Pablo J. Cagnoni, M.D.
President, Head of Research and Development at Incyte
Thank you, Herve, and good morning, everyone. Since joining Incyte one year ago, the R&D organization and I have been centered on accelerating the transformation of our pipeline to expand our leadership in treating patients with inflammatory diseases, MPNs, cancer, and graft-versus-host disease.
By harnessing a culture of rigorous decision-making, intense focus, and excellence in execution, we have made considerable progress in advancing our goal of delivering best-in-class and/or first-in-class differentiated medicines in areas where there are no or limited treatment options. As a result, we anticipate delivering more than 10 high-impact launches by 2030, several of which are new molecular entities. As Herve mentioned, we recently completed a strategic review of our pipeline to focus resources and programs with novel biology that hold the highest potential impact for patients.
Based on available data, the evolving treatment landscape, and the evolution of our internal pipeline, we have decided to discontinue a number of programs, including our oral PD-L1 programs, our LAG-3 monoclonal antibody program, our TIM-3 monoclonal antibody program, and our LAG-3xPD-1 bispecific program. These data-driven decisions will enable us to fully realize the potential of our pipeline by delivering significant value to patients and our shareholders. With a strong sense of urgency, we plan to achieve a number of important clinical milestones in the coming months.
We will advance the development of 12 new molecular entities and we will achieve up to seven pivotal readouts as well as eight readouts that will provide proof-of-concept in new indications for existing programs or for new molecular entities.
In the next few slides, I will highlight a number of these programs. In inflammation and autoimmunity, we continue to expand the breadth and novelty of our pipeline and expect to deliver multiple data sets beginning this year and beyond. We continue to evaluate the potential of ruxolitinib cream and povorcitinib across several new indications, including pediatric atopic dermatitis, prurigo nodularis, hidradenitis suppurativa, chronic spontaneous urticaria, and asthma.
With the recent acquisition of Escient Pharmaceuticals, we have added two potential first-in-class medicines that aim to address a number of debilitating conditions, including chronic spontaneous urticaria, chronic inducible urticaria, atopic dermatitis, and cholestatic pruritus. We believe that with the introduction of these new medicines for these conditions, we will see a greater number of patients seeking treatment who are currently underserved with available therapies or who are currently not receiving treatment.
On Slide 16, we continue to advance the development of ruxolitinib cream beyond AD and vitiligo to additional indications where it can provide significant value as either the first-ever FDA-approved therapy or first approved topical therapy for patients living with these dermatologic conditions.
Based on the positive Phase III data in pediatric atopic dermatitis, the supplementary NDA submission is on track to be filed in the third quarter of this year, with a potential approval in 2025, which could provide an effective nonsteroid topical options of the 2 million to 3 million pediatric patients with AD in the U.S. In the most severe cases of this inflammatory disorder, pediatric edema interfere with development, emphasizing the importance of delivering this medicine to these children as soon as possible.
Now turning to Slide 17. We're currently conducting a Phase III study evaluating ruxolitinib cream in patients with prurigo nodularis, a chronic skin disorder that presents us multiple firm nodules commonly located on the extensive services of the extremities and that are intensely pruritic. This study is enrolling well, and we're on track to report results in the pivotal study next year with a potential approval as early as 2026.
With no topical therapies currently approved for PN and over 100,000 patients on treatment, we see this as an important additional option for patients and a significant opportunity for ruxolitinib cream.
As shown on Slide 18, we're continuing to execute a broad development plan for povorcitinib, our oral small molecule, highly selective JAK1 inhibitor. Povorcitinib is currently being evaluated in Phase III studies in hidradenitis suppurativa, vitiligo, and prurigo nodularis, and in randomized Phase II proof-of-concept studies in asthma and chronic spontaneous urticaria with data in both expected in 2025.
Povorcitinib has already demonstrated outstanding efficacy and safety in a randomized Phase II study in moderate to severe hidradenitis suppurativa, an extremely painful inflammatory disease.
As a reminder, we reported that at week 52, up to 29% of patients experienced a high-score 100 response, which is complete resolution of all manifestations.
Povorcitinib also had rapid and profound impact on reducing pain as highlighted in the chart on the bottom of Slide 19 and represents the first potential oral therapy for the treatment of HS with the opportunity to change the current standard of care.
The two Phase III studies, STOP-HS1 and STOP-HS2 are enrolling quite well, given the strong Phase II data and the limited number of effective treatment options. We anticipate Phase III data in early 2025 with a potential launch in 2026.
With ruxolitinib cream and povorcitinib, we believe we will be the only company to potentially provide both the topical and oral option for a number of indications, expanding their momentarium of effective therapies for certain conditions, including HS, vitiligo, and prurigo nodularis.
Moving to Slide 20 and our two newest IAI programs. We are pleased to have closed the Escient transaction, and now add two Mas-related G protein-coupled receptor antagonists or MRGPRs to our pipeline with significant potential in multiple indications.
MRGPR antagonism is a specific novel mechanism for blocking mast cell activation, independent from IgE, and has been a high-priority target to add to our IAI pipeline as a paradigm-changing therapeutic approach. Mast cells play a central role in initiation and perpetuation of inflammatory responses and their disregulation can contribute to the development and progression of many inflammatory diseases.
262 is a first-in-class medicine, which entered the clinic in January 2023 and is currently being evaluated in three proof-of-concept clinical studies. By blocking the activation of mast cells, 262 holds great promise across a broad range of mast cell-mediated diseases as a once-daily oral treatment, potentially devoid of the side effects observed with other therapies.
As a reminder, in a Phase I healthy volunteer study, 262 was well-tolerated at low interpatient PK variability and achieved exposures well above predicted efficacious levels. We believe the excellent safety profile, along with the potential for compelling efficacy could be a key differentiator for this program.
262 is currently in a Phase Ib open-label study in chronic inducible urticaria or CIndU and in a randomized Phase II study in chronic spontaneous urticaria or CSU, with data for the studies expected during the first quarter of 2025. Marked by painful and pruritic hives, CIndU and CSU are currently treated with antihistamines, but nearly 50% of patients do not experience symptom control, which can lead to anxiety, depression, and inability to work in social isolation, underscoring the need for safe and effective oral therapeutic options.
262 is also currently being evaluated in a randomized Phase II study in atopic dermatitis and data for this study is also expected during the first quarter of 2025. There is continued need for additional safe and effective oral treatment options in AD, and we believe success in this indication could further build on our leadership in AD.
547 is a highly selective antagonist of MRGPRX4, a cell surface receptor expressed on neurons in the dorsal root ganglia that is activated by bile acids, bilirubin, and other heme metabolites and thought to be a key mediator of the often intense unrelenting pruritus experienced by patients with cholestatic liver disease.
547 has the potential to become the first targeted therapy for cholestatic pruritus, lacking the side effects observed with other approaches. A randomized double-blind study is being conducted in patients with cholestatic pruritus due to primary biliary cirrhosis, or PBC, or primary sclerosing cholangitis, or PSC, with clinical proof of concept anticipated also during the first quarter of 2025.
Moving to MPNs and graft-versus-host disease on Slide 24. We highlight there a number of ongoing programs where we have the goal of developing new transformative therapeutic options to build upon the significant impact Jakafi has had on patients. For our BET inhibitor, dose escalation is ongoing, both monotherapy in combination with ruxolitinib, and we have reported reductions in spring length and volume as well as improvements in both symptoms and hemoglobin, suggesting this is an active compound.
We plan to advance this program into Phase III development and expect to provide an update later this year. For zilurgisertib, our ALK2 inhibitor, we have observed early signals of clinical activity in patients with myelofibrosis through hepcidin reduction in monotherapy and in combination with ruxolitinib. Zilurgisertib was well tolerated with a favorable safety profile and continues to dose escalation. We plan to provide an update later this year.
As previously disclosed, we submitted a BLA for axatilimab for the treatment of third-line chronic graft-versus-host disease late last year based on a positive randomized Phase II study. In February, the filing was accepted for priority review, and we anticipate an FDA decision in late August.
We are excited by the possibility of bringing a new treatment option to patients with this devastating complication of hematopoietic stem cell transplant. Additionally, we anticipate initiating a Phase III trial in combination with steroids and a Phase II study in combination with ruxolitinib later this year.
Putting on Jakafi, which is the foundational therapy for MF and PV, we are concentrated on improving outcomes in the near-term by combining Jakafi with other therapies as well as through approaches that have disease-modifying potential and that can significantly expand the addressable patient population to more than 200,000 patients. Our novel first-in-class anti-mutant CALR targeted monoclonal antibody has the potential to eradicate the malignant clone in patients with mutant CALR positive MPNs and to significantly modify disease outcomes.
989 binds with high affinity to mutant CALR and inhibits oncogenesis in cells expressed in this oncoprotein and antagonizes CALR oncogenic function resulting in selective inhibition of JAK-STAT signaling only CALR mutated cells with no effect on normal cells. This selectivity results in the specific killing of tumor cells harboring the mutation and is suggestive of the potential to alter the cause of the disease in patients with CALR mutant MF and essential thrombocythemia. Mutant CALR mutations are present in approximately 25% to 35% of patients with MF and ET. The Phase I studies are currently enrolling, and we are on track to share data in 2025.
As a reminder, the JAK2V617F mutation is the most common somatic mutation in MPNs and is present in 55%, 60% and 95% of patients with MF, ET and PV, respectively. Unlike ruxolitinib, which inhibits both wild-type and V617F mutation positive cells, 058 selectively binds to the JAK2 JH2 site, disrupting the V617F into confirmation and thus allowing selective inhibition mutant activity in the JAK2 receptor while sparing wild-type, making our JAK2V617F inhibitor a potentially transformative therapy for patients with PV, MF, and ET. Data for this program is expected in 2025.
Moving to our oncology pipeline on Slide 29. We continue to build a robust portfolio with increased emphasis on first-in-class and/or best-in-class and novel immuno-oncology programs with the potential for large treatment effects. Tafasitamab is currently approved in combination with lenalidomide for patients with relapsed or refractory DLBCL is on track to deliver Phase III results in follicular lymphoma and marginal zone lymphoma later this year with a potential approval in 2025. Our Phase III data for first-line DLBCL in combination with R2-CHOP is expected next year.
Today, we unveiled positive top-line results from two pivotal Phase III retifanlimab programs. Retifanlimab met the primary endpoints in both the squamous cell anal carcinoma and non-small cell lung cancer Phase III studies. In non-small cell lung cancer, we saw a statistically significant and clinically meaningful improvement in overall survival, and squamous cell anal carcinoma, we observed a statistically significant and clinically meaningful improvement in progression-free survival.
Both studies show retifanlimab was generally well tolerated and no new safety signals were detected. Retifanlimab could represent the first ever PD-1 or PD-L1 antibody approved for the first-line treatment of patients with SCAC. We believe that retifanlimab also has substantial strategic value as a combination of therapy without other programs in our pipeline, and we look forward to sharing the full results of these studies at an upcoming medical meeting later this year. Additionally, we plan on meeting with regulatory agencies to determine next steps and look forward to providing additional clarity in the coming weeks and months.
Our potentially first-in-class small molecule CDK2 inhibitor has shown evidence of clinical activity, demonstrating partial responses or stable disease in patients with CCNE1 overexpressing tumors. We expect to share this data as well as the development plan at ESMO in September. We believe our CDK2 inhibitor could be a foundational therapy for patients with ovarian cancer as well as other CCNE1 overexpressing tumor types.
KRAS mutations are one of the most common genetic abnormalities in cancer, especially lung, colon, and pancreatic cancers and potentially first-in-class, best-in-class KRASG12Di, small molecule inhibitor 734 is a potent, selective and orally bioavailable KRASG12Di inhibitor that has shown excellent efficacy in several preclinical models.
With no currently approved G12D targeting agents, 734 could address an important patient need as the KRASG12Di mutation is found in 40% of pancreatic ductal adenocarcinoma, 15% of colorectal cancers, and 5% of non-small cell lung cancers. Our Phase I clinical trial is enrolling well, and we are on track to share initial data in 2025.
The TGF-beta signaling pathway plays a complex role in cancer biology and progression with different functions in early and late-stage cancer cells. Early-generation therapies have been unsuccessful due in large part to the toxicity associated with systemic pathway inhibition with our bispecific antibody inhibiting PD-1 and TGF-beta receptor to signaling on T cells.
We have precisely tuned the binding arms against PD-1 and TGF-beta receptor 2, which we believe will result in the complete inhibition of TGF-beta signaling without the unwanted on-target effects. Our TGF-beta receptor 2 by PD-1 bispecific antibody has the potential to target multiple immunosuppressive pathways across a number of cancers. And if successful, could represent a meaningful contributor to our growth. We expect to share data from the Phase I program in 2025.
In closing, this slide summarizes the considerable number of milestones across 2024 and 2025 that will continue the transformation of our pipeline with a strong focus on new molecular entities with the potential to make an indelible impact on patients.
With that, I would like to turn the call over to Christiana for the financial update.
