Good day, everyone. Welcome to Pfizer's Analyst and Investor Call to review data presentations at scientific conferences during the week of June 15th, 2020. Today's call is being recorded. At this time, I would like to turn the call over to Mr. Chuck Triano, Senior Vice President, Investor Relations. Please go ahead, sir.
Thank you, operator. Good morning, everyone, thanks for joining us today to review clinical data for our hemophilia A gene therapy program that was presented this morning at the World Federation of Hemophilia Virtual Summit, to also review data from our oral GLP-1R agonist, which was presented this past Monday at the American Diabetes Association Scientific Sessions.
I'm joined today by Mikael Dolsten, our Chief Scientific Officer and President of Pfizer Worldwide Research and Development, as well as by several other Pfizer colleagues in our scientific and development areas, who Mikael will introduce. Before we start, I want to remind everybody that we will be making forward-looking statements on today's call and actual results may differ from those statements. Forward-looking statements speak only as of the original date of this presentation, we undertake no obligation to update or revise any of these statements. With that, I'll now turn the call over to Mikael Dolsten. Mikael?
Thank you, Chuck. Thank you to all of you who are joining us on the call today. On the heels of our DMD data presentation a few weeks ago, I am excited to talk to you about the hemophilia A gene therapy data just presented with our partner, Sangamo, at the World Federation of Hemophilia Virtual Summit. I'm joined today by Seng Cheng, our Rare Disease Chief Scientific Officer, will share the details of the hemophilia A gene therapy data presented this morning, and who will be joined later for Q&A by Dr. Brenda Cooperstone, our Rare Disease Chief Development Officer. You will also hear from Mori Birnbaum, our Internal Medicine CSO. Mori will share exciting new data on our oral small molecule GLP-1 receptor agonist program, which we just presented at the ADA 80th Scientific Sessions.
Aditi Saxena, the clinical lead that was presenting the data at ADA, will be joining us for the Q&A. These presentations underline opportunity in our pipeline in two therapeutic areas, rare disease and internal medicine, that I believe are underappreciated externally at this point. They also showcase our overall approach to advancing potential next-generation breakthrough science through both partnerships and homegrown efforts. Both programs break new ground. In hemophilia A, our investigational gene therapy may have the potential to provide a long-term, durable response for patients, a vast improvement from the weekly infusions of current standard for hemophilia A. Likewise, a small molecule oral treatment to take on diabetes would also mean an improvement over the injected standard of care for people living with type 2 diabetes and potentially improve the treatment of obesity.
I will briefly discuss how we see both programs fit within Pfizer's strategy and the potential opportunity for patients. First, a few comments and context on gene therapy and where it fits within our strategy based on a question we often get asked. We expect phase III gene therapy development programs ongoing by the end of this year in hem A and B and in Duchenne muscular dystrophy. I believe this will make us the only company in the world with that number of gene phase III of development. a few short weeks ago, we presented the data from our investigational minidystrophin gene therapy program for DMD at the ASGCT annual meeting. We have continued to make robust progress with this program and look forward to starting a pivotal trial for this potential therapy later this year.
Pfizer's gene therapy programs will be using drug products manufactured with a commercial process at commercial supply scale. To increase our manufacturing capacity, we have invested approximately $800 million in three manufacturing facilities in North Carolina. Now, I want to share why we're excited about the hemophilia A data that was presented this morning, giroctocogene fitelparvovec, formerly known as SB-525. This hem A gene therapy program from our partnership with Sangamo Therapeutics benefits from our heritage in hemophilia and is one of several potential innovative therapies for patients with hemophilia. The data presented today in this program demonstrated that five subjects receiving the gene therapy have at between 30 and 61 weeks of follow-up, sustained robust functional Factor VIII activity without the need for additional factor replacement following an initial use of prophylactic factor.
This shows the potential for our gene therapy to be a differentiated one from other hemophilia A gene therapies currently evaluated in the clinic. Pfizer is currently enrolling subjects phase III lead-in study for the hem A gene therapy program, which will serve as the phase III registrational study. we remain on track to dose the phase III later this year. At Pfizer, phase III programs for the treatment of patients with hemophilia. You will hear more about them soon. More broadly, and looking to next year, in 2021, we have the potential to have five rare disease programs phase III trials.
I want now briefly to discuss the potential in diabetes and obesity of our oral small molecule GLP-1 receptor agonist, which was homegrown in our Internal Medicine Research Unit led by Mori, who you will hear from shortly in more detail. Whereas some of our peers have pulled back from internal medicine, we see great opportunity. Internal Medicine has assembled a novel, science-driven and balanced early mid-stage pipeline focused on a few key areas. Nonalcoholic steatohepatitis, for short NASH, cardiovascular, type 2 diabetes and obesity, cachexia or muscle wasting. We have important momentum across our Internal Medicine pipeline with more than five phase II-b programs that, if successful, phase III starts between 2021 and 2022. Today, we'll be focusing on our oral small GLP-1 receptor agonist, sharing new, exciting data on this potential medicine that was all discovered in-house at Pfizer.
The data demonstrated a real potential opportunity for patients, our aspiration is to develop the most efficacious oral therapy for type 2 diabetes mellitus and develop the first small molecule oral GLP-1 receptor agonist for both obesity and type 2 diabetes. In doing so, we hope to help address these two growing global epidemics and their devastating impact on patients, society, and economies. The GLP-1 receptor agonist class may also show promise as a NASH therapy. More to come on that at a later time. I want to turn over to Seng for us to walk us through the hemophilia data.
Thank you, Mikael. I'm very pleased with the opportunity to present this morning an update of our hemophilia gene therapy program that was just shared at the World Federation of Hemophilia Virtual Summit. As you indicated, Mikael, our hemophilia gene therapy program is part of a broader pipeline of genetic medicines that we're developing that presently also includes efforts in hemophilia B, as well as in Duchenne muscular dystrophy, all of which phase III testing in the second half of this year. In addition, we also have a partner gene therapy program in Wilson's disease that is also poised to enter clinical testing, as well as a pipeline of preclinical programs that are at different stages of maturity in four therapeutic areas of declared interest to this category, and these being rare dermatology, neurology, metabolic diseases, as well as in rare cardiology.
Our approach in any of these disease areas, as is our normal practice, is one that seeks to be comprehensive and that fully addresses all aspects of the patient's disease journey. For example, we may introduce a first transformational product, but then follow up with a next-generation product concept that exhibits significantly improved characteristics and that is designed to address aspects of the disease that still remain unmet. This is indeed the approach that we're applying to our patients with hemophilia A as well as hemophilia B, where we had initially introduced recombinant factor replacement therapies and are now developing non-factor replacement, as well as gene therapies that, if successful in gaining regulatory approval, will significantly improve the quality of care that we can provide to our patients.
As you can see in this slide, and many of you are aware, hemophilia A and B are X-linked genetic diseases that impact approximately 35,000 males in the U.S. and over 400,000 globally. They're caused by mutations in the gene encoding either Factor VIII in hemophilia A or factor IX in hemophilia B that are involved in blood clotting. Patients who have a deficiency in these factors suffer from severe bleeding into their joints that leads to pain, subsequent joint abnormalities that can limit their motion and thereby affect their quality of life. Early treatments that were developed include the use of plasma-derived clotting factors, but they carried the risk of contamination with pathogens. In part because of these medicines were subsequently eclipsed by the availability of recombinant factor therapy, such as ReFacto, BeneFIX, and Xyntha, among others.
More recently, these therapies have also been supplemented with longer-acting recombinant factors, bypass agents, factor mimetics that reduce the frequency as well as increase the ease of administration. If you move to the next slide. At Pfizer, in addition to gene therapy, we've also been researching the potential of a non-factor therapy, namely an anti-TFPI antibody or marstacimab, to reduce the burden of treatment as indicated here. By leveraging the extrinsic clotting pathway with marstacimab, we have the opportunity to address both hemophilia A and B patients with a single agent. Because this is not a factor replacement therapy, it also offers the opportunity to address patients with inhibitors. This is particularly pertinent for the hemophilia B patients with inhibitors who are not adequately managed by current therapies.
I hope you agree that if this development program is successful, the availability of such an anti-TFPI antibody-based therapy would indeed represent a breakthrough first-in-class therapy for this specific patient population. As you see in this slide, I'm pleased to report that results from our Phase I-B/II studies and extension study demonstrated that indeed, weekly subcutaneous delivery of marstacimab led to a reduction in annualized bleeding rates of ABRs ranging from 82%-96% relative to the six months prior to the study entry, depending on the respective cohort. Both the 150 and 300 mg flat dosing regimens that were tested were well-tolerated, and there were no treatment-related SAEs in the 20 patients that are treated so far. In this study, I'm sorry.
Importantly, there were also no indications of excessive pharmacological effects or thrombotic events to date, including the subjects who received up to 15 months of marstacimab prophylaxis. Based on these encouraging results, the program was granted Fast Track phase III pivotal study has been initiated across 24 countries with the 150 mg dose. If successful, this could support a submission for regulatory approval within the 2023 timeframe. In addition to marstacimab, as I show on the next slide, we've also been developing gene therapeutics for hemophilia A and B using the common AAV vectors that offer the potential for one-time, long-term solution for phase III hemophilia b gene therapy program, which we will not present today, began recruiting patients in 2019.
The lead-in phase has fully enrolled. We are on schedule to generate data that we hope will support regulatory filing in the second half of 2021. However, as Mikael indicated earlier this morning, I would like to provide you with an update on our gene therapy efforts in hemophilia A, which is being co-developed with Sangamo Therapeutics, and in particular, our findings in the high-dose cohort in the Alta study. Which, as you can see here, is a phase I/II dose-ranging, single-dose, multi-center study with giroctocogene fitelparvovec or SB-525, as it's been used before in adult patients with severe hemophilia A. As illustrated on this slide, the gene delivery vector is an AAV6 serotype vector encoding a B-domain deleted Factor VIII that replaced under the transcriptional control of a liver-restricted promoter.
A B-domain deleted Factor VIII variant, which had previously been shown to have the same activity as wild-type factor, was selected to allow it to be incorporated into the limiting packaging capacities of the AAV vector. We have previously shared the initial findings from this program at the ASH meeting in December 2019, during which we presented Factor VIII expression data up to 36 weeks. Today, I will report on our follow-up observations that include expression data in the five patients who were treated at a 3E13 vector genomes per kilogram dose 61 weeks or 14 months. The key exclusions for the study were patients with neutralizing antibodies to the viral capsid or inhibitor to Factor VIII. Anyone who had a history of hypersensitivity to Factor VIII replacement therapy, significant liver dysfunction, or whose steroids were contraindicated were also excluded.
The study primary endpoints were safety and tolerability, as assessed by the incidence of adverse events and serious adverse events, and by changes in clinical lab assessments, vital signs, EKG, and liver imaging. Changes in circulating Factor VIII levels were also mentioned in these studies. Secondary endpoints included changes in baseline use of Factor VIII replacement therapy and the frequency and severity of bleeding episodes, as well as Factor VIII inhibitor levels. On the next slide, from a safety perspective, we observed that infusion of a dose of 3E13 vector genomes a kilogram of giroctocogene fitelparvovec, which is the dose administered in the high-dose cohort in five patients, was generally well-tolerated. However, one patient did experience a serious adverse event of hypertension and fever of six hours post-infusion that resolved by 12 hours from onset.
Importantly, with the implementation of additional supportive care guidelines, we have not observed similar severity events in the subsequent four subjects who were dosed. Among the five patients in this high-dose cohort, four received treatment with corticosteroids for liver enzyme elevations. Three of these patients had subsequent ALT elevations, which also resolved following a repeated course of corticosteroids. All episodes of ALT elevations were controlled with oral corticosteroids, and importantly, with maintenance of sustained functional Factor VIII activity levels. The next slide shows the rise in Factor VIII activity that was observed over the course of the study in the five subjects who had been administered this high dose of 3 E13 vector genomes per kilogram, including one at 61 weeks post-treatment.
As you can see, patients appeared to achieve steady-state levels of Factor VIII activity by approximately nine weeks post-infusion. These levels were sustained and remained undiminished in all the patients through the last data point prior to the data cut. The median steady-state Factor VIII levels was estimated to be 64.2%. This actually represents the median of the patient-level geometric means since week nine post-infusion using the chromogenic assay, which is in the normal range. Important, I should say, that associated with this expression profile, none of the patients experienced bleeding episodes or required Factor VIII replacement therapy subsequent in the first three weeks, including the patient at the 61-week time point. The next slide, the data for the high-dose cohort is summarized here in a box and whisker plot.
It again reflects the rise in Factor VIII levels we saw, reaching a stable plateau at about week nine that was then maintained through 36 weeks. We only show data up to 36 weeks here because the number of patients with follow-up beyond that timeframe is too low for this analysis. It's important to note that the mean Factor VIII levels calculated for these five patients for the nine-week time point, shown here as a dotted blue line, is above the lower bounds of what has been specified as a normal threshold, indicated here by the red line at 50%. In the next slide, in summary, the new data that we've showed since the time of the last update and now containing the additional follow-up observations, including up to the 61-week time point in one patient, continue to demonstrate that gene encoding Factor VIII is generally well-tolerated.
Sustained expression of functional Factor VIII levels was achieved, which resulted in no bleeding episodes or requirement for exogenous Factor VIII in the treated patients. There was one treatment-related SAE associated with Factor VIII infusion that did not have a recurrent sequela. I should add that follow-up for the lower dose cohorts that now extends up to over two years did not show any clinical significance safety as well. Collectively, the encouraging safety and efficacy data are strongly supportive of further development of the gene therapy concept, and we have phase III leading study with the first dosing in the pivotal study expected to occur later this year. I should also mention that this program has been granted FDA Fast Track as well as our RMAT designation.
With this important milestone, as Mikael indicated, we will become the only company to have phase III programs in the clinic this year. When combined with our gene therapy program in hemophilia B, as well as our marstacimab for panhemophilia, we are building the next generation of therapies for hemophilia patients. In doing so, we believe are working to provide meaningful therapeutic options to help patients manage their hemophilia. In closing, I would like to say that we're extremely pleased and excited with our having identified a dose for hemophilia A that's well-tolerated and importantly, that has demonstrated ability to consider sustained and undiminished expression of Factor VIII through 61 weeks in the absence of any associated bleeding events, and therefore the potential to be a differentiated hemophilia A gene therapy program.
I look forward to the opportunity of providing you with additional updates as the data matures further. With that, I will turn it over to Dr. Mori Birnbaum , who will share his insights on our GLP-1 agonist for diabetes.
Thanks very much, Seng. As Mikael said earlier this week, at the American Diabetes Association meeting, my colleague, Aditi Saxena, presented the data from a phase I-B study utilizing our first oral small molecule GLP-1 receptor agonist. This morning, I'm delighted to have the opportunity to briefly summarize those data, to also give you a sense of where this particular drug fits into the larger context, larger portfolio in Internal Medicine. Of course, I'd be happy to answer questions later. The Internal Medicine R&D strategy really seeks to build on the long successful legacy at Pfizer for developing cardiovascular and diabetes drugs. In recent years, there's been remarkable success at developing therapeutics for serious diseases, cancer, blood pressure. We've reduced smoking and contributed also by our smoking cessation agent from Internal Medicine, Chantix.
All of these have led to an extension of lifespan, but at the same time, we're improving the quality of life and extending lifespan for many in Western societies and throughout the world. There's also been an adoption of the so-called Western lifestyle, which is defined by overconsumption of calorie-rich meals and a decrease in exercise. The result of all of this has been a worldwide epidemic of obesity, which carries with it the potential for serious disturbances in metabolism. Now, the most widely recognized manifestation of abnormal metabolism is the disease diabetes, which is widely recognized as the major predisposing factor for cardiovascular disease and non-alcoholic fatty liver disease or NASH. All of these symptoms have shared common underlying metabolic abnormalities that really cause the disease. Our goal in the Internal Medicine R&D group is to target those underlying metabolic disorders which cause these related diseases.
At present, there are phase II studies ongoing in internal medicine, each of which has the potential to phase III in the 2021/2022 timeframe. We have three trials in NASH phase II, each targeting a different metabolic pathway, each utilizing a small molecule completely developed in Pfizer, and each at present, a first-in-class target or combination of targets. Recently, we licensed an antisense oligonucleotide directed against the angiopoietin-like 3 protein, the so-called vupanorsen. Angiopoietin-like 3 is a genetically validated protein, and we anticipated by reducing its levels in serum, we will also reduce the levels of atherogenic lipids that represent much of the residual cardiovascular risk, even after correction of LDL cholesterol levels. We've added cachexia to our portfolio because we see that as a medically important metabolic disease for which there are no approved therapies.
Today, I want to tell you about our GLP-1 receptor agonist, which I'll refer to as PF-2961. Again, this is a small molecule that can be taken orally without any dietary restrictions or fasting. It was developed completely in-house at Pfizer and promises to be the first small molecule of GLP-1 receptor agonist, and also the first GLP-1 receptor oral agonist of any kind to be available for obesity. Could I have the next slide, please? In spite of many drugs that are available for the treatment of diabetes, for most people with this disease, their diabetes is not optimally controlled. In the U.S., for example, fully one-third of individuals with diabetes go undiagnosed. Of the two-thirds who are diagnosed and under active treatment, less than 50% actually achieve their target hemoglobin A1C levels.
As poorly controlled as this disease is, the opportunities for medical treatment for obesity are even fewer. I think the vast amount of data available now clearly defines the safest and most effective therapy for obesity to be the GLP-1 receptor agonist class of drugs. In spite of this, remarkably few people who are obese or overweight are actually taking this therapy. We believe the primary factor leading to such a small adoption of such an effective therapy is the resistance of patients and primary care practitioners alike to an injectable therapy. This is all the more so because this is a largely asymptomatic disease, and in fact, is perceived by many, not as a disease, but as a lifestyle choice. Well, however you view obesity, there is no doubt that obesity predisposes to a large number, over 200 medically serious diseases, including diabetes and cancer.
The next slide, please. As I said, I'm going to tell you briefly about a Phase I-B study addressing the safety and tolerability of the Pfizer glucagon-like peptide 1 receptor agonist, PF-2961, a small molecule administered twice daily. This is a four-week study, randomized, placebo-controlled, which is of a classic multiple ascending dose design. As is true of all members of this drug class, in order to achieve maximally therapeutic drug levels, it's necessary to uptitrate in order to reduce some of the adverse effects. Like all other GLP-1 receptor agonists, that's the design of this study. In this case, what we did was for all but the lowest doses, there was a two-week period of titration followed by two weeks of stable administration.
The next slide shows that the results of the study showed a safety and tolerability profile that was entirely consistent with prior members of the GLP-1 receptor agonist class. There were no serious adverse effects, there were no deaths, and there were only two drug-related withdrawals of the 98 folks enrolled in the study. The most frequently reported adverse effects were to be anticipated by a GLP-1 receptor agonist, and they were related to gastrointestinal disturbances, nausea, dyspepsia, vomiting, and so forth. In addition, there was an increase in heart rate. Again, this is very typical of the GLP-1 receptor agonists. It was at a level typical of GLP-1 agonists in four-week studies. It is known that the increase in heart rate tolerates over time, but much more importantly, in longer studies using injectable GLP-1 receptor agonists, it's well recognized that this class of drug actually produces cardiovascular protection.
Again, overall, the GLP-1 receptor agonist, PF-2961, has a tolerability profile very typical of prior injectable members of this drug class. The next slide shows you a summary of the type of efficacy we saw in this brief study. The participants in the study were all, on average, afflicted with mild to moderate diabetes. You can see this evidenced by the fasting plasma glucose in the high 100s and a baseline of hemoglobin A1C at 8.3%. As you can see in the first row across, administration of PF-2961 led to a dose-dependent reduction in fasting plasma glucose, which was significant at all doses of the drugs administered. Remarkably, at the highest doses and the mid-to-highest doses, PF-2961 produced a near complete normalization of the increase of fasting plasma glucose that these participants had at baseline.
I should note that this decrease in glucose was not associated with any report of hypoglycemia. Another way of looking at this is by examining the hemoglobin A1C. This is a very short study to see changes in A1c, and yet, again, at the mid to high doses, there was both a statistically significant as well as a clinically significant reduction. The hemoglobin A1C placebo-corrected decreased 0.8%, which I should note is on a par with many of the widely available and utilized oral anti-diabetic agents on the market today. Lastly, of course, body weight was measured. Again, at the highest dose, there was a striking decrease in body weight, almost eight kilograms decrease at four weeks or about 8% decrease in body weight, since on the whole, the patient started at about 100 kg.
This is an impressive early sign of efficacy for a study in which the highest dose, 120 mgs BID, was administered only for two weeks. I should point out also that in the short study, it is very unlikely that neither the blood glucose nor the weight loss has reached maximal effect. We anticipate in longer studies, the fasting blood glucose to continue to decrease or to stabilize and hemoglobin A1C to continue to decrease over the next eight to 10 weeks. Of course, we don't know yet until we do those studies exactly what the ultimate reduction in hemoglobin A1C will be. Experience with this and other drugs allows us to model it. When we do submit the mean daily glucose model, it predicts a steady state hemoglobin A1C reduction of about 1.7% or perhaps more.
Again, this would put PF-2961 at an equivalent efficacy of injectable GLP-1 receptor agonists. Next slide. In summary, today, what I've done is I've shown you evidence that PF-2961 is an effective glucose-lowering agent. I've shown you some early signs that it holds great promise as an effective anti-obesity drug. Importantly, it can be administered orally without any need for fasting or any other dietary restriction. In addition, its formulation makes it available for fixed-dose combinations, which historically has been quite important for these individuals with diabetes, especially because of their higher pill burden. In view of the early successes with PF-2961, we're in the process of initiating phase II study in diabetes, which we anticipate will start dosing next month in July. Later this year, we will also begin phase II study in obesity, which will run in parallel.
Lastly, I should point out that we are cognizant of the success that GLP-1 receptor agonists have had early on in treating NASH, and we look forward to integrating PF-2961 into our already exciting and robust NASH portfolio. With that, I thank you. I will turn it back to Chuck, and I look forward to answering your questions.
Great. Thank you, Mori, Seng, and Mikael for your prepared comments. At this time, operator, can we please poll for questions? Thank you.
Ladies and gentlemen, if you would like to ask a question, please press star then the number one on your telephone keypads. Your first question comes from the line of David Risinger from Morgan Stanley.
Thanks so much. I have three questions on the oral GLP-1, and thanks very much for the detailed presentations today. The first is, could you discuss the very phase II dosing range, which will include 2.5 mg up to 120 mg or I think 48 x the lowest dose? Second, after patients are dosed, how long do they have to wait to eat or drink phase II? third, are you working on reformulation efforts? I believe that currently it is BID four pills at the high doses. Thank you.
Thank you, Dave. Please. Thanks. All great questions. I think I'll take them backwards. First of all, yeah, we're always in the process of improving formulation. I should point out that the number of pills that were administered in the past study really was just given that way to maintain blinding in such a multi-dose study. We anticipate ultimately that this will probably be administered by a single pill twice a day. There will be, in reference to your question about how fasting will be a priority to before or after administered PF-2961, we anticipate absolutely no restrictions in eating at all. This is well-absorbed, whether taken with fasting or with food, and therefore, there will be no dietary restrictions. I think for the questions on our choice of dosing, I think I'll turn it over to Aditi and let her answer the question. Aditi?
Thank you, Mori. The dose range that's being assessed in phase II study, as you mentioned, does range from 2.5 mg BID up to 120 mg BID because we are trying to assess the efficacy across that broad dose range. Our lowest dose in our phase I-B study that we administered for two weeks was five mgs BID, and our modeling of the mean daily glucose data from that low dose of five mgs BID indicates that it may be at least as, if not more, efficacious as the currently available oral agents to treat diabetes, excluding the GLP-1 class. We're really trying to understand the full range of the efficacy across this range of doses, both for glycemia and for weight loss.
Thank you. I thought it was very encouraging to hear that we are projecting to be as efficacious or more efficacious than currently available injectable, and we anticipate no food restrictions, which is different from any reformulated. Next question, please.
Your next question comes from Terence Flynn from Goldman Sachs.
Hi. Great. Thanks for taking the questions, and thanks for hosting the event today. I guess, again, another question on the oral GLP. I was wondering if you're looking at all ways to try to optimize the GI profile further. I recognize some of these are class effects, but at least at first pass, when we look at diarrhea and vomiting rates, it looks somewhat higher than oral semaglutide. That was the first question. With respect to the heme A program, can you tell us what percentage of patients met the exclusion criteria for anti-AAV6 antibodies? How do you think about enrollment of the pivotal trial given the competitive landscape? Thank you.
That was terrific with the multiple question on both sub-presentations. Mori, you start with the oral GLP-1 and the GI, and then we have followed in by Seng and Brenda to comment on individually the exclusion, the presented with pre-formed antibodies and aspects of enrollment.
Thanks, Mikael. Thanks for the question. As you note, the GI disturbances that we saw in this study are very typical of the class. I really don't think they are any more than have reported with semaglutide. Remember that most of the studies, in fact, all the studies you're seeing with semaglutide are very extended studies. It's well known that these GI effects tolerate over time. I think if you go back and look at some of the four-week studies with the injectables, you'll find that the GI effects we're seeing are very comparable or in some cases considerably less.
As far as titration schemes, the reality is that in a four-week study where we wanted desperately to get two weeks of stable dosage, the two-week titration was much faster than we really anticipate we're going to use in the latter studies and certainly when this drug is ultimately approved. It's faster, and I think that increased it. I just want to point out that one of the real advantages of the oral therapy, and we've been told this by a lot of practitioners, is unlike the injectables, it really gives you a chance to back-titrate. In other words, if you get too much vomiting, you can easily drop the doses of an oral and have an individual with diabetes or obesity respond.
One of the issues with using some of the injectables is if you go too quickly and get too much GI upset, the patient has to live with that for a while, a week or two, and that turns a lot of patients off. Overall, I don't think our tolerability is any worse than the injectables, and I think you'll see it reduce quite a bit as we go into longer studies with slower titration schedules. Seng?
Number of patients that were excluded because of neutralizing antibodies, but I know from the literature that's been reported previously for AAV6, that's around the 20% benchmark.
Thank you. Brenda, on the recruitment plans?
The pivotal program is actually in two parts. The first is the six-month lead in where patients are assessed on their ongoing prophylaxis, and that has already begun, actually began in 2019. We have not had an issue with respect to enrollment, notwithstanding COVID. We anticipate coaching patients coming off of that starting in the second half of this year, and don't anticipate that enrollment in and of itself, even in this competitive environment, will be any issue given that this is a global trial and that Pfizer has a long-standing relationship with the hemophilia patient community and healthcare providers.
Thank you, Brenda. I thought that was a very encouraging answer. We should note also that durability and a very robust level well above 50% of normal factor. This is in stark contrast to recent reports by another company where you see number of patients dropping to below detection levels. I do think, as Brenda summarized, we would expect high patient and physician interest in this best-in-class product, and that's what we've seen so far. Next question.
Your next question comes from Louise Chen from Cantor.
Hi. Thanks for taking my questions here. First question I had for you is, how do you see the market shaking out for GLP-1s oral versus injectable? There are also these GIP/GLP combos amongst others. Where do you think you'll fit in here? Second question is on the durability of your heme A drug. Do you expect to see potential decline in Factor VIII level expression like we've seen in other competitive drugs, or do you think it'll be stabilized? Lastly is, how deeply do you think gene therapy products will penetrate the market? Thank you.
Mori, start with the aspect of how you see this product penetrate, and maybe you could speak about both the existing GLP-1 injectable and the oral market that is existing. Then we can move to Brenda to share thoughts about durability and the share of gene therapy in the future, particular for those that are sustainable.
All right. Thanks, Mikael. There's been an enormous amount of success with getting the injectable GLP-1 therapy to patients with diabetes, less so getting that same therapy to individuals with obesity. Nonetheless, as I mentioned, still a large percentage of people with diabetes, and especially so with obesity, are just unwilling to take the injectable or just find it inconvenient. Compliance has not been what one would have hoped with injectable type of therapy. In diabetes, we think there's a tremendous opportunity for the oral in getting to those patients who are either unwilling to take injectables who are taken care of by primary physicians who are ill-equipped to train patients in terms of injections. In the case of obesity, I think the opportunity is even greater. We anticipate that PF-2961 will be the first GLP-1 receptor agonist approved for obesity.
To our knowledge, the current peptides that are being developed for obesity have not been disclosed I'm sorry, which are being developed for diabetes, so far, we have not heard anything about them being developed for obesity. So quite possibly, PF-2961 will be the only orally available anti-obesity GLP-1 receptor agonist. Right now, less than one in 20 people who are eligible for an obesity drug are being treated, and as of that, less than one in 20 are being treated with GLP-1 receptor agonists by injection. So really, the potential and the enormity of the untreated patient group is very impressive.
Thank you. Brenda.
Thank you, Mikael. As Mikael said, we've shown excellent sustained factor levels out through up to 61 weeks duration. This is the data that we have available. We think there is hope that this sustained factor levels will continue beyond the 61-week point and that this will phase III. We also believe that this is a very sophisticated patient population and treating healthcare providers and they will wait to see which therapeutic option would be best for the patients themselves. As Seng referred to, we have created a holistic approach to hemophilia so that we have factor replacement as well as non-factor replacement and gene therapy so that we can cover the entire spectrum of needs of this patient population. Our market assessment gives us an estimate of approximately 20% of eligible patients will avail themselves of gene therapy.
As I said, I do believe that we will see that patients and hemophilia specialists will wait to see what the best technology and treatment option will be for their patients, given this is a once-in-a-lifetime therapy.
Thank you. One observation is that some other companies have had needed for repeat use of steroids under long time after initial transfusion, and that likely is related to the drop in activity observed as you deplete for liver cells that are genetically transfected. We have seen mainly during the first early period, the need for steroids in general in patients. I think there is a good rationale why we see a durability that haven't been reported by all companies here. Next question, please.
Your next question comes from Geoff Meacham from Bank of America.
Hey, guys. This is Scott on for Geoff. Thanks for taking our question. I had a question on hemophilia A. Any thoughts on how frequently we can expect phase III trial? just wondering if it may be beneficial to update to show more durability to alleviate any concerns from the competitor that will already be on the market. Given what you've seen in the data provided to date, what are the expectations for steroid use phase III trial? thanks.
Thank you. Brenda?
The expectation, I can tell you with regard to steroid use, as Seng said, four out of the five patients did require some steroids, but that their levels of factor were sustained, and we did not see any drop as a result. They did not require prolonged steroid application. phase III, the data from our phase I trial will inform the decisions phase III steroid dosing. As of now, we do not anticipate that we will be using prophylactic steroids, but we will use it reactively as the phase I trial was designed.
Thank you. Next question, please.
Your next question comes from Steve Scala from Cowen.
Thank you. I also have some questions on the hemophilia A program and the LFT elevations. Just to be clear, based on your answer to the last questions, the LFTs did not go back up after cessation of steroid treatment. Is that true? Second, have you considered extending the duration of steroid treatment? Can you clarify, is the filing in the second half of 2021? That was not clear. That's on the hemophilia A program. On the oral GLP-1, you have two programs, one's phase II and one's in phase I. Maybe you could tell us the difference between them. Thank you.
Yeah. I think, Brenda, you want to speak about the hem A and, Seng, if you want to add anything to Brenda's comment, please do that. Then we'll follow with Mori on why you have explored two different GLP-1.
Of the five patients that were discussed in this presentation, three of those did have a repeat increase that was well-controlled with repeat steroids. One did not have any increase in AST/ALT that required steroids, and one had only a single elevation. That is the steroid result for all those five patients. Again, we will use the data that is generated in the phase I to inform the decision with regard to phase III. with that, I'd ask Seng if he has anything to add.
Let me just add that the resolution occurred very quickly, within two weeks, and that prompt intervention appeared to preserve the therapeutic benefit. To reiterate that we maintained Factor VIII levels in the follow-up period despite the elevations that we saw.
Thank you very much. Anything about the filing in addition to what you stated in your oral remarks?
Yes. Excuse me. The anticipated filing for hem A is in 2023. I believe the date of 2021 in Seng's presentation was in reference to the filing for hemophilia B.
Okay. As always, we'll keep options for looking for acceleration opportunity, which has been quite successful in our hands. Good to have you confirm the plan. Now, Mori, the oral GLP-1, the additional molecule that you did not speak about today.
Right. Thank you. Thanks for pointing out we do have additional molecule. In addition to PF-2961, there is another molecule that just completed single ascending dose. In non-clinical studies, it has very much the same profile as PF-2961. I think right now it looks like the major differences, if there are some, will be pharmacokinetic. I just want to say, make it clear, that this isn't backup. PF-2961 so far has looked quite good, and we're determined to take it forward for diabetes and obesity. However, it is notable that the GLP-1 receptor agonism mechanism has shown to be, in early studies, effective for quite a few diseases. Mikael mentioned that it's been shown to be effective in NASH, and there are other even more preliminary studies suggesting that GLP-1 receptor agonism might actually help folks with neurodegenerative disease, both Alzheimer's and Parkinson's.
Given what a long time it has been, how difficult it has been for us and others to develop this class of small molecule agonists, we just thought that the best we could do to put ourselves in the optimal position to have two effective therapies going forward. Really, all we're trying to do is increase the range of our opportunities as we bring forward this novel oral therapy.
Thank you very much. I noted there was a lot of questions on the durability and steroid use, and I think I pointed out the transient and moderate need for steroids in our patients. The robust durability of factor, substantial above 50% of normal, is quite distinct and different from what you're seeing with another company reporting recently. That gives us quite some confidence that we have a unique best-in-class profile. Of course, we can see that in an area of hemophilia A or B being very important, that you don't lock yourself out from the ability of maybe decade-long benefit by using infusion of AAVs that cause significant immune reaction and cross-reactivity for later gene therapy. We are eager to follow how this develops, but we currently have a very positive view from our own and key opinion leaders. Next question.
Your next question comes from Umer Raffat from Evercore.
Hi. Thanks so much for taking my question. On the gene therapy first, if I may. There's now the second patient who's dropped off, I believe patient 11. I know we previously knew that patient nine, which had reported some drop-off, had a 50% drop in their von Willebrand factor. Was it the same issue that happened to patient 11, or was it liver inflammation? I ask because I know you mentioned three patients required repeat steroids because of liver enzymes. Was it patients eight, nine, and 11 that was the repeat steroid dose given to? Just a quick one on oral GLP-1. The baseline weight loss for the 120 mg BID group, I think that'll be very helpful because I believe the baseline for weight was reported across the whole trial, across doses.
If we could just have the baseline weight for the 120 BID dose in particular or just a confirmation that it is around 92, which was reported for overall. Thank you so much.
Thank you. Great detailed questions here. Seng, you want to comment on what we can learn from the individual patient here?
If I recall, the patient nine, the Factor VIII level indeed had remained stable since week 18. In patient 11, I can't remember which one that is. I would have to pull up that data. Brenda, do you remember that patient 11 by any chance?
Yeah. Patient 11 had a very late elevation in ALT, which we don't believe had any relationship at all to the dosing or the presence of the transgene. It is very difficult to draw any conclusions for a single patient experience. We believe that any changes in ALT, although they were treated with steroids, it was not as a result of the construct itself.
Thank you. That was very clarifying. Mori, can you give the baseline weight for that oral GLP-1 high dose?
I can't recall, but let me ask Aditi if she has within easy reach the baseline weight specifically for the 120 BID group. Do you remember that, Aditi?
Yes, I'm here, and I can answer that question. As we presented in the ADA presentation, there were differences in baseline parameters across the cohorts. This was because there were 12 participants per cohort. There was some variability in the baseline parameters across cohorts, and this did include body weight. We presented the range of body weight across the cohorts, and they range from about 85 kg in one cohort up to 101.6 kg in another cohort. If I remember correctly, the specific baseline body weight for the 120 mg BID cohort was on the top end. It was around that 100 kg. The percentage change from baseline would need to be taken into that context. I would again remind the audience that this was a 28-day study.
We expect with longer duration of dosing and also a larger study phase II, there would be, of course, much more similarity in baseline parameters across the dosing regimens there, and it's much more clear. Yep.
Sorry, Aditi. I just thought it could help you to clarify. When you looked across the 12 patients or so in the 120, did you see a consistent, robust weight loss in all of them?
Yes. Absolutely, yes. There was consistent, robust, and statistically significant weight loss. It's just that when you start from a higher baseline, there can be greater short-term declines. We saw robust declines. I should actually maybe mention that the 70 mg BID cohort, which also saw declines of sort of an average of 4.4 kg, I believe, had a baseline body weight that was in the range of the mean recorded.
Mikael, this is Brenda. I do want to make a clarification. The patient I was referring to was actually patient seven who had the late steroid application. Patient 11, which is what your question was about, that patient had a Grade 2 ALT elevation, and his steroid taper was the quickest. It's very difficult to draw, again, any conclusions from that single patient's experience, but his levels have been sustained since the point where he stabilized. We have seen no further drop in levels in that particular patient. Thank you.
That's very reassuring. Thank you, both of you. Next, last question, I think.
Your final question comes from the line of Navin Jacob from UBS. Navin, your line is open. Please proceed with your question.
Are you on mute, Navin?
Hello?
Yeah, now we can hear you.
Hello.
We exited the queue. Operator, we exited the queue.
Thank you. That question has been withdrawn.
Great. This is Chuck again. We'd like to thank all of you for your attention this morning. I'd like to thank our Pfizer colleagues for the presentation and the Q&A session. Mikael, any closing remarks you want to make?
I would thank you. Yeah. Similar thought. There were some great questions from our colleagues in the analyst investor community, and we are pleased to be able to do more regular updates on the type of breakthrough science that we are sustaining. In this particular discussion today, you could see from two areas, rare disease, our comprehensive portfolio in hemophilia for multiple patient offerings in A and B. We remain very enthusiastic about both our Hem A and B gene therapies with potential for best-in-class profile. As we pointed out in the previous update a couple of weeks ago on DMD, also there, we continue to accumulate very encouraging data as we have refined the medical practice in those patients. We learn across all of our programs, and that's a strength of having such a comprehensive portfolio.
Similarly in internal medicine, as you noted, there is a great combination and synergy effect of being active in broad aspects of metabolic and cardiovascular disease, crossing diabetes, obesity, and NASH. You will hear more about the unique opportunities at Pfizer to combine drugs. Of course, oral GLP-1 could be by itself a pipeline in a pill. Look forward to hear more from Mori as we now move swiftly forward. Thank you, everyone.
Ladies and gentlemen, that does conclude today's conference. We thank you for your participation and ask that you please disconnect at this time.