INCA-033989

Ajax Therapeutics is among about 10 publicly-announced acquisitions by Eli Lilly so far this year.\n Eli Lilly’s up-to-$2.3 billion acquisition of Ajax Therapeutics is facing its first major public test, and the initial clinical data show why the pharma giant made the bet. The Ajax acquisition was a familiar story of an early investor turned buyer. Behind the deal was a novel idea that targeting the Type II conformation of the JAK2 kinase might offer a better approach compared with existing Type I-bound JAK inhibitors, such as Incyte’s blockbuster Jakafi, for myeloproliferative neoplasms (MPNs), including myelofibrosis. Lilly invested in the startup early on, with Ross Levine, M.D., chief scientific officer at Memorial Sloan Kettering Cancer Center, serving as the biotech’s scientific cofounder, whom Lilly’s business development and oncology head, Jake Van Naarden, said he has known “for a super long time.”Over the years, Lilly kept investing in the business as it produced AJ1-11095, a candidate that looked promising preclinically. Then, with the right clinical trial showing “this medicine started working right out of the gate, with a good safety profile,” Lilly deepened its commitment to a buyout, Van Naarden told Fierce in an interview.“To their credit, they designed the right study. It was an entirely JAK2 pre-treated myelofibrosis population, so you don\'t have to guess as to whether or not the signal is real,” Van Naarden said. “It is the right population.”The public now gets to see the data that fueled Lilly’s multibillion-dollar conviction and why the candidate could threaten Incyte’s stranglehold on the myelofibrosis market. ‘Working right out of the gate’Debuting at the European Hematology Association (EHA) 2026 annual meeting, AJ1-11095 showed strong early results from a phase 1 trial, which, according to Van Naarden, were better than what was historically recorded in similar patients with pretreated myelofibrosis.An impressive 70% of patients (16 out of 23) achieved a best response of at least a 35% reduction in spleen volume, an endpoint known as SVR35. The readout came from a May 28, 2026, data cutoff of the phase 1 AJX-101 trial evaluating AJ1-11095 across five dose levels—from 25 mg to 125 mg once daily—in its dose-escalation phase. All patients had previously failed a Type I JAK inhibitor, and their median line of prior therapies was two. Historically, post-JAK inhibitor SVR35 response rates ranged from 0% to 32%, according to an EHA presentation by John Mascarenhas, M.D., from the Icahn School of Medicine at Mount Sinai and principal investigator of the AJX-101 study.At week 12, 70% of patients achieved a 50% or greater reduction in their total symptom score, an endpoint known as TSS50. The rate was 65% at week 24 or 96% at any point in the study. Another unique promise of Type II JAK2 inhibitors is the potential to reduce mutant JAK2 allele burden that drives MPNs. In its initial data set, AJ1-1109 triggered a reduction in driver mutation variant allele frequency (VAF) in 21 out of 23 patients. Among the 17 patients who reached week 24 of treatment, 59% saw a reduction of 20% or greater on this measure and 35% saw a reduction of 50% or greater.In terms of safety, the drug saw no dose-limiting toxicities, and 78% of patients enrolled in the dose escalation phase remained on therapy as of a May 12, 2026, data cutoff.Among 23 patients, grade 3 or above anemia happened in 12 (52%) patients, and seven (30%) patients had a grade 3 or above platelet count decrease, although 19 patients entered the trial already with anemia. Altogether, five treatment discontinuations have been reported so far, none due to drug-related toxicity. These include one transplant, one for logistics reasons, two non-response cases and one unrelated adverse event.“These early clinical findings suggest that selective targeting of the type II conformation of JAK2 may provide a differentiated approach,” Mascarenhas said in a June 13 statement. “With an encouraging safety profile, meaningful spleen size reduction, symptom improvement, and decrease in underlying mutant disease burden, these data, while early, point to the potential to meaningfully impact treatment options for people with certain myeloproliferative neoplasms.” Putting Incyte on noticeLilly’s latest data place a target on Incyte’s myelofibrosis franchise. The Jakafi maker is developing candidates for specific myelofibrosis mutation subtypes. One of them, INCA033989, is an antibody against myelofibrosis harboring CALR mutations, which account for around one-fourth to one-third of all myelofibrosis cases. At the 2025 American Society of Hematology annual meeting in December, Mascarenhas presented early phase 1 data showing 31.3% (15/48) patients achieved SVR35 as best SVR while on INCA033989 monotherapy dosed intravenously every two weeks between 24 mg to 2,500 mg. A small number of patients had received no prior JAK therapy before entering the trial.Among patients resistant or intolerant to an existing JAK inhibitor, at week 24, the SVR35 rate was 27.6%, and the TSS50 rate was 35.7% in this study. Sixty percent of patients achieved TSS50 as best response throughout the study.At that time, Pablo Cagnoni, M.D., Incyte’s president and head of R&D, said the results—along with other data in another MPN called essential thrombocythemia—reinforced the company’s confidence in the mutCALR-targeted agent’s “transformative potential.” Based on those data, William Blair analysts estimated the drug’s peak sales could reach $1.9 billion.Incyte provided an updated look at the INCA033989 program at EHA 2026. With additional patients from the dose expansion cohort evaluating the drug at 250 mg and 2000 mg doses, the results do not look materially different from its ASH numbers.Counting 69 patients, best SVR35 rate was 39%. At Week 24, 27% (17/62) patients achieved SVR35, including 47% from those who were JAK-ineligible and 20% among JAK-experienced individuals.As for symptom improvements, best TSS50 was met in 53% (37/70) of patients. At Week 24, 32% (18/56) of patients achieved the endpoint. At least based on the ASH data, “the efficacy quotient there is meaningfully less than what we’re seeing here,” Lilly’s Van Naarden noted. Besides, while the Incyte candidate targets CALR mutations, Lilly’s Type II JAK2 inhibitor is meant to be more inclusive. Its VAF reduction was observed in patients across JAK2, MPL and CALR mutations. At least for now, Lilly didn’t spot any specific subtype that AJ1-11095 doesn’t work in, although Van Naarden cautioned that data are very early with only 23 patients. Incyte has also explored combining INCA033989 with Jakafi, although efficacy data there were immature and not materially different from monotherapy. In that cohort, three of 12 patients (25%) achieved SVR35 at week 24, and three of nine (33.3%) achieved TSS50 at that point.For Lilly, Van Naarden said the focus will be on monotherapy development for now.“The efficacy here is pretty striking, so I think the initial plan is to declare a dose and get into phase 3 in the second-line MF setting as quickly as we can,” Van Naarden said.Lilly is now treating patients in the dose-expansion phase, first using the 75 mg dosage, and then the study will “probably have a couple more cohorts,” he said. The 125 mg dose is “probably off the table” as the company started to see some toxicity, he added. Liver enzyme elevations were observed primarily at that high dose, although they were described as transient and were resolved following treatment. Besides second-line myelofibrosis, Lilly plans to investigate the drug in patients with high-risk polycythemia vera and JAK2 inhibitor-naïve myelofibrosis.“Could this be a better version of Jakafi? I don’t know. We have to build to that level of conviction over time,” Van Naarden said. “And then along the way, if there are rational combinations to do, we could consider that for sure.” A two-pronged BD strategyAjax is among about 10 acquisitions by Lilly that have been announced so far this year.“We are not done,” Van Naarden said. The Lilly exec is currently running two strategies in dealmaking. One model draws a comparison to early venture capital investment. Over the past few years, the Indianapolis pharma has been making high-volume, early-stage deals that are “generally not that expensive,” according to the executive. Van Naarden noted that in 2025, the company signed roughly 40 deals but only spent $4 billion in total. Many of these transactions were so small that they were never publicly announced in a press release.“The strategy there is, most of these things won’t work,” Van Naarden explained. “But we haven’t spent that much money in total, so if one or two work, it easily pays for the entire endeavor.”But 2025 ushered in a new era for Lilly, triggered by the company’s skyrocketing commercial success with its obesity and diabetes business. Meanwhile, some macro risks—such as government pricing talks and manufacturing bottlenecks—have largely been resolved. Lilly found itself flush with an unprecedented amount of capital to deploy. Coupled with the brutal reality of the pharmaceutical life cycle, where even the biggest blockbusters must eventually be replaced, Lilly’s leadership recognized the need to use this window of time to reinvent its pipeline. It is against this backdrop that Van Naarden took on the additional role of head of corporate business development toward the end of 2025.Now, Lilly is ramping up a strategy that invests in candidates that “at the time of the deal, you know are real,” Van Naarden said. That’s different from early-stage assets, where the assumption is that most projects won’t pan out. These more validated assets are more expensive, but they give Lilly the luxury of proof-of-concept clinical data. Recent buyouts like Ajax, orexin receptor 2 player Centessa Pharmaceuticals and in vivo CAR-T company Kelonia Therapeutics fit this paradigm, according to Van Naarden.“On the balance of 2026 but also going forward, we’re not done with either of these two strategies,” he said.Lilly is not setting price limits on deals, Van Naarden said. But hunting for de-risked assets also accentuates the importance of maintaining financial discipline.“My general observation is that the more mature the company is, the more Wall Street knows how to value it, and the more difficult therefore it is for us to do a deal where the price actually makes sense for us,” Van Naarden said.Without strict price discipline, Van Naarden warned that the second strategy would quickly become “a very time-consuming way of allocating capital badly.”Editor\'s Note: This story was updated at 12:05 p.m. ET to include Incyte\'s updated EHA data.

WILMINGTON, Del. --(BUSINESS WIRE)--Jun. 13, 2026-- Incyte (Nasdaq:INCY) today announced updated clinical data from two Phase 1 studies evaluating the safety, tolerability and efficacy of INCA033989, a first-in-class mutant calreticulin (mutCALR)-targeted monoclonal antibody, in patients with mutCALR-expressing myeloproliferative neoplasms (MPNs). INCA033989 demonstrated rapid, clinically meaningful responses and consistent molecular activity across both myelofibrosis (MF) and essential thrombocythemia (ET), with convergent evidence supporting the potential for disease modification. These findings are being presented in oral and poster presentations at the European Hematology Association (EHA) 2026 Congress in Stockholm, Sweden (Session: Myeloproliferative neoplasms – Clinical, Presentation numbers: S216, PS1983, PF884). “The data presented at EHA 2026 demonstrate clinically meaningful and consistent responses with INCA033989 across both myelofibrosis and essential thrombocythemia,” said Pablo J. Cagnoni , M.D., President of Incyte and Global Head of Research and Development. “What distinguishes INCA033989 is its potential to deliver disease control while targeting the biology that drives it. We remain on track to initiate our pivotal ET study by mid-2026 and are actively engaging regulators on a pivotal MF program.” Results in Patients with Myelofibrosis (MF) The safety, tolerability, and efficacy of INCA033989 in Type 1 and non-Type 1 patients with MF harboring a CALR mutation is being evaluated in two ongoing Phase 1 studies. Results demonstrate that INCA033989 delivers broad, clinically meaningful improvements across spleen volume, symptom burden and anemia in patients with MF. As a monotherapy and in combination with ruxolitinib, INCA033989 had a manageable safety profile and the majority of patients remained on treatment – no dose-limiting toxicities were observed, and a maximum tolerated dose was not reached. Monotherapy: INCA033989 was evaluated as monotherapy in patients who were resistant, refractory or intolerant to JAK inhibitor treatment after >12 weeks (JAK R/R/I), or ineligible to JAK inhibitor therapy. The dose escalation cohort evaluated INCA033989 from 24-3500 mg, and the dose expansion cohort evaluated 250 mg and 2000 mg. INCA033989 monotherapy demonstrated durable clinical benefit, with clinically meaningful improvements across spleen volume, symptoms and anemia across both JAK R/R/I and JAK ineligible patients. INCA033989 was generally well-tolerated, with 84% (70/83) of patients remaining on therapy at the time of the data cut off. Treatment emergent adverse events (TEAEs) occurred in 92% (76) of patients, with 27% (22) of patients experiencing Grade ≥3 TEAEs, the most frequent of which were cytopenias. No dose-limiting toxicities were observed, and discontinuations due to TEAEs were limited (n=2). Combination therapy: INCA033989 (dose range: 70 to 2,500 mg) was evaluated in combination with ruxolitinib in patients with MF who experience a suboptimal response to ruxolitinib monotherapy. INCA033989 demonstrated additive, multi-domain clinical activity in patients when administered in combination with ruxolitinib. INCA033989 in combination with ruxolitinib was generally well-tolerated, with 76% (16) of patients remaining on treatment at the time of the data cut off. In the combination arm (n=21), all patients experienced TEAEs. Grade ≥3 TEAEs were reported in 67% (14) of patients, most commonly anemia (33%). Translational data "Patients with CALR-mutated MF have distinct disease biology and often respond poorly to available therapies, underscoring the need for treatments targeting the underlying driver of disease," said Claire Harrison , M.D., Professor of MPNs and Deputy Chief Medical Officer, Guy’s and St. Thomas’ NHS Foundation Trust . "What stands out in these data is that INCA033989 produced rapid and robust spleen, symptom and anemia responses, alongside reductions in mutCALR allele burden regardless of HMR mutations, pointing to activity at the level of the disease-initiating clone." Results in Patients with Essential Thrombocythemia In patients with ET, INCA033989 demonstrated rapid, deep and durable hematologic and molecular responses across both Type 1 and non-Type 1 CALR patients, supporting potential for disease modification in a population resistant or intolerant to prior cytoreductive therapy. Hematologic Response: Molecular Response and Disease Biology: INCA033989 was well tolerated with 95% of patients remaining on treatment. The median duration of INCA033989 exposure was 8.1 months (range from 0.59 to 27.0 months). A low incidence of Grade ≥3 adverse events was observed (19%); the most common were neutropenia (4.4%) and lipase increase (3.5%). Grade ≥3 cytopenia TEAEs occurred in 6% (7/114) of patients; no Grade ≥3 thrombocytopenia TEAEs were observed. “In patients with ET who were resistant to or intolerant of prior cytoreductive therapy, INCA033989 resulted in rapid and durable normalization of platelet counts with accompanying molecular responses, with the majority of patients achieving a CHR," said John Mascarenhas , M.D., Professor of Medicine at the Icahn School of Medicine at Mt. Sinai and Director, Center of Excellence for Blood Cancers and Myeloid Disorders, The Tisch Cancer Institute . "As there are currently no mutation-specific treatments available for patients with ET, this approach is critically important for this high-risk patient population. These results provide a strong foundation for advancing INCA033989 into a registrational Phase 3 study." In November of 2025, INCA033989 was granted Breakthrough Therapy designation by the U.S. Food and Drug Administration (FDA) for the treatment of patients with ET harboring a Type 1 CALR mutation who are resistant or intolerant to at least one cytoreductive therapy. A Phase 3 study of INCA033989 in mutCALR positive patients with ET who are resistant or intolerant to at least one prior cytoreductive therapy (EXCALIBUR-ET2, NCT07623200) is being initiated in mid-2026. More information regarding the EHA 2026 Congress can be found on the EHA website: https://ehaweb.org/connect-network/eha2026-congress. About Myeloproliferative Neoplasms (MPNs) and Mutations in Calreticulin (mutCALR) Calreticulin (CALR) is a protein involved in the regulation of cellular calcium levels and normal protein folding. Somatic, or non-inherited, DNA mutations in the CALR gene (mutCALR) can result in abnormal protein function and lead to the development of myeloproliferative neoplasms (MPNs),1 a closely related group of clonal blood cancers in which the bone marrow functions abnormally, overproducing blood cells.2,3 Among two types of MPNs, essential thrombocythemia (ET) and myelofibrosis (MF), mutCALR drives 25-35% of all cases.4 In MF, it is estimated that 70-83% of CALR mutations in the U.S . are identified as Type 1, with 15-30% identified as non-Type 1.4,5 There are currently no targeted therapies for CALR mutations. Incyte is at the forefront of developing novel therapies for patients with mutCALR ET or MF that target only malignant cells, sparing normal cells, including INCA033989, a first-in-class, mutCALR-specific therapy. INCA033989 received Breakthrough Therapy designation by the U.S. Food and Drug Administration (FDA) for the treatment of patients with ET harboring a Type 1 CALR mutation who are resistant or intolerant to at least one cytoreductive therapy. A Phase 3 study of INCA033989 in patients with ET with a Type 1 or non-Type 1 CALR mutation who are resistant or intolerant to at least one cytoreductive therapy is being initiated (EXCALIBUR-ET2, NCT07623200). About the INCA33989-101 & INCA33989-102 Trials The clinical trial program for INCA033989 includes two multicenter, open-label Phase 1 studies, INCA33989-101 (NCT05936359) and INCA33989-102 (NCT06034002). The studies are evaluating the safety, tolerability and efficacy of INCA033989 in ~455 adult (≥18 years old) patients with mutCALR-expressing myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET) and myelofibrosis (MF). The primary endpoint of the studies is measured by the number of participants with dose limiting toxicities (DLTs), treatment-emergent adverse events (TEAEs) and the number of participants with TEAEs leading to dose modification or discontinuation. Secondary endpoints include response rates, mean change of ET total symptom score, percentage of MF patients achieving spleen volume reduction, MF patient anemia response, mean change in disease-related allele burden and various pharmacokinetics measures. For more information on the studies, please visit: https://clinicaltrials.gov/study/NCT05936359 and https://clinicaltrials.gov/study/NCT06034002. About Incyte® Incyte is redefining what’s possible in biopharmaceutical innovation. Through deep scientific expertise and a relentless focus on patients, we have built an established portfolio of first-in-class medicines and an extensive portfolio of next-generation medicines across our key franchises: Hematology, Oncology and Inflammation & Autoimmunity. To learn more, visit Incyte.com and Investor.Incyte.com. Follow us on social media: LinkedIn, X and Instagram. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 and other federal securities laws, including statements regarding the presentation of data for INCA033989; the potential for disease modification and the potential to benefit patients offered by INCA033989; expectations regarding ongoing and future clinical trials, including the timing of such trials; and Incyte’s aspirations and goals as set forth under the heading “About Incyte.” Actual results may differ materially from those indicated in the forward-looking statements as a result of various important factors, including the sufficiency of clinical trial data to meet applicable regulatory standards or warrant continued development; the ability to enroll sufficient numbers of subjects in clinical trials and the ability to enroll subjects in accordance with planned schedules; actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials and marketing approval; the efficacy or safety of Incyte’s products; Incyte’s ability to achieve commercial success for its products, once approved; Incyte’s ability to obtain and maintain protection of intellectual property for its products and technology; Incyte’s reliance on third parties and partners; the acceptance of Incyte’s products in the marketplace; market competition, sales, marketing, manufacturing and distribution requirements; greater than expected expenses, including expenses relating to litigation or strategic activities; and those risks and uncertainties discussed in greater detail in Incyte’s reports filed with the U.S. Securities and Exchange Commission, including its annual report on Form 10-K for the year ended December 31, 2025, and its quarterly report on Form 10-Q for the quarter ended March 31, 2026. Incyte disclaims any intent or obligation to update these forward-looking statements. 1 Raghavan, M., Wijeyesakere S.J., Peters L.R., Del Cid N. (2013) Calreticulin in the immune system: ins and outs. Trends in Immunology, 34(1):13-21. Link to source (https://www-cell-com.libproxy1.nus.edu.sg/trends/immunology/abstract/S1471-4906(12)00131-7?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1471490612001317%3Fshowall%3Dtrue) 2 Nangalia J. Massie C.E., Baxter E.J., Nice F.L., et al. (2013) Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. New England Journal of Medicine, 369(25):2391-2405. Link to source (https://www-nejm-org.libproxy1.nus.edu.sg/doi/10.1056/NEJMoa1312542?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200www.ncbi.nlm.nih.gov) 3 Klampfl T., Gisslinger, H., Harutyunyan A.S., et al. (2013) Somatic mutations of calreticulin in myeloproliferative neoplasms. New England Journal of Medicine, 369(25):2379-2390. Link to source (https://www-nejm-org.libproxy1.nus.edu.sg/doi/10.1056/NEJMoa1311347?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200www.ncbi.nlm.nih.gov) 4 Salzman G. and Mullally A. (2026) Novel strategies targeting mutant calreticulin in essential thrombocythemia and myelofibrosis. Blood, 147(12):1267-1277. Link to source (https://doi-org.libproxy1.nus.edu.sg/10.1182/blood.2025028642) 5 Guglielmelli, P., Maccari, C., Sordi, B. et al. Phenotypic correlations of CALR mutation variant allele frequency in patients with myelofibrosis. Blood Cancer J. 13, 21 (2023). Link to source (https://doi-org.libproxy1.nus.edu.sg/10.1038/s41408-023-00786-x) View source version on businesswire.com: https://www.businesswire.com/news/home/20260613021335/en/ Contacts: Media media@incyte.com Investors ir@incyte.com Source: Incyte