George D. Yancopoulos
Co-Founder, President & Chief Scientific Officer at Regeneron Pharmaceuticals
Thanks, Len.
I would like to briefly walk you through our pipeline's progress in 2022 and touch upon what lies ahead in 2023. In ophthalmology, we presented pivotal -- positive pivotal results for aflibercept 8 milligram in wet AMD and DME. These trials showed that aflibercept 8 milligram extended dosing intervals to every 12 or even 16 weeks for the vast majority of patients through 48 weeks without compromising the visual improvement or safety seen with EYLEA. These are truly unprecedented and potentially game-changing results who have not -- which have not been achieved using any other anti-VEGF agents.
Moving to Dupixent, in 2022, Dupixent became the only biologic approved in atopic dermatitis, for infants as young as 6 months of age, the first treatment for prurigo nodularis and the first treatment in the United States for eosinophilic esophagitis. And just this week, we obtained the European Commission approval for eosinophilic esophagitis as well. In addition, we submitted a supplemental BLA for chronic spontaneous urticaria and shared positive Phase 3 data in children with the eosinophilic esophagitis. Dupixent is now approved in 5 related Type 2 allergic conditions. And our data shows that these diseases are mediated by IL-4 and IL-13 driven Type 2 inflammation. Because many patients suffer from systemic Type 2 inflammation, they often suffer from several of these diseases concurrently. And thus, Dupixent has the potential to holistically address these patients multiple Type 2 conditions for which Dupixent is approved.
While many other immunomodulators are associated with worrisome immunosuppression and carry boxed warnings, Dupixent's safety profile supports its approval in infants. In 2023, we are looking forward to the initial results of BOREAS, the first Dupixent Phase 3 study in patients with chronic obstructive pulmonary disease, or COPD. Our Dupixent COPD Phase 3 studies have enrolled patients with elevated blood eosinophils aiming to select for patients with COPD driven by Type 2 inflammation. The BOREAS study passed an interim futility analysis in 2020, an encouraging event, which triggered the start of the replicate Phase 3 NOTUS study. We are looking forward to the readout of BOREAS with the primary endpoint of annualized rate of acute, moderate and severe COPD exacerbations expected in the first half of '23.
Moving on to oncology, 2022 was an important year for our oncology programs. Libtayo was approved by the FDA in combination with chemotherapy in first-line non-small cell lung cancer, irrespective of histology or PD-L1 expression levels, an achievement met by only one other PD-1 or PD-L1 targeting agent. Libtayo is also emerging as an essential backbone of our oncology pipeline as several programs in combination with Libtayo are starting to yield encouraging data.
First, I will discuss our LAG-3 antibody, fianlimab in combination with Libtayo, where we have recently shown positive data from a second confirmatory cohort of PD-1 naive metastatic melanoma patients and reported encouraging results from a smaller dataset in non-small-cell lung cancer patients. These initial results suggest that the fianlimab Libtayo combination has a potentially best-in-class profile in melanoma. And we are advancing broad pivotal programs in both melanoma and lung cancer. Phase 3 studies in metastatic melanoma and adjuvant melanoma are already enrolling and we have plans to soon initiate another Phase 3 study in perioperative melanoma as well as Phase 2/3 studies in first-line advanced as well as perioperative non-small cell lung cancer.
Other notable Libtayo combination used from this year was the early but very encouraging data with our PSMA by CD28 costimulatory bispecific in advanced metastatic castrate-resistant prostate cancer, a tumor type considered immunologically cold with multiple recent Phase 3 failures demonstrating that prostate cancer is largely unresponsive to anti-PD-1 therapy in other end as well as in other types of chemo combination. In our proof-of-concept study of our PSMA by CD28 costimulatory bispecific, we observed first evidence that combining this new class of bispecifics with anti-PD-1 can confer profound responsiveness to tumors previously thought to be cold and unresponsive to anti-PD-1 therapy with 3 out of the 4 patients treated at the highest dose levels showing greater than 90% reductions within 6 weeks of initiating combination therapy in the prostate cancer biomarker PSA.
Following up on these early but exciting results, we are continuing to enroll patients in this study and we are planning to present additional data at medical meetings in 2023. We also presented our first clinical data for a CD3 bispecific in a solid tumor for ubamatamab, our MUC16xCD3 bispecific in development for advanced ovarian cancer. As a single agent in a Phase 1 dose escalation study in heavily pretreated recurrent ovarian cancer patients, we observed a 4% overall response rate with a 31% response rates in a small subset of patients with high MUC16 expressing tumors. We expect initial dose escalation data later this year for ubamatamab with Libtayo as well as for our MUC16xCD28 costimulatory bispecific with Libtayo in advanced ovarian cancer. We also expect updated clinical data for our EGFRxCD28 costimulatory bispecific in combination with Libtayo in various solid tumors later this year.
Moving on to our hematology oncology pipeline, at the American Society of Hematology, or ASH Annual Meeting, we presented new data from odronextamab, our CD20xCD3 bispecific as well as linvoseltamab our BCMAxCD3 bispecific. For odronextamab, we presented pivotal Phase 2 ELM-2 data. Odronextamab in third or later line relapsed or recurrent follicular lymphoma has a potential best-in-class efficacy profile with 82% of patients responding and 92% of these responders achieving a complete response with encouraging durability. Our optimized step-up dosing regimen has improved odronextamab's safety profile while retaining efficacy similar to the prior dosing regimen. In third or later -- in relapse or recurrent diffuse large B-cell lymphoma, odronextamab demonstrated efficacy regardless of prior CAR-T experience and a safety profile generally similar to that seen in follicular lymphoma.
We are planning regulatory submissions in the second half of 2023 for both indications, which we hope will support potential accelerated approvals. In 2023, we anticipate initiating several Phase 3 studies in follicular lymphoma and diffuse large B-cell lymphoma, including in earlier lines of therapy. These trials will serve as confirmatory studies which could potentially support conversion to full approval. We also expect to initiate a proof-of-concept study of our CD22xCD28 costimulatory bispecific in combination with odronextamab in diffuse large B-cell lymphoma, which we hope could further add to the anticancer benefit for these patients.
For linvoseltamab, our BCMAxCD3 bispecific antibody we presented efficacy and safety data from our pivotal Phase 2 study in third or later line multiple myeloma at ASH. Early, deep and durable responses were observed in patients with high disease burden and these responses may improve with longer follow-up. In 2023, we plan to initiate a confirmatory Phase 3 study of linvoseltamab in second line multiple myeloma and are on track for a BLA submission in the second half of the year. As with odronextamab, we plan to initiate combination studies for linvoseltamab with costimulatory bispecifics in the near future. I'd also like to update some additional clinical programs. Our antibody blocking Factor XI for anticoagulation and our antibody that activates the NPR1 receptor for heart failure are both completing proof of mechanism trials.
Moving on to Regeneron Genetics Medicine, regarding our collaboration with Alnylam and siRNA Therapeutics, we are planning a broad and multi-pronged approach to develop treatments for NASH, nonalcoholic steatohepatitis. We are initiating a Phase 2 study of ALN-HSD and NASH patients with genetic risk factors. We also dosed first subjects in the first-in-human study of another siRNA medicine in development for NASH, ALN-PNP, which targets a different gene and can be potentially combined with ALN-HSD in appropriate patients. We have discovered additional NASH targets, which we have validated using our Regeneron Genetics Center, including side B, which will potentially be the next NASH therapeutic candidate to enter the clinic.
With regard to our collaboration with Alnylam for central nervous system targets, our initial dose escalation study is ongoing. Our collaboration with Intellia and CRISPR-based therapeutics, this is expected to progress further in 2023, building on continuing data readouts from the Phase 1 study of NTLA-2001 in transthyretin amyloidosis in both cardiomyopathy and neuropathy patients, which provided the first demonstration in humans that CRISPR-based technologies can deliver up to 90% reduction of the pathological gene product for over a year.
Regarding our gene therapy efforts, our collaborators at Decibel Therapeutics recently announced that a clinical trial has been authorized by both the US FDA and the UK MHRA for DB-OTO, a virally delivered gene therapy designed to restore hearing to individuals with otoferlin-related hearing loss. A Phase 1/2 study in patients 2 years of age and younger is expected to initiate in the first half of 2023 with initial data from the first cohort of patients anticipated in the first quarter of 2024.
I'd like to conclude with our next-generation COVID-19 efforts. As we recently announced, we have identified a potent broadly neutralizing COVID-19 antibody, which, unlike other neutralizing antibodies find outside of the so-called receptor binding domain, or RBD, of the spike protein. This antibody retains activity against all the viral variants seen throughout the pandemic because it binds to an atop that has remained highly conserved, greater than 99.9% across all known variants. The vast majority of antiviral antibodies generated as a result of vaccination or due to natural infection target the RBD domain, which results in overwhelming selective pressure driving the emergence of these resistant variants. We hope that by targeting this unique and conservative to outside of the RBD this antibody will also retain its activity in the face of future variance. We plan to initiate clinical trials to test this antibody this year, and we are looking to develop it in both treatment and prophylactic setting.
In conclusion, Regeneron's R&D engine continues its productivity, including the early-stage pipeline. Just in the first weeks of this year, we have initiated clinical studies for two new drug candidates and we anticipate clinical trials starting or IND submission for up to 10 new therapeutic candidates this year as well as for additional indications for candidates that are already in the clinic.
So with that, I will turn it over to Marion.
