Vertex at ADA 85th Scientific Sessions: Promising Diabetes Breakthrough

On Saturday, June 21, 2025, Vertex Pharmaceuticals (NASDAQ:VRTX) presented at the American Diabetes Association ADA 85th Scientific Sessions, unveiling promising advancements in Type 1 Diabetes treatment. The focus was on Zamyla Cell, a potential game-changer for patients with severe hypoglycemic events. While the data showcased significant clinical progress, the company also acknowledged the challenges of regulatory approval and market launch.

Key Takeaways

• Vertex Pharmaceuticals introduced Zamyla Cell as a transformative treatment for Type 1 Diabetes, showing promising results in restoring insulin production.
• The company plans regulatory submissions in 2026, with a commercial launch anticipated soon after.
• Zamyla Cell’s development is supported by regulatory designations like RMAT and Fast Track, indicating its potential impact.

Operational Updates

• Pivotal Trial Progress: The Phase I/II/III pivotal study is advancing swiftly, with completion expected by summer. It aims to enroll around 50 participants.
• Regulatory Submissions: Vertex plans to submit regulatory filings globally in 2026.
• Commercialization Readiness: Preparations are underway for the Zamyla Cell launch, focusing on a specialty commercial model.
• Manufacturing Capabilities: Expansion efforts include partnerships with Lonza and TreeFrog to ensure production scalability.
• Regulatory Designations: The treatment has received RMAT and Fast Track designations in the US, Prime designation in Europe, and the innovation passport in the UK.

Future Outlook

• Serial Innovation: Vertex is investing in additional Type 1 Diabetes programs, exploring novel immunotherapies and gene editing technologies.
• Target Patient Population: The initial indication for Ximilocel targets approximately 60,000 patients with severe hypoglycemic events.
• Potential for Redosing: Zamyla Cell offers the possibility of redosing, being an off-the-shelf therapy.
• Expanding Indications: Future applications may include patients post-kidney transplant or those with total pancreatectomy.

Q&A Highlights

• Target Patient Population: Ideal candidates are adults with Type 1 Diabetes and impaired awareness of hypoglycemia.
• FDA Interactions: Vertex has engaged in positive discussions with the FDA, focusing on Zamyla Cell’s transformative potential.
• Primary Endpoint: The Phase III study’s primary endpoint has been upgraded to insulin independence.
• Pricing: Pricing benchmarks for Zamyla Cell are yet to be determined.
• Competition: While liver-selective glucokinase activators are in development, Zamyla Cell aims for broader glycemic control.
• Adverse Events: Adverse events are manageable with dose adjustments and monitoring.

In summary, Vertex Pharmaceuticals is poised to revolutionize Type 1 Diabetes treatment with Zamyla Cell, backed by strong clinical data and strategic regulatory plans. Readers are encouraged to refer to the full transcript for detailed insights.

Full transcript - American Diabetes Association ADA 85th Scientific Sessions:

Susie Lisa, Senior Vice President of Investor Relations, Vertex Pharmaceuticals: For your patience. Good evening, everyone. My name is Susie Lisa, I’m the senior vice president of investor relations for Vertex Pharmaceuticals. Thank you so very much for those of you joining us here in the room in Chicago at the American Diabetes Association eighty fifth Scientific Sessions for Arzamyla Cell Update. It’s an exciting day for Vertex with the update today at ADA, with the Nijam article, and the summer solstice.

Big day. So thank you for all of you joining us online as well. We will be making forward looking statements on this call. They’re subject to the risks and uncertainties discussed in detail in our filings with the Securities and Exchange Commission. These statements include without limitation those regarding expectations for Vertex’s T1D programs, and actual outcomes and events could differ materially.

So here’s the agenda, and we’ll begin our event with our very own Felicia Palaiuca, who is the senior vice president of cell and genetic therapy research. She earned her PhD in biology from Cambridge University, where she was a Marshall Scholar, and did her postdoc fellowship at Harvard in the Stem Cell Institute as a member of Doug Melton’s lab. She went on to become a scientific co founder of Summit Therapeutics and their VP of Cell Biology R and D before joining Vertex via our acquisition of SEMA back in 2019. After Felicia gives us an overview of our type one diabetes approach and portfolio, We’re extremely pleased to have two physicians here for you tonight to share their views on the Zamyla cell data, the type one diabetes landscape, and the potential for Zamyla cell in the real world. Our first speaker is Doctor.

Michael Rickels. He’s a professor in diabetes and metabolic disease at the Perelman School of Medicine at the University of Pennsylvania, and has extensive clinical research and experience in islet cell transplantation in patients with type one diabetes. Doctor. Rickel serves as the co chair of the external steering committee for the Vertex t one d portfolio, which includes Zamyla Cell. We’re also very pleased to have us to be joined by Doctor.

James F. Markman, a professor of surgery and vice president of transplant services at UPenn. Doctor. Markman has been directly involved in pancreas and islet transplant programs and caring for patients during and after procedures. He is the principal investigator at the University of Pennsylvania clinical trial site for the FORWARD trial of Zamyla Cell.

For the Q and A session, we’ll have all of our speakers here to answer your questions, and because we’re also webcasting this live, we ask during the Q and A that you wait for a microphone with my colleagues, Minesha Pai and Kristen Hodis, and thanks for all their help for making this happen tonight. For those on the webcast, we recommend that you access the webcast slides as you listen to the call. The call is being recorded, and a replay will be available on our website. Now it’s my pleasure to hand it over to Felicia.

Felicia Paluca, Senior Vice President of Cell and Genetic Therapy Research, Vertex Pharmaceuticals: Alright. Thank you, Susie, and welcome, everyone. My name is Felicia Paluca, and I’m very pleased to be here with you this evening, especially on such a special day for all of us working on the type one diabetes program at Vertex. You’re here tonight to hear about Zamyla cell, our most advanced program for t one d, which as you know is a serious disease caused by destruction of one particular cell type in the body, the insulin producing beta cells that reside within the pancreas. In this cartoon, you can see on the left hand side a picture of a pancreas, and the pancreas is dotted with these, clusters of cells called the pancreatic islets.

And the purple cell depicted here is the very special cell, the insulin producing beta cell. In type one diabetes, the immune system goes awry and destroys all of those essential insulin producing beta cells. And so you can see what that looks like on the right hand side here. In people with type one diabetes, they don’t make any of their own insulin as a result of this immune destruction of the beta cell. And so they end up in a situation where they no longer produce any of their own insulin and rely for the rest of their lives on insulin treatment, which requires very careful glucose monitoring.

And although that insulin therapy is lifesaving, it is essentially the same way that we’ve treated type one diabetes since 1921 when insulin was first discovered more than a hundred years ago. This is entirely inadequate to meet the needs of patients and their families, both in terms of acute health complications, serious secondary complications that occur over time, as well as the tremendous burden on quality of life. If we look here on this slide, I’ll highlight just a few of the the, difficulties faced by people living with type one diabetes. As I mentioned, type one requires intensive lifelong management. And despite advances in technology, the unmet need is very high.

Almost four million people have been diagnosed with type one diabetes in North America and Europe, and we expect the initial Ximilocel indication could serve about sixty thousand of those patients. These sixty thousand patients have the highest unmet medical need. These are patients who experience severe hypoglycemic events, a serious and potentially life threatening complication of insulin therapy. Serious hypoglycemic events are events where one’s blood sugar drops so low, so quickly that it requires the assistance of a third party, spouse, paramedic, or other in order to recover. And as you can see on the right hand side, those severe hypoglycemic events can result in seizures, cardiac arrhythmia, coma, and even death.

Importantly, those individuals who experience recurrent severe hypoglycemic events can have increased mortality rate up to fivefold those who don’t experience SHEs. And despite available therapies today, including pumps and continuous glucose monitors, nearly ten percent of individuals living with type one diabetes experience these dangerous recurrent severe hypoglycemic events. So as you can see, despite optimal medical care, type one diabetes is associated with substantial morbidity, including, microvascular microvascular and macrovascular complications, reduced life expectancy, and the incredible burden of living with this disease day in and day out and treating it with a medicine like insulin with such a tight, narrow therapeutic, range that results in these potential severe hypoglycemic ends, events at one end of the spectrum and the consequences of living with hyperglycemia or too high blood sugar, which has negative impacts on many organ systems leading to those secondary complications. So imagine there was a better way. Imagine there was a way to replace those cells that have been destroyed by the immune system.

Let me tell you about zemyla cell. Zemyla cell is our investigational islet cell therapy. This is a cell therapy that we manufacture starting from stem cells, which we fully differentiate into those glucose responsive, insulin producing stem cell derived islets. These are off the shelf allogeneic cells that have the potential to replace those islet cells that are destroyed in people living with type one diabetes. Zamyla cell itself, as a cell therapy, is delivered via an infusion, into the hepatic portal vein in a simple procedure, and it’s protected from immune destruction with a standard steroid free induction and maintenance immunosuppressive regimen.

This protects the cells from the immune system. Both the cell infusion procedure and the immunosuppression regimen are well established and well understood. And while we’ll talk about Zamyla cell today, which we see as an incredible advance for this patient population, as is the case for all of our work at Vertex, our research continues, and we continue to serially innovate. We’re working on projects to, invent alternate immunosuppression agents and regimens. We’re working on gene edited hypoimmune approaches as well as other technologies which are advancing through research.

Before I hand it over to doctor Rickles, I wanna summarize where we are with somila cell. Most importantly, our pivotal trial, our phase one, two, three study is progressing rapidly. As we disclosed, earlier, this year and and late last year, we have converted our study into a phase one, two, three pivotal study, which is expected to enroll approximately 50 subjects, and it’s expected to complete enrollment and dosing this summer. Importantly, the we have had very positive engagements with regulatory agencies and believe our regulatory designations underscore the recognized high unmet need and transformative potential for zamylosel. Those designations include the regenerative medicine advanced therapy designation or RMAT as well as fast track designation here in The US, prime designation in Europe, and the innovation passport on under the innovative licensing and access pathway in The United Kingdom.

Lastly, we expect now to submit regulatory submissions next year in 2026, and as a result, are actively preparing for the launch and commercialization of Zamyla Cell. We see this as a highly concentrated market that can be served with a specialty commercial model consistent with our overall, approach and strategy at Vertex. So with that, I’m gonna hand it over to doctor Rickles to talk you through, some of the data that has us so excited about bringing this potential therapy to patients with type one.

Michael Rickels, Professor in Diabetes and Metabolic Disease, Perelman School of Medicine at the University of Pennsylvania: Thank you, Felicia, thank you, Susie, and colleagues at Vertex for the opportunity to present on the data from the FORWARD 101 study that we presented just earlier here at the American Diabetes Association meeting. Is this are the slides oh, I get them I think you Yeah. Okay. All right. So this is the presentation given just in the hour preceding this meeting of durable glycemic control and elimination of exogenous insulin use with VX-eight eighty in patients with type one diabetes.

And I had the privilege of presenting this here at ADA on behalf of my colleague, co investigators, steering committee members, and, Vertex Pharmaceuticals. These are my disclosures, which include, as Felicia mentioned, serving as co chair of the steering committee as well as as a site co investigator for the FORWARD study. So as you’ve heard, Zamyla Cell is an islet cell therapy in clinical development for those individuals with type one diabetes experiencing severe hypoglycemia. And this, cell product is investigational allogeneic stem cell derived, and a fully differentiated insulin producing islet cell therapy. So myelo cells administered, by portal vein infusion for intrahepatic engraftment under a steroid free induction and maintenance immunosuppression regimen, as has been established both as the site and for the immunosuppression with deceased donor islet transplantation.

The FORWARD study has been a Phase III study that’s completed enrollment, and as Felicia mentioned, has now been converted to a Phase III pivotal study. For the Phase III portion, it was completed under three sequential parts as an open label design: Part A, with two individuals receiving half the target dose in Part B, five individuals receiving sequentially the full, target dose, and in Part C, individuals, concurrently, treated with the full target dose of zamylosel. These individuals have been adults with type one diabetes, complicated by impaired awareness of hypoglycemia, and having experienced at least two severe hypoglycemic events in the year prior to screening. The primary efficacy endpoint for the phase onetwo portion were freedom from severe hypoglycemia from day 90 to three sixty five, and the achievement of a hemoglobin A1c less than 7% or at least a one percentage reduction in hemoglobin a1c during the first year of follow-up. The data being presented, are cut as of October 2024 when the phase onetwo portion of this trial was completed and prior to its conversion to the phase three pivotal phase.

So the efficacy data, will be, those for the 12 individuals receiving a full target dose of Zamyla cell and having at least twelve months of follow-up. The safety data will also include the two individuals receiving a half, target dose in Part A. So these 14 individuals have been you can see adults, non obese, with long standing type one diabetes, hemoglobin A1c by design, this had to be greater than seven and less than 10%, with undetectable, C peptide and typical insulin requirements for individuals with type one diabetes, all using, real time venous glucose monitoring, and, the majority insulin delivery via infusion pump with, the majority of those, on hybrid closed loop systems. And, these individuals had all experienced, between two and four severe hypoglycemic events in the year prior to screening. All 12, participants, have restored, clinically meaningful and, sustained glucose responsive endogenous insulin production and improved glucose tolerance as demonstrated through standardized mixed meal tolerance testing.

You can see on the left the C peptide, levels, which is our measure of endogenous insulin secretion, is undetectable, both fasting and with meal stimulation at baseline, and that both fasting and meal stimulated C peptide is restored by ninety days following zamylosel infusion. These this degree of endogenous insulin production is further, improved by six months, where you see increases in fasting and stimulated C peptide that are then, well maintained throughout the twelve months of follow-up. And on the right, you can see the, glucose response and and, with, at baseline, marked hyperglycemia, developing after ingestion of the standardized meal, and already at ninety days, substantial reduction in both fasting as well, most importantly, in this meal stimulated c peptide. And again, we see that further improvement with the increasing insulin production at six months. It’s then again very well maintained throughout the year of follow-up.

These, 12 participants, all had reduction in hemoglobin a1c, to targets under 7%, as you can see on on the left with all starting above 7%, all came well under that recommended, threshold, and maintained excellent glycemic control throughout follow-up. Insulin requirements, you can see becoming substantially reduced in in ten of twelve individuals, eliminating insulin requirements. It seems to occur most often by about six months following Xamylosel infusion, and in ten of twelve, off insulin at twelve months, with two individuals remaining on reduced dose of insulin who had who had all, who had both received some steroids during the peri transplant period that was not part of the protocol. All 12 participants demonstrated substantial improvements in time spent in the target glucose range of 70 to 180 milligrams per deciliter. So for high risk individuals, such as these experiencing severe hypoglycemia, the ADA recommends considering a lower target of fifty percent, which was even, this cohort unable to achieve prior to a transplant.

But the recommended target of being more than seventy percent, which we know is important for preventing long term diabetes related complications, already achieved, by this cohort at day 90, and, becoming further improved, as you saw with the physiologic meal tolerance test data, that by six months, almost 90% time spent in that normal glucose range of 70 to a 180, and that really being maintained throughout the year of follow-up. So substantial improvement in time and range that we don’t really see with any other current treatment for type one diabetes. This, can see, together with the substantial reduction of insulin requirements occurring over time coinciding with the improvement in glucose control, and overall, more than 1.5 percentage point reduction in hemoglobin A1c. All 12 individuals, in the phase onetwo portion met the primary endpoint of absence of severe hypoglycemia through the evaluation period and meeting those recommended targets for glycemic control. The majority of adverse events were mild or moderate, in severity, and those with a causal relationship to, any study drug were mostly attributed to immunosuppressive therapy.

Those attributed to zamyla cell were mostly transient, elevations in, liver transaminase levels that we see with any portal vein administration of, an islet cell therapy. There were no severe adverse events considered related to Zamyla cell. There have been two deaths that were previously reported and not considered related to Zamyla cell. The most common adverse events were diarrhea, headache, nausea, and these together with I mentioned already the transient increases in liver function tests, the decreased white blood cells, decreased renal function. These also all expected and common with the immunosuppression regimen that’s used, and generally manageable with dose modification and close monitoring of drug levels and the patient’s status.

And this is all consistent with what we know from these medications and the infusion procedure from our experience with deceased donor islet transplantation. So to summarize, all 12 participants who received a full dose of zamylosel in a single infusion demonstrated engraftment of the islet cells with restored glucose responsive endogenous insulin production as measured by C peptide that was associated with elimination of severe hypoglycemic events and improvement in glycemic control to meet and really exceed ADA, current ADA target levels of an A1c under 7% and time in range above 70%. And this with 10 of the 12 individuals eliminating use of insulin, and all meeting the phase onetwo primary endpoint of the elimination of severe hypoglycemic event together with meeting those ADA glycemic control targets. And the safety profile that we’ve seen is consistent with the immunosuppression regimen and infusion procedure that’s well established. And the now phase three portion of this study is well underway and anticipated to complete enrollment and dosing later this summer.

And with that, I’d just like to thank all of the study participants, their families, the investigators, their teams, and steering committee members, colleagues of Vertex Pharmaceuticals, who’ve all put a tremendous amount of, energy into, making this study possible. And this is the QR code for the New England Journal of Medicine article where this study is now appearing for the first time online coinciding with the presentation here at ADA. And thank you for your attention. I am going to now turn it over to my friend and colleague, Jim Markman.

James F. Markman, Professor of Surgery and Vice President of Transplant Services, UPenn: Thank you, Mike, and good evening, everyone. As you heard, my name is Jim Markman. I’m a multi organ transplant surgeon at Penn. Previously, I was the chief of transplant at Mass General and co director of the Center for Transplant Sciences at Massachusetts General Hospital. So I specialize in pancreas, islet, liver, and kidney transplantation.

I completed my MD PhD and training and residency at Penn and my transplant surgery fellowship at UCLA. I’ve had continuous NIH funding for more than twenty five years and published more than 400 papers, most related to immune tolerance and pancreas and islet transplantation. And my disclosure is listed at the bottom of the slide. So I wanted to tell you a bit about my practice and the patients I care for, and why we’re so excited about the potential to have a therapy like Zemila cell. So I was fortunate to become involved in eyelid transplantation just out of college when I joined the lab at Penn, and rapidly understood the reasons why everybody on the team was so excited about developing islets as an allotherapy for patients with Le Viol type one diabetes.

The Edmonton trial and the studies that followed proved that transplanted islet cells from deceased donors could be effective at reversing diabetes. However, this was clearly an imperfect approach. There was an inadequate supply of pancreatic, processing was very inefficient, islet quality and number was variable, And on average, it required processing four pancreases to get enough islets to achieve insulin independence in the recipient. So the key point is that islet quality and supply quantity are major barriers to helping more patients. And Zemila cell is anticipated to directly address these shortcomings.

So to try and address diabetic patients’ needs while at Penn, I developed one of the first successful pancreatic islet programs in the country, and later went on to do the same at Mass General. I conducted many successful islet transplantations with deceased donor cells, and yet recognized, as I just noted, that there are significant shortcomings with that approach, principally the supply, quantity, and quality of the islets. When a type one diabetic patient who qualifies for islet transplant based on issues of severe hypoglycemia and hypoglycemic unawareness, and then first decides they’d like to consider an islet cell therapy, we spend a lot of time with the patient talking about the procedure, educating them about post transplant care, including immunosuppression to protect the cells, and then post transplant, making sure that they have the support they need. And generally, Doctor. Rickles and I do this together when we see a diabetic patient.

These discussions also often reveal the depth of the burdens these patients carry with them that are caused by the disease that go beyond the challenges of meeting glycemic targets to avoid the well known complications that affect eyes, kidneys, nerves, and cardiovascular system. So I thought it would be worth mentioning a couple of patients that really stand out to me to illustrate these points. So one patient was an individual with a long history of type one diabetes and a history of multiple severe hypoglycemic episodes, and one that caused a terrible motorcycle accident, among many other debilitating episodes. When we discussed the specifics of undergoing transplant, including the potential risks and unknowns, their response was quite striking. Paraphrasing the comments, they were adamant that they understood and accepted the potential risks and indicated that if undergoing the procedure could give them even a chance of avoiding severe hypoglycemic events, each one carrying with them the risk of death, then it would all be worth it.

And they were especially interested that if their case was not a success, if we learned by it, that they would be very satisfied with the outcome. The other patient was middle aged and had been managing their diabetes for thirty to forty years and was interested in learning about islet cell therapy. At one point in the conversation, they said, do you mean there’s a chance I might not need to continue using my pump and sensor? And after a moment or two, they burst out into tears with the thought that their burden could be alleviated. It was really a very powerful interaction.

The burden of our diabetic patients, that our diabetic patients experience is difficult to appreciate until we speak with them in-depth about the possibility that they might be able to recover a more normal existence. So to recap, the patients come for consideration for islet transplants, struggle with problematic hypoglycemia that can lead to unpredictable and potentially fatal side effects. This is compounded by the overall burden of managing type one diabetes as well as struggling to manage their disease effectively to minimize the devastating longer term effects of type one diabetes when glucose levels are not well controlled. So this slide shows the general approach to the transplant of Zamyla cell. And this is an approach that, Mike, can you turn yours off?

This is an approach that had been, that had been used for many years with prior islet protocols. The patient generally comes in a couple of days before transplant just to initiate immunosuppression. The infusion occurs on day zero. And generally, the patients are discharged on day two and continue on immunosuppression thereafter. So overall, about a five day hospital length of stay, beginning with induction immunosuppression and then maintenance immunosuppression.

So, Myla cell is delivered by an intravenous infusion into the liver through the hepatic portal vein where the islets lodge in the liver and function there. The procedure is done by either a transplant surgeon or an interventional radiologist. And overall, the portal vein is considered a minimally invasive procedure compared to other transplant surgeries, such as pancreas or liver. Any transplant cells need to be protected from the immune system and the current practice is to give patients immunosuppressive therapy. The regimen we use is a well established steroid free immunosuppressive regimen that’s been developed specifically for eyelid transplantation.

The regimen is designed to optimally protect the eyelid cells from the immune system with an induction phase at the time of the procedure that includes antithymocyte globulin and a maintenance regimen of tacrolimus and sirolimus. So, I think it’s worth talking about some of the considerations of immunosuppressive therapy as this is an area where sometimes details are misunderstood. While immunosuppressive therapy does carry some risks, these are all very well characterized from decades of experience with multiple transplant types, and these are generally manageable, for most patients. In fact, there’s a large experience, prior experience with a similar immunosuppressive regimen with deceased donor allogeneic islets, and this was very well managed and received. So we use multiple tactics to ensure the best outcomes for patients, including dose monitoring and dose adjustments, as well as counseling on expected side effects and mitigation strategies, such as hygiene techniques and use of antimicrobials.

As I’ve already mentioned, for many patients, taking immunosuppressant with a predictable, well known risk profile that can be mitigated is a welcome trade off that enables them to receive transformative, potentially curative therapy that could greatly reduce their burden of care. I believe many patients will view Zamyla cell as having a very favorable risk benefit profile and leading to tangible improvements in their quality of life. In contrast to deceased donor islets with Zamyla cell, we know the islets are high quality, expected to work, and there’s a sufficient supply and quality of cells for transplant. For our T1D patients with significant challenges in management and achieving clinical goals, we believe this has the potential to be a great addition to our treatment armamentarium that could shift the paradigm for severe type one diabetes patients. And I’m very optimistic about the potential role in the real world for Zamyla cell.

I will stop there and turn it over to Felicia.

Felicia Paluca, Senior Vice President of Cell and Genetic Therapy Research, Vertex Pharmaceuticals: Thank you so much. Is it back on? Yep. Thank you so much, Mike and Jim, for your presentations. I’ll just leave you with one slide to wrap up what we’ve discussed today.

I think our top conclusion is that Zamylosel has clearly shown transformative benefit for people living with type one diabetes. Type one diabetes, as you know, is a large patient population with a high unmet need. That is acutely the case for the patients that we’re talking about today and the patients that Mike and Jim care for. Those are the individuals with recurrent severe hypoglycemic events, and those are the approximately sixty thousand individuals that could potentially be eligible for zamylosel if it’s approved. The updated zamylosel data you’ve seen today demonstrated durable therapy with curative potential for people living with type one diabetes.

And with potential global regulatory filings in 2026, we’re expanding our manufacturing and commercial capabilities to ensure launch readiness so that we can be ready to reach those patients. Serial innovation is underway with additional t one d programs in preclinical stage, and we could not be more excited about the potential of cell therapy for people living with type one diabetes. With that, I’ll hand it back to Susie, and I think we’ll open it up for questions.

Unidentified speaker: Great. Thanks. Yes. Please ask for the I think there’s Mohit right there behind you. Manisha, you want go ahead.

Please state your name firm and then ask the question.

James F. Markman, Professor of Surgery and Vice President of Transplant Services, UPenn: Thank very

Mohit Bansal, Analyst, Wells Fargo: much. My name is Mohit Bansal. I’m from Wells Fargo. My question is for doctors. Great presentation and great data so far.

In your practice, how do you think about the patient population which could benefit from these patients? I mean, like how patients would you say that could be? In the context of CGMs as well lately, like what we have seen with the continuous glucose monitoring, the episodes of severe hypoglycemic events have been coming down significantly. So how do you think about the opportunity here? Thank you.

Michael Rickels, Professor in Diabetes and Metabolic Disease, Perelman School of Medicine at the University of Pennsylvania: Thank you. That’s a great question. So clearly, what we’ve seen with real world data in the management of type one diabetes in in The United States, probably with, continuous glucose monitoring has had the greatest impact on reducing the incidence of severe hypoglycemic events. And within that, there’s a more modest effect of whether you, take injections or a pump or a hybrid closed loop delivery for insulin. But even with hybrid closed loop, therapy in The United States, we still have about fifteen percent of individuals, reporting the experience of severe hypoglycemic events.

And, and beyond that, forty percent of that population is unable to achieve the current, American Diabetes Association recommended targets for time in the, glucose range, 71, 80 being being 70%. So, in addition to the the the group that is continuing to experience And and we know that even with with continuous glucose monitoring, impaired awareness of hypoglycemia is not addressed by, by those technologies. And so there remains a physiologic impairment to defend against low glucose regardless of the improvements in technology. And so that group, we really feel, has been a tremendous unmet need for novel therapies in type one diabetes.

Unidentified speaker: Do you want to comment as well? No. Okay, great. Next question? Terrence?

Terrence Flynn, Analyst, Morgan Stanley: Terrence Flynn, Morgan Stanley. I had a two part question. The first is just on the primary endpoint for Phase three. This is for the company. Have you guys commented what the minimum percent response needed for approval is?

What’s the minimum bar the FDA wants to see? And then the second part is the FDA announced this new national priority review program. Just wondering if eight eighty would meet the criteria that they’ve laid out and if you’ve had any discussions there with the FDA? And then the second one third part, guess, the ability to dose. I know that’s a question that we’ve talked about in the past, but any update in terms

Susie Lisa, Senior Vice President of Investor Relations, Vertex Pharmaceuticals: question was on redosing.

Unidentified speaker: I think we lost it there. Felicia?

Felicia Paluca, Senior Vice President of Cell and Genetic Therapy Research, Vertex Pharmaceuticals: Yes. So I can start with the first part of the question was around the primary endpoint. The primary endpoint in the Phase IIIII study was upgraded to insulin independence based on the really powerful efficacy data that we’ve seen so far. So you saw in the Phase onetwo study, the primary endpoint is around elimination of severe hypoglycemic events while maintaining or improving their licensing and control and everybody hit the market. What we also saw is profound benefit with the vast majority of patients achieving insulin independence.

And so I think the data that we’ve seen, the data that we’ve shared with the FDA makes us confident that this is the type of is going to be supportive of potential people with the somato cell. Felicia,

Unidentified speaker: sorry, I think can we just check the mic there?

Felicia Paluca, Senior Vice President of Cell and Genetic Therapy Research, Vertex Pharmaceuticals: Can you hear me? That’s better. Yeah. Alright. Did you hear the first response, or do I need to start over?

Hopefully, everyone got the the primary endpoint component of this. The second question was around, new news coming out of FDA on priority reviews. And, obviously, when we think about transformative therapies that could really have a tremendous impact on on on patients here in The US, This is absolutely one of those therapies, and I can say that we’ve certainly been very encouraged by the conversations that we’ve had over the past months with with FDA, including our end of phase two meeting, and really look forward to continuing to collaborate to bring therapies with this kind of benefit risk profile as quickly as we possibly can to people across this country. I think the last question was on redosing. And as Mike and Jim alluded to, with a therapy like Zamyla cell, you do have the potential for redosing if needed because this is an off the shelf therapy that we can supply on demand, and and certainly that’s something that has precedent in the donor islet, field.

So certainly a possibility as needed.

Susie Lisa, Senior Vice President of Investor Relations, Vertex Pharmaceuticals: Vish, maybe just in case, you wanna repeat the answer about the primary endpoint from phase two to phase three?

Felicia Paluca, Senior Vice President of Cell and Genetic Therapy Research, Vertex Pharmaceuticals: Sure. Thank you. Sorry about

Unidentified speaker: the

Felicia Paluca, Senior Vice President of Cell and Genetic Therapy Research, Vertex Pharmaceuticals: microphone difficulties, but the first question was around the primary endpoint. And as you saw in the slides, the primary endpoint for the phase one two portion of the study was elimination of severe hypoglycemic events with, maintenance or improvement in glycemic control. And we upgraded that primary endpoint to insulin independence as we converted the study to a phase three after collaboration, with regulators, across the globe. And we’re very excited that the data is strongly supportive of our ability to deliver that kind of benefit to the majority of patients in the study.

Unidentified speaker: Do you have a question, Dina?

Dina, Analyst, Jefferies: Hi. This is Dina on for Mikey from Jefferies. Just quick two questions about, I guess, just moving on or digging more into the point about the FDA. What have the conversations been like given the new administration and specifically talked with CBERT about what they want to see and also sign off on. Okay.

I think it’s again now working. And then I guess just a question about the next gen programs. I know you guys mentioned that you’re working on a couple more in preclinical and I know that you’ve had a recent update about the device program. Just kind of wondering what are what is the innovation that’s going on there? And then I guess capacity wise, how many patients would you be able to treat within the first year if this was to get approved?

Thank you.

Felicia Paluca, Senior Vice President of Cell and Genetic Therapy Research, Vertex Pharmaceuticals: Alicia? Yeah. So, back on the FDA question, as I said, I think the conversations that we’ve had with the FDA have been very collaborative, very encouraging. And I think you know, all of the leaders that that we see at FDA really care about bringing truly transformative medicines to patients. And I think when you look at the kind of data and the kind of impact, of getting to insulin independence for patients with type one diabetes, of getting to insulin independence with vastly improved glycemic control, of getting to insulin independence with no more severe hypoglycemic events.

I think when we look at that, that’s a perfect case study for the kind of medicines that we wanna invent, that we wanna develop, that we wanna get improved, here in The US. So we’re really encouraged by that, and and as I said, looking forward to working collaboratively with the FDA here and and with regulators globally to bring this to patients. The second question you had was, the next generation, and as you can imagine, Zamyla cell is a major breakthrough for these patients. It’s a major breakthrough we see, for type one diabetes, and it is also the pioneer medicine as and this foundation for serial innovation, in type one diabetes. And so you can imagine that, we have a very deep and broad portfolio of research happening, at Vertex on using these cells in different ways to get more get to more and more patients.

So we have work ongoing on novel immunotherapies. We have work ongoing on, various kinds of gene editing that we think, has the potential to render these cells hypoimmune. We have work ongoing on next generation technologies, including understanding, the potential for devices and what we can learn from the the early clinical study that we recently completed. So I think in in summary, we’re we’re very optimistic that this is a very important starting point that we will build on over years to come for for people living with type one diabetes. I think your last question was around capacity, and I’m very excited about the investment that we have made in manufacturing at Vertex.

We have an incredibly talented manufacturing team that lives side by side with our research teams in Boston and are actively preparing for the the commercial launch of, of ZemylaCell. You’ve also heard that we’ve invested externally in partnerships that are gonna be enabling to meet the demand that we expect for this product, including, partnership with Lonza, where we’re building out manufacturing capacity in New Hampshire, partnership with TreeFrog where we’re really inventing new technologies to scale this production. So very encouraging work ongoing on the manufacturing side for Zamyla cell.

Unidentified speaker: Please go ahead.

Jarwei, Analyst, Citi: Hi, good evening. This is Jarwei on for Geoff Meacham from Citi. Maybe a question first for the docs. What would you describe would be the ideal candidate for this type of treatment given the immunosuppressive regimen? Is there perhaps an age group that would be ideal to undergo this type of procedure?

And then the second part would be more commercial angle. What do you think is the patient awareness of eight eighty with this type of stem cell transplant procedure? What type of patient uptake could you envision at launch? Could there be a bolus of initial patients? Or could there be limiting factors based on chair availability?

Thanks.

Michael Rickels, Professor in Diabetes and Metabolic Disease, Perelman School of Medicine at the University of Pennsylvania: Thanks. I’ll be happy to start with the first one. And the patient population, considering the need currently for for immunosuppression, is adults with with type one diabetes. And those who’ve developed impaired awareness of hypoglycemia typically have had, you know, at least five to ten years of of of diabetes, with type one diabetes having a peak incidence in childhood. There are and and with adulthood being, you know, quite a long period of time, there are a a very large number of adults, who have had what we consider to be sort of established or longstanding type one diabetes, where they have, as you’ve seen from the cohort demonstrated here, no residual, capacity for insulin secretion on their own.

And that renders these individuals also, unable to defend against, hypoglycemia physiologically because of the absence of a glucagon counterregulatory response from their their native islets. And, and so with that, the exposure to hypoglycemia increases with the disease duration, and and that’s what drives the then adaptation to no longer recognize and be able to either respond physiologically or through symptom generation to the fact that their glucose is is is getting low. And and this impaired awareness of hypoglycemia, even with modern technologies, is present in about thirty percent of adults with with type one diabetes. And and so there’s a very large portion of the of of the population who is at currently still sixfold increased risk for severe hypoglycemia when you have impaired awareness of hypoglycemia. And, and while current immunosuppression does also mean, being cautious about kidney function, that current protocols in in, immunotherapy for other, forms of solid organ transplantation are becoming much safer in terms of reducing possible risk for kidney function.

So we’re really hopeful that we’ll be able to extend the disease eligible population in the not too distant future.

Unidentified speaker: Doctor. Member, you want talk about patient awareness?

James F. Markman, Professor of Surgery and Vice President of Transplant Services, UPenn: I think that’s better. So just to follow on Mike’s comment, there may be other indications or populations that would benefit from zamylosel. We think of the patients who have had a kidney transplant that are already immunosuppressed. There, we don’t need to have the condition of severe hypoglycemic unawareness and ongoing hypoglycemia. And they’re already obligated to immunosuppression.

So it’s sort of a no brainer. Perhaps other patients such as patients who have had a total pancreatectomy that have really debilitating labile disease because they don’t have counter regulatory hormones to go and keep their sugars up. So there may be other populations besides the traditional one we’ve thought about so far that would be excellent candidates as well.

Unidentified speaker: There. Lisa Baco from Evercore ISI. Just a couple of questions for me. First of all, I know it may be a little early, but if you could give us any pricing benchmarks or way to think about that? And then also, I was curious about this new class of liver selective glucokinase activators and how those, you know, may or may not, you know, kind of also treat severe hypoglycemia if that’s what you’re trying to solve for here, and what the role would be for Zamylosel in the context of those therapies as well.

Thanks.

Unidentified speaker: Please, do you want to start on benchmarks?

Felicia Paluca, Senior Vice President of Cell and Genetic Therapy Research, Vertex Pharmaceuticals: Can you hear me? Yeah. Yeah. I think it’s it’s too early really to comment on pricing. As as you can tell, we are, nearing the end of enrolling the study but haven’t yet completed the study, so too early to say on on that.

Perhaps I’ll hand it over to Mike or Jim on the second question around the GKAs.

Michael Rickels, Professor in Diabetes and Metabolic Disease, Perelman School of Medicine at the University of Pennsylvania: Yeah. So the liver selective glucocorticoidase activator, the, BTV has, one that’s, in phase three, clinical trials, and we’re we’re all hopeful for some, continuation of the effect that’s been shown in their phase two program for, reducing exposure to hypoglycemia. But, I think we’re we’re still, it’s addressing one part of the the the problem in in type one diabetes. It’s, But the bigger problem that we’re really hoping to move towards in the future is really normalizing glucose control and regulation. And so as I I believe that what the future will bear out is that having a cell therapy that not only can address the the low end of the range, but also more, you know, importantly, the high end of the range, and and really help people maintain normal glucose levels that, we know are important for preventing the long term diabetes related complications that affect the eyes, kidneys, nerves, cardiovascular system, in addition to helping them to mitigate the day to day challenges of, of avoidance of hypoglycemia.

Unidentified speaker: No. I’m going try this one.

Felicia Paluca, Senior Vice President of Cell and Genetic Therapy Research, Vertex Pharmaceuticals0: How about now?

Unidentified speaker: There we go.

Felicia Paluca, Senior Vice President of Cell and Genetic Therapy Research, Vertex Pharmaceuticals0: Hi, Malcolm Hoffman here for Evan from BMO Capital Markets. Question for Doctor. Rickels. It was noted in the Q and A of the oral presentation prior to this event that some were concerned about the possibility of spontaneous hypoglycemia early and longer after transplantation. You had provided some context as to where this could happen in some other therapies.

Could you explain again why you may or may not be concerned about this for VX-eight eighty? Thanks.

Michael Rickels, Professor in Diabetes and Metabolic Disease, Perelman School of Medicine at the University of Pennsylvania: So, I guess I’m not concerned about this for Vague State 80 because it hasn’t been our experience to date with the forward study. The and as I try to explain, early is in the context of deceased donor islet transplantation. Some of those isolation preps are the the quality is not always great, and you may be, infusing a lot of dead cells with, released, insulin in the in the media, and that could lead to some experience of hypoglycemia shortly after the infusion. That’s not something that we’re seeing in this program. And the long term hypoglycemia is not present in deceased donor islet transplantation, but in autologous islet transplantation, which is for individuals who require a total pancreatectomy for benign disease.

And so that’s typically in in The United States recurrent acute or chronic pancreatitis. And as doctor Markman explained, when you remove the entire pancreas, you’re, not only dependent on insulin, but also you’ve removed any glucagon kind of regulatory cells as well. And these individuals can have very challenging times with glucose control. So to mitigate that, the islets can be isolated from the diseased pancreas and infused into the portal vein for intraepatic engraftment, as we do for allogeneic, islets. Some of those individuals do have spontaneous hypoglycemia long term, and that is even in individuals who are not requiring, insulin.

In that situation, it’s a very apples to oranges kind of ex comparison because, those islets are, in an individual who now has a, when you remove the pancreas, you remove the duodenum, a part of the stomach, and reconstruct the biliary and gastrointestinal system. So you kinda it’s basically like Roux en Y gastric bypass without the without restricting the the side of the stomach. And we know that those individuals have elementary hypoglycemia that occurs spontaneously. And and and so there are other reasons for those people, so it’s not something that we’re concerned about with this population.

Felicia Paluca, Senior Vice President of Cell and Genetic Therapy Research, Vertex Pharmaceuticals1: Thank you. This is Adam on for Jess, JPMorgan. So following up on Mohit’s and Jess’ question earlier, what portion of Type one patients you take care of would you expect to pursue $8.80 in early launch phase and maybe looking out longer say five years post launch? And maybe as a follow-up, if Vertex can develop a next generation version that avoids the need for immunosuppression or significantly reduces it, what proportion of patients would you expect to pursue it then?

Michael Rickels, Professor in Diabetes and Metabolic Disease, Perelman School of Medicine at the University of Pennsylvania: That’s for me again. You know, I mean, that’s a really hard question to to to answer. We have a substantial number of patients who I and and also, I would say my practice is a bit biased because patients seek me out because they want a cell therapy solution for their diabetes. And so I think there’s a very large portion that that want, islet cell therapy and would would line up for this. Currently, in phase one, two, and now phase three, our clinical trial parameters off you know, limit the, eligible population.

So it’s a little hard for me to go give you exact percentage numbers, but, but there’s a a substantial portion of adults with with with diabetes who would would really do anything for the chance to, be alleviated from the burden of daily, you know, self management and and hour to hour concerns about where their glucose is, what they’re doing with their insulin, their activity, what they’re eating, you know, how they’re gonna sleep, what if they’re traveling, what do they do with these time zones, how do I you know, my partner’s traveling? They usually are the one that catch me when I’m getting low. So there’s a substantial proportion of and again, my practice is biased, but I would say, of the adult population with type one diabetes who would be very interested in in an available, cell therapy.

Unidentified speaker: Doctor. Markman, anything? No? Okay. Next question.

Go ahead, Brian.

Felicia Paluca, Senior Vice President of Cell and Genetic Therapy Research, Vertex Pharmaceuticals2: Yes. Thanks. Brian Dallinger on behalf of Dave Risinger, Leerink Partners. So my question was related to the portal veins often considered a pretty suboptimal transplantation site. One of the questions that I had was, is Vertex making any effort for extrahepatic engraftment?

And if so, when might we see this develop? Thank you.

James F. Markman, Professor of Surgery and Vice President of Transplant Services, UPenn: So there have been lots of sites tried that are extrahepatic in experimental models, and they do work. You do have hyperinsulinism and probably not as quite a perfect regulation. As you noted, the liver site isn’t perfect. There’s an inflammatory response where we lose a lot of the islets. So I think there is a lot of opportunity to explore other sites potentially.

I’m not commenting on whether Vertex is interested in doing that right now, but as you know, there’s been work from the Chinese putting it in the subrectus, below the rectus sheath, and some other examples of extra hepatic cells that are functional. We don’t have any idea about the potency or the comparison between, so I think it’s early to really comment on that except to say that, you know, at least in theory, there’s quite a number of extra portal sites that could carry islets, and they would each have different safety profiles in terms of what’s required to get the cells there.

Felicia Paluca, Senior Vice President of Cell and Genetic Therapy Research, Vertex Pharmaceuticals: And I’ll just add, you know, as I said, we have a a very deep and broad, research effort ongoing on all things type one diabetes cell therapy. But I have to say that the data really speak for themselves. The portal vein works. The efficacy is profound for patients who’ve received Zamyla cell via portal vein infusion. And as you heard from Jim, it’s a relatively simple, minimally invasive procedure that we see, the potential for many physicians, whether it’s interventional radiology or surgeons, to perform across the country.

So we really see great potential for Zamyla Cell delivered through the portal vein for for these patients.

Unidentified speaker: One final question, or we can wrap it there. Great. Thank you very much, everyone. Felicia, Mike, Jim, thank you very much. We really appreciate it, thanks to all of you for coming.

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