et al. we reported an average beta cell replication rate of ∼4% in betatrophin-injected mice (n = 7); with five additional experiments (n = 52 mice in total), the average beta cell replication rate in betatrophin-injected mice drops to 1.2%. While still significantly above control levels (p = 0.016 for all experiments) of beta cell replication (0.6%), the conclusion from Yi et al. must be corrected and modified with respect to the magnitude of the effect.

It’s now unclear what the fate of the 2013 Betatrophin paper will be moving forward given that its central argument is incorrect and even the naming of the molecule “Betatrophin” is indeed perhaps not appropriate any more.