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Treatment with the noncovalent BTK inhibitor pirtobrutinib (Jaypirca) led to an objective response rate (ORR) of 81.6% (95% CI, 76.5%-85.9%) in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) previously treated with a covalent BTK inhibitor, according to findings from the final analysis of the phase 1/2 BRUIN trial (NCT03740529) that were presented at the 2025 ASH Annual Meeting.¹

Best responses included complete response (CR; n = 11; 3.9%), CR with incomplete blood count recovery (n = 1; 0.4%), non–partial response (PR; n = 3; 1.1%), PR (n = 189; 67.0%), and PR with lymphocytosis (n = 26; 9.2%). In subgroup analysis, the highest ORRs were seen in patients with deletion 11q (n = 47; ORR, 91.5%; 95% CI, 79.6%-97.6%), complex karyotype (n = 33; ORR, 90.9%; 95% CI, 75.7%-98.1%), and 17p deletion and/or TP53 mutation (n = 104; ORR, 87.5%; 95% CI, 79.6%-93.2%). The populations that appeared to derive the least benefit were patients with mutated PLCg2 (n = 18; ORR, 55.6%; 95% CI, 30.8%-78.5%), unmutated BTK C481 (n = 97; ORR, 74.2%; 95% CI, 64.3%-82.6%), and mutated IGHV (n = 32; ORR, 75.0%; 95% CI, 56.6%-88.5%).

“Pirtobrutinib continues to show favorable efficacy and promising overall survival [OS],” William G. Wierda, MD, PhD, lead study author and Endowed Distinguished Professor Jane and John Justin Distinguished Chair in Leukemia Research in the Department of Leukemia, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, and coauthors wrote in the poster.

What Stands Out From the Final BRUIN Dataset

1. Pirtobrutinib achieved an ORR of 81.6% in patients previously treated with covalent BTK inhibitors, with promising durability and survival outcomes.

1. The agent remained well tolerated, showing low rates of treatment-related discontinuation and fewer high-grade toxicities than typically seen with covalent BTK inhibitors.

1. Efficacy was consistent across subgroups, although responses were lower in patients with PLCg2 mutations, unmutated BTK C481, and mutated IGHV.

What challenges drive the need for a non-covalent BTK inhibitor like pirtobrutinib?

Intolerance or treatment resistance remains an issue with covalent BTK inhibitors despite their valued integration into the CLL/SLL armamentarium. Pirtobrutinib is a selective, noncovalent BTK inhibitor that was designed to work against common mechanisms associated with resistance to covalent inhibitors.

Earlier findings from the BRUIN trial illustrated the agent’s efficacy and safety in patients with relapsed/refractory disease, including those with prior exposure to covalent inhibition. Data from the trial led to the agent’s accelerated approval from the FDA in December 2023, which was converted to full approval on December 3, 2025.^2,3 

The phase 1 dose-escalation and -expansion portion of the trial modeled a 3+3 design, which allowed for intra-patient dose escalation, cohort expansion at doses deemed safe, and treatment with 25 to 300 mg of once daily pirtobrutinib via 28-day cycles.¹ In phase 2, patients received 200 mg of once-daily pirtobrutinib.

A total of 778 patients were enrolled: 166 with mantle cell lymphoma, 317 with CLL/SLL, and 295 with other malignancies. Of the 317 patients with CLL/SLL, 35 were BTK naive, and 282 had been exposed to covalent BTK inhibition. Of the latter group, 154 patients were BCL2 naive, and 128 had received BCL2 inhibition.

Eligible patients were at least 18 years old and had previously treated, active disease in need of therapy, and an ECOG performance status between 0 and 2.

Key end points included safety/tolerability, determination of the maximum tolerated dose/recommended phase 2 dose, pharmacokinetics, ORR, progression-free survival (PFS), time to next treatment (TTNT), and OS.

Baseline characteristics across the board of patients with prior exposure to covalent BTK inhibition, BCL2 inhibition, and those naive to BCL2 inhibition revealed that most were male; had received prior BTK inhibition, anti-CD20 therapy, and chemotherapy; had discontinued treatment because of progressive disease; and had unmutated IGHV.

How effective is pirtobrutinib after prior covalent BTK inhibition?

The median duration of response (DOR) was 18.4 months (95% CI, 14.8-20.3), and the 36-month DOR rate was 28.0% (95% CI, 21.6%-34.7%). At median follow-up of 49.9 months the median TTNT was 23.2 months (95% CI, 20.3-29.4). The 12-, 24-, 36-, 48-, and 60-month TTNT rates were 74.7%, 49.9%, 34.1%, 23.3%, and 21.5%, respectively.

Median PFS was 18.7 months (95% CI, 16.6-21.8) at median follow-up of 44.2 months. The 12-, 24-, 36-, 48-, and 60-month PFS rates were 67.1%, 38.1%, 25.0%, 21.6%, and 17.6%, respectively. PFS was also subdivided between patients who were BCL2 naive and exposed. The median PFS was 15.9 months (95% CI, 13.6-17.5) in the exposed population and 22.3 months (95% CI, 19.3-27.6) in the naive population. The 12-, 24-, 36-, 48-, and 60-month PFS rates in the exposed cohort were 60.8%, 25.0%, 14.0%, 14.0%, and 14.0%, respectively. The 12-, 24-, 36-, 48-, and 60-month PFS rates in the naive cohort were 72.1%, 47.9%, 32.9%, 27.7%, and 21.7%, respectively.

In all patients who received covalent BTK inhibition, the median OS was not estimable (95% CI, 47.8 months-NE) at a median follow-up of 46.5 months. The 12-, 24-, 36-, 48-, and 60-month OS rates were 85.5%, 72.2%, 62.0%, 56.0%, and 54.2%, respectively.

What does the safety profile reveal about pirtobrutinib’s tolerability?

The median time on treatment was 20.0 months (IQR, 9.6-37.7). TRAEs leading to dose reduction and discontinuation occurred in 11 (3.9%) and 9 (3.2%) patients, respectively.

All-cause adverse effects (AEs) that occurred in at least 20% of patients included fatigue (any grade, 38.7%; grade ≥3, 1.8%), neutropenia (35.8%; 29.8%), diarrhea (30.5%; 0.4%), cough (29.8%; 0%), contusion (27.7%; 0%), COVID-19 (28.4%; 6.0%), dyspnea (23.4%; 2.5%), nausea (23.4%; 0%), and abdominal pain (21.6%; 2.1%). AEs of interest included infections (76.2%; 36.5%), bruising (31.2%; 0%), rash (25.2%; 1.1%), arthralgia (23.0%; 1.4%), hemorrhage (25.2%; 3.2%), hypertension (16.0%; 5.3%), and atrial fibrillation/flutter (5.0%; 2.1%).

Treatment-related adverse effects (TRAEs) that occurred in at least 20% of patients included fatigue (any grade, 3.9%; grade ≥3, 0%), neutropenia (20.6%; 16.3%), diarrhea (8.9%; 0%), cough (2.1%; 0%), contusion (18.8%; 0%), COVID-19 (0.7%; 0%), dyspnea (0.7%; 0.4%), nausea (3.9%; 0%), and abdominal pain (2.1%; 0.4%). AEs of interest included infections (14.9%; 5.7%), bruising (20.2%; 0%), rash (5.7%; 0.4%), arthralgia (4.6%; 0%), hemorrhage (8.2%; 1.4%), hypertension (3.9%; 0.7%), and atrial fibrillation/flutter (1.4%; 0.7%).

“Pirtobrutinib remains well tolerated with low rates of dose reduction or discontinuation due to TRAEs and low rates of grade 3 or greater hypertension, hemorrhage/hematoma, and atrial fibrillation/atrial flutter, which are risks with covalent BTK inhibitor treatment,” the authors concluded.

Disclosures: No disclosures were listed.

References

1. Wierda W, Brown J, Ghia P, et al. Pirtobrutinib in post-BTKi CLL/SLL: final update from the phase 1/2 BRUIN study with more than 5-years follow-up. Blood. 2025;146(suppl 1):2115. doi:10.1182/blood-2025-2115
2. FDA grants accelerated approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. FDA. Updated December 7, 2023. Accessed December 7, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic
3. FDA grants traditional approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. FDA. December 3, 2025. Accessed December 7, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-traditional-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic

More than half of patients with newly diagnosed large B-cell lymphoma (LBCL) may reduce or remove chemotherapy with a targeted therapy–first strategy, according to data from the primary analysis of the Smart Stop trial (NCT04978584) presented at the 2025 ASH Annual Meeting.¹ Further, the “smart” strategy of utilizing targeted therapy first appeared to be successful and preserve curative intent and did not impact patient response to chemotherapy.

“In this study, we showed very promising outcomes, both in terms of response rates and durability of response,” Jason Westin, MD, professor in the Department of Lymphoma and Myeloma, director of the Lymphoma Clinical Research Program, executive leader of the Lymphoma & Myeloma Service Line, and chief of Aggressive and Indolent Lymphoma at The University of Texas MD Anderson Cancer Center, in Houston, said during a presentation of the data.

How effective is the “smart” strategy in treating LBCL?

In the study, 61 patients were treated in 21-day cycles with 25 mg lenalidomide (Revlimid) daily on days 1 through 10; 12mg/kg intravenous (IV) tafasitamab (Monjuvi) weekly on day 1, 8, and 15; 375 mg/m2 IV rituximab (Rituxan) on day 1; and 100 mg oral acalabrutinib (Calquence) twice daily on days 1 to 21 (LTRA). Patients received LTRA only for the first 4 cycles. All patients continued the LTRA regimen for 6 additional cycles, which included 6 cycles of CHOP if patients did not achieve an initial CR (groups B and D). In cohort 1, those in CR received only 2 cycles of CHOP (group A); in cohort 2, those in CR continued without CHOP (group C).

After 4 cycles of the LTRA regimen, the overall response rate (ORR) was 90%, including complete response (CR) and partial response (PR) rates of 57% and 33%, respectively. In addition, the CR rate at the end of treatment was 96.7%.

In particular, cohort 1 experienced a 100% ORR, which included CR and PR rates of 63% and 37%, respectively. “Remember, these patients already had a complete response at the end of LTRA, so they maintain that throughout the duration of their treatment,” Westin said. Cohort 2 demonstrated CR and PR rates of 52% and 29%, respectively.

The 2-year progression-free survival (PFS) and overall survival (OS) rates were 86.5% and 98.4%, respectively, after a median follow-up of 25.3 months. “In patients who had the two cycles of CHOP, their progression-free survival has been outstanding,” Westin explained.

After a median follow-up of 19 months, 12 patients are ongoing with a CR. Westin noted that all 4 patients who had progression have achieved a complete response with subsequent frontline chemotherapy regimens.

Among those who had less than a CR after 4 cycles of LTRA and went on to receive CHOP plus LTRA therapy for 6 cycles, CR rate was 92%. “This is important. This shows that lack of response to the target therapy did not compromise the ability to deliver and have a promising result to the chemotherapy,” Westin said.

Why focus on administering targeted therapy first in newly diagnosed LBCL?

Westin noted that the CHOP regimen, although successful over the past 50 years, fails to cure 1 in 3 patients with newly diagnosed LBCL. “It’s poorly targeted,” he said, adding that the current classification system is also limiting in this disease setting. “We don’t have access to our current classification systems in real time to make treatment decisions, and I would also argue that they have limited utility in determining which treatment will benefit which patient.”

However, he acknowledged that the budding problem in the LBCL space may be a good one to have, in that there are a variety of emerging therapies. “We have an emerging problem in large B-cell lymphoma of an incredible wealth of new agents that are [are being evaluated] in phase 3 [trials]. But effectively, these studies are all 1970s chemotherapy vs 1970s chemotherapy with a novel agent added to it,” Westin said. “But I would argue we’ve got a coming challenge, which I like to call a coming chaos of choice. We have so many cool new drugs coming along that we are going to enter an era very soon [where] all of these great new agents showing promise in phase 3 trials [will be met] with uncertainty as to which patient will benefit from which therapy.”

With that, he added that the question of the role of chemotherapy in this era of emerging therapies remains. To this end, the investigators conducted the Smart Stop trial, which was designed to evaluate whether chemotherapy could be reduced or removed in patients with newly diagnosed LBCL who respond to initial targeted therapy.

How was the Smart Stop trial conducted?

The phase 2, open-label, single center trial enrolled patients with newly diagnosed LBCL who were at least 18 years of age, had an ECOG performance status of less than 3, and had adequate organ and bone marrow function. Patients were ineligible if they had central nervous system involvement with their lymphoma. The primary objectives of the study were to determine the ORR after 4 cycles of LTRA and CR at the end of therapy with LTRA, with or without CHOP.

The median patient age was 61 years (range, 23-91). More than half of patients reported with an ECOG performance status of 1 (56%), 70% had elevated lactate dehydrogenase, 75% of patients reported with stage III or IV disease, and, of note, 56% had an International Prognostic Index score of 3 to 5, with 72% of patients being high risk in the study. Further, Westin noted that there was an enrichment for the non–Germinal Center B-cell (GCB)–like subtype. “However, more than one-third of patients had the GCB subtype on this study, and notably via FISH testing, we had 16% of patients with MYC and BCL2 or BCL6 translocations, aka double hit.”

Preliminary results from cohort 1 (n = 30), previously reported at the 2023 ASH Annual Meeting,² showed that 63% of patients achieved a CR by PET/CT and 33% had undetectable circulating tumor DNA using the phasED-Seq assay after 4 cycles of targeted therapy. Further, at end of treatment, 100% of patients experienced a CR.

The majority of planned doses of lenalidomide (88%), tafasitamab (93%), and acalabrutinib (100%) were received. The median number of LTRA cycles delivered was 10 (range, 1-10).¹

What was the safety profile of the Smart Stop approach?

The most common any-grade adverse effects were anemia (90%), neutropenia (87%), platelet count decreased (77%), fatigue (67%), maculopapular rash (46%), transaminitis (43%), nausea (38%), headache (36%), increased creatinine (36%), infections and infestations (33%), infusion-related reaction (31%), constipation (31%), edema (28%), peripheral sensory neuropathy (23%), COVID infection (21%), cough (18%), dizziness (16%), diarrhea (15%), vomiting (15%), oral mucositis (12%), and febrile neutropenia (7%).

“The smart strategy of targeted therapy first is successful, and it preserves curative intent,” Westin said. “In this study, we showed very promising outcomes, both in terms of response rates and durability of response. The smart strategy of targeted therapy first showed that more than half of patients may reduce or remove chemotherapy for newly diagnosed diffuse large B-cell lymphoma…Smart strategy, targeted therapy first does not impact the response to chemotherapy. So, for those patients who did not achieve a complete response or had a complete response and ultimately had progression of their disease, they had very favorable outcomes when they received CHOP regimens.”

What are the next steps for this research?

Next, Westin noted that the investigators plan to expand the Smart Stop trial to a multisite trial, as well as evaluate glofitamab (Columvi), polatuzumab (Polivy), and golcadomide as a smart strategy.

“We’re also very optimistic about the potential for multiple randomized trials using the smart strategy of targeted therapy combinations, saving chemotherapy for those who don’t benefit, randomized against our chemotherapy,” Westin concluded.

Disclosures: Westin disclosed serving in a consultancy role for Allogene Therapeutics, AbbVie/Genmab, Regeneron, Genentech/Roche, AstraZeneca, Chugai Pharma, ADC Therapeutics, Bristol Myers Squibb, Nurix, Kite/Gilead, Morphosys/Incyte, Novartis, Pfizer, and Janssen. Research funding was provided by Allogene Therapeutics, Regeneron, Genentech/Roche, AstraZeneca, ADC Therapeutics, Bristol Myers Squibb, Nurix, Kite/Gilead, Morphosys/Incyte, Novartis, and Janssen.

References

1. Westin J, Fayad L, Steiner R, et al. Primary analysis of the smart stop trial: Lenalidomide, tafasitamab, rituximab, and acalabrutinib alone and with combination chemotherapy in newly diagnosed diffuse large B-cell lymphoma. Blood. 2025;146(suppl 1):abstract 477. doi:10.1182/blood-2025-477
2. Westin J, Steiner RE, Chihara D, et al. Smart Stop: Lenalidomide, tafasitamab, rituximab, and acalabrutinib alone and with combination chemotherapy for the treatment of newly diagnosed diffuse large B-cell lymphoma. Blood. 2023;142(suppl 1):856. doi:10.1182/blood-2023-180381

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“In a world where sovereign data retention matters, people want to know that if they input data to a model, the model won’t train on their data,” David McQuarrie, HP’s chief commercial officer, told Fortune in October. Using an AI locally provides that reassurance.

HP, like many of its devicemaking peers, is exploring the use of AI PCs, or devices that can use AI locally as opposed to in the cloud. “Longer term, it will be impossible not to buy an AI PC, simply because there’s so much power in them,” he said. 

More broadly, smaller companies might be served just as well by a smaller model running locally than a larger model running in the cloud. “A company, a small business, or an individual has significant amounts of data that need not be put in the cloud,” he said. 

Asian governments have often had stricter rules on data sovereignty. China, in particular, has significantly tightened its regulations on where Chinese user data can be stored. South Korea is another example of an Asian country that treats some locally sourced data as too sensitive to be housed overseas. 

Governments the world over, and particularly in Asia, are also investing in local sovereign AI capabilities, trying to avoid relying entirely on systems and platforms housed wholly overseas. South Korea, for example, is partnering with local tech companies like search giant Naver to build its own AI systems. Singapore is investing in projects like the Southeast Asian Languages in One Network (SEA-LION), which are better tailored to Southeast Asian countries. 

Asian AI adoption

Asia is HP’s smallest region, but also its fastest-growing. Revenue from Asia-Pacific and Japan grew by 7% over the company’s 2025 fiscal year, which ended in October, to hit $13.3 billion. That’s around a quarter of HP’s total revenue of $55.3 billion. (HP’s other two regions are the Americas; and Europe, the Middle East, and Africa.)

McQuarrie also suggested that there was an opportunity to be “disruptive” in Asia. While many business leaders have been eager to embrace AI, at least rhetorically, actual adoption is proving more difficult. A recent survey from McKinsey reports that two-thirds of companies are still in the experimentation phase of AI. 

But McQuarrie believed that AI adoption in Asia could be “just as quick, if not quicker,” than other regions. 

Asia seems to be more comfortable with the use of AI, at least when it comes to users. An October survey from Pew found that fewer people in countries like India, South Korea and Japan reported feeling “more concerned than excited” about AI compared to the U.S. 

When it comes to convincing more companies to adopt AI, let alone AI PCs, McQuarrie said the answer was to make AI functions as seamless as possible, so “that it doesn’t really matter whether you understand that you’re embracing AI or not.”

“What we’re doubling down on is the future of work,” McQuarrie said. “The future of work is a device that makes your experience better and your productivity greater.”

“The fact that we’re using AI in the background? They don’t need to know that.”

(Bloomberg) — The bond market’s reaction to the Federal Reserve’s interest-rate cuts has been highly unusual. By some measures, a disconnect like this, with Treasury yields climbing as the central bank lowers rates, hasn’t been seen since the 1990s.

What the divergence indicates is a matter of heated debate. Opinions are all over the place, from the bullish (a sign of confidence that recession will be averted) to the more neutral (a return to pre-2008 market norms) to the favorite culprit of the so-called bond vigilantes (investors are losing confidence the US will ever rein in the constantly swelling national debt).

Most Read from Bloomberg

But one thing is clear: the bond market isn’t buying President Donald Trump’s idea that faster rate cuts will send bond yields sliding down and, in turn, slash the rates on mortgages, credit cards and other types of loans.

With Trump soon able to replace Chair Jerome Powell with his own nominee, on top of everything else is the risk of the Fed squandering its credibility by caving to political pressure to ease policy more aggressively — which could backfire by fanning already elevated inflation and pushing yields higher.

“Trump 2.0 is all about getting long-term yields down,” Steven Barrow, head of G10 strategy at Standard Bank in London. “Putting a political figure at the Fed will not get bond yields down.”

The Fed started pulling its benchmark rate down from a more than two-decade high in September 2024 and has since cut it by 1.5 percentage points to a range of 3.75% to 4%. Traders see another quarter point cut after the next meeting on Wednesday as virtually assured and are pricing in two more such moves next year, which would bring its rate to around 3%.

Yet, key Treasury yields — which serve as the main baseline for the borrowing costs paid by American consumers and corporations — haven’t come down at all. Ten-year yields have risen nearly half a percentage point to 4.1% since the Fed started easing policy and 30-year yields are up over 0.8 percentage point.

Normally, when the Fed moves short-term policy rates up and down, long-term bond yields tend to follow. Even in the only two easing cycles outside of recessions over the past four decades – in 1995 and 1998, when the Fed cut only 75 basis points each time — the 10-year yield dropped outright or rose less than they have during the current episode.

Jay Barry, head of global rates strategy at JPMorgan Chase & Co., sees two factors behind it. The scale of the Fed’s hikes during the post-pandemic inflation surge was so steep that markets started pricing-in the Fed’s about-face well before it started, with 10-year yields peaking in late 2023. That blunted the impact once it began.

Moreover, by slashing interest rates even when inflation remains elevated, he said, the Fed is lessening the risk of a recession, limiting the scope for yields to fall.

“The Fed is looking to sustain this expansion, not end it,” said Barry. “That’s why rates have not moved aggressively lower.”

Others see a less benign interpretation in the so-called term premium, a measure of the extra yield investors demand in return for holding long-term bonds.

That compensates them for potential risks down the line — like elevated inflation or an unsustainable federal debt load. And that premium has risen nearly a full percentage point since the rate-cut cycle began, according to the New York Fed estimates.

For Jim Bianco, president of Bianco Research, it’s a signal that bond traders are worried that the Fed is cutting rates even as inflation remains stubbornly above its 2% target and the economy keeps defying recession fears.

“The market is really concerned about the policy,” said Bianco. “The concern is that the Fed has gone too far.”

If the Fed continues to cut rates, the mortgage rates will go “vertical,” he added.

There’s also angst that Trump — after breaking sharply from his predecessor’s deference to the Fed’s independence — will succeed in pressuring policymakers to continue cutting rates. Kevin Hassett, the White House National Economic Council Director and a Trump loyalist, is the betting market’s favorite to succeed Powell when his term ends in May.

What Bloomberg Strategists say…

If rate cuts increase the likelihood of stronger growth, they won’t be met with lower yields. We’ll end up with higher ones. In many respects, this is because we’re going back to a normal interest rate regime, where 2% real returns and a 2% Fed inflation target produces a 4% floor for long-term yields. Add in stronger growth and the numbers go higher from there.

—Ed Harrison, Bloomberg Markets Live strategist. Read more here.

So far, though, the broader bond market has remained relatively stable, with 10-year yields hovering not far from 4% over the past few months. And breakeven rates — a main gauge of the bond market’s inflation expectations — have been stable as well, indicating that fears of a Fed-fueled inflation surge down the line may be overstated.

Robert Tipp, chief investment strategist fixed income at PGIM, said it looks more than anything like a return to the normal levels seen before the Global Financial Crisis, which ushered in a long era of unusually low interest rates that abruptly ended after the pandemic.

“We’re back at the normal level of rates world,” he said.

Standard Bank’s Barrow said the Fed’s lack of control over the longer-term yields reminds him of a similar — if opposite — bind the central bank faced in the mid-2000s that became known as the Greenspan conundrum.

At that time, Chair Alan Greenspan was puzzled why the long-term yields remained low even as he jacked up the short-term policy rate. Greenspan’s successor Ben Bernanke later attributed the conundrum to too much savings from overseas flooding into Treasuries.

Today, Barrow said, that dynamic is reversed as governments around major economies are borrowing too much. That saving glut, in other words, has turned into a bond-supply glut that’s keeping consistently upward pressure on yields.

“It’s possibly a structural move that bond yields are not going down,” Barrow said. “At the end of the day, central banks don’t determine the long term rate.”

What to Watch:

(Updates wording of first and second paragraphs.)

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All three dose groups (50 mg, 100 mg and 200 mg) showed impressive monotherapy efficacy, with VGPR+ (very good partial response or better) of ≥70% despite limited follow-up; evidence shows that these responses are expected to deepen over time

Across all dose groups, 95% (19 of 20 patients) of all evaluable VGPR+ patients achieved minimal residual disease negative status

Data featured in an ASH oral presentation; LINKER-MM4 is the first clinical trial to evaluate a BCMAxCD3 bispecific monotherapy in NDMM and is part of a broad clinical development program evaluating Lynozyfic-based regimens in earlier lines of treatment

Regeneron to host virtual ‘Regeneron Roundtable’ investor event to discuss its multiple myeloma development program on Wednesday, December 10 at 8:30 a.m. ET 

TARRYTOWN, N.Y., Dec. 07, 2025 (GLOBE NEWSWIRE) — Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) today announced encouraging data from the Phase 1/2 LINKER-MM4 trial evaluating Lynozyfic™ (linvoseltamab) in adults with newly diagnosed multiple myeloma (NDMM) who were transplant eligible or ineligible were shared in an oral presentation at the American Society of Hematology (ASH) Annual Meeting. These data build on results from a broad clinical development program evaluating Lynozyfic in early lines of treatment, including precursor conditions, as monotherapy and in combination with standard-of-care or novel agents.

“The treatment of newly diagnosed multiple myeloma often relies on complicated combinations of quadruplet or triplet regimens, each with its own toxicities, in order to achieve rapid and durable responses, which can be incredibly burdensome for these patients,” said Robert Orlowski, M.D., Ph.D., Deputy Chair, Professor of Medicine, and Director of Translational Myeloma Research in the Departments of Lymphoma/Myeloma and Experimental Therapeutics at The University of Texas MD Anderson Cancer Center and the lead investigator for the LINKER-MM4 trial. “As the first to evaluate a BCMAxCD3 bispecific monotherapy in this setting, LINKER-MM4 seeks to understand whether frontline intervention with a single agent can deliver strong efficacy, enabling the simplification and potentially greater tolerability of these regimens. Lynozyfic monotherapy is already achieving MRD negativity rates comparable to quadruplet regimens but earlier in the treatment course, and these compelling results are expected to deepen with longer follow up. These results underscore Lynozyfic’s potential as a foundational component of frontline treatment regimens for multiple myeloma – or even a monotherapy regimen – for both transplant-eligible and transplant-ineligible patients.”

LINKER-MM4 is an ongoing, open-label Phase 1/2 trial investigating Lynozyfic in adults with NDMM. During a Phase 1A (dose escalation) cohort, patients were treated with a step-up dosing regimen followed by 50 mg, 100 mg or 200 mg doses of Lynozyfic. The lowest (50 mg) and highest (200 mg) tolerated doses were selected for further evaluation in the Phase 1B (dose-expansion) cohort. Among the 45 treated patients in both Phase 1A and 1B, 28 were transplant eligible, and 17 were transplant ineligible.

Across all dose levels (n=45), there was a 1.2 months median time to onset of response (range: 1-4.5 months). All three dose groups (50 mg, 100 mg and 200 mg) showed impressive efficacy, with a VGPR+ (very good partial response or better) of ≥70% with limited follow-up. Evidence shows that these responses are expected to deepen over time. Across all dose groups, 95% (19 of 20 patients) of all minimum residual disease (MRD) evaluable VGPR+ patients achieved MRD negative status at 10^-5 sensitivity.

Across all dose levels, the most common treatment-emergent adverse events (TEAEs) were cytokine release syndrome (CRS; all Grade 1: 44%) and neutropenia (any Grade: 38%; Grade 3/4: 33%). Among other adverse events of special interest, one patient in the 50 mg cohort experienced Grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS). Infections occurred in 84% of patients (Grade 1/2: 51%; Grade 3: 33%) with the majority occurring within the first three months of treatment and the rate of infections decreased over time. There were no ≥Grade 4 infections, Grade 5 TEAEs or dose-limiting toxicities. Ten patients elected to undergo an autologous stem cell transplant, all of whom had an acceptable CD34+ stem cell yield post-induction (range: 2.5-11.5 x 10⁶/kg).

A broad clinical development program investigating Lynozyfic in early stages of the disease is underway. This includes the Phase 2 portion of the LINKER-MM4 trial evaluating Lynozyfic at the recommended 200 mg dose, as well as LINKER-MM6 (EMN39), a trial evaluating a combination of daratumumab, lenalidomide and dexamethasone (DRd) followed by Lynozyfic monotherapy compared with continued DRd in transplant-ineligible NDMM.

The use of Lynozyfic described above is investigational, and its safety and efficacy has not been evaluated by any regulatory authority for this indication.

About the ‘Regeneron Roundtable’ Investor Event 
Regeneron will host a virtual investor event to discuss its multiple myeloma program on Wednesday, December 10 at 8:30 a.m. ET. This is the next webcast in a new investor event series called the ‘Regeneron Roundtable,’ intended to highlight programs from the company’s innovative investigational pipeline. 
  
Links to the webcast and to register via telephone may be accessed from the ‘Investors and Media’ page of Regeneron’s website at https://investor.regeneron.com/events-and-presentations. Upon registration, all telephone participants will receive a confirmation email detailing how to join the conference call, including the dial-in number along with a unique passcode and registrant ID that can be used to access the call. A replay of the conference call and webcast will be archived on the company’s website for at least 30 days. 

About Multiple Myeloma
As the second most common blood cancer, there are over 187,000 new cases of MM diagnosed globally every year, with more than 36,000 diagnosed and 12,000 deaths anticipated in the U.S. in 2025. The disease is characterized by the proliferation of cancerous plasma cells (MM cells) that crowd out healthy blood cells in the bone marrow, infiltrate other tissues and cause potentially life-threatening organ injury. Despite treatment advances, MM is not curable, and while current treatments are able to slow progression of the cancer, most patients will ultimately experience cancer progression and require additional therapies.

About Lynozyfic
Lynozyfic was invented using Regeneron’s VelocImmune^® technology and is a fully human BCMAxCD3 bispecific antibody designed to bridge B-cell maturation antigen (BCMA) on MM cells with CD3-expressing T cells to facilitate T-cell activation and cancer-cell killing. Lynozyfic is approved to treat certain adults with R/R MM: in the U.S. after four lines of therapy and in the European Union after at least three prior therapies.

In the U.S., the generic name for Lynozyfic in its approved indications is linvoseltamab-gcpt, with gcpt as the suffix designated in accordance with Nonproprietary Naming of Biological Products Guidance for Industry issued by the U.S. FDA. Outside of the U.S., the generic name of Lynozyfic in its approved indications is linvoseltamab.

Lynozyfic is being investigated in a broad clinical development program exploring its use as a monotherapy as well as in combination regimens across different lines of therapy in MM, including earlier lines of treatment, as well as plasma cell precursor disorders. These potential uses are investigational, and their safety and efficacy have not been evaluated by any regulatory authority.  

In addition to LINKER-MM4, ongoing trials include:

• LINKER-MM1: Phase 1/2 dose-escalation and dose-expansion trial evaluating the safety, tolerability, dose-limiting toxicities and anti-tumor activity of Lynozyfic monotherapy in R/R MM
• LINKER-MM2: Phase 1b, open-label trial evaluating Lynozyfic in combination with other cancer treatments in patients with R/R MM
• LINKER-MM3: Phase 3 confirmatory trial evaluating Lynozyfic monotherapy compared to the combination of elotuzumab, pomalidomide and dexamethasone in R/R MM
• LINKER-MM5: Phase 3 trial evaluating Lynozyfic monotherapy or in combination with carfilzomib compared to standard of care combination regimens in patients with R/R MM
• LINKER-MM6 (EMN39): Phase 3 trial, in collaboration with the European Myeloma Network, evaluating daratumumab, lenalidomide and dexamethasone induction followed by Lynozyfic monotherapy compared to continued daratumumab, lenalidomide, and dexamethasone in NDMM who are transplant-ineligible
• Phase 1 trial evaluating Lynozyfic in combination with a Regeneron CD38xCD28 costimulatory bispecific in R/R MM
• LINKER-SMM1: Phase 2 trial evaluating Lynozyfic monotherapy in high-risk smoldering MM
• LINKER-MGUS1: Phase 2 dose-ranging trial evaluating Lynozyfic monotherapy in high-risk monoclonal gammopathy of unknown significance and non-high-risk SMM
• LINKER-AL2: Phase 1/2 trial evaluating Lynozyfic monotherapy in R/R systemic light chain amyloidosis 

For more information on Regeneron’s clinical trials in blood cancer, visit the clinical trials website, or contact via clinicaltrials@regeneron.com or 844-734-6643.

IMPORTANT SAFETY INFORMATION FOR U.S. PATIENTS

What is the most important information I should know about LYNOZYFIC?
LYNOZYFIC may cause serious or life-threatening side effects, including Cytokine Release Syndrome (CRS) and infusion-related reactions (IRR), or neurologic problems.

Cytokine Release Syndrome (CRS) and infusion related reactions (IRR). CRS is common during treatment with LYNOZYFIC and can also be serious or life-threatening. Tell your healthcare provider or get medical help right away if you develop any signs or symptoms of CRS or IRR, including:

fever of 100.4ºF (38ºC) or higher
	dizziness or light-headedness

Neurologic problems. LYNOZYFIC can cause neurologic problems that can be serious or life-threatening. Tell your healthcare provider or get medical help right away if you develop any signs or symptoms of neurologic problems, including:

• headache
• agitation, trouble staying awake, confusion or disorientation, seeing or hearing things that are not real (hallucinations)
• trouble speaking, writing, thinking, remembering things, paying attention, or understanding things
• problems walking, muscle weakness, shaking (tremors), loss of balance, or muscle spasms
• numbness and tingling (feeling like “pins and needles”)
• burning, throbbing, or stabbing pain
• changes in your handwriting
• seizures

Due to the risk of CRS and neurologic problems, you will receive LYNOZYFIC on a “step-up dosing schedule” and should be hospitalized for 24 hours after the first and second “step-up” doses.

• During the “step-up dosing schedule”:
  • For your first dose, you will receive a smaller “step-up” dose of LYNOZYFIC on Day 1 of your treatment.
  • For your second dose, you will receive a larger “step-up” dose of LYNOZYFIC, which is usually given on Day 8 of your treatment.
  • For your third dose, you will receive the first treatment dose of LYNOZYFIC, which is usually given on Day 15 of your treatment.
  • Your healthcare provider may repeat one or both of the “step-up” doses depending on side effects or if your treatment is delayed.
  • Before the “step-up” doses and the first two treatment doses of LYNOZYFIC, you will receive medicines to help reduce your risk of CRS and IRR. Your healthcare provider will decide if you need to receive medicine to help reduce your risk of side effects with future doses.

LYNOZYFIC is available only through the LYNOZYFIC Risk Evaluation and Mitigation Strategy (REMS) due to the risk of side effects of CRS and neurologic problems. You will receive a Patient Wallet Card from your healthcare provider. Carry the LYNOZYFIC Patient Wallet Card with you at all times and show it to all of your healthcare providers. The LYNOZYFIC Patient Wallet Card lists signs and symptoms of CRS and neurologic problems. Get medical help right away if you develop any of the signs and symptoms listed on the LYNOZYFIC Patient Wallet Card. You may need to be treated in a hospital.

Your healthcare provider will monitor you for signs and symptoms of CRS and neurologic problems during treatment with LYNOZYFIC, as well as other side effects, and may treat you in a hospital if needed. Your healthcare provider may temporarily stop or completely stop your treatment with LYNOZYFIC if you develop CRS, neurologic problems, or any other severe side effects.

If you have any questions about LYNOZYFIC, ask your healthcare provider.

Before receiving LYNOZYFIC, tell your healthcare provider about all of your medical conditions, including if you:

• have an infection.
• are pregnant or plan to become pregnant. LYNOZYFIC may harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think that you may be pregnant during treatment with LYNOZYFIC.
  Females who are able to become pregnant:
  • Your healthcare provider should do a pregnancy test before you start treatment with LYNOZYFIC.
  • You should use an effective form of birth control (contraception) during treatment with LYNOZYFIC and for 3 months after your last dose of LYNOZYFIC.
  • are breastfeeding or plan to breastfeed. It is not known whether LYNOZYFIC passes into your breast milk. Do not breastfeed during treatment with LYNOZYFIC and for 3 months after your last dose of LYNOZYFIC.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

How will I receive LYNOZYFIC?

• LYNOZYFIC will be given to you by your healthcare provider by infusion through a needle placed in a vein (intravenous infusion).
• After the “step-up dosing schedule”, the treatment dose of LYNOZYFIC is usually given 1 time each week for 11 doses, and then 1 time every other week for 5 doses. After these doses and based on how your disease responds, your healthcare provider will decide if you are able to receive LYNOZYFIC less often (every 4 weeks) or will continue to have every other week treatment.
• Your healthcare provider will decide how long you will receive treatment with LYNOZYFIC.
• If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment. It is important for you to be monitored closely for side effects during treatment with LYNOZYFIC.

What should I avoid while receiving LYNOZYFIC?
Do not drive, or operate heavy or potentially dangerous machinery, or do other dangerous activities for 48 hours after completing each of your “step-up” doses or at any time during treatment with LYNOZYFIC if you develop new neurologic symptoms, until the symptoms go away.

What are the possible side effects of LYNOZYFIC?
LYNOZYFIC may cause serious side effects, including:

• Infections. LYNOZYFIC can cause bacterial, viral, or fungal infections that are serious, life-threatening, or that may lead to death. Upper respiratory tract infections and pneumonia are common during treatment with LYNOZYFIC.
  • Your healthcare provider will monitor you for signs and symptoms of infection before and during treatment with LYNOZYFIC.
  • Your healthcare provider may prescribe medicines for you to help prevent infections and treat you as needed if you develop an infection during treatment with LYNOZYFIC.
  • Tell your healthcare provider right away if you develop any signs or symptoms of infection during treatment with LYNOZYFIC, including:
    • fever of 100.4 °F (38 °C) or higher
    • chills
    • cough
    • shortness of breath
    • chest pain
    • sore throat
    • pain during urination
    • feeling weak or generally unwell
• Decreased white blood cell counts. Decreased white blood cell counts are common during treatment with LYNOZYFIC and can also be severe. Fever can happen with low white blood cell counts and may be a sign that you have an infection. Your healthcare provider will check your blood cell counts before you start treatment and during treatment with LYNOZYFIC, and will treat you as needed.
• Liver problems. LYNOZYFIC can cause increased liver enzymes and bilirubin in your blood. These increases can happen with or without you also having CRS. Your healthcare provider will do blood tests to check your liver before starting and during treatment with LYNOZYFIC. Tell your healthcare provider if you develop any of the following signs or symptoms of liver problems:
  • tiredness
  • loss of appetite
  • pain in your right upper stomach-area (abdomen)
  • dark urine yellowing of your skin or the white part of your eyes

The most common side effects of LYNOZYFIC include:

diarrhea tiredness or weakness

The most common severe abnormal blood test results with LYNOZYFIC include: low white blood cell counts and low red blood cell counts.

These are not all of the possible side effects of LYNOZYFIC.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Please see full Prescribing Information, including Boxed WARNING, and Medication Guide for LYNOZYFIC.

What is LYNOZYFIC?
LYNOZYFIC is a prescription medicine used to treat adults with multiple myeloma who:

• have already received at least 4 treatment regimens, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody to treat their multiple myeloma, and
• their cancer has come back or did not respond to prior treatment.

It is not known if LYNOZYFIC is safe and effective in children.

About Regeneron in Hematology 
At Regeneron, we’re applying more than three decades of biology expertise with our proprietary VelociSuite^® technologies to develop medicines for patients with diverse blood cancers and rare blood disorders.

Our blood cancer research is focused on bispecific antibodies that are being investigated both as monotherapies and in various combinations and emerging therapeutic modalities. Together, they provide us with unique combinatorial flexibility to develop customized and potentially synergistic cancer treatments.

Our research and collaborations to develop potential treatments for rare blood disorders include explorations in antibody medicine, gene editing and gene-knockout technologies, and investigational RNA-approaches focused on depleting abnormal proteins or blocking disease-causing cellular signaling. 

About Regeneron‘s VelocImmune Technology  
Regeneron‘s VelocImmune technology utilizes a proprietary genetically engineered mouse platform endowed with a genetically humanized immune system to produce optimized fully human antibodies. When Regeneron’s co-Founder, President and Chief Scientific Officer George D. Yancopoulos was a graduate student with his mentor Frederick W. Alt in 1985, they were the first to envision making such a genetically humanized mouse, and Regeneron has spent decades inventing and developing VelocImmune and related VelociSuite technologies. Dr. Yancopoulos and his team have used VelocImmune technology to create a substantial proportion of all original, FDA-approved or authorized fully human monoclonal antibodies. This includes Dupixent^® (dupilumab), Libtayo^® (cemiplimab-rwlc), Praluent^® (alirocumab), Kevzara^® (sarilumab), Evkeeza^® (evinacumab-dgnb), Inmazeb^® (atoltivimab, maftivimab and odesivimab-ebgn) and Veopoz^® (pozelimab-bbfg). In addition, REGEN-COV^® (casirivimab and imdevimab) had been authorized by the FDA during the COVID-19 pandemic until 2024. 
  
About Regeneron  
Regeneron (NASDAQ: REGN) is a leading biotechnology company that invents, develops and commercializes life-transforming medicines for people with serious diseases. Founded and led by physician-scientists, our unique ability to repeatedly and consistently translate science into medicine has led to numerous approved treatments and product candidates in development, most of which were homegrown in our laboratories. Our medicines and pipeline are designed to help patients with eye diseases, allergic and inflammatory diseases, cancer, cardiovascular and metabolic diseases, neurological diseases, hematologic conditions, infectious diseases, and rare diseases.

Regeneron pushes the boundaries of scientific discovery and accelerates drug development using our proprietary technologies, such as VelociSuite, which produces optimized fully human antibodies and new classes of bispecific antibodies. We are shaping the next frontier of medicine with data-powered insights from the Regeneron Genetics Center^® and pioneering genetic medicine platforms, enabling us to identify innovative targets and complementary approaches to potentially treat or cure diseases.

For more information, please visit www.Regeneron.com or follow Regeneron on LinkedIn, Instagram, Facebook or X.

Forward-Looking Statements and Use of Digital Media 
This press release includes forward-looking statements that involve risks and uncertainties relating to future events and the future performance of Regeneron Pharmaceuticals, Inc. (“Regeneron” or the “Company”), and actual events or results may differ materially from these forward-looking statements. Words such as “anticipate,” “expect,” “intend,” “plan,” “believe,” “seek,” “estimate,” variations of such words, and similar expressions are intended to identify such forward-looking statements, although not all forward-looking statements contain these identifying words. These statements concern, and these risks and uncertainties include, among others, the nature, timing, and possible success and therapeutic applications of products marketed or otherwise commercialized by Regeneron and/or its collaborators or licensees (collectively, “Regeneron’s Products”) and product candidates being developed by Regeneron and/or its collaborators or licensees (collectively, “Regeneron’s Product Candidates”) and research and clinical programs now underway or planned, including without limitation Lynozyfic™ (linvoseltamab-gcpt); the likelihood, timing, and scope of possible regulatory approval and commercial launch of Regeneron’s Product Candidates and new indications for Regeneron’s Products, such as Lynozyfic as a monotherapy and/or in combination with standard-of-care agents across different lines of therapy in multiple myeloma (“MM”) and plasma cell precursor disorders, including the treatment of adults with newly diagnosed MM as discussed in this press release; uncertainty of the utilization, market acceptance, and commercial success of Regeneron’s Products (such as Lynozyfic) and Regeneron’s Product Candidates and the impact of studies (whether conducted by Regeneron or others and whether mandated or voluntary), including the studies discussed or referenced in this press release, on any of the foregoing or any potential regulatory approval of Regeneron’s Products and Regeneron’s Product Candidates; the ability of Regeneron’s collaborators, licensees, suppliers, or other third parties (as applicable) to perform manufacturing, filling, finishing, packaging, labeling, distribution, and other steps related to Regeneron’s Products and Regeneron’s Product Candidates; the ability of Regeneron to manage supply chains for multiple products and product candidates and risks associated with tariffs and other trade restrictions; safety issues resulting from the administration of Regeneron’s Products (such as Lynozyfic) and Regeneron’s Product Candidates in patients, including serious complications or side effects in connection with the use of Regeneron’s Products and Regeneron’s Product Candidates in clinical trials; determinations by regulatory and administrative governmental authorities which may delay or restrict Regeneron’s ability to continue to develop or commercialize Regeneron’s Products and Regeneron’s Product Candidates; ongoing regulatory obligations and oversight impacting Regeneron’s Products, research and clinical programs, and business, including those relating to patient privacy; the availability and extent of reimbursement or copay assistance for Regeneron’s Products from third-party payors and other third parties, including private payor healthcare and insurance programs, health maintenance organizations, pharmacy benefit management companies, and government programs such as Medicare and Medicaid; coverage and reimbursement determinations by such payors and other third parties and new policies and procedures adopted by such payors and other third parties; changes to drug pricing regulations and requirements and Regeneron’s pricing strategy; other changes in laws, regulations, and policies affecting the healthcare industry; competing drugs and product candidates that may be superior to, or more cost effective than, Regeneron’s Products and Regeneron’s Product Candidates (including biosimilar versions of Regeneron’s Products); the extent to which the results from the research and development programs conducted by Regeneron and/or its collaborators or licensees may be replicated in other studies and/or lead to advancement of product candidates to clinical trials, therapeutic applications, or regulatory approval; unanticipated expenses; the costs of developing, producing, and selling products; the ability of Regeneron to meet any of its financial projections or guidance and changes to the assumptions underlying those projections or guidance; the potential for any license, collaboration, or supply agreement, including Regeneron’s agreements with Sanofi and Bayer (or their respective affiliated companies, as applicable), to be cancelled or terminated; the impact of public health outbreaks, epidemics, or pandemics on Regeneron‘s business; and risks associated with litigation and other proceedings and government investigations relating to the Company and/or its operations (including the pending civil proceedings initiated or joined by the U.S. Department of Justice and the U.S. Attorney’s Office for the District of Massachusetts), risks associated with intellectual property of other parties and pending or future litigation relating thereto (including without limitation the patent litigation and other related proceedings relating to EYLEA^® (aflibercept) Injection), the ultimate outcome of any such proceedings and investigations, and the impact any of the foregoing may have on Regeneron’s business, prospects, operating results, and financial condition. A more complete description of these and other material risks can be found in Regeneron’s filings with the U.S. Securities and Exchange Commission, including its Form 10-K for the year ended December 31, 2024 and its Form 10-Q for the quarterly period ended September 30, 2025. Any forward-looking statements are made based on management’s current beliefs and judgment, and the reader is cautioned not to rely on any forward-looking statements made by Regeneron. Regeneron does not undertake any obligation to update (publicly or otherwise) any forward-looking statement, including without limitation any financial projection or guidance, whether as a result of new information, future events, or otherwise.

Regeneron uses its media and investor relations website and social media outlets to publish important information about the Company, including information that may be deemed material to investors. Financial and other information about Regeneron is routinely posted and is accessible on Regeneron‘s media and investor relations website (https://investor.regeneron.com) and its LinkedIn page (https://www.linkedin.com/company/regeneron-pharmaceuticals).

Source: Regeneron Pharmaceuticals, Inc.

Treatment with INCA033989 as monotherapy or in combination with ruxolitinib (Jakafi) was well tolerated and led to spleen and anemia responses in patients with CALR exon 9–mutated myelofibrosis who were resistant or intolerant to prior JAK inhibitor therapy, or were ineligible for JAK inhibitor therapy, according to data from the phase 1 INCA033989-101 (NCT05936359) and INCA033989-102 (NCT06034002) trials.¹

Findings presented at the 2025 ASH Annual Meeting and Exposition demonstrated that no dose-limiting toxicities (DLTs) were reported in patients treated with INCA033989 monotherapy (n = 52). Treatment-emergent adverse effects (TEAEs) of any grade occurred in 96.2% of patients, including 57.7% who had any-grade treatment-related AEs (TRAEs), 30.8% who had grade 3 or higher TEAEs, and 9.6% who had serious TEAEs. TEAEs led to treatment discontinuation and dose reductions in 3.8% of patients each, infusion interruption in 5.8% of patients, and dose delays in 23.1% of patients.

In patients treated with INCA033989 plus ruxolitinib (n = 20), all had any-grade TEAEs, including 65.0% with any-grade TRAEs, 55.0% with grade 3 or higher TEAEs, and 25.0% with serious TEAEs. No DLTs were reported with the combination. TEAEs led to treatment discontinuation in 10.0% of patients, dose reductions in 5.0% of patients, infusion interruption in 5.0% of patients, and dose delays in 40.0% of patients.

Regarding efficacy, INCA033989 monotherapy (n = 36) yielded a spleen volume reduction of at least 25% (SVR25) at week 24 in 41.7% of patients and an SVR of at least 35% (SVR35) at week 24 in 33.3% of patients. Best SVR was 47.9% for SVR25 and 31.3% for SVR35. In patients without any prior JAK inhibitor exposure (n = 7), the 24-week SVR25 and SVR35 rates were 71.4% and 57.1%, respectively. In patients who were relapsed/refractory or intolerant to a JAK inhibitor (n = 29), these respective rates were 34.5% and 27.6%.

For patients treated with the combination, evaluable patients at week 24 (n = 12) experienced SVR25 and SVR35 rates of 50% and 25%, respectively. A best SVR of SVR25 occurred in 11 total patients; SVR35 was reported in 8 patients.

“INCA033989 is really well tolerated both as monotherapy and in combination with ruxolitinib,” lead study author John O. Mascarenhas, MD, said in a presentation of the data. “We saw rapid spleen and anemia responses in both cohorts.”

Mascarenhas is a professor of medicine at the Icahn School of Medicine at Mount Sinai in New York, New York, where he also serves as director of the Center of Excellence for Blood Cancers and Myeloid Disorders. He is also a member of The Tisch Cancer Institute, where he is director of the Adult Leukemia Program and leader of clinical investigation in the Myeloproliferative Disorders Program.

What was the rationale of the investigation into INCA033989 in myelofibrosis?

INCA033989 in CALR Exon 9–Mutated Myelofibrosis: Key Takeaways

• INCA033989 alone and in combination with ruxolitinib was well tolerated in patients with CALR exon 9–mutated myelofibrosis who were resistant to, intolerant to, or ineligible for a JAK inhibitor.

• No DLTs were reported with the agent as monotherapy or in combination with ruxolitinib.

• Both regimens produced spleen volume reductions and anemia responses.

Mascarenhas reported that approximately 25% to 35% of patients with myelofibrosis harbor CALR exon 9 mutations, and higher CALR variant allele frequency (VAF) has been associated with more advanced disease featuring anemia and elevated peripheral blasts.

INCA033989—a novel, fully human, high-affinity, Fc-silenced, immunoglobulin G1 monoclonal antibody—is a therapy designed to target CALR exon 9 mutations through selective targeting in complex with the thrombopoietin receptor.

INCA033989-101 is being conducted outside the United States (US), while INCA033989-102 is including US patients specifically. Both studies are enrolling patients at least 18 years of age with primary or post–essential thrombocythemia myelofibrosis harboring CALR exon 9 mutations.^1-3 

Patients need to have a spleen volume of at least 450 mL or palpable splenomegaly of at least 5 cm.¹ To be included in the monotherapy arm, patients need to be intolerant to a JAK inhibitor, resistant to a JAK inhibitor for at least 12 weeks, or ineligible for a JAK inhibitor. Those in the combination arm needed to have a suboptimal response to ruxolitinib given for at least 12 weeks of prior treatment.

During dose escalation, patients in both arms received INCA033989 at 24 mg to 2500 mg intravenously once every 2 weeks. The dose-expansion portion of the study includes monotherapy and combination arms, along with a randomized portion where JAK inhibitor–naive patients are being randomly assigned to INCA033989 with or without ruxolitinib.

The primary end points of dose escalation are evaluating the incidence of DLTs and TEAEs. Secondary end points comprised SVR25 and SVR35 at weeks 12 and 24; anemia response; symptom improvement; and change in CALR exon 9 VAF.

In the monotherapy and combination arms, the median age was 59.5 years (range, 34-76) and 61.0 years (range, 38-82), respectively. The rates of female patients were 32.7% and 20.0%, respectively, and patients had respective median times from initial diagnosis of 7.4 years (range, 0-25.3) and 3.1 years (range, 0.4-16.4). CALR exon 9 mutation type included type 1 (monotherapy arm, 57.7%; combination arm, 60.0%), type 2 (21.2%; 35.0%), and other (21.2%; 5.0%). The median CALR VAF was 36% (range, 24%-53%) in the monotherapy arm and 39% (range, 30%-85%) in the combination arm.

What other efficacy data were reported for INCA033989?

In the monotherapy arm, 93.3% of evaluable patients (n = 45) experienced symptom improvements, and 60.0% achieved at least a 50% reduction in total symptom score (TSS50).

For those evaluable for anemia response (n = 25), best responses comprised major response (40.0%), minor response (16.0%), stable anemia (32.0%), progressive anemia (8.0%), and missing (4.0%). In patients with transfusion-dependent anemia, best responses were major response (20.0%), minor response (40.0%), stable anemia (20.0%), and progressive anemia (20.0%). Those without transfusion-dependent anemia (n = 20) had best anemia responses of major response (45.0%), minor response (10.0%), stable anemia (35.0%), progressive anemia (5.0%), and missing (5.0%).

Notably, a reduction of CALR exon 9 mutation VAF occurred in 89.4% of evaluable patients in the monotherapy arm (n = 47), and 10.6% of patients achieved a best reduction of at least 25%.

In the combination arm, 81.3% of patients (n = 16) experienced symptom improvements, and 33.3% (n = 9) achieved TSS50 at week 24. In evaluable patients (n = 14), 86% had stable anemia during the study, and 1 patient had a major anemia response.

What were the most common TEAEs with each INCA033989 regimen?

In the INCA033989 monotherapy group, the most common any-grade TEAEs reported in at least 15% of patients included anemia (30.8%), fatigue (26.9%), thrombocytopenia (25.0%), arthralgia (21.2%), increased aspartate aminotransferase (AST; 21.2%), cough (21.2%), diarrhea (21.2%), headache (21.2%), leukopenia (21.2%), nausea (21.2%), pruritus (21.2%), hyperglycemia (19.2%), neutropenia (19.2%), nasal congestion (15.4%), and extremity pain (15.4%).

In the combination arm, the most frequent TEAEs of any grade that occurred in at least 15% of patients consisted of anemia (45.0%), thrombocytopenia (35.0%), increased alanine aminotransferase levels (20.0%), diarrhea (20.0%), fatigue (20.0%), increased AST (15.0%), and cough (15.0%).

References

1. Mascarenhas J, Al-Ali HK, Gupta V, et al. Safety and efficacy of the mutant calreticulin-specific monoclonal antibody INCA033989 as monotherapy or in combination with ruxolitinib in patients (pts) with myelofibrosis (MF): preliminary results from dose escalation of two global phase 1 studies. Blood. 2025;146(suppl 1):484. doi:10.1182/blood-2025-484
2. A study to evaluate INCA033989 administered as a monotherapy or in combination with ruxolitinib in participants with myeloproliferative neoplasms. ClinicalTrials.gov. Updated November 18, 2025. Accessed December 7, 2025. https://www.clinicaltrials.gov/study/NCT05936359
3. A study to evaluate INCA033989 administered as a monotherapy or in combination with ruxolitinib in participants with myeloproliferative neoplasms. ClinicalTrials.gov. Updated October 30, 2025. Accessed December 7, 2025. https://clinicaltrials.gov/study/NCT06034002

The Philippines central bank makes its rate decision Thursday, where it could deliver a fifth consecutive cut as inflation stays benign and growth soft.

The Southeast Asian country is facing mounting headwinds from a domestic corruption scandal involving the alleged misuse of public funds for state flood-management initiatives.

Economic growth slowed to a more than four-year low in the third quarter, while inflation undershot the Bangko Sentral ng Pilipinas’s 2025 inflation target of 2% to 4% for a ninth straight month in November.

“Recent GDP numbers raise concerns that soft government spending could become a longer-term drag, weighing not only on fiscal outlays but also on business and private-sector sentiment,” ING’s Deepali Bhargava and Lynn Song wrote in a note.

The BSP looks poised to lower its policy rate, with an expected additional cut in the first quarter of next year, as governance-related issues weigh on growth amid benign inflation, ANZ Research economists said in a report.

At its meeting in October, the BSP cut its policy rate unexpectedly, as it flagged a weaker growth outlook.

  India 

  India's inflation data on Friday will likely show that price pressures remain at multi-decade lows, reinforcing the central bank's decision to cut interest rates at its final meeting of the year. 

  The main drag will likely continue to come from food prices, the ANZ Research team said. While headline inflation could tick up from the nadir reached in October, household goods and services prices likely continued to decline due to GST rate cuts, they wrote. 

  Inflation is likely to average just below 2% for the current fiscal year, HSBC economists said. Only a third of the impact of GST tax cuts has fed through to inflation, signaling room for further cooling ahead, they said. 

  Core inflation is also easing but is more long-lasting than before, which could influence monetary policy, they added. 

  Taiwan 

  Taiwan is set to release its trade data for November on Tuesday, which will probably show that exports continued their run of torrid growth. 

  The island's economy has been supported by resilient export growth through the year, as frontloading to get ahead of tariffs combined with the AI boom to keep its shipments in high demand. 

  "AI-related demand for GPUs, graphics cards, and servers-alongside year-end seasonal demand for new consumer electronics-is likely to continue supporting export momentum," DBS economists said. 

  Taiwan's U.S.-bound shipments should also get a lift from the delay in semiconductor tariffs. 

  That said, non-tech traditional industries will likely continue to face headwinds, the DBS team expects. "The 20% U.S. reciprocal tariff on Taiwan-higher than that applied to Japan and South Korea-keeps Taiwanese manufacturers in these sectors at a competitive disadvantage." 

  Any references to days are in local times. 

  Write to Jessica Fleetham at jessica.fleetham@wsj.com and  Fabiana Negrin Ochoa at fabiana.negrinochoa@wsj.com 

  (END) Dow Jones Newswires

  December 07, 2025 16:14 ET (21:14 GMT)
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