Mikael Dolsten, M.D., Ph.D.
Chief Scientific Officer and President of Worldwide Research, Development and Medical of Pzifer Inc. at Pfizer
Thank you, Albert. I'd like to start by highlighting two recent leadership appointments. I've appointed Annaliesa Anderson to lead Vaccine Research & Development, succeeding Kathrin Jansen, who previously announced her retirement. With more than two decades of biopharma R&D experience, Liesa most recently served as CSO for Bacterial Research and Hospital. Over the last two years, she has led a team of infectious disease biologists that designed and delivered PAXLOVID to an Emergency Use Authorization. Under her leadership, we also advanced several bacterial vaccine programs into clinical development and approval. I've also named Charlotte Allerton CSO for Anti-Infectives, a new research unit. Creating this new research unit allows us to expand our focus beyond medicines that typically are used in hospitals. Charlotte is an esteemed scientist who will broaden our antiviral strategies with additional efforts in antibacterial and antifungal science and medicines.
Charlotte has been our Head of Medicine Design, most notably co-leading the discovery and development of PAXLOVID, and will continue in that role as well. I have had the privilege to work closely with Liesa and Charlotte for more than 10 years and have been continuously impressed by them as world-class scientists in their respective fields of expertise. Both have demonstrated good product-hunting skills and a sound business mindset. I'm looking forward to working with them in their new roles. Let's begin with COVID-19. The pandemic continues to evolve into a disease, which is causing significant disease burden, including high rates of acute disease, medical care utilization, hospitalization and deaths during the entire year. A growing number of patients affected by acute COVID infections are developing chronic disease and suffering from long COVID symptoms affecting multiple organs, such as the lungs, heart, kidney, brain and the vascular system.
We have seen major waves of variants of concern emerge quickly, become dominant, then be superseded by the next variant. Omicron and its sublineages are the most antigenically distant compared to prior variants of concern, more transmissible and show evidence of partial immune escape from existing vaccines. As the composition of SARS-CoV-2 changes, it is essential we advance new approaches to extend the level of protection that COMIRNATY originally conveyed. In a clinical trial, we evaluated the safety, tolerability and immunogenicity of mono- and bivalent Omicron BA.1 modified vaccines administered as a fourth dose in more than 1,900 participants over age 55. We are also evaluating different doses of mono- and bivalent BA.1 in participants 18 to 55 years of age.
While we saw promising responses to both mono- and bivalent versions in the over-55 population, we moved forward with bivalent following guidance from regulators. The BA.1 vaccine candidate elicited a superior immune response for BA.1 compared to the current version of the vaccine, a seroresponse rate which exceeded non-inferiority, and neutralization activity which increased substantially. The BA.1 vaccine neutralized wild-type and Delta similarly to the current version of the vaccine, suggesting that Omicron-modified version maintained response for the ancestral and other viral variants. Based on these data and following guidance from regulators, we have completed regulatory submissions in Europe, U.K. and Canada for the 30-microgram bivalent vaccine individuals 12 and older and plan submissions in other markets soon. The data also showed this vaccine candidate neutralized Omicron BA.4 and five, though to a lesser extent than BA.1.
This suggested a need to develop both a BA.1-modified vaccine and a BA.4/5-modified vaccine. We studied BA.4/5 monovalent and bivalent booster candidates in mice and found a substantial increase in neutralization responses to all Omicron variants of concern. Neutralizing titers against BA.4/5 increased 11-fold for the monovalent and 4.8-fold for the bivalent compared to monovalent BA.1 vaccine. These data were shared at the recent FDA Advisory Committee meeting as a potential surrogate to help expedite development of a BA.4/5 vaccine. We plan to submit the BA.4/5 bivalent vaccine candidate for Emergency Use Authorization in the U.S. in preparation for the fall booster campaign. To adapt more rapidly, we've agreed with FDA that this submission will be based on safety and immunogenicity data generated in adults with an Omicron-modified BA.1 vaccine and supported by BA.4/5 bivalent-specific preclinical data and BA.4/5 bivalent Chemistry, Manufacturing and Controls data.
This strategy is bolstered by previous experience showing that overall responses have been similar between human clinical and mouse data, our clinical experience with Beta- and Omicron-modified vaccine candidates and by leveraging our mRNA platform and manufacturing experience for the current vaccine. To support future potential U.S. licensure and global registrations, we plan to initiate a clinical study to evaluate the BA.4/5 bivalent vaccine. The clinical study design is under discussion with FDA. We aspire to continue leading with the science and are working to identify vaccines that would help provide strong and durable protection as new SARS-CoV-2 variants emerge. We aim to deliver a next-generation COVID-19 vaccine that can provide durable antibody and T cell immune protection against severe disease and hospitalization for at least one year. We plan to take a stepwise approach by designing and testing different candidates that engage multiple arms of the immune system, including antibodies and T cells. First, yesterday, we announced the start of a Phase II study evaluating a bivalent modRNA vaccine candidate, which consists of RNAs encoding novel enhanced pre-fusion spike proteins for the SARS-CoV-2 ancestral strain and an Omicron variant. The enhanced spike protein encoded from the mRNA has been modified with the aim of increasing the magnitude and breadth of antibody neutralization response that could better protect against COV19.
We project delivering key clinical data this fall. Second, we plan to initiate a proof-of-concept study with a potential pan-SARS-CoV-2 vaccine candidate by the end of the year. This combines the super-stabilized spike sequences with a T cell-enhancing construct, aiming to extend durability of protection against severe disease and new emerging SARS-CoV-2 variants. Now turning to PAXLOVID. Last month, we submitted a new drug application to U.S. FDA seeking approval for the treatment of COVID-19 in both vaccinated and unvaccinated adults and pediatric patients 12 years and over, weighing at least 40 kilograms and at high risk for progression to severe illness. We anticipate a PDUFA date in the first quarter of 2023. We plan to generate further data in those who are immunocompromised, hospitalized with severe COVID-19 and at increased risk for poor outcomes due to the disease or who are pregnant. We also are considering multiple collaborative studies to evaluate potential treatment for long COVID.
Finally, we're working with FDA to finalize a protocol to study patients who may be in need of retreatment. According to CDC, a brief return of symptoms may be part of the natural history of SARS-CoV-2 infection in some people. We believe the occurrence of COVID-19 rebound is uncommon and not uniquely associated with any specific treatment. At this time, cases are being reported at a rate consistent with the EPIC-HR trial. Turning now to flu. We know that currently available vaccines are not optimal in addressing the unmet need as each year, many people are infected, hospitalized and die, resulting in tremendous public health and economic impact. In part, this is because the flu vaccine development cycle is inefficient. And even when the current seasonal vaccine strains match circulating strains well, they typically confer only 40% to 60% protection. Potential advantages of the mRNA platform include: shortened timeline to enable a quicker response each season; improved strain matching; faster and more reliable manufacturing; and broader immune response from both antibody and T cells, the latter needed particularly in older adults.
Based on our experience with COVID-19, T cell responses appear to be critical for the protection against severe disease and hospitalization in infectious viral disease. Here, we show Phase II T cell data for our quadrivalent modRNA flu vaccine candidates in subjects 65 and older. We believe this is the first evidence of a flu vaccine candidate inducing substantial responses for both CD4 and CD8 T cells. On the left, at day seven, the CD4 T cell response was more than twofold for all four flu strains for our vaccine compared to a current high-dose vaccine now recommended in the U.S. for adults 65 and older. Over half of the cohort receiving our vaccine candidate had a more than twofold response. On the right, at day seven, the CD8 T cell response and responder rates were greater for all four strains for our vaccine candidate versus the comparator. Our belief is that these encouraging T cell responses, combined with higher seroconversion rates for flu A strains, which are the most predominant circulating strains and have pandemic potential, may translate into improved efficacy over current seasonal flu vaccines, particularly in those 65 and older.
Based on these data, we plan to initiate the Phase III efficacy study this year. We are excited to share that new data on our oral GLP-1 receptor agonists, two abstracts on twice-daily danuglipron and one on our once-daily candidate known as 1532, have been accepted for the European Association for the Study of Diabetes Conference in September. These investigational medicines were decided in-house by Pfizer's innovative chemistry and discovery teams. In a Phase I study in adults with type two diabetes, after only six weeks of treatment, 1532 drug robustly reduced mean daily glucose to almost near-normal levels. Participants also experienced weight loss of up to five kilograms compared with two kilograms for placebo.
We believe this to be a potentially best-in-class profile across both injectables and orals. Similar changes in body weight were observed in participants with nondiabetic obesity. 1532 is characterized by favorable once-daily pharmacokinetics, low risk for drug-drug interaction, robust efficacy across multiple metabolic endpoints and GLP-1 receptor agonist class-like tolerability, which overall encouraged us to plan for a Phase II study to pick the winning candidate prior to a potential Phase III study start. These development programs may lead to potential indications in type two diabetes, obesity, NASH and cardiovascular risk reduction in type two diabetes and obesity patients. Over the 12 past months, we have built a strong Inflammation & Immunology portfolio with diverse products to help address multiple drivers of disease and unmet need. CIBINQO was approved for atopic dermatitis in adults and last week, received priority review designation in U.S. for adolescents 12 to 18 years.
We are nearing a regulatory submission for etrasimod in ulcerative colitis. We have submitted regulatory application in U.S., Europe and U.K. for ritlecitinib for alopecia areata and are awaiting acceptances. We also plan to start a Phase III study of ritlecitinib in vitiligo this year. We are pleased to now share promising new updated data from our anti-interferon beta monoclonal antibody in specialized rheumatology. Patients with dermatomyositis show elevated Type I interferon gene signature in blood, skin and muscle correlating with disease activity in skin. As we continue our development of these candidates, a potential breakthrough therapy for hard-to-treat dermatomyositis which attacks skin and muscles, we believe it may have the ability to address a broader set of inflammatory autoimmune diseases, possibly including polymyositis and lupus. On our third quarter 2021 call, I shared data from our ongoing Phase II dermatomyositis study focused on skin inflammation and showing significant reduction in disease activity when compared with placebo in just three months of treatment.
Now both doses met the primary efficacy endpoint in skin-predominant disease. The disease also manifests with progressively debilitating muscle weakness and fatigue. Early data suggests that in a small cohort of patients with muscle-predominant disease, our candidate resulted in numerically better efficacy scores across all key muscle endpoints, including patient-reported outcomes, after three weeks. We plan to submit the data for presentation once the study completes. Now a promising update on elranatamab, our investigational B cell maturation antigen CD3-targeted bispecific antibody. At ASCO, we presented data from a Phase I trial in people with relapsed/refractory multiple myeloma, whose disease is refractory to at least one agent in each of the three major classes of medications approved for the disease.
We saw a confirmed overall response rate of 64%. And 35% of patients achieved a stringent complete response or complete responses. More than half who received prior BCMA-directed therapy, such as antibody drug conjugate or chimeric antigen receptor T cell therapy, achieved a response. Responders' probability of being event-free at nine months was 77%. Elranatamab elicited a durable minimal residual disease, or MRD, negativity, meaning no disease was detected after treatment in all evaluable patients who experienced a complete response or stringent complete response. Molecular responses were durable as well with 60% -- 62% of those complete responders documented to have MRD negativity at more than six months, including two patients who were MRD-negative beyond the 18 months. MagnetisMM-1 results and emerging data for MagnetisMM-3, which is studying triple-class refractory multiple myeloma, supports further development across a broader program with potential registration-enabling studies, MagnetisMM-5 in patients with double-class exposed multiple myeloma and MagnetisMM-7 in newly diagnosed post-transplant patients with multiple myeloma.
There is potential for deep and durable results that can be broadly accessible to patients due to off-the-shelf, subcutaneous and convenient dosing. The efficacy and safety profile we have seen to date in a challenging patient population supports advancement into earlier lines of treatment. Finally, here is a snapshot of select milestones for this year, showing healthy progress in the pipeline. It was an important quarter for COVID execution, and we look forward to sharing complete readouts from anti-interferon beta and the modFlu candidate before the end of the year. Thank you for your attention. Let me turn it over to Dave.
