George D. Yancopoulos
Board co-Chair, President and Chief Scientific Officer at Regeneron Pharmaceuticals
Thanks, Len. Since Len covered the status of the Dupixent and itepekimab programs in COPD in great detail, I'd like to start with a bit more about our innovative treatment approach for severe allergies, a first-ever combination of an immunomodulatory antibody that is DUPIXENT with a bispecific antibody. Despite the remarkable benefit demonstrated by DUPIXENT across multiple diseases characterized by allergic or type two inflammation, DUPIXENT alone does not immediately reverse severe allergies by itself. These allergies are caused by high levels of an immunoglobulin class known as IgE made by long-lived plasma cells. This has caused some to refer the E in IgE as E for evil. Although DUPIXENT will prevent formation of new IgE plasma cells, it does not eliminate those that have already formed.
Regeneron scientists have shown that these allergy causing IgE plasma cells can be rapidly eliminated with a short course of treatment with our bispecific antibody known as linvoseltamab. While Dupixent treatment will then prevent these cells from returning as recently highlighted in our publication and Science Translational Medicine. We have commenced our proof-of-concept clinical trial to explore the potential for this combination approach to eliminate severe food allergy. We are hoping to see initial observations from this small study later this year, which will inform next steps. Moving on to oncology and libtayo combinations. Early clinical results of our LAG-3 antibody fianlimab in combination with libtayo suggest that these antibodies represent one of the most promising checkpoint inhibitor combinations in clinical development.
Recall, fianlimab libtayo demonstrated potential for best-in-class efficacy in first-line metastatic melanoma with objective response rates of approximately 60% across three independent cohorts from our first-in-human study with a safety profile that is similar to that seen with anti-PD-1 monotherapy with longer-term follow-up, these initial responses continue to deepen, including patients converting into complete responses. We look forward to presenting updated results from these expansion cohorts in the second half of this year. Encouraged by these initial results, last year, we initiated a Phase II/III study of the combination of fianlimab and libtayo in first-line metastatic melanoma. This study is enrolling faster than expected and will now be conducted solely as a Phase III study with the final analysis to be reported during 2025.
These pivotal melanoma data will inform whether fianlimab and libtayo have the potential to emerge as a new standard of care in melanoma. Next, to our bispecifics for hematology oncology. Regarding odronextamab, our CD20 timesCD3 bispecific, as announced in March, we received complete response letters from the FDA for our BLA for relapsed/refractory follicular lymphoma and relapsed/refractory diffuse large B-cell lymphoma. The only approvability issue was related to the limited enrollment of these confirmatory trials, which we intend to address as we continue to enroll patients in these studies. The EU decision on odronextamab application is expected in the second half of this year. Moving on to linvoseltamab. As Len noted, this bispecific continues to demonstrate a potentially best-in-class profile in late-line myeloma in terms of efficacy, safety, dosing and hospitalization burden.
In an oral presentation at the recent AACR medical meeting, we presented results of an 11-month median follow-up of 117 patients. A 71% objective response rate with 46% of patients achieving a complete response or better. We are planning to present updated 14-month follow-up results at the upcoming EHA meeting in which we anticipate observing a further deepening of responses. Regarding the ongoing FDA review, we believe the confirmatory study will be sufficiently enrolled to support approval. We're also evaluating linvoseltamab in earlier stages of myeloma and in precursor conditions such as smoldering myeloma and monoclonal gammopathy of unknown significance or MGUS. Next, to bispecifics for solid tumors. Our cost inventory bispecific antibodies are being tested in numerous studies, including as monotherapies as well as in combination with CD3 bispecifics and with libtayo.
Our EGFR by CD28 bispecific in combination with libtayo, we are planning to present updated dose escalation results in an oral presentation at ASCO, most notably, in microsatellite stable colorectal cancer, a tumor historically unresponsive to immunotherapy. EGFR by CD28 in combination with libtayo demonstrated antitumor activity. Regarding safety, to date, we have not observed severe immune-related adverse events with this agent at our recommended Phase II dose. Based on these data, we are enrolling dose expansion cohorts testing our EGFRxCD28 costim bispecific plus libtayo in various cancers, including non-small cell lung cancer with or without EGF receptor mutations. Microsatellite stable colorectal cancer, head and neck squamous cell carcinoma and others. On to our PSMA by CD28 costimulatory bispecific, which is already demonstrating promising activity in prostate cancer in combination with libtayo.
We will soon initiate combination treatment of our PSMA by CD28 costim bispecific with our PSMA by CD3 bispecific, which based on preclinical studies, may maintain efficacy but with better tolerability. We're also evaluating our MUC16 timesCD28 costimulatory bispecific with ubamatamab, or MUC16 timesCD3 bispecific as well as with libtayo, or CD3 timesCD28 BCMAxCD3 costim with linvoseltamab for myeloma and our CD22 timesCD28 costim with odronextamab for lymphoma. Moving on to our classical hematology pipeline. Our C5 approach involves a first-in-class combination of an sRNA with an antibody for a more complete target blockade in our initial clinical data supports potential best-in-class efficacy in paroxysmal and external hemoglobinuria or PNH. Results from the preliminary cohort of the PNH Phase III study will be presented at the EHA conference in June with additional results expected later this year.
In addition to PNH and myasthenia gravis, which are already enrolling their respective pivotal trials, we are planning on extending the systemic combination approach to geographic atrophy in dry AMD with the first pivotal study in GA expected to get underway this year. We are also anticipating proof-of-concept data later this year for our two complementary Factor XI antibodies in the setting of prevention of venous thromboembolism after knee replacement surgery. Depending on these data, one or both of these antibodies could remain on a rapid path to registrational studies, which could begin by late 2024 or early 2025. We -- our first-in-class antibody TMPRSS6, a genetically validated target for iron overload diseases such as beta thalassemia, is also making progress. This antibody has potential to meaningfully reduce toxic organ iron in patients whom iron chelation is inadequate or intolerable.
Updated proof of mechanism data in healthy volunteers will be presented at the upcoming EHA conference. These results demonstrated deep sustained reductions in serum iron and robust induction of the liver hormone hepcidin, supporting the potential to release iron from organs. We are on track to start a Phase II proof-of-concept study in beta-thalassemia patients in the second half of the year. Moving to obesity. Our most advanced approach is designed to address potential negative consequences of widespread use of GLP GIP receptor agonist. As it has been widely reported, the profound weight loss caused by these agents, unfortunately, can also result in substantial loss of muscle, which is particularly concerning in older, obese patients. Our antibodies to myostatin-related pathways may prevent this muscle loss.
Indeed, our data in obese nonhuman primates show that combining semaglutide with trevogrumab, or an antibiotic targeting myostatin with or without pertuzumab, our antibody targeting active NA, or myostatin 2, demonstrated a comparable reduction in body weight at week 20 relative to semaglutide monotherapy, but with improved quality of weight loss resulting in more fat loss while preserving or even increasing lean mass. Part A of our proof-of-concept study in healthy volunteers intended to demonstrate safety of a higher dose of trevogrumab, has completed enrollment note that over 400 subjects, including healthy volunteers in sarcopenic patients have been dosed with trevogrumab throughout its clinical development with no meaningful safety or tolerability concerns observed to date.
Part B of the study, which will evaluate muscle preservation antibodies in combination with semaglutide in obese participants remains on track to start enrolling mid-year assuming a reasonable pace of enrollment, we expect to report top line results, including changes in body weight, fat mass and muscle mass in second half of 2025. I will conclude with our genetic medicines effort. At the upcoming ASGCT conference, we will present updated data from our DB-OTO gene therapy program for genetic hearing loss. The first patient treated with this therapy, a 10-month old girl who is profoundly deaf at baseline. Now at 24 weeks after treatment had hearing in the normal range and the second treated patient is following a similar trajectory of improvement through earlier stages of follow-up.
We are aiming to enroll several more patients this year, potentially enabling regulatory submissions by the end of next year, and we also look forward to bringing additional auditory gene therapy programs to the clinic in the coming years with the potential to address more common forms of monogenic hearing loss. Our collaboration with Intellia on CRISPR gene editing continues to advance. We have begun to enroll patients in the Phase III magnitude study of Intellia 2001 for a lead indication of TTR amyloidosis with cardiomyopathy. The first in vivo CRISPR program clear to enter Phase III studies in the United States. We're also on track to be the first to use CRISPR technology to insert a corrective gene in vivo for a deficiency disease.
We have now achieved clearance from both the U.S. and EU authorities for our insertion program for Factor IX, and we have already enrolled initial patients into the leading portion of this program. Moving on to our sRNA collaboration with Alnylam, which has not only demonstrated successful silencing of genes in the liver, but also for the first time for siRNA in the brain. Additionally, we're excited about potentially initiating later this year a potentially pivotal study for our ALN SOD treatment in ALS patients with SOD1 mutations.
With that overview, I will turn the call over to Mary.
