George D. Yancopoulos
Scientific Founder, President, Chief Scientific Officer at Regeneron Pharmaceuticals
Thanks, Len. I will start with ophthalmology. We are looking forward to the upcoming Phase III readouts of aflibercept eight milligram in patients with diabetic macular edema and in wet age-related macular degeneration. PHOTON in patients with DME and PULSAR in patients with wet AMD will test whether the patients treated with eight milligrams dose every 12 weeks or every 16 weeks can achieve non-inferior best corrected visual acuity at week 48 compared to the currently approved EYLEA 2-milligram dose every eight weeks. Unlike studies from other sponsors in which patients were assigned to a dosing interval based on disease activity assessment following the loading phase, patients enrolled in the PHOTON and PULSAR studies were randomized at baseline into one of the three treatment groups, we believe will allow us to determine whether extent dosing can truly be achieved.
If the studies are positive and the high safety standard established with EYLEA is maintained, we believe aflibercept eight milligram would represent a significant clinical advance for patients, and we would target a U.S. regulatory filing by early 2023. Moving to Dupixent, which continued to deliver notable milestones in the second quarter of the year. Dupixent was recently approved and chosen with atopic dermatitis as young as six months old, making Dupixent the first and only biologic medicine approved to treat atopic dermatitis from infancy through adulthood.
Marion will talk more about this as well as about our recent earlier-than-expected FDA approval for a brand-new gastroenterology indication, eosinophilic esophagitis or EoE. Since receiving approval in adults and in adolescents age 12 and over, we have reported positive data in pediatric patients with EoE as young as one year of age. Our Phase III study in children one to 11 years of age met the primary endpoint, with 68% of patients on the higher Dupixent dose and 58% of the lower Dupixent dose achieving histological disease remission compared to 3% of children on placebo at 16 weeks.
EoE symptoms can be difficult to assess in these young patients, however, we also observed a numerical improvement in the EoE symptom score and in exploratory analysis, we recorded a 3.1% increase from baseline and body weight for age percentile for the higher dose group compared to 0.3% of the placebo on. These data will be discussed with the regulatory authorities, starting with the FDA, later this year. Regarding approvals for new indications expected in the near future.
For prurigo nodularis, we received a PDUFA action date from the FDA of September 30 and the European Commission decision expected in the first half of 2023. Also in the first half of next year, we're also looking forward to the readout of the first Dupixent study in chronic obstructive pulmonary disease or COPD. Moving on to Libtayo and oncology.
As Len mentioned, we are excited to have acquired Sanofi stake in Libtayo, thereby gaining exclusive worldwide rights to a PD-1 inhibitor review as foundational for our oncology franchise, which has the potential to be utilized in numerous combinations with other candidates in our pipeline such as our costimulatory bispecifics, our CD3 bispecifics and novel checkpoint inhibitors such as fianlimab.
Regarding such combinations, I'd like to provide a brief update on our first clinical data from our costimulatory pipeline involving REGN5678, our PSMAxCD28 costimulatory bispecific, in combination with Libtayo. This combination is being studied in patients with advanced metastatic castrate-resistant prostate cancer, who have previously progressed on multiple antiandrogen therapies.
These patients, unfortunately, have a poor prognosis, with approximately one to two years of life expectancy and with limited treatment options. Metastatic castrate-resistant prostate cancer is considered an immunologically cold tumor and is largely resistant to immune checkpoint inhibitor, with large trials of PD-1 antibodies showing monotherapy response rates in the single digits.
As just announced today by Merck, the challenge of metastatic castrate-resistant prostate cancer in terms of the lack of efficacy for checkpoint inhibitors used in standard way is emphasized by the failure of their large Phase III trial in an earlier stage of this disease. Our costim program was designed to innovatively enhance responsiveness in these types of cold tumor classes such as prostate cancer and essentially turn these cold tumors into hot tumors.
I remind you of the extensive preclinical data we have published supporting this hypothesis. Since 2019, we have been in careful dose escalation for this prostate cancer program in close collaboration with the FDA. In our study, patients are dosed weekly with REGN5678 in every three weeks with Libtayo. However, first dose of Libtayo was not co-administered until week 4, permitting a period of PSMAxCD28, leading to evaluate monotherapy safety and efficacy.
Earlier today, we announced the first clinical data from 33 patients across 8-dose levels, which show dose-dependent antitumor activity. The key efficacy endpoint in the study is objective response rate defined as a greater than 50% decline of prostate-specific antigen or PSA from baseline and/or tumor shrinkage. PSA is a protein produced by the prostate gland and by prostate tumors and is most commonly used as a biomarker to diagnose and follow-up prostate cancer, as many metastatic castration-resistant prostate cancer patients have disease limited to bone lesions and cannot be assessed by conventional RECIST criteria.
Preliminary data from the ongoing dose escalation portion trial across 8-dose level cohorts in a total of 33 patients showed dose-dependent antitumor activity as assessed by PSA values at the five lowest dose levels, which our preclinical models predicted might be subtherapeutic. There was almost no evidence of any antitumor activity, with only one of 17 patients showing a decrease in PSA. There were no greater than greater or equal to Grade three immune-related adverse events or irAEs these doses.
The lack of antitumor activity among these patients was consistent with the approximate 6% response rate reported in other trials with anti-PD-1 monotherapy. At the next three dose levels, we began to see clear evidence of dose-dependent antitumor activity, which was generally seen within six weeks of starting the combination treatment. At dose level 6, one of four patients experienced a 100% decrease in PSA and a complete response in target lesions based on RECIST criteria.
The patients discontinued therapy due to a grade three immune-related adverse events of the skin. That was considered to be a recurrence of preexisting condition, and have since resolved with treatment per investigator report. Despite termination of the treatment, he has maintained his 100% decrease in PSA and complete response in target lesions were approximately 10 months to date per investigator report. We continue to see antitumor activity at the next dose level or dose level 7.
And in our eighth and most recent dose level, three out of four patients had dramatic and rapid PSA reductions, two with greater than 99% reductions and one with an 82% reduction. Of the two patients with greater than 99% PSA reductions, one experienced a grade three case of mucositis, which has resolved, and the other experienced a grade three case of acute inflammatory demyelinating polyradiculopathy, which is ongoing. In terms of safety, very importantly, no grade three or higher irAEs were observed in patients without antitumor activity.
And the occurrence of irAEs was correlated with antitumor activity. This is consistent with previous trials with anti-PD-1 immunotherapy wherein irAEs have been reported to occur at a higher rate in responding patients. No grade four irAEs or greater than or equal to grade two cytokine release syndrome have been observed in the trial to date. There was one death that was considered unrelated to treatment. In this trial, irAEs are being treated according to standard management practices used for checkpoint inhibitors.
We are planning on sharing more detailed data from this study at an upcoming medical meeting. Let me remind you that through extensive preclinical research, we have hypothesized that augmenting T cell costimulation alongside PD inhibition could be a key to turning immunologically cold tumors hot. These preliminary data for our PSMAxCD28 costimulated bispecific provides the first clinical evidence supporting the promise of our broader pipeline of costimulatory bispecifics in diverse solid tumors as well as hematologic malignancies.
By combining these costimulatory bispecific with Libtayo or with our CD3 bispecifics, we have the opportunity to create novel therapeutic synergies to address some of the most difficult-to-treat cancers. We look forward to partnering with the oncology community on this ambitious and potentially groundbreaking efforts. In addition to these exciting early data, we anticipate several important oncology milestones in the second half of the year.
At the upcoming ESMO conference, we will provide updates on fianlimab, our LAG3 antibody in combination with Libtayo, in a Phase II cohort of metastatic melanoma that will hopefully confirm the encouraging combined efficacy that we previously reported in this setting. In addition, we will present initial data for ubamatamab, our MUC16 timesCD3 bispecific in metastatic ovarian cancer, where I'd like to remind you that we have also combination studies ongoing with both costimulatory bispecifics and Libtayo.
We will also report initial data for our METxMET bispecific in advanced MET-altered non-small cell lung cancer as well for Libtayo monotherapy in neoadjuvant cutaneous squamous cell carcinoma. Moving on to our hematology pipeline. Odronextamab has the potential to be the first C20 timesCD3 bispecific to be approved for both major types of advanced B-cell lymphomas, that is both follicular lymphoma and diffuse large B-cell lymphoma. Based on interim data from a cohort of patients, goes with our recently modified step-up regimen.
We believe odronextamab may have the lowest rates of Grade three or higher cytokine release syndrome for this class of bispecifics, in follicular lymphoma and diffuse large B-cell lymphoma, while still maintaining the efficacy profile previously reported. We look forward to presenting these updated data and potentially submit a BLA for both indications in the second half of this year, pending feedback from the FDA. We also plan to share updated data for our BCMAxCD3 bispecific study in relapsed or refractory multiple myeloma by the end of the year. Pending regulatory feedback, we are planning to submit for regulatory approval in 2023.
An umbrella study in multiple myeloma investigating BCMAxCD3 in combination with various standard of care products and investigational candidate is now open to enrollment, while we plan to initiate an additional study in early lines of multiple myeloma later this year. As you can see, the pace of innovation in our oncology pipeline has been accelerated, building upon Libtayo as a foundation, with data readouts for novel mechanisms for cancer indications that historically have not responded to immunotherapy, including with our Regeneron Genetics' medicines where we in collaborate continue to progress our pipeline and discovery engine.
Our siRNA collaboration with Alnylam, a nonalcoholic steatohepatitis or NASH contains product candidates addressing various targets, including those discovered by the Regeneron Genetics Center. First data in NASH for ALN-HSD are anticipated this fall. We are progressing a second target, PNPLA3, into the clinic later this year, and we have recently identified an additional novel promising target for NASH SIP. As we just published in the New England Journal of Medicine, we found unprecedented association of very rare SIP loss of function variants with lower risk of liver disease.
In the largest association study examining protection from liver disease ever described, individuals with loss of function SIP bearing had about 53% lower risk of developing nonalcoholic fatty liver disease and about 54% lower risk of developing non-alcoholic cirrhosis. Regeneron and Alnylam are developing siRNA therapeutic candidate leads to advance to the clinic.
And with that, I will turn the call over to Marion.
