Good day, everyone, and welcome to Pfizer's Analyst and Investor Call to review data presentations at scientific conferences during the week of June 15. Today's call is being recorded. At this time, I would like to turn the call over to Mr. Chuck Triano, Senior Vice President of Investor Relations. Please go ahead, sir.
Thank you, operator. Good morning, everyone, and 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 and 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 Michael 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 Michael 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 and we undertake no obligation to update or revise any of these statements.
With that, I'll now turn the call over to Michael Dylton. Michael?
Thank you, Shai. Thank you to all of you who are joining us on the call today. On the heels of our D and D data presentation a few weeks ago, I'm 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 Feng Cheng, our Rare Disease Chief Scientific Officer, which share the details of the hemophilia A gene therapy data presented this morning and who will be joined later for Q and A by Doctor. Brenda Cooperstone, our RadCity's Chief Development Officer.
You will also hear from Maury Bienbaum, our internal medicine CSO. Morrie will share exciting new data on our oral small molecule GLP-one receptor agonist program, which we just presented at the ADA Aedes Scientific Sessions. Aditi Saxena, the clinical lead that was presenting the data at ADA will be joining us for the Q and A. These presentations underlying opportunity in our pipeline in 2 strategic 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 weak infusion of current standard rheumab EIA. 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 that 3 Phase III gene therapy development programs ongoing by the end of this year in hem A and B and in Duchenne's muscular dystrophy. I believe this will make us the only company in the world with that number of gene therapy programs in Phase III of development. A few short weeks ago, we presented the data from our investigational immunity stroking 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 the pivotal trial for this potential therapy later this year. Pfizer's gene therapy programs will be using drug product manufactured with a commercial process at commercial supply scale.
To increase our manufacturing capacity, we have invested approximately $800,000,000 in 3 manufacturing facilities in North Carolina. Now I want to share why we're excited about the hemophilia A data that was presented this morning. Gyroctogen fritelparlovec, formerly known as SP-five twenty five. This 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 5 subjects receiving the INTERP have between 30 61 weeks of follow-up sustained robust functional Factor VIII activity without the need for additional factor replacement following an initial use of PROFIT 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 in a 6 month Phase III lead in study for the Hema gene therapy program, which will serve as the foundation of the Phase III registrational study. And we remain on track to dose the trust patient in Phase 3 later this year. At Pfizer, we have 3 Phase 3 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 5 rare disease programs in Phase 3 trials. I want now briefly to discuss the potential in diabetes and obesity of our oral small molecule GLP-one 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 or short NASH cardiovascular, type 2 diabetes and obesity, cathexia or muscle wasting. We have important momentum across our internal medicine pipeline with more than 5 ongoing Phase IIb program that if successful could enable multiple Phase III starts between 2021 2022.
Today, we'll be focusing on our oral small GLP-one 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 And our aspiration is to develop the most efficacious oral therapy for type 2 diabetes as Melatus and developed the 1st small molecule oral GLP-one receptor agonist for both obesity and type 2 diabetes. In doing so, we hope to help address these 2 growing global epidemics and our devastating impact on physicians, society and economies. The GLP-one receptor leggromine class may also show promise as a NASH therapy, More to come on that at a later time. Now I want to turn over to Seng first to walk us through the hemophilia data.
Well, thank you, Michael. I'm very pleased with the opportunity to present this morning an update of our hemophilia aging therapy program that was just shared at the World Federation of Hemophilia Virtual Summit. As you indicated, Michael, our hemophilia aging therapy program is part of the broader pipeline of genetic medicines that we're developing that presently also includes FS in hemophilia B as well as in Duchenne muscular dystrophy, all of which will be in Phase III testing in the second half of this year. In addition, we also have a partnered gene therapy program in Rosen'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 4 therapeutic areas that declare interest to this category, and these being rare hematology, 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.
So for example, we may introduce a first transformation of 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. And 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 the common 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. So as you can see in this slide and many of you are aware, hemophilia A and B are excellent genetic diseases that impact approximately 35,000 males in the United States and over 400,000 globally. They're caused by mutations in the gene, including Factor VIII in hemophilia A or Factor IX in hemophilia B that involve in blood clotting. Patients who have a deficiency in these factors suffer from severe bleeding into their joints that leads to pain, subsequent joint abnormality that can limit their motion and thereby affect their core of human life.
Early treatments that were developed include the use of plasma derived clotting factors that are carried to risk of contamination with pathogens. And in part because of these, these medicines were subsequently eclipsed by the availability of recombinant factor therapies such as Refactor, Benfix and Vinta among others. And 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. So 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 mafrastamab to reduce the burden of treatment as indicated here.
By leveraging the extrinsic chronic pathway with nastasumab, we have the opportunity to address both hemophilia A and B patients with a single agent. And because this is not a factory replacement therapy, it also offers the opportunity to address patients with inhibitors. And this is particularly pertinent for the hemophilia D patients with inhibitors who are not adequately managed by current therapies. And I hope you agree that if this development program is successful, the durability of such an anti TSPI antibody based therapy would indeed represent a breakthrough 1st in class therapy for this specific patient population.
So as you
can see in this slide, I'm pleased to report that results from our Phase IbII studies and extension study demonstrated that indeed weekly subcutaneous delivery of nastasumab led to a reduction in annualized bleeding rates, or ADRs, ranging from 82% to 96% relative to the 6 months prior to the study entry depending on the respective cohort. Both the 150 milligram and 300 milligram flat dosing regimens that were tested were well tolerated, and there were no treatment related SAEs in the 20 patients that treated so far in this study, I'm sorry. Importantly, there were also no indications of extensive pharmacological effects or thrombotic events to date, including the subjects who received up to 15 months of mastasumab prophylaxis. Based on these encouraging results, the program was granted fast track designation and a Phase III pivotal study has been initiated across 24 countries with the 150 milligram dose. If successful, this could support a submission for regulatory approval within the 2023 time frame.
In addition to nastafimab, 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 our patients. Our Phase 3 hemophilia DG therapy program, which we will not present today, began recruiting patients in 2019. The leading phase has fully enrolled, and we are on schedule to generate data that we hope will support work we're filing in the second half of twenty twenty one. However, as Michael indicated earlier this morning, I would like to provide you with an update on our gene therapy assets in Hemophilia A, which has been 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 III dose ranging, single dose, multi standard study with gyratocargine phytocarvopabovac or SB-five twenty five as we've used before in adult patients with severe hemophilia A. And as illustrated on this slide, the gene delivery factor is an AAV6 serotype vector, including a B domain deleted Factor VIII gene that is placed 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 capacity 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 5K8 expression data up to 36 weeks. Today, I will report on our follow-up observations that include expression data in the 5 patients that were treated at the 3e13 vector genomes per
kilogram
dose of 64 weeks or 14 months. The key exclusions for the study were patients with neutralizing antibodies in the viral capsid or inhibitor to Factor VIII. Anyone who has a history of hypersensitivity to Factor VIII replacement therapy, significant liver dysfunction or new steroids with contraindications were also excluded. The study primary endpoints with safety and tolerability as discussed 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 the Factor VIII inhibitor levels. So on the next slide from a safety perspective, we observed that infusion of a dose of 3 13 hectorgene per kilogram of gyratopagene phytopavodact, which is the dose administered in the high dose cohort in 5 patients, was generally well tolerated. However, one patient did experience a serious adverse event of hypertension and fever of 6 hours post infusion that resolved by 12 hours from onset. Importantly, with the implementation of additional supportive care guidelines, we have now observed similar severity events in the subsequent 4 subjects luer dose. Among the 5 patients in this high dose cohort, 4 received treatment with corticosteroids for liver enzyme elevations.
3 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's observed over the course of the study in the 5 subjects that have been administered high dose of 3e13factors genomes per kilogram, including 1 at 61 weeks post treatment. NSCC patients appear to achieve steady state levels of Factor VIII activity by approximately 9 weeks post infusion, and these levels will sustain and remain 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 mean since week 9 post infusion using the chromogenic assay, which is in the normal range. Important that you say that associated with this extra expression profile, none of the patients experienced leading episodes or required Factor VIII replacement therapy subsequent in the 1st 3 weeks, including patients at the 61 week time point. The next slide, the data for the high dose cohort is summarized here in the box in Whisker plot. It again reflects the rise in Factor VIII levels we saw, reaching a stable plateau of about week 9 that was then maintained through 36 weeks. We only show data up to 36 weeks here because the number of patients who follow-up beyond that time frame is too low for this analysis.
It's important to note that the mean Sacagate levels calculated for these 5 patients, 4 in the 9 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%. So in the next slide, in summary, the new data that we've shared 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 gylatolgene phytocarbam 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 recurrence sequela. I should add that follow-up for the lower dose cohorts that now extends up to over 2 years did not show any clinical significant safety as well.
Collectively, the encouraging safety and efficacy for the development of the gene therapy concept, and we have consequently initiated a 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 mass vaccinations. With this important milestone, as Michael indicated, we will become the only company to have 3 gene therapy Phase III programs in the clinic this year. Also, when combined with our gene therapy program in hemophilia B as well as our nastafimab for pan hemophilia, we are building the next generation of therapies for hemophilia patients. And in doing so, we believe, are working to provide meaningful therapy options to help patients manage their hemophilia.
So 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 the ability to confirm a sustained and underimmunize 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 this opportunity of providing you with additional updates as the data matures further. So with that, I would like to turn it over to Doctor. Mario Berndam, who will share his insights on our GLP-one agonist for diabetes.
Thanks very much, Zeng. As Michael said earlier this week, at the American Diabetes Association meeting, my colleague, Didi Sethsiner, presented the data from a Phase Ib study utilizing our first oral small molecule GLP-one receptor agonist. This morning, I'm delighted to have the opportunity to briefly summarize those data, but to also give you a sense of where this particular drug fits into the larger context, larger portfolio in internal medicine. And of course, I'd be happy to answer questions later. The internal medicine R and 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 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 nonalcoholic fatty liver disease or NASH. All of these symptoms have shared common underlying metabolic abnormalities that really cause the disease. So our goal in the internal medicine R and D group is to target those underlying metabolic disorders, which cause these related diseases. So present, there are 5 Phase II studies ongoing in internal medicine, each of which has the potential to advance to pivotal Phase III in the 2020 onetwenty two time frame.
We have 3 trials in NASH in Phase II, each targeting a different metabolic pathway, each utilizing a small molecule completely developed in Pfizer and each at present a 1st in class target or combination targets. Recently, we licensed an antisense oligonucleotide directed against the angiopoietin like 3 protein, the so called buprenorphine. 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 TATEXIA to our portfolio because we see that as a medically important metabolic disease for which there are no approved therapies. But today, I want to tell you about our GLP-one receptor agonist, which I'll refer to as PF-two thousand nine hundred and sixty one.
Again, this is a small molecule that can be taken orally without any dietary restrictions or fasting, who has developed completely in house at Pfizer and promises to be the 1st small molecule GLP-one receptor agonist and also the 1st GLP-one receptor oral agonist of any kind to be available for obesity. Can 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 United States, for example, solely onethree of individuals with diabetes go undiagnosed. Of the twothree who are diagnosed and under active treatment, less than 50% actually achieved 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-one receptor agonist class of drugs. And yet 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. And this is all the more so because this is 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 of the 200 medically serious diseases, including diabetes and cancer. The next slide, please. So as I said, I'm going to tell you briefly about a Phase Ib study addressing the safety and tolerability of the Pfizer Glucagon like peptide 1 receptor agonist of PF2961, a small molecule administered twice daily. This is a 4 week study of randomized placebo controlled, which is of a classic multiple ascending dose design. Now as is true of all members of this drug class, in order to achieve maximally therapeutic drug levels, it's necessary to up titrate in order to reduce some of the adverse effects.
So like all other GLP-one 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 2 week period of titration followed by 2 weeks of stable administration. The next slide shows that the results of this study showed a safety and tolerability profile that was entirely consistent with prior members of the GLP-one receptor agonist class. There were no serious adverse effects, there were no deaths and there were only 2 drug related referrals of the 98 folks enrolled in the study. The most frequently reported adverse effects were to be anticipated by a GLP-one 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-one receptor agonists, resulted at a level typical of GLP-one agonists in 4 week studies. It is known that the increase in heart rate tolerates over time, but much more importantly, in longer studies using injectable GLP-one receptor antagonists, it's well recognized that this class of drug actually produces cardiovascular protection. So again, overall, the GLP-one receptor agonist 2961 PF2,961 has a tolerability profile, very, very typical of prior injectable members of this drug class. The next slide shows you a summary of the type of efficacy where we saw in this brief study.
Now the participants in the study were all on average afflicted with mild to moderate diabetes. You can see this by the evidenced by the fasting plasma glucose in the high 100s and at baseline hemoglobin A1c of 8.3%. Now as you can see, in the 1st row across, administration of PF-two thousand nine hundred and sixty one 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, in the mid to highest doses, PF-two thousand nine hundred and sixty one produced a near complete normalization of the increase of fasten plasma glucose that these participants had at baseline. And 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, which 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 heat of golbin E1cplacebo 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, on body weight was measured. And again, at the highest dose, there's a striking decrease in body weight, almost 8 kilograms decrease at 4 weeks or about 8% decrease in body weight since on the whole the patient started at about 100 kilograms.
Again, this is an impressive early sign of efficacy for a study in which the highest dose, 120 milligrams PID, was administered only for 2 weeks. I should point out also that in the short study, it is very unlikely that either 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 8 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. But experience with this and other drugs allows us to model it.
And when we do submit the mean daily glucose model, it predicts a steady state hemoglobin A1c reduction of about 1.7% or perhaps more. And again, this would put PF-two thousand nine hundred and sixty one at an equivalent efficacy of injectable GLP-one receptor agonists. So next slide. In summary, today, what I've done is I've shown you evidence that PF-two thousand nine hundred and sixty one is an effective glucose lowering agent. I've shown you some early signs that it holds great promise as an effective anti obesity drug.
And importantly, it can be administered orally without any need for fasting or any other dietary restriction. In addition, its formulation is extremely is available 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-two thousand nine hundred and sixty one, we're in the process of initiating a Phase II study in diabetes, which we anticipate will start dosing next month of July. Later this year, we will also begin a Phase II study in obesity, which will run-in parallel. Lastly, I should point out that we are cognizant of the success that GLP-one receptor agonists have had early on in treating NASH.
And we look forward to integrating PF-two thousand nine hundred and sixty one into our already exciting 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, Maury, Sang and Michael for your prepared comments. At this time, operator, can we please poll for questions? Thank you.
Your first question comes from the line of David Risinger from Morgan Stanley.
So I have three questions on the oral GLP-one, and thanks very much for the detailed presentations today. The first is, could
you discuss the
very wide Phase 2 dosing range, which will include 2.5 milligrams up to 120 milligrams or I think 48 times the lowest dose? 2nd, after patients are dosed, how long do they have to wait to eat or drink in Phase II? And then 3rd, are you working on reformulation efforts? I believe that currently it is BID 4 pills at the high doses. Thank you.
Thank you, David. Thank you
very much, First of all, yes, 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. And we anticipate ultimately that this will probably be administrated by a single pill twice a day. There will be, in reference to your question about how fastening will be required either before or after administrative PF2961, we anticipate absolutely no restrictions in eating at all. This is well absorbed, whether taking with fasting or with food and therefore there will be no dietary restrictions.
And 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, Maury. So the dose range that's being assessed in our Phase 2 study, as you mentioned, does range from 2.5 milligrams CID up to 120 milligrams CID because we are trying to assess the efficacy across that broad dose range. Our lowest dose in our Phase Ib study that we administered for 2 weeks was 5 milligrams CID And our modeling of the data, the immune daily glucose data from that low dose of 5 milligrams CID indicates that it may be at least better, if not more efficacious than currently available oral agents to treat diabetes, excluding the GLP-one class. So we're really trying to understand the full range of the efficacy of COPSIS range of doses, both for glycemia and for weight loss.
Thank you. And I thought it was very encouraging to hear that we are projecting to be efficacious or more efficacious than currently available injectable. And we anticipate no food restrictions, which is different from any reformulated septic. Next question, please.
Your next question comes from Terence Flynn from Goldman Sachs.
Hi, great. Thanks for taking the questions Thanks for hosting the event today. I guess, again, another question on the oral glyph. I was wondering if you're looking at all at ways to try to optimize the GI profile further. I recognize some of these are class effects.
But at least at first pass, when you look at kind of diarrhea and vomiting rates, it looks somewhat higher than oral sema. So that was kind of the first question. Then with respect to the Hem A program, can you tell us what percentage of patients met the exclusion criteria for anti AAV6 antibodies? And then how do you think about enrollment of the pivotal trial given kind of the competitive landscape? Thank you.
Well, it was terrific with multiple question on both sub presentations. So Morrie, you start with the oral GLP and the GI and then we have followed in by Sang and Brenda to comment on individually the exclusion presented with preformed antibodies and aspects of involvement.
Thanks, Michael. As you know, thanks for the question. As you note, the GI disturbances that we saw in this study are very typical of the class. And 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.
And it's well known that these GI effects tolerate over time. I think if you go back and look at some of the 4 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 4 week study where we try want to desperately to get 2 weeks of stable dosage, the 2 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. So it was faster and I think that increased. 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 2, and that turns a lot of patients off. So 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.
A number of patients that were exclivity goes on neutralizing antibodies. But I know from the literature that's been reported previously for AAV6, that's around the 20% benchmark.
Thank you. And Brenda, on the recruitment plans?
So the pivotal program is actually in 2 parts. The first is the 6 month leave in where patients are assessed on their ongoing prophylaxis and that has already begun actually began in 2019. And we have not had an issue with respect to enrollment notwithstanding COVID. And so we anticipate go to 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, Brett. That was a very encouraging answer. And 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. So 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 GIPGLIP combos amongst others. Where do you think you'll fit in here? 2nd question is on the durability of your Hem 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 will be stabilized? And then lastly, how deeply do you think gene therapy products will penetrate the market? Thank you.
So, Maury, you start with the aspect of how you see this product penetrate and maybe you could speak about both the existing Lip-one injectable and the oral market that is existing. And then we can move to Brenda to share thoughts about durability and the share of gene therapy in the future, particularly for those that are sustainable?
All right. Thanks, Michael. Yes, there's been an enormous amount of success with getting the injectable GLP-one therapy to patients with diabetes, less so getting that same therapy to individuals with obesity. But 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.
So in diabetes, we think there's a tremendous opportunity for the oral in getting to those patients who are either unwilling to take injectables or 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 PF2961 will be the first GLP-one 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, 2961 will be the only orally available anti obesity GLP-one receptor agonist. Right now, less than 1 in 20 people who are eligible for an obesity drug are being treated. And as of that, less than 1 in 20 are being treated with GLP-one receptor agonist by injection. So really the potential and the enormity of the untreated patient group is very impressive.
Thank you. Brenda?
Thank you, Michael. As Michael said, we've shown excellent sustained factor levels out through the up to 61 weeks duration. And 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 be carried into Phase 3. 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 Sang 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. But 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. And 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. And we have seen mainly during the first early period the need for steroid in general in patients. So 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. So any thoughts on how frequently we can expect updates from the Phase 3 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?
And then given what you've seen in the data provided to date, what are the expectations for steroid use in the Phase 3 trial? Thanks.
Thank you. Brenda?
So the expectation, so I can tell you with regard to steroid juice, as Frank said, 4 out of the 5 patients did require some steroids, but that their levels were up back to were sustained. And they and we did not see any drop as a result. They did not require prolonged steroid application. In terms of Phase 3, the data from our Phase 1 trial will inform the decisions with regard to Phase 3 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 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? And second, have you considered extending the duration of steroid treatment?
Also, can you clarify, is the filing in the second half of twenty twenty one that was not clear? So that's on hemophilia A program. And then on the oral GLP-one, you have 2 programs, one is in Phase 2 and one is in Phase 1. Maybe you could tell us the difference between them? Thank you.
Yes. I think Brenda, you want to speak about the Heme and Sang if you want to add anything to Brenda's comment, please do that. And then we'll follow with Morrie on why you have explored 2 different clip 1?
So,
of the 5 patients that were discussed in this presentation, 3 of those did have a repeat increase that was well controlled for 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. So that is the steroid result for those for all those 5 patients. And again, we will use the data that is generated in the Phase 1 to inform, the decision with regard to steroid dosing in Phase 3. And with that, I'd ask Zeng if he has anything to add.
Let me just add that the resolution occurred very quickly within 2 weeks and that prompt intervention appeared to preserve the therapeutic benefit. And 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. So the anticipated filing for hem A is in 2023. I believe the date of 2021 was, in Sang'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. But good to have you confirmed the plan. And now, Mori, the oral GLP-one, the additional molecule that you did not speak about today.
Right. Thank you. And thanks for pointing out we do have additional molecule. In addition to 2961, there is another molecule that just completed single ascending dose. And in nonclinical studies, it has very much the same profile as PF2961.
And 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-two thousand nine hundred and sixty one so far has looked quite good and we've determined to take it forward for diabetes and obesity. However, it is notable that the GLP-one receptor agonism mechanism has shown to be in early studies effective for quite a few diseases. I mean, Michael mentioned that it's been shown to be effective in NASH and there are other even more preliminary studies suggesting that GLP-one receptor agonism might actually help folks with neurodegenerative disease, both Alzheimer's and Parkinson's.
So 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 2 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. And I noted there was a lot of questions on the durability and steroid use. And I think as pointed out, the transient and moderate need for steroids in our patients, the robust durability of Factor substantially above 50% of normal, is quite distinct and different from what you've seen with another company reporting recently. And that gives us quite some confidence that we have a unique best in class profile. And 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.
So we're eager to follow how this develops, but we are 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. And I know we previously knew that patient 9, which had reported some drop off, had a 50% drop in their Von Willebrand factor. Was it the same issue that happened in patient 11 or was it liver inflammation? And I asked because I know you mentioned 3 patients required repeat steroid because of liver enzymes.
Was it patients 8, 9 and 11 that was the repeat steroid dose given to? And then just a quick one on oral GLP. The baseline weight loss for the 120 milligram PID group, I think that will 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's around 92, which was reported for overall?
Thank you so much.
Thank you. Great detailed questions here. Zheng, you want to comment on what we can earn from the individual patients here?
So if I recall, the patient 9 the Factor VIII level indeed has remained stable since week 18. And in patient 11, I'm just I can't remember which one that is. I'm going to try to pull out that data. Brenda, do you remember that patient you're learning by the parent?
Yes. Patient 11 had a very late elevation in ALT and which we don't believe had any relationship at all to the dosing or the presence of the transgene. And so it is very difficult to draw any conclusions for a single patient experience, but 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. And Morrie, can you give the base line weight for that oral GLP 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. So as we presented in the ADA presentation, there was differences in 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. So we presented the range of body weight across the cohorts and they range from about 85 kilograms in 1 cohort up to 101.6 kilograms in another cohort.
And if I remember correctly, the specific baseline body weight for the 120 milligram BID cohort was on the top end. It was around that 100 kilograms So the percentage change from baseline would need to be taken into that context. But I would again remind the audience that this is a 28 day study. So we expect with longer duration of dosing and also a larger study in Phase 2, there would be, of course, much more similarity in baseline parameters across dosing regimen there and it's much more clear. Yes.
Sorry, Aditi. I just thought it could help you to clarify, when you looked across the 12 patients and so in the 120, did you see a consistent robust weight loss in all of them?
Yes, Absolutely, yes. So there was consistent robust and significantly and statistically significant weight loss. It's just that when you start from a higher baseline, there can be greater short term decline. But we saw robust declines. And I should actually maybe mention that the 70 milligram BID cohort, which also saw declines of sort of an average of 4.4 kilograms I believe, had a baseline body weight in the range of the epineum reported.
Michael, this is Brenda. I do want to make a clarification. The patient I was referring to was actually patient 7 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. And it's very, very difficult to draw again any conclusion from that single patient experience, but his levels have been sustained since the point where he stabilized.
So 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, Naveem?
Hello?
Yes, now we can hear you.
Operator, we exited the queue.
Thank you. That question has been withdrawn.
Right. So we'd like to this is Chuck again. So we'd like to thank all of you for your attention this morning. And I'd like to thank our Pfizer colleagues for the presentation and the Q and A session. Michael, any closing remarks you want to make?
Thank you. Yes, I 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 2 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. And 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. So we learn across all of our programs and that's the strength of having such a comprehensive portfolio.
And similar in internal medicine, as you noted, there is a great combination and synergy effect of being active in broad aspect of metabolic and cardiovascular disease crossing diabetes, obesity and NASH and you will hear more about the unique opportunities at Pfizer to combine drugs. And of course, oral GLP-one could be by itself the pipeline in appeal and look forward to hear more from Morrie 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.