CDK4

ROCKVILLE, Md. and SUZHOU, China, April 28, 2025 (GLOBE NEWSWIRE) -- Ascentage Pharma (NASDAQ: AAPG; HKEX: 6855), a global biopharmaceutical company engaged in discovering, developing, and commercializing therapies to address global unmet medical needs primarily for hematological malignancies, today announced that it has presented results from five preclinical studies during poster presentations at the 2025 American Association for Cancer Research (AACR) Annual Meeting, taking place April 25-30, 2025, in Chicago, Illinois, USA. These poster presentations feature five of the company’s drug candidates: novel tyrosine kinase inhibitor (TKI) olverembatinib (HQP1351), Bcl-2 inhibitor lisaftoclax (APG-2575), FAK/ALK/ROS1 TKI APG-2449, embryonic ectoderm development (EED) inhibitor APG-5918, and IAP antagonist AS03157. Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma, said, “The encouraging data from our investigational assets, presented at this year’s AACR Annual Meeting, are another testament to our strong and innovative pipeline. In particular, the combination of olverembatinib and lisaftoclax, two of our key drug candidates, has demonstrated strong synergistic effects in preclinical models of acute myeloid leukemia and T-cell acute lymphoblastic leukemia. These preclinical studies are expected to complement and further catalyze our clinical development. Moving forward, we will actively advance the clinical development of these programs in order to bring more treatment options to patients in need.” Detailed data presented at this year’s AACR Annual Meeting are as follows: Olverembatinib (HQP1351) in combination with lisaftoclax (APG-2575) overcomes venetoclax resistance in preclinical models of acute myeloid leukemia (AML) Abstract#: 5652Session: Novel Antitumor Agents 3 Introduction: Combining Bcl-2 inhibitor venetoclax with hypomethylating agents is the standard of care for patients with AML who are older or ineligible for intensive chemotherapy. However, resistance to venetoclax is a major clinical challenge, necessitating alternative therapeutic options. Olverembatinib, a multikinase inhibitor, targets kinases associated with leukemogenesis and venetoclax resistance in AML, including FLT3, cKIT, PDGFR, Src family kinases, PI3K, and FGFR. Lisaftoclax is an investigational, novel, selective Bcl-2 inhibitor currently being tested clinically for several hematologic malignancies, including relapsed/refractory AML. In this study, we evaluated the effects of olverembatinib combined with lisaftoclax in venetoclax-resistant (VEN-R) AML models. Summary: In VEN-R AML cell lines, the combination of olverembatinib and lisaftoclax synergistically inhibited cellular proliferation and induced cellular apoptosis. Olverembatinib in combination with lisaftoclax synergistically suppressed tumor growth in a MOLM-13-VEN-R AML xenograft model in vivo. Mechanistically, western blot analysis revealed that the combination synergistically downregulated several leukemogenic signaling pathways, including those associated with venetoclax resistance, such as FLT3, AKT, MCL-1, and activated apoptosis. In summary, olverembatinib in combination with lisaftoclax overcame venetoclax resistance in preclinical AML models, warranting further clinical investigation as a new therapeutic strategy for VEN-R AML. Effects of olverembatinib (HQP1351) in combination with Bcl-2 inhibitor lisaftoclax (APG-2575) in T-cell acute lymphoblastic leukemia (T-ALL) Abstract#: 5648Session: Novel Antitumor Agents 3 Introduction: T-ALL is a high-risk hematologic cancer arising from malignant transformation of T-cell progenitors, affecting approximately 15% of newly diagnosed pediatric and 25% of adult ALL cases. Survival in patients with relapsed or refractory disease is poor, with limited treatment options. Some T-ALL subtypes depend on pre-TCR/Src signaling and antiapoptotic Bcl-2 family proteins for growth and survival. Olverembatinib, a novel multikinase inhibitor, targets oncogenic Src-family kinases (Lck, Fyn, and YES1), which are essential for T-cell differentiation, survival, and activation. Lisaftoclax is a novel Bcl-2 inhibitor under investigation in late-stage clinical trials for multiple hematologic malignancies. We evaluated antitumor effects of olverembatinib combined with lisaftoclax in human T-ALL cell lines and xenograft models and explored potential mechanisms of action. Summary: Olverembatinib in combination with lisaftoclax synergistically inhibited proliferation and augmented apoptosis in T-ALL cells in vitro. The combination synergistically suppressed tumor growth in a MOLT4 xenograft model in vivo. Mechanistically, olverembatinib inhibited Lck phosphorylation, and when combined with lisaftoclax, synergistically reduced downstream NF-kB p65 and BCL-xL, which is typically upregulated in T-ALL. The combination also downregulated phosphorylation of AKT and GSK3b kinases, resulting in degradation of MCL-1 and c-MYC, an essential pro-oncogenic protein in T-ALL. In summary, our findings provide a scientific rationale for further clinical evaluation of this novel combination therapy in patients with T-ALL. Embryonic ectoderm development protein (EED) inhibitor APG-5918 exhibits potent antitumor activity and synergizes with androgen receptor (AR) inhibitor enzalutamide in preclinical prostate cancer (PCa) models Abstract#: 446Session: Experimental and Molecular Therapeutics Introduction: Castration-resistant prostate cancer (CRPC) remains incurable due to resistance to therapies including the new generation of androgen receptor pathway inhibitors (ARPIs) such as enzalutamide. Dysregulation of polycomb repressive complex 2 (PRC2) is common in PCa and is associated with poor prognosis and metastasis. The catalytic subunit of PRC2, enhancer of zeste homolog 2 (EZH2), promotes tumor suppressor gene silencing by methylating histone H3 on lysine 27 (H3K27me3) and directly activates AR gene expression. Another core PRC2 component, EED, is essential for the histone methyltransferase activity. Targeting EED has emerged as a promising strategy to inhibit PRC2 function. This study aims to evaluate the antitumor activity and molecular mechanisms of APG-5918, a potent and selective EED inhibitor, alone or in combination with enzalutamide, in preclinical PCa models. Summary: APG-5918 demonstrated superior inhibitory effects on PCa cell proliferation in vitro. APG-5918 in combination with enzalutamide synergistically suppressed cell proliferation. APG-5918 induced dose-dependent cell cycle arrest in LNCaP and C4-2B cells. Combining enzalutamide with APG-5918 deepened G0/G1 cell cycle arrest. APG-5918 showed significant antitumor activity in human LNCaP and enzalutamide-resistant 22Rv1 xenograft models in castrated nude mice. Mechanistically, APG-5918 downregulated key on-target PD markers (e.g., H3K27me3, EED, EZH2, SUZ12) and AR pathway proteins. APG-5918 also suppressed oncogenic driver ERG, DNA methylation factors (UHRF1, DNMT1), and antiapoptotic protein MCL-1, and reduced pRb, CDK4, cyclin B1 and cyclin D1—crucial mediators of cell cycle regulation. APG-5918 combined with enzalutamide further enhanced the downregulation of PRC2 components, AR pathway proteins, cell cycle regulators, oncogenic drivers, and DNA methylation factors. Our findings support EED inhibition, alone or in combination with enzalutamide, as a promising therapeutic strategy for the treatment of patients with prostate cancer, which is being further evaluated in the ongoing Phase 1 clinical trial. APG-2449, a novel focal adhesion kinase (FAK) inhibitor, enhances the antitumor activity of chemotherapy in preclinical models of small-cell lung cancer (SCLC) with activated FAK Abstract#: 1679Session: Drug Combination Strategies for Cancer Treatment Introduction: SCLC is a genetically heterogeneous disease with no standardized targeted therapy options. Despite the recent advancement of immune checkpoint inhibitors, improvements in overall survival have been modest, and platinum-based chemotherapy combined with topoisomerase inhibitors remains the standard of care in SCLC. FAK, a nonreceptor tyrosine kinase, has been reported to regulate cellular proliferation, migration, invasion, and DNA-damage repair. Previous studies have shown that FAK is amplified and overexpressed in approximately 69% of SCLC tumors. Although non-small-cell lung cancer cells harboring FAK (splicing isoform of FAK that increases phosphorylation of FAK [pFAK]) are more sensitive to FAK inhibition than wild-type FAK (FAKWT), the expression and implications of FAK expression in SCLC remain unclear. Given the role of FAK in cancer progression, we hypothesized that inhibition of FAK would augment the antitumor effects of chemotherapy in SCLC. The aim of this study was to evaluate the antitumor activity of investigational agent APG-2449, a novel FAK inhibitor, alone and in combination with chemotherapy in SCLC. Summary: Novel FAK inhibitor APG-2449 demonstrated synergistic antitumor effects when combined with first- and second-line chemotherapies in SCLC. APG-2449 combined with chemotherapy can enhance DNA damage and increase apoptosis in SCLC cells. These encouraging findings support further clinical development of APG-2449 for the treatment of patients with SCLC. Discovery of AS03157 as a highly potent and orally active antagonist of inhibitor of apoptosis proteins (IAPs) Abstract#: 5651Session: Novel Antitumor Agents 3 Introduction: Overexpression of antiapoptotic proteins, such as cellular inhibitor of apoptosis protein 1 (cIAP1) and 2 (cIAP2) and X-linked IAP (XIAP), occurs in various hematologic and solid cancers, and is associated with drug resistance and a poor prognosis. IAP inhibitors bind to IAP proteins, displace and activate caspases, and induce degradation of cIAP1/2 and XIAP, thereby inhibiting pro-survival signaling and promoting apoptosis in cancer cells. Several small molecules targeting IAPs are being investigated clinically as monotherapy or in combination therapy in hematologic malignancy and solid tumors. Investigational AS03157, a novel and structurally distinct IAP antagonist, was identified with enhanced specificity toward cIAP1 and XIAP. Here, we characterized the pharmacologic profiles of AS03157 in vitro and in vivo. Summary: AS03157 bound to cIAP1 and XIAP with high affinity and efficiently targeted cIAP1 for degradation, thereby generating potent antiproliferative activities (with IC50 values below 30 nM) in tested cancer cell lines. AS03157 demonstrated a favorable druggability profile. AS03157 showed promising in vivo activity in preclinical cancer models and displayed an acceptable safety profile. In summary, AS03157 appears to be a promising candidate for further clinical development. * Olverembatinib, lisaftoclax, APG-2449, APG-5918 and AS03157 are all investigational drugs and have not been approved by the U.S. FDA. About Ascentage PharmaAscentage Pharma is a global, integrated biopharmaceutical company engaged in discovering, developing and commercializing therapies to address global unmet medical needs primarily in hematological malignancies. Ascentage Pharma has been listed on the Main Board of the Stock Exchange of Hong Kong Limited with the stock code 6855.HK since October 2019 and has also been listed on the Nasdaq Global Market under the ticker symbol “AAPG” since January 2025. The company has built a rich pipeline of innovative drug candidates that includes inhibitors targeting key proteins in the apoptotic pathway, such as Bcl-2 and MDM2-p53; and next-generation TKIs that target kinase mutants emergent during cancer treatment. Ascentage Pharma is also the only company in the world with active clinical programs targeting all known key apoptosis regulators. Olverembatinib, one of the company’s lead assets, is already approved in China with all of its approved indications included into the China National Reimbursement Drug List (NRDL). Meanwhile, a New Drug Application (NDA) for another one of Ascentage Pharma’s key drug candidates, the novel Bcl-2 selective inhibitor lisaftoclax (APG-2575), has already been accepted and granted the Priority Review designation by the China CDE. To date, Ascentage Pharma has obtained a total of 16 ODDs from the US FDA and 1 Orphan Designation from the EMA of the EU for 4 of the company’s investigational drug candidates. Leveraging its robust R&D capabilities, Ascentage Pharma has built a portfolio of global intellectual property rights and entered into global partnerships and other relationships with numerous leading biotechnology and pharmaceutical companies such as Takeda, AstraZeneca, Merck, Pfizer and Innovent; and research and development relationships with leading research institutions such as Dana-Farber Cancer Institute, Mayo Clinic, National Cancer Institute and the University of Michigan. The company has built a talented team with a wealth of global experience in the discovery and development of innovative drugs and fully functional commercial manufacturing and Sales & Marketing teams. One pivotal aim of Ascentage Pharma is to continuously strengthen its R&D capabilities and accelerate its clinical development programs, in order to fulfil its mission of addressing unmet clinical needs in China and around the world for the benefit of more patients. Forward-Looking StatementsThis press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 and Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. All statements, other than statements of historical facts, contained in this press release may be forward-looking statements, including statements that express Ascentage Pharma’s opinions, expectations, beliefs, plans, objectives, assumptions or projections regarding future events or future results of operations or financial condition. These forward-looking statements are subject to a number of risks and uncertainties as discussed in Ascentage Pharma’s filings with the SEC, including those set forth in the sections titled “Risk factors” and “Special note regarding forward-looking statements and industry data” in its Registration Statement on Form F-1, as amended, filed with the SEC on January 21, 2025 and the Form 20-F filed with the SEC on April 16, 2025, the sections headed “Forward-looking Statements” and “Risk Factors” in the prospectus of the Company for its Hong Kong initial public offering dated October 16, 2019, and other filings with the SEC and/or The Stock Exchange of Hong Kong Limited we made or make from time to time that may cause actual results, levels of activity, performance or achievements to be materially different from the information expressed or implied by these forward-looking statements. The forward-looking statements contained in this presentation do not constitute profit forecast by the Company’s management. As a result of these factors, you should not rely on these forward-looking statements as predictions of future events. The forward-looking statements contained in this press release are based on Ascentage Pharma’s current expectations and beliefs concerning future developments and their potential effects and speak only as of the date of such statements. Ascentage Pharma does not undertake any obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise. Contact InformationInvestor Relations:Hogan Wan, Head of IR and StrategyAscentage PharmaHogan.Wan@ascentage.com+86 512 85557777 Stephanie CarringtonICR HealthcareStephanie.Carrington@icrhealthcare.com(646) 277-1282 Media Relations:Sean LeousICR HealthcareSean.Leous@icrhealthcare.com(646) 866-4012

CDK2 molecular glue degrader (MGD) in combination with CDK4/6 inhibition and anti-estrogen therapy achieved superior tumor regression in vivo compared to standard of care CDK4/6 inhibition and anti-estrogen therapy CDK2 MGD delayed resistance to CDK4/6 inhibition in vitro and displayed superior selectivity versus clinical-stage CDK2 inhibitors BOSTON, April 28, 2025 (GLOBE NEWSWIRE) -- Monte Rosa Therapeutics, Inc. (Nasdaq: GLUE), a clinical-stage biotechnology company developing novel molecular glue degrader (MGD)-based medicines, today announced the company will present preclinical data on the potential of its highly selective cyclin-dependent kinase 2 (CDK2)-directed molecular glue degrader, MRT-51443, to treat HR-positive/HER2-negative breast cancer at the American Association for Cancer Research (AACR) Annual Meeting 2025, being held April 25-30 in Chicago, IL. “In preclinical models of HR-positive/HER2-negative breast cancer, the combination of MRT-51443 with a CDK4/6 inhibitor and anti-estrogen therapy drove robust tumor regressions, demonstrating notably deeper tumor responses than the standard of care combination alone,” said Sharon Townson, Ph.D., Chief Scientific Officer of Monte Rosa Therapeutics. “These results suggest that our highly selective, oral CDK2 degrader MRT-51443 has the potential to improve on current standard of care therapy for HR-positive/HER2-negative breast cancer. In addition, we believe our MGD approach could avoid many of the toxicities associated with less selective CDK2 inhibitors, which is critically important for a potentially differentiated therapy in this patient population. The degree to which CDK2 degradation with MRT-51443 delayed resistance to CDK4/6 inhibition in vitro was also striking, as patients treated with CDK4/6 inhibitors often relapse because their tumors become reliant on the CDK2 pathway. We anticipate an IND submission for our cell cycle program in 2026.” The poster, entitled, “Selective Targeting of CDK2 Using Molecular Glue Degraders for the Treatment of HR-Positive/HER2-Negative Breast Cancer” (Poster Number LB422), will be displayed on April 30, 2025, from 9am to 12pm CST in Poster Section 51, Poster Board 4. The poster will be presented by Sofia Gkountela, Associate Director, Biology, and Nina Ilic-Widlund, Director, Biology, Monte Rosa Therapeutics. Summary of findings: MRT-51443 exhibited potency, selectivity, and favorable drug-like properties. MRT-51443 demonstrated superior selectivity as compared to several clinical-stage small molecule CDK2 inhibitors. In cellular assays, MRT-51443 induced deep CDK2 degradation, resulting in CDK2-dependent cancer cell growth inhibition. Degradation of CDK2 with MRT-51443 delayed resistance to CDK4/6 inhibition in vitro and exhibited strong anti-tumor activity in combination with CDK4/6 inhibitors in vivo. MRT-51443 in combination with CDK4/6 inhibition and anti-estrogen therapy drove deep tumor regressions and achieved superior tumor regression compared to standard of care CDK4/6 inhibition and anti-estrogen therapy in HR+/HER2- breast cancer models. Specifically, in the MCF7 model, the combination of MRT-51443 + ribociclib + fulvestrant demonstrated median tumor growth of -77% versus -3% for ribociclib + fulvestrant. In the T47D model, MRT-51443 + ribociclib + fulvestrant demonstrated median tumor growth of -61% versus -10% for ribociclib + fulvestrant. The combination of MRT-51443 + ribociclib also resulted in robust tumor regression in both models. About CDK2 MGDs and MRT-51443 Cyclin-dependent kinase 2 (CDK2) is a key driver of cell cycle progression in cancer, acting in coordination with CDK4 and CDK6 to drive cell proliferation. CDK4/6 inhibitors, in combination with endocrine therapy, are FDA-approved agents for the treatment of HR-positive/HER2-negative breast cancer; however, many patients become resistant because their tumors become reliant on CDK2. Targeting CDK2 in conjunction with CDK4/6 inhibition has the potential to provide more sustained clinical responses. In preclinical studies, Monte Rosa’s next-generation CDK2-targeted MGD, MRT-51443, has demonstrated highly selective degradation of CDK2, with no detectable off-target activity. MRT-51443 induced robust downstream CDK2 pathway suppression and drove deep tumor regression, achieving greater anti-tumor activity than current standard of care therapeutics, in preclinical models of HR-positive/HER2-negative breast cancer when combined with either a CDK4/6 inhibitor or a CDK4/6 inhibitor plus an anti-estrogen therapy. Targeting CDK2 with MRT-51443 represents a potentially novel approach to treating HR-positive/HER2-negative breast cancer in combination with current standard of care therapies. About Monte Rosa Monte Rosa Therapeutics is a clinical-stage biotechnology company developing highly selective molecular glue degrader (MGD) medicines for patients living with serious diseases in the areas of oncology, autoimmune and inflammatory diseases, and more. MGDs are small molecule protein degraders that have the potential to treat many diseases that other modalities, including other degraders, cannot. Monte Rosa’s QuEEN™ (Quantitative and Engineered Elimination of Neosubstrates) discovery engine combines AI-guided chemistry, diverse chemical libraries, structural biology, and proteomics to identify degradable protein targets and rationally design MGDs with unprecedented selectivity. The QuEEN discovery engine enables access to a wide-ranging and differentiated target space of well-validated biology across multiple therapeutic areas. Monte Rosa has developed the industry’s leading pipeline of MGDs, which spans oncology, autoimmune and inflammatory disease and beyond. Monte Rosa has a global license agreement with Novartis to advance VAV1-directed molecular glue degraders and a strategic collaboration with Roche to discover and develop MGDs against targets in cancer and neurological diseases previously considered impossible to drug. For more information, visit www.monterosatx.com. Forward-Looking Statements This communication includes express and implied “forward-looking statements,” including forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include all statements that are not historical facts and in some cases, can be identified by terms such as “may,” “might,” “will,” “could,” “would,” “should,” “expect,” “intend,” “plan,” “objective,” “anticipate,” “believe,” “estimate,” “predict,” “potential,” “continue,” “ongoing,” or the negative of these terms, or other comparable terminology intended to identify statements about the future. Forward-looking statements contained herein include, but are not limited to, statements about the therapeutic potential of CDK2 degradation, including using the company’s CDK2-directed MGDs, including MRT-51443, that degrading CDK2 in conjunction with CDK4/6 inhibition and hormone therapy has the potential to provide more sustained responses in patients with HR-positive/HER2-negative breast cancer than current standard of care therapy including CDK4/6 inhibition and hormone therapy, about preclinical data presented at the American Association for Cancer Research (AACR) Annual Meeting 2025 supporting the potential of its highly selective cyclin dependent kinase 2 (CDK2)-directed molecular glue degrader to treat HR-positive/HER2-negative breast cancer, and about the Potential of CDK2-directed MGDs, including MRT-51443, to provide more sustained responses in a difficult-to-treat patient population while avoiding toxicities typically associated with limited selectivity of CDK2 inhibitors, among others. By their nature, these statements are subject to numerous risks and uncertainties, including those risks and uncertainties set forth in our most recent Annual Report on Form 10-K for the year ended December 31, 2024, filed with the U.S. Securities and Exchange Commission on March 20, 2025, and any subsequent filings, that could cause actual results, performance or achievement to differ materially and adversely from those anticipated or implied in the statements. You should not rely upon forward-looking statements as predictions of future events. Although our management believes that the expectations reflected in our statements are reasonable, we cannot guarantee that the future results, performance, or events and circumstances described in the forward-looking statements will be achieved or occur. Recipients are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date such statements are made and should not be construed as statements of fact. We undertake no obligation to publicly update any forward-looking statements, whether as a result of new information, any future presentations, or otherwise, except as required by applicable law. Certain information contained in these materials and any statements made orally during any presentation of these materials that relate to the materials or are based on studies, publications, surveys and other data obtained from third-party sources and our own internal estimates and research. While we believe these third-party studies, publications, surveys and other data to be reliable as of the date of these materials, we have not independently verified, and make no representations as to the adequacy, fairness, accuracy or completeness of, any information obtained from third-party sources. In addition, no independent source has evaluated the reasonableness or accuracy of our internal estimates or research and no reliance should be made on any information or statements made in these materials relating to or based on such internal estimates and research. Investors Andrew Funderburk ir@monterosatx.com Media Cory Tromblee, Scient PR media@monterosatx.com

Step back from the multitude of details that go into every big pharma pipeline, and you’ll see the influence that blockbusters have on the entire field. These days, making your mark in R&D at the level the top 15 spenders play requires not just one, two or three experimental drugs that can earn a billion dollars a year. It’s typically about a slate that includes candidates that can bring in $3 billion to $5 billion a year, preferably more. The numbers keep getting bigger. When Merck execs look at the $30 billion-plus hole they have to fill once Keytruda goes off-patent, they know that anything under a billion won’t count for much. And you can see the same math dominating discussions at J&J, Pfizer, Bristol Myers Squibb and more. On the plus side, the drive to move the dial on sales includes changing standards of care for large numbers of patients. That can open up some hard targets that have defied investigators for years. The hunt for first- and best-in-class drugs inspires truly innovative development work. But for patients — including me — who suffer from diseases that aren’t among the major league targets, it can be hard to find much interest among a set of companies that have to think big in order to survive. These days, with IPOs still out of favor, the blockbuster strategy of the big cap players is more influential than ever. Those R&D alliances that can sustain a biotech will be skewed to the companies that are breaking new ground where pharma sees the biggest upsides. And it will bend an entire global industry’s decision-making process. Success breeds success in this field. AstraZeneca, which once struggled to turn around the industry’s weakest pipeline, can now devote close to $14 billion a year for drug research in a variety of fields. And that has helped alter the landscape of the R&D 15, which once was long dominated by Roche. Other key themes emerge here. One of the most important is the emergence of China as a force in drug discovery. BD teams looking for R&D shortcuts have begun picking up drug candidates in bulk in China, presenting a thorny new reality for US and European biotechs that aren’t able to move as quickly. This year, I’m concentrating on public pharma companies, which have always dominated the list. But it excludes the privately-owned Boehringer Ingelheim, where it’s harder to find details on the pipeline. Takeda also drops off this year’s list, falling just short of the dollar mark needed. And Regeneron marks its arrival as the big biotech invests heavily in its pipeline. — John Carroll The big picture: During 2023, Merck bulked up on M&A deals that pumped up its R&D budget line to a whopping $30.5 billion. In 2024, the pharma giant continued shelling out the big bucks, but without a scale-tipping deal like the $10.8 billion Prometheus acquisition we saw included in the R&D line in 2023. Nevertheless, Merck easily held on to the top spot among the 15 biggest public company R&D spenders on the planet. By the end of last year, Merck had once again dwarfed the old R&D spending leaders like Basel-based Roche, where budget discipline remains a constant. Merck has been shoveling cash into the R&D engine because it’s three years away from a titanic collision with a key patent loss for Keytruda, the $30 billion — and counting — PD-1 behemoth that went a long way to changing the way cancer is treated. Merck continues to rack up big annual increases in Keytruda revenue, which has been essential as the company’s other big earner — Gardasil — fizzled in the face of some ambitious sales projections for the China market. There’s one ace in the hole, with analysts arguing over just how much Merck can make from their late-stage subcutaneous version of Keytruda, which will come with a whole new patent life to profit off of. But whether it’s $6 billion or $7 billion a year, that still leaves a Grand Canyon-sized gap in the budget that must be filled. And the rep of CEO Rob Davis and R&D chief Dean Li will be made or lost on their pipeline strategy for a Keytruda replacement. Or replacements. “The future is less monolithic Keytruda,” Davis said . “It’s going to be a lot of smaller, precision-based therapies aimed at specific tumors or indications.” It’s going to take a lot of smaller drugs to mend a rip that size. That means a long string of deals, including a move to elbow its way to the future of immunotherapy with a rival to Summit’s PD-1/VEGF combo. And that required a turn to China, following what is now a well-beaten path for new drugs that they’ve bet big on. Merck kept the focus on China when it inked a deal just days ago for an oral Lp(a) inhibitor from Hengrui . Novartis recently delayed the timeline for wrapping its Phase 3 study for an antisense candidate for Lp(a) (partnered with Ionis), pushing the results for data on 8,000 patients to the first half of 2026. Merck put up a $200 million down payment on a $2 billion deal for an oral treatment that will need to go through a global program. That’s a low-cost deal in front of a major trial expense, and it offers a chance to leap into a race where orals may well end up ruling the franchise. But it’s no Keytruda. Investors don’t care much for the overall picture. Merck’s shares have dwindled more than 21% over the past year, even as sales kept climbing. Wall Street wasn’t crazy about Merck’s decision to withdraw guidance on Gardasil, at all. And the Keytruda dilemma has created a narrative that has dominated the company for years now. Merck execs can project confidence, but R&D spending illustrates a high level of anxiety. The big picture: You can bet that Roche execs were paying particularly close attention to AstraZeneca’s recent release of a positive, preliminary slice of late-stage data for camizestrant, its oral SERD for hormone receptor-positive, HER2-negative breast cancer. The Basel-based pharma giant has been angling — alongside Eli Lilly — to beat a path to the market with a best-in-class oral SERD that can be expected to rack up billions a year, provided they get in early on a field that has been a primary concern for years. Roche CEO Thomas Schinecker has pegged giredestrant as one of its top late-stage drugs, putting it in the pole position of a chart of potential blockbusters as it waits for late-stage data from their persevERA and evERA trials. It’s in a group of seven pipeline therapies that Roche believes can pave the way to new franchises worth $3 billion or more. AstraZeneca has pegged its rival as a $5 billion-plus earner, offering some added insight here on where the market is focused. But the others include some high flyers that face daunting odds in the clinic, as well as a cluster of rivals that Roche has to race for best-in-class status. Take, for example, the amyloid buster trontinemab, which recently offered an early picture of its ability to target the plaque — cognition was not part of that study, though. And the road for Alzheimer’s drugs is long and frequently twisted, with a questionable marketing future if it fails to do more than slow progression. Prasinezumab has failed a couple of mid-stage studies for Parkinson’s, as investigators try to find a population where it works. Parkinson’s remains one of the toughest targets in the industry, with repeated setbacks for key players — including a rival with the mechanism as Roche’s drug. Trontinemab and prasinezumab are both up for Phase 3 enabling readouts this year. Astegolimab is a dark horse Phase 3 candidate in a group of drugs aimed at taking on Dupixent’s dominant role in COPD. That drug — which inhibits the IL-33 receptor ST2 — was flagged for pivotal readouts this year from the ALIENTO and ARNASA trials. A couple of years ago, Roche fronted $310 million to partner with Alnylam on the RNAi drug zilebesiran for hypertension, which has posted positive mid-stage data. That makes the cut as a major potential player. NXT007 offers a new shot at hemophilia A after Roche took a hit on its gene therapy out of the Spark buyout. Long term, Roche wants to keep building around the Hemlibra franchise, which brought in $5 billion in 2024. In the follow-up category of potential blockbusters, Roche counts four drugs with $2 billion to $3 billion in peak sales potential. That group includes their BTK inhibitor fenebrutinib, which has reportedly done well in Phase 2 for MS. That’s up for a pivotal readout this year, along with vamikibart, which is in two studies called SANDCAT and MEERKAT for uveitic macular edema. As one of the biggest R&D operators in the world, Roche can afford a big pipeline with a number of misses. It’s the one or two big successes in each group of contenders that sustain a company of this size, as it proved yet again with their Regeneron rival Vabysmo, which broke through the $4 billion barrier last year as Tecentriq flattened out and exhibited signs of erosion. Polivy also jumped into the blockbuster club, marking a key marketing success. The key thing for Roche R&D is putting up a slate of credible contenders, with a group of late-stage candidates tackling big diseases and at least one big prospect that looks competitive in the multibillion-dollar class. To that end, Roche continues to selectively snap up new candidates and forge new alliances around the globe. In recent months we’ve tracked an antibody pact with UK biotech Oxford BioTherapeutics, heavily weighted to biobucks as is common in discovery deals. And they went back to the China well for a new deal with Innovent on small cell lung cancer that cost $80 million in upfront cash. Paying $1 billion for the off-the-shelf CAR-T tech at Poseida amounted to a small bolt-on in this world. Roche paid $2.7 billion for Carmot, and had some positive early data to exhibit last year. A lot of this will sour or fizzle out. TIGIT was once a hot prospect, but it’s all been bad news on that front. You win some, you lose some in Big Pharma. Roche has been winning enough to stay on top, but the pressure is always on. The big picture: Pascal Soriot took plenty of painful shots during his early years as CEO of a woeful AstraZeneca — including more than a couple from me — with each setback cause for fresh concern. Slowly building a slate of giant franchises in oncology, and buying Alexion to beef up earnings, ended the fretting. By the end of 2024, AstraZeneca’s top execs could boast of full-year revenue growth of 21%. Industry buzz has Soriot spending big chunks of every year in China, where the company has been working to make a confrontation with the government into a commercial speed bump, hoping to continue to romp and stomp while using its international status and UK headquarters to steer clear of the showdown between the US and China. And it recently underscored the connection by unveiling plans for an expansion of its R&D work in China. Its growing commercial success with proven oncology drugs has spurred Soriot to invest heavily in the pipeline, stretching past cancer into other fields, like obesity. Five years ago, AstraZeneca shelled out $6 billion for R&D in 2019. In 2024, that tally had more than doubled as AstraZeneca surged from a cash-strapped player to an industry leader in research, trailing only Merck as the US outfit urgently tries to engineer a replacement set of drugs for an aging Keytruda franchise. Quite a few analysts are ready to offer their thumbs-up for AstraZeneca’s progress, but the question now is likely to center on whether AstraZeneca can keep its winning streak on track. Case in point: Camizestrant has been built into a $5 billion+ annual prospect. Some observers are ready to sign off on a blockbuster future for the oral SERD drug, especially after a recent Phase 3 win, but temper the enthusiasm with somewhat lower sales expectations. Baxdrostat also gets star billing, as Soriot touts “more than 90 late-stage trials underway with an average non-risk adjusted peak year revenue per trial of $1 billion.” The focus now is on performance in the clinic, but AstraZeneca’s financial results give it considerable range to consider more deals. Soriot picked up baxdrostat — exploring a new mechanism of action for hypertension that investigators have been exploring for close to 20 years — in a $1.8 billion deal for CinCor two years ago. And the pharma giant has helped blaze the BD path through China, leaving it in a position to scoop up fresh assets at discount prices. R&D risk is always huge, but investors have liked the odds. $AZN is up 16% over the past year. The big picture: With biosimilar competition ramping up this year for Stelara, one of J&J’s mainstay mega-franchises ($10.4 billion in 2024), the pharma giant needs to rack up some regulatory wins from the late-stage pipeline. The company’s R&D group breathed a sigh of relief when icotrokinra, its big program for IBD brought in from Protagonist, recently delivered — at least on the major points we could see in the company statement — in an important mid-stage trial of the oral IL-23 therapy. J&J execs, who have been slowly unfolding a pipeline-in-a-product strategy for this drug, believe icotrokinra can be a $5 billion-a-year earner, putting it at the tip of the big phalanx of R&D projects now in the pipeline. Another late-stage drug that gets a lot of attention at J&J is nipocalimab for generalized myasthenia gravis, which has nabbed breakthrough drug status at the FDA as it looks for an OK. And there’s a new fast-track designation for this drug in moderate-to-severe Sjögren’s disease. J&J is a behemoth with a long list of marketed drugs, a fact that comforts risk-averse investors. But the churn tends to deter anyone looking for some quick upside. Its medtech group spent $3.7 billion on R&D last year, helping maintain a stable of products that deliver on the bottom line. That helps keep the numbers steady. And it helps when one-time blockbusters-to-be — I’m talking about aticaprant here — flounders in its Phase 3. J&J had slated the anti-depressant in the $1 billion to $5 billion category, up until a few weeks ago when the drug giant wrote it off for insufficient efficacy. Anyone who’s been following depression R&D for the past 20 years wouldn’t have been too surprised to see yet another Phase 3 fail here. But neuro is still surging on increased confidence that scientists can deliver major drugs for unmet needs. For J&J, the belief helped inspire the Intra-Cellular Therapies buyout for $14.6 billion during JPM, finally breaking the year-plus drought of M&A deals that broke the $5 billion barrier. That deal, like the top drugs in its pipeline, underscores a well-known fact about J&J. The company is a global player in R&D — helping break the mold on China deals when it picked up the cancer drug Carvykti. But while the company can be a world-class drug picker, it’s not known for discovery work. J&J has also long been operating under a cloud brought on by its talc settlement talks, where the numbers people have set aside billions and appear to be close to finally completing a deal to shunt talc into a subsidiary and settle up with the bulk of the lawsuits. It’s manageable, but after 16 years and thousands of suits, J&J’s investors would like to move on. Following its spinout of the consumer division, J&J is on an R&D path — sticking with diseases its researchers understand well — it’s likely to follow for years. And that will keep BD busy. The big picture: AbbVie’s story in recent years has centered primarily around its fierce development and then commercialization of Rinvoq and Skyrizi to bridge its way past the revenue gorge created by Humira’s slow-motion loss of exclusivity. Once the biggest drug in the world, Humira is being steadily eclipsed by biosimilars, but the R&D group has kept the ball rolling with new studies to expand their pair of cash cows. The Botox buyout remains another key storyline as AbbVie proves yet again that it has an excellent set of marketing skills. Mission accomplished on the big moves, which isn’t to be underestimated. That may not add up to be the most exciting R&D story in biopharma in 2025, but it has certainly kept investors happy as AbbVie worked through a top-level executive transition and began to try kickstarting some fresh enthusiasm with a few ambitious deals. AbbVie took a major stab at neuroscience when it bought out Cerevel a couple of years ago for $8.7 billion , landing a lead asset in the field. But that strategy largely came a cropper recently with the failure of emraclidine, once intended to help change the standard for treating schizophrenia. Big Pharma has been making a few careful moves in neuro, but the unknowns are still legion, and the risks are extremely high. Roche’s setback on prasinezumab for Parkinson’s in late 2024 underscored that universal truth. AbbVie is still talking up the prospects of tavapadon as it racks up Phase 3 wins, but the upside isn’t as great, as far as the analysts are concerned. AbbVie was a late arrival to the obesity scene, talking up its potential for less frequent dosing and relatively competitive weight loss data with Gubra’s amylin drug. The BD team brought that in for $350 million upfront. There are some ADCs that the R&D group thinks highly of and a host of low-cost early-stage deals intended to raise its prospects for the future. For now, though, AbbVie is clearly relying on its marketing muscle and experienced research groups to keep building key franchises — which it is really, really good at. The jury’s out on whether AbbVie can add some major new franchises to grow the company faster. But they have time now. The big picture: Every time a CEO or biotech investor starts making the case for more M&A, often on background, they inevitably point to Bristol Myers as the poster child for Big Pharma pipeline demand. It faces huge looming patent losses — let’s start with Opdivo — and has a couple of years to wait for the kind of registrational data needed for its most promising late-stage drugs. The pharma giant has certainly been a player in the M&A club, snapping up Karuna ( $14 billion ), RayzeBio ( $4.1 billion for a radiopharmaceutical drug in a hotly contested arena) and Mirati ( $5.8 billion for KRAS) along the way. But recent moves aimed at cutting costs while boosting work in Phase 3 underscore just how tricky this can be. And all the buzz about its need for pricey buyouts hummed right along through a muted year of dealmaking in 2024. By all accounts, a few analysts on the Street seem satisfied that Cobenfy — out of Karuna — is on track to a blockbuster future, starting with schizophrenia and potentially expanding into Alzheimer’s. But its launch late last year didn’t come close to satisfying the skeptics rooting for more BD — which has been encouraged by a set of execs ready and willing to talk up their expectations on the acquisitions side of the business. Among the drugs in late-stage work, you’ll find new multiple myeloma therapies, which Samit Hirawat talked up in the last quarterly run-down. “ … It is very important to continue to develop small molecules, which are easy to deliver and can be combined with the standard of care therapies. And that’s exactly where iberdomide, mezigdomide sit,” he added, highlighting head-to-heads with pomalidomide (Pomalyst) — facing near-term generic competition — and Revlimid — already losing ground to copycats. Overall, costs have been headed up in R&D at Bristol Myers, and with all hands on deck for a Phase 3 revival of the portfolio, the pharma giant is poised to keep pouring money into drug development. The big picture: The CEO/R&D chief duo of David Ricks and Daniel Skovronsky took home the big prize with the successful launch of the drug juggernaut Zepbound/Mounjaro, which has emerged as the leading obesity/type 2 diabetes treatment in a world hungry for effective fat busters. They aced the main prize in the GLP-1+ field with their own particular take, and they are following up with additional studies to prove efficacy where it can gain reimbursements — while following up with an oral that is aimed at cementing this category in its favor for years to come. That storyline has proved enormously persuasive with investors, as Eli Lilly’s share price has grown 64% over the past two years and its biggest supporters among the analysts glow with enormous projections. But with that much money on the table, it’s no major surprise to see Novo Nordisk double down on its own obesity franchise — a story that’s had a few problems — while the competition aims at doing it better with fewer side effects and a more appealing form of administration has grown into a mob of biopharma companies. It does make you wonder where peak obesity lies. But Lilly is determined to hold onto the lead, no matter how rough this ride may get. And it promises to pay off in the tens of billions per year. To that end is a prospective 2026 launch of orforglipron, an oral GLP-1. Analysts have been on high alert for upcoming T2 data, which Lilly forecasts should look good in comparison to Novo’s semaglutide. That’s the key competitive number they’re looking for. There’s also the multi-targeted retatrutide in the pipeline to consider, where investigators tracked a 12% weight loss in a mid-stage study. Novo certainly has, inking a deal with China’s United Laboratories for an early-stage rival treatment as it looks to be competitive in a range of targets aside from GLP-1. That deal also underscores how Big Pharma can steal a march on a rival drug by scouting R&D programs in China. There’s also remternetug for Alzheimer’s, a quarterly injection to remove amyloid plaque, versus the monthly injection their approved drug donanemab (Kisunla) uses. Analysts once projected billions in upside for the new Alzheimer’s drugs making their way into the market, but skeptics wonder if their modest benefits for patients will win doctors and large numbers of patients over. Lilly’s late-stage cardio drug lepodisiran often earns a mention from leadership, along with their oral follow-up muvalaplin. Then there’s the KRAS contender olomorasib. Add in the occasional buyout — like Morphic — and you’ll get a picture of an ambitious pipeline funded with growing revenue from an effectively marketed drug with the kind of legs that can sustain a company like this for years to come. Given the company’s credibility in drug development, you’re likely to agree that Eli Lilly should never be underestimated. The big picture: By the end of 2022, Pfizer’s rep was pure gold. There was a king’s ransom in revenue for the multinational operation as it capitalized big time on its rapidly successful alliance with BioNTech for their mega-franchise mRNA vaccine to combat Covid. And CEO Albert Bourla basked in the glow of accolades for helping save the world — with the exception of some stray trolls. Then the world turned, vaccine demand plummeted far past most projections and Pfizer was left to pick up the pieces with a revised R&D game plan and revenue that only modestly improved in 2024 after bottoming out at $59.5 billion in ’23. Now, instead of continuing accolades for a truly historic vaccine rollout, analysts were reminded of Pfizer’s long track record for hit-and-miss performance in R&D and commercial ops. And it remains a big player in vaccines, where the long reach of the new Trump administration and its vaccine critics has extended to scrubbing out references to mRNA. Those persistent doubts led Pfizer to recruit Citi analyst — and longtime Pfizer doubter — Andrew Baum to help sell the company’s innovation plans. And he likely is more aware than most of just how hard that is as Pfizer looks to largely tread water on the numbers side this year. Buying Seagen set its course for a higher profile in oncology, which was on display as Bourla cheered their late-stage programs in his recent assessment of what’s ahead. Bourla earlier tapped oncology chief Chris Boshoff to take over R&D from Mikael Dolsten, signaling that it’s relying on a slate of cancer drugs to help replace Ibrance and Xtandi as those big blockbusters lose exclusivity in a couple of years — mere ticks of the clock in drug development cycles. So it’s no surprise to see company execs talking up prospects for the CDK4 inhibitor atirmociclib, now in a Phase 3 breast cancer study. But they took a nasty hit a few weeks ago when vepdegestrant, its protein degrader partnered with Arvinas, fell short in another breast cancer study. Baum also has his work cut out for him talking up Pfizer’s big plans for their oral obesity drug danuglipron, with analysts shaking their heads over a twice-daily dosing as rivals make progress on that front with drugs that may be much better positioned. Its cachexia drug ponsegromab, meanwhile, has had its late-stage development plan trimmed. Underscoring the doubts about Pfizer, analysts haven’t liked watching its sales of RSV vaccine Abrysvo plunge in a turbulent market for everyone involved. The pharma player has to perform consistently on sales if it expects to overcome the skeptics at this point. Add it all up and Pfizer looks like it will continue to operate under a cloud for some time to come, needing to establish a solid track record of significant new approvals and reliable marketing success. In the meantime, look for the company to keep shelling out big dividends to keep investors happy. The big picture: Under the watchful eye of chairman Joerg Reinhardt, Novartis CEO Vas Narasimhan has always proved ready to bring out the scalpel — or the axe — to trim away at its enormous global structure. So no analyst would have been surprised to see Novartis cutting away at its commercial ops in anticipation of a looming patent loss for its heavyweight therapy Entresto. A cliff like that would make many pharmas amp up R&D spending in a big way. Novartis actually cut back in 2024. The other Basel-based pharma giant is playing this one carefully for Wall Street, defending what’s left of patent exclusivity while signaling an LOE for Entresto in the middle of the year. It’s boosted revenue from Entresto in advance of the inevitable decline of its star drug — like pumping money from a dying well — and it’s pushing its other portfolio drugs hard, looking to make up for its blockbuster losses. That push includes building the franchises for Fabhalta, which just won its third approval, along with other drugs like Leqvio and Scemblix. Novartis has maintained a big focus in R&D on its radioligand portfolio, along with cell and gene therapies and RNA. Its late-stage pipeline includes OAV101 IT for spinal muscular atrophy, using a new delivery method aimed at widening the patient population for Zolgensma and now lining up for regulatory approvals. And there’s a big emphasis on votoplam (PTC518) for Huntington’s, in-licensed from PTC. Earlier this year Narasimhan and his execs spent a fair amount of time talking up the prospects of votoplam, which has to complete a mid-stage program successfully before Novartis takes over Phase 3. Huntington’s is wide open for anyone who can move the bar on this fatal neurodegenerative disease. But it’s also incredibly difficult to master, as Novartis knows from its own recent failure in the field with branaplam. Sage has also hit the wall here. But Novartis feels it’s learned a lot from its own setback — enough to believe that they can take the command here. Novartis, despite a busy pipeline overall, has a pretty thin set of late-stage drugs to tout, which led the Wall Street Journal to ask where Narasimhan expects to get its next round of drugs as Novartis sets out to perform with annual revenue increases in the mid-single digit range. Novartis spent a billion in cash on its Huntington’s alliance, underscoring just how careful they are with the R&D budget, which fell year-over-year in 2024. Not surprisingly, he centered on “smaller deals” while insisting he won’t make a move in obesity unless the BD team can line up something particularly distinctive. He also counts himself happy with their 2022/2023 reorganization. Happy, though, doesn’t mean content to leave things be. Novartis is always turning over stones to see where else it can cut. It adds up. And it’s shown zero interest in doing anything splashy. Its recent buyouts underscore that careful approach: MorphoSys was on the outer edge of the $1 billion to $3 billion range where Novartis prefers to play in M&A. At Novartis, financial discipline is a core value. And it’s part of the buttoned-down Swiss approach that isn’t expected to change. The big picture: There are a lot of moving parts at GSK, and not all are headed in the right direction. Its RSV vaccine sales have been on a roller coaster ride. The UK pharma’s big bet on Shingrix was dinged by slipping sales last quarter, all while the Trump administration helped cast a pall over vaccines in general that may well endure for four years. The vaccine market in China has also been wobbly, as Merck can attest to with Gardasil. On the other hand, GSK once again has high hopes for Blenrep, which was yanked from the market in 2022 after flunking a confirmatory study. The IL-5 therapy depemokimab has excited great expectations for £3 billion in annual sales, following up on the success of their asthma drug Nucala. All the while the BD group keeps turning up new deals that bolster their case without weighing heavily on the numbers side. And CEO Emma Walmsley, now an eight-year veteran in the top spot, is promising to move its top line to $50 billion, moving from £31.4 billion last year to 40 billion — a 27% increase in seven years. A lot of that increase will depend on how GSK’s commercial arm can capitalize on new therapeutics like their newly approved antibiotic gepotidacin. Commercial chief Luke Miels has cited analysts’ estimates for up to $1.25 billion for that program, but not everyone is nearly that enthusiastic about the near-term chances for a new antibiotic that could take years to gain a firm footing in the market. GSK has never been flashy. The stock is down about 10% over the past year. If you pull back over a three-year timeline, since GSK spun off its commercial group, the stock is down 19%, all of which has some analysts wondering if the large-cap company may once again become a target of the activist crowd. The big picture: I met Paul Hudson in Paris five years ago, when he stepped in as the new Sanofi CEO after a lengthy dry spell in R&D. Since then, he’s proven time and again that he’s ready and willing to invest in drug research, despite the inevitable ups and downs associated with bigger pipelines. A bit more than two years ago he was concentrating on what he called three major blockbuster candidates (€5 billion-plus): The OX40 drug amlitelimab, frexalimab and SAR441566, an oral TNFR1. And he was ready to sacrifice some profitability to move a pipeline where he counted another nine blockbuster candidates, mostly in immunology and inflammation. He kept that promise, with a boost in R&D spending of 14% in 2024 as Sanofi joined the industry migration out of consumer — staking its future on its ability to push new drugs to big futures. A few days ago Leerink noted that Sanofi was still juggling OX40 drugs to see whether amlitelimab, or its OX40L/TNF bispecific nanobody, would go into Phase 3 for hidradenitis suppurativa. That drug is in Phase 3 in atopic dermatitis and in Phase 2 in asthma and several other indications. Frexalimab failed a Phase 2 for Sjögren’s syndrome last year, narrowing its potential. That came with a Phase 3 failure of venglustat — another one of Hudson’s original top prospects — which nicked off part of its attraction as well. The next tier, where Hudson forecasts sales of €2 billion to €5 billion includes: Sanofi had one huge ace in the hole when Hudson took over the hand. It could rely on big sales of Dupixent ($13 billion in global sales last year) to keep it going in search of a new portfolio. And their marketing expertise in the field — built thanks to their alliance with Regeneron, which did the heavy lifting on the innovation side — would benefit any new drugs to warrant a regulatory approval while easing Aubagio out as generics took hold. The big picture: After hustling its way to the front of the GLP-1 line, Novo Nordisk is now all about the fierce rivalry it’s facing from Eli Lilly while positioning itself against any other entries that could sap its brilliant future in obesity. And that is no easy task, as execs have learned over the past year, while its stock plummeted 45% after peaking out as an obesity darling last summer. It turns out that superheating the stock price set up a supercooling series of events. After seeing explosive growth in revenue last year, Novo’s executive team is counseling analysts about a more modest growth path in 2025 as Eli Lilly brings the heat and pricing pressure grows. One of the big jobs they had to complete ASAP was being able to make enough semaglutide to satisfy the market and get off the drug shortage list — battling back against compounders who were carving up market share. While Novo Nordisk hasn’t been keeping up with average R&D spend among the top 15 — which generally comes in around the low 20s as a percentage of revenue — even 16.5% allowed for a 50% hike in R&D spending last year. In recent weeks Novo not only reorganized its growing R&D ops, it also struck back-to-back deals for new obesity drugs in an effort to stay ahead of the mob out to grab a share of the action. Now diabetes/obesity/MASH will be one R&D cluster focus, with cardio/chronic kidney disease and rare diseases making up the other two legs of its three-pronged research strategy. And like every other company in the R&D 15, it will rely on AI to make better bets on experimental drugs. Normally, that might make an intriguing proposition for investors, but analysts have been more focused on repeated setbacks in the clinic than the prospective benefits of a revised strategy. Novo Nordisk recently aired lackluster data for CagriSema, its follow-up drug that is a combination of the amylin analog cagrilintide and GLP-1. One of the big downsides to GLP-1 is the side effects of the drug, which the amylin analog is thought to limit while building weight loss. But it barely edged a high dose of Zepbound, leaving Lilly in the lead of the expectations game. And it earlier fell far short of the company’s stated expectation that it could trigger 25% weight loss. There’s lots more on the way, but Novo Nordisk has a lot riding on a head-to-head between CagriSema and Zepbound. Those data will come later this year, and failure is not an option. The big picture: Amgen has added a meaningful amount to its R&D budget, but it’s still hanging on in the second tier of the R&D 15. As always with CEO Bob Bradway, there’s a well-thought-out strategy that he’s pursuing — and selling to investors as the best path forward. And as always, the stakes are incredibly high. While looking to build on some existing drug franchises, Bradway once again used his Q4/2024 call with analysts to put the spotlight squarely on Amgen’s top prospect in the pipeline. This year it’s MariTide, an obesity drug that is looking to find a patch of marketing sun in the Big Kahuna of all drug rivalries. But it’s one tough sale. A few months ago, in a story covered by Max Bayer at Endpoints News , Amgen saw its stock take a dive on positive mid-stage data that illustrated a 20% weight loss for the drug. Once upon a time, you could have parlayed that into star status on Wall Street. But no more. It looked a little second-rate compared to the megablockbuster leaders in obesity, Novo Nordisk and a romping, stomping Eli Lilly, even if it can be effective at lower dosing. Amgen has a new take on the glucose-dependent insulinotropic polypeptide (GIP) receptor, blocking it instead of activating it. But it may just be the amped-up GLP-1 component that is delivering the benefit. Amgen has a huge Phase 3 for this one to answer all its questions, but you can see a few analysts are taking to the sidelines on this one, not quite won over by the dosing and design. On the upside: Any significant piece of obesity can be huge, even if in this case it’s relatively small compared to the leaders’ market share. On the downside: A big lead counts for a lot when you’re breaking new ground in therapeutic research, and Amgen definitely does not have the lead here. Amgen, though, will stick to its story. While it’s far from the top 10 in terms of R&D spending, the company has always punched above its weight when it comes to touting an experimental drug. So it was no surprise to see ex-Novartis vet Jay Bradner pick up his first Q4 call at Amgen by keeping his sights set on MariTide. But Bradner is also quick to highlight other late-stage prospects, topped by its Lp(a) drug olpasiran — now one of several drugs in the mix for this target — while waiting on the FDA decision for Uplizna. There’s also the Phase 3 program for rocatinlimab in atopic dermatitis, which has the potential to pursue other pathways, provided the data are strong. That could prove a major caveat, though, While Tim Anderson sees Amgen as 12 to 18 months ahead of Sanofi’s rival OX40 mab amlitelimab, he called one of the mid-stage data cuts “underwhelming” compared to Dupixent, hampered by some safety concerns. The big picture: Gilead has been anchored by HIV for years now, able to take multiple hits on the R&D side without triggering too much angst among investors. And Gilead CEO Daniel O’Day — who celebrated six years in the top post — has been winning over some mild converts to the cause recently, including Tim Anderson. Anderson, like the rank-and-file investor group, is comforted by Biktarvy’s big role in the HIV arena, where Gilead mints money. And he’s intrigued by the upside of a couple of late-stage plays, including anito-cel, which Gilead — partnered with Arcellx — believes can cut down Carvykti from J&J and Legend. That depends a lot on the safety profile that has been emerging in clinical trials. But at this stage, Gilead has seen a slate of oncology prospects go down in flames, which hasn’t done much to increase confidence in a cancer drug now. On the other hand, maybe they are due for a win. If they can cut into line with Carvykti, which is linked with Parkinson’s and other serious side effects, it has the potential to earn billions. And that would push them to their goal of getting 30% of revenue from oncology, rather than continue to rely so heavily on its longtime dominance in HIV. But there are some big ifs along the way, including the developers’ plans to look for an accelerated approval of the CAR-T. The big picture: Regeneron was close to making the R&D 15 in 2023, and it made it through last year with a surge of research spending in 2024 that slipped ahead of Takeda, based on their last four quarters. Regeneron arrives as the only company that still counters its two remarkable founders in the top posts: Science chief George Yancopoulos and CEO Len Schleifer. They got to this point by creating a company that is frequently held up as the gold standard of biotech startups, building two giant franchises in Dupixent (partnered with Sanofi) and Eylea. Now Eylea has biosimilar trouble, but Dupixent is still romping and stomping on the numbers side, giving Regeneron a nice runway to build new drugs. Tim Anderson at Bank of America counts two key drugs in the late-stage pipeline, and one to watch now in Phase 2. There’s fianlimab, a LAG3 treatment in frontline melanoma that hasn’t received a ton of attention. Anderson notes that Regeneron is several years behind Bristol Myers in LAG3, with 2030 sales set under the $900 million mark. LAG3 has had a number of problems in the clinic, though, and the jury is definitely out on what the potential is here. And there’s IL-33 mAB itepekimab, also partnered with Sanofi. Not the next-gen successor to Dupixent as once billed, Anderson still sees blockbuster potential. Then there’s trevogrumab — an anti-myostatin — and the anti-activin A garetosmab for obesity, in Phase 2 development with a host of rivals in the clinic. Of more immediate importance commercially, Regeneron has tagged linvoseltamab , its BCMAxCD3 drug delayed for manufacturing reasons, as a likely near-term entry for multiple myeloma. Sales projections are relatively muted, though. There’s also a CRISPR drug partnered with Intellia, NTLA-2001 for ATTR amyloidosis . Of everyone on the R&D 15, Regeneron is reinvesting a larger percentage of its revenue than any other player. Thirty-seven years after the biotech was created, the founders still see themselves on the cutting edge of drug research.