Mikael Dolsten
Chief Scientific Officer and President, Worldwide Research, Development and Medical at Pfizer
Thank you, Albert. I'm delighted to share some highlights from Pfizer's R&D pipeline, which continues to be one of our greatest strengths. Today, I will share updates on eight select programs in which we are pursuing first-in-class breakthrough science and which have estimated approvals before 2030 and the potential to have profound impacts on millions of patients.
Last week, we announced a global collaboration with Arvinas to develop and commercialize ARV-471, potentially the first PROTAC, or PROteolysis TArgeting Chimera, estrogen receptor protein degrader. ARV-471 represents breakthrough drug design technology. PROTAC protein degraders efficiently eliminate rather than inhibit disease-causing proteins. To our knowledge, ARV-471, which was designed to be an oral, high-potency estrogen receptor degrader with a favorable safety profile, is the only ER-targeting PROTAC degrader in clinical development and has a distinct mechanism of action from the many SERDs in development. In the future, novel assets like ARV-471 have the potential to be the new endocrine therapy backbone either alone or in combination with CDK inhibitors such as IBRANCE, other targeted therapies, and/or therapies with novel mechanisms of action.
Early clinical data show ARV-471 has the potential to be an endocrine therapy of choice across treatment settings in breast cancer. ARV-471 is being evaluated as a treatment for metastatic breast cancer in a Phase 1 dose escalation study, a Phase 1b combination study with IBRANCE, and a Phase 2 monotherapy dose expansion study. Starting in 2022, we expect to initiate Phase 3 studies across lines of therapy in metastatic breast cancer, including in combination with IBRANCE, followed by pivotal studies in the early breast cancer setting.
Let me share some of the pre-clinical data that has us excited. The chart on the left shows ARV-471 demonstrated impressive anti-tumor activity in combination with IBRANCE (palbociclib) in pre-clinical studies. In the Phase 1 interim analysis of 21 patients, ARV-471 demonstrated a compelling efficacy signal in heavily pretreated patients, the majority with prior fulvestrant treatment and all with prior CDK4/6 inhibition treatment.
The images on the right show one patient on ARV-471 monotherapy who had a confirmed partial response after four cycles with a 51% reduction in target lesion size, as indicated by the arrows. Two patients had unconfirmed partial responses and one patient demonstrated stable disease with more than 50% target lesion shrinkage. Five paired tumor biopsies demonstrated ER degradation up to 90%, with an average of 62%.
The next program is ROBO2, details of which we have not shared previously. No disease-specific treatments are currently available for focal segmental glomerulosclerosis, or FSGS for short. We have developed in collaboration with Boston University and Boston Medical Center, a potentially novel and first-in-class disease modifying biological therapy comprising a SLIT-2 ligand antibody Fc trap that lowers activation of the ROBO2 receptor for treating FSGS as well as adjacent renal glomerulopathies. Preliminary results from an interim analysis of our ongoing Phase 2a study in adult patients with steroid resistant FSGS demonstrated promising data with a statistically significant and clinically meaningful reduction in urine protein to creatinine ratio, or UPCR. We are advancing the program to potentially demonstrate proof of concept in '22 and preparing for pivotal studies.
This chart shows the change in UPCR, a marker of renal function, from baseline in steroid treatment resistant patients in the Phase 2a study. There was a favorable reduction in proteinuria at 13 weeks based on data from approximately half of the first dose cohort of the study. Please note after stopping the treatment as per study protocol, the UPCR deteriorated indicating the need for continuous therapy. Treatment every two weeks was well tolerated with no significant safety signals to date.
Next, let's turn to our gene therapy programs in Hemophilia A and B and Duchenne Muscular Dystrophy. Pfizer continues to advance the broadest late-stage gene therapy portfolio of potentially transformational treatments. We expect phase 3 interim analyses for all three programs in '22. In a Phase 1/2 hemophilia A study, we have seen durable expression of Factor 8 through 78 weeks with an annual bleed rate in the first 52 weeks of zero.
In a Phase 1/2 hemophilia B study, we have seen sustained expression of Factor 9 activity into year four of the phase 1/2 long-term follow-up study, with an annual bleed rate of less than one. In a Phase 1b Duchenne Muscular Dystrophy study, statistically significant expression of mini-dystrophin and a 3.5 point increase in the North Star Ambulatory Assessment score have been observed.
Now we'll turn to our Lyme disease vaccine. The only active Lyme vaccine candidate in clinical development today being co-developed with Valneva.
The ongoing Phase 2 study, which completed recruitment of adult and pediatric participants last week, will evaluate the optimal vaccination schedule for use in Phase 3. We expect potential proof of concept in January '22 and a Phase 3 study start in the first half of '22.
This chart shows that more than 90% of subjects seroconverted to all six serotypes with a three-dose vaccination schedule at zero, two and six months in the Phase 2b study, demonstrating a favorable immune response.
Our respiratory syncytial virus vaccine is the most advanced bivalent protein-based vaccine with Phase 2 data published showing high neutralizing titers against both RSV A and B subtypes, which has not been demonstrated in clinical development by a monovalent prefusion F vaccine. We have been advancing this asset for both adults through direct vaccination and infants through maternal immunization.
Today, I will focus on adults. In 2020, we initiated a Phase 2a study to evaluate the safety, immunogenicity, and efficacy of the recombinant RSV pre-Fusion vaccine in a virus challenge model in healthy adults 18 to 50 years of age. I will show you data on the next slide which we plan to submit for peer reviewed publication soon.
Results from a Phase 2 challenge study of 62 subjects show the vaccine was 100% effective against mild-to-moderate symptomatic infection and most participants in the study experienced minimal to no side effects. As a performance benchmark, the Ad26.RSV preF vaccine showed 52% observed efficacy in the same human challenge model.
In this slide we show very favorable protective changes of the vaccine on viral load (left side) and in reducing drastically RSV disease severity (right side). Based on these overwhelmingly positive data, we will accelerate the development of our RSV vaccine in adults. We plan to initiate a global Phase 3 trial in the third quarter and hope to conclude the study swiftly, in part due to the recent spike in RSV infections reported by the CDC.
The swift delivery of the world's first mRNA-based vaccine made the scientific opportunity of mRNA technology clear. Our strategy to advance and unlock the full potential of mRNA is focused in three core areas. We are strengthening the core COVID-19 vaccine franchise, growing an infectious disease vaccine pipeline
And exploring therapeutic areas like rare disease and oncology with the strongest potential.
Let's start with the mRNA flu vaccine, which we began working on with BioNTech in 2018. Having a flu vaccine with much better efficacy, better T cell and innate immune responses, and more timely manufacture soon after strains are known could dramatically change the trajectory of disease. We are projected to start first in human trials for a modified RNA, or modRNA, flu vaccine in the third quarter, subject to regulatory approval. Preclinical studies were performed with a first generation modified mRNA tetravalent flu vaccine and the data were compared to data from a marketed FluAd vaccine. Immunogenicity in mice for a first generation modRNA flu candidate across the 2018-2019 northern hemisphere strains were higher or as high as the trivalent adjuvanted subunit vaccine.
We are encouraged by these data and look forward to progressing this program.
We now turn to our COVID-19 vaccine program, in collaboration with BioNTech. The Delta variant, which is the most transmissible we've yet seen, is expanding rapidly worldwide and now represents approximately 83% of sequenced cases in the U.S. We continue to believe it is likely that a third dose booster may be needed within six to 12 months after full vaccination to maintain the highest levels of protection, and studies are underway to evaluate the safety and immunogenicity of a third dose.
We are in ongoing discussions with regulatory agencies regarding a potential third dose booster of the current vaccine and, assuming positive results, anticipate an Emergency Use Authorization submission as early as August. Pending regulatory approval, we also plan to start an immunogenicity and safety study in August to evaluate an updated version of our vaccine specifically designed to target the Delta variant.
Here we show initial data from a small number of patients receiving a third dose of the existing vaccine. We observed a significant boost in neutralizing antibodies following a third dose of the current vaccine for both wild type and the Beta variant. At eight months post dose two, antibody levels start to decline from earlier peaks. In our initial analysis, a third dose given more than six months after the second dose elicited neutralizing antibodies which are more than five times higher than the wild type and more than 10 times higher against the Beta variant than after two primary doses. The third dose elevates the neutralizing antibodies in our laboratory studies to up to 100 times higher levels post-dose three compared to pre-dose three. Just as we saw in the analysis of neutralizing antibodies from those in the original Phase 3 trial, the levels in the older population were comparable to the younger population.
Here, we show new breaking data from a small number of participants that a third dose boost with the current vaccine elicited neutralizing titers that when tested against the Delta variant were more than five-fold post-dose two in younger people and more than 11-fold post-dose two in older people. Receiving a third dose more than six months after vaccination, when protection may be beginning to wane, was estimated to potentially boost the neutralizing antibody titers in participants in this study to up to 100 times higher post-dose three compared to pre-dose three. These preliminary data are very encouraging as Delta continues to spread.
Finally, let's turn to our potentially first-in-class oral COVID-19 anti-viral protease inhibitor. If successful, our protease inhibitor has the potential to provide patients infected with COVID-19 with a new oral therapy that could be prescribed for a five-day treatment course at the first sign of infection, before
Patients are hospitalized or in critical care.
For patients who are in close contact with someone who contracts COVID-19, we will study both five-day and 10- day post-exposure prophylaxis courses. The goal is to reduce SARS-Cov-2 viral load, thereby hopefully decreasing or preventing symptoms of COVID-19 and minimizing the risk of hospitalization. In July, we initiated a Phase 2/3 trial to evaluate the efficacy, safety, and tolerability of the orally administered protease inhibitor in participants with COVID-19. If successful, we project a potential U.S. Emergency Use Authorization submission in the fourth quarter.
Our protease inhibitor exhibits potent, selective in vitro antiviral activity against SARS-CoV-2 and other coronaviruses, and potentially all currently known COVID-19 variants. It also has demonstrated a robust preclinical antiviral effect on cells and in SARS-Cov-2 infected animals, enabled by selectivity that is more than 100 times higher for coronavirus 3L proteases than human proteases. The chart on the left shows robust dose-dependent reductions in disease microscopical scores in mice.
In Phase 1 human studies to date, we have seen desirable drug exposure, good tolerability and no safety findings up to a dose of 500 mg twice a day over 10 days in healthy volunteers. The chart on the right, of the phase 1 pharmacokinetic study, shows high drug exposure over the entire treatment period exceeding greater than five times the exposure predicted to inhibit SARS-Cov-2 viral replication.
This concludes our review of eight selected breakthrough programs among many more to come this decade. Now, let me turn it over to Frank.
