George D. Yancopoulos
Board Co-Chair, President and Chief Scientific Officer at Regeneron Pharmaceuticals
Thanks, Len. That was really impressive overview I have to say. 2023 was another year of first delivered by Regeneron as well as together with our collaborators, all of which have the potential to change the practice of medicine. Starting with inflammation and immunology. As you heard from Len, we are planning yet another launch for DUPIXENT, this time in eosinophilic COPD, which would represent the sixth disease if this remarkable medicine is approved to treat and the fifth for which it would be first-in-class.
DUPIXENT's transformative potential in COPD is based on the unprecedented results from our first Phase 3 trial BOREAS, which would then confirm our second Phase 3 trial notice demonstrating that DUPIXENT treated patients had a 34% reduction in the annualized rate of moderate to severe COPD exacerbations [Technical Issues] IL-33 blocking antibody. The pivotal AERIFY-1 and 2 studies passed an interim futility analysis last year. The studies are now on track to complete enrollment in 2024 with an anticipated readout in 2025. If the Phase 3 results from these studies even approach the Phase 2 data reported in former smokers where a 42% reduction in annualized exacerbation rate was observed, itepekimab has the potential to further transform the treatment paradigm for COPD.
Later this year, we are planning on testing an innovative new treatment approach for severe food allergies using a combination of transient BCMAxCD3 bispecific intervention in patients receiving DUPIXENT therapy. As many of you know, allergic responses are driven by pathologically high levels of Immunoglobulin E or IgE. This is why many say the E in IgE stands for evil. About 40 years ago, it was discovered that interleukin-4 and interleukin-13 were the switch factors required for switching to IgE production.
Based on exciting preclinical data including in nonhuman primates as well as human data, our innovative approach has the potential to reverse severe allergies by first eliminating the long lived plasma cells that serve as an IgE reservoir with the BCMAxCD3 followed by blocking of de novo immunoglobulin class switching to IgE with DUPIXENT. We are looking forward to starting a small proof-of-concept study, which will inform next steps for this program. We believe this approach has the potential to benefit the millions of people suffering from severe allergies who are at constant risk as tragically highlighted just last week by the widely reported death of yet another young person unknowingly exposed to food a allergen.
Moving to Oncology. LIBTAYO is the leading PD-1 antibody for non-melanoma skin cancers, including metastatic cutaneous squamous cell carcinoma or CSCC and basal cell carcinoma. We are looking forward to potentially expanding the currently approved CSCC indication to include adjuvant CSCC and we expect results from potentially pivotal interim analysis in this setting in the second half of the year. Regarding LIBTAYO combinations, our most advanced is the combination with a LAG-3 antibody fianlimab.
As a reminder, our early clinical data in three separate first line metastatic melanoma cohorts demonstrated potential for best-in-class efficacy when compared cross trial with the approved anti-LAG-3 PD-1 combination highlighted by objective response rates greater than 60% and estimated median progression-free survival of longer than 15 months. These early clinical data suggested that the LIBTAYO fianlimab combination maybe one of the most exciting examples of a checkpoint inhibitor combination with clinically meaningful benefit and with the safety profile that is similar to that seen with anti PD-1 monotherapy. We are expecting a potentially pivotal initial readout from our first line metastatic melanoma trial by the end of this year. We also anticipate Phase 2 data in non-small cell lung cancer in late 2024.
Onto by specifics, starting with solid tumors. In the dose escalation trial of our EGFR by CD28 costimulatory bispecific combined with LIBTAYO, we have observed promising activity in microsatellite stable colorectal cancer with higher doses of the costim. In terms of safety, so far, we have not seen an increase in immune related adverse events with this costim. Based on these encouraging early data which will be presented at a scientific forum later this year, we will be initiating expansion cohorts across several solid tumors in the first half of the year. In 2024, we are also planning to provide updates for our MUC16xCD3 and MUC16xCD28 programs in advanced ovarian cancer.
Next, a bispecific for hematology oncology. For linvoseltamab, our BCMAxCD3 bispecific for multiple myeloma, FDA acceptance of our BLA submission is expected later this month and the EMA recently accepted our MAA submission. These submissions were supported by potentially best-in-class profile in late line myeloma in terms of efficacy, safety, dosing as well as convenience. The confirmatory Phase 3 study as well as studies in earlier stages of myeloma and pre-malignant disease are enrolling or will soon begin enrolling patients. For odronextamab, our CD20xCD3 bispecific for non-Hodgkin's lymphoma, the FDA decision for our BLA is expected by its March 31 PDUFA date and the new decision is expected in the second half of the year.
In terms of additional recent news for our oncology and immunology pipeline, this week, we announced the formation of Regeneron Cell Medicines unit and that we are acquiring full development and commercialization rights for 2Seventy Bio's pipeline of investigational immune cell therapies. We have work with 2Seventy since 2018 on many of these programs and are excited about the opportunity to continue advancing our collective efforts. After deal closing, certain 2Seventy employees will join Regeneron Cell Medicines and continue to work on addressing cancer and other serious diseases in novel ways including by combining Regeneron's antibody capabilities with CAR-T therapies.
Moving from immunology and oncology to obesity and metabolic diseases. Despite all the enthusiasm surrounding GLP-1 agonist for obesity, it has been increasingly recognized that the profound weight loss is accompanied by substantial muscle loss accounting for up to as much as 40% of the weight loss. This potentially retrievable muscle loss can be catastrophic for patients and may even lead to major public health concerns in the future. We have previously shown that our antibodies targeting myostatin in Activin A have the potential to preserve and grow muscle in human trials.
Based on these data as well as additional data in obese non-human primates, we believe that inhibiting these pathways on top of GLP-1 receptor agonism has the potential to achieve comparable overall reductions in body weight, but with improved quality of weight loss resulting in more fat was while preserving or actually increasing muscle mass. In mid-2024, we plan to start our first clinical trial to evaluate the combination of our muscle preservation antibodies in combination with semaglutide.
Also in 2024, we are anticipating proof-of-concept data for our Factor XI antibodies in the setting of prevention of venous thromboembolism after knee replacement surgery. Based on preclinical and healthy volunteer data, our antibody approach demonstrated more complete Factor XI blockade compared to competing approaches in development for coagulation disorders and the program is on rapid path to a registrational trial starting late this year or early next year.
We will now conclude with our efforts in genetic medicines. Our siRNA collaboration with Alnylam has demonstrated successful silencing of genes in the liver and for the first time for siRNA in the brain. Proof of principle was achieved for and ALN-APP last year and we are anticipating additional data from that program this year, including from patients who have received multiple doses. Based on this success, we are looking forward to new siRNA programs targeting CNS diseases entering the clinic this year such as ALN-SOD for ALS patients with SOD1 mutations.
Our collaboration with Intellia on CRISPR gene editing continues to advance where we together produced the first example of CRISPR based gene editing of a pathological gene in human beings. This initial program for our lead indication of TTR amyloidosis with cardiomyopathy is now in the first in vivo CRISPR program clear to enter Phase 3 studies in the United States. Together with Intellia, we also hope to be the first to use CRISPR technology to insert a corrective gene for deficiency disease. We recently achieved IND clearance for our CRISPR based gene insertion programs for Factor IX and initiated the leading portion of the clinical trial to evaluate it as a potential cure for hemophilia B.
Moving to genetic hearing loss. We were the first U.S. based company to announce hearing restoration in a young child suffering from genetic hearing loss after treatment with our novel gene therapy approach. We're excited by these early results for this ultra rare disease and look forward to advancing to the clinic, additional progress potentially to address more common forms of monogenic hearing loss. These data represent validation of our viral-based gene therapy program, in this case, locally delivered to the cells of the inner ear. Beyond these efforts, we have made significant investments in leveraging our monoclonal and bispecific antibody expertise to use these agents to systematically deliver virally based genetic payloads directly to specific tissues in the body non-amenable to local delivery such as to muscle and the central nervous system. Based on encouraging preclinical data, we will be progressing these approaches to the clinic in the coming years.
Finally, concluding with another notable first-in-class program involving a combination of an siRNA with an antibody, in this case, to block the C5 complement target. Normally, one needs very high levels of infusing antibody to achieve sufficient efficacy because of high targets levels regarding C5, but our siRNA cotreatment dramatically lowers C5 target burden allowing lower and more convenient antibody dosing. We recently shared encouraging initial data from a Phase 3 study in-patients with PNH which supported our hypothesis that this combination approach could provide better efficacy and control of breakthrough hemolysis with more convenient dosing.
Based and building on these data, we continue to enroll our Phase 3 studies in PNH and myasthenia gravis. We're also planning to extend this combination approach to geographic atrophy and dry AMD. While this combination is expected to have manageable systemic toxicities, including elevated risk of infections, we believe that our approach has several potential advantages over recently approved complement inhibiting agents for GA, which are delivered directly into the eye and have resulted in rare, but serious cases of retinal vasculitis sometimes resulting in permanently impaired vision.
In conclusion, Regeneron's R&D engine continues to grow and deliver many firsts, including differentiated early mid and late stage opportunities and we're looking forward to additional progress in 2024. Before I turn the call over to Marion, I would like to add my thanks and appreciation to Bob for his many years of devoted efforts and leaderships and welcoming and look forward to adding Chris Fenimore to our leadership team.
With that, I will turn it over to Marion.
