2025 Pipeline Report: The Edge of Greatness?
Pharm Exec’s 20th Annual Pipeline Report examines the emerging drug development trends and surging investments in five expanding therapeutic areas.
The biopharmaceutical industry has long been at the forefront of innovation. From the rise of precision medicine, to artificial intelligence technologies accelerating drug development, to the advent of small-molecule drugs, recent revolutions in pharmaceuticals are delivering better results for patients and more options for drug manufacturers.
Now, emerging developments in antibody-drug conjugates (ADCs) for oncology; hopeful treatments on the rise for idiopathic pulmonary fibrosis (IPF), a long-elusive disease to target; the transforming—and overarching—promise of GLP-1 agonists; growing investment around advanced therapy medicinal products (ATMPs); and a concerted push for new approaches in antibiotics are challenging the boundaries of what’s possible.
Pharmaceutical Executive’s 20th Annual Pipeline Report profiles the most promising activity and efforts in development across these five therapeutic areas.
ADCs revolutionize oncology treatment
Cancer therapy has undergone a significant amount of research in recent years, with the global oncology drugs market expected to reach a value of $532.91 billion by 2031.1 One new emerging oncology development is the rise of ADCs, which oncologists view as very promising.
Used in treating blood cancers and solid tumors, ADCs combine targeted therapy with chemotherapy to attack cancer cells while leaving healthy cells alone.
As the name implies, an antibody-drug conjugate consists of a monoclonal antibody that attaches to tumor antigens and a chemotherapy drug. A linker protein binds the two compounds together, keeping them connected as they travel to the tumor and releasing the chemotherapy drug where it needs to be.
Darja Irdam, PhD, is a partner at global insights agency Hall & Partners in London, a part of the Escalent Group. Irdam says that ADCs are an extremely promising new development in oncology that is opening new frontiers for targeting tumors and treating diseases that were previously untreatable. She explains that ADCs were the topic of the day at the 2024 annual American Society of Clinical Oncology meeting last spring in Chicago.
“One of the key trends that was discussed and that we’ll definitely see this year is better linkers for ADCs,” notes Irdam. “One of the core goals for linkers is stability. The stability of the linker is critical because it prevents the cytotoxic payload from being released too early. If the cytotoxic payload is released into the bloodstream, then the cancer cells aren’t targeted properly and the rest of the body is exposed to unnecessary toxicity.”
Irdam predicts that in addition to their oncology applications, ADCs will also become a major treatment for autoimmune conditions and infectious diseases. First, though, researchers will need to improve the compounds’ tolerability. Irdam says that the efficacy of an ADC depends on its dose, and patients often cannot tolerate high ADC doses.
Furthermore, Irdam predicts that the manufacturing process for ADCs will become simplified over time. The current process of manufacturing these types of treatments is quite complex, which means developing ADCs is prohibitively expensive. As manufacturers improve their processes and global supply chains adjust, Irdam predicts that ADCs will become more economically viable.
There are currently several ADCs in various stages of clinical development. In January 2024, BioNTech and DualityBio announced the beginning of a Phase III trial of their ADC candidate, BNT323/DB-1303. Designed to target metastatic breast cancer, the agent has shown promising results in treating HER-2 positive metastatic breast cancer in a combined Phase I/II study.2 A Phase III study, the DYNASTY-Breast02 study, is currently underway and is expected to finish in 2028.3
Another ADC hopeful, AstraZeneca and Daiichi Sankyo’s datopotamab deruxtecan, recently finished Phase II trials. The TROPION-Lung05 trial examined the effects of the ADC in patients with locally advanced or metastatic non-small cell lung cancer.4 Based on the results of that study, AstraZeneca and Daiichi Sankyo have submitted a new biologics license application to the FDA for accelerated approval.5
IPF drugs hold promise for patients
IPF is a difficult-to-treat condition because, as an idiopathic disease, its cause is unknown. Sujith Eramangalath, vice president of life sciences at Escalent, says the IPF space mostly focuses on anti-fibrotic treatments that are designed to reduce inflammation and halt the advancement of the disease.
“There are about 15 drugs in the pipeline, but only two are on the market,” notes Eramangalath. “The activity in this space is fairly low, but where I do see activity in the future is a lot of diagnosis happening via biomarkers. One of the challenges with IPF is that there’s no genetic-based research or integration happening. There’s no extensive gene-based or microbiome-based therapy that’s been happening at this point, at least not in a commercial sense.”
Eramangalath says that one of the most recent IPF drugs in development was pamrevlumab by FibroGen. He points out that the drug, a monoclonal antibody, failed to meet its Phase III endpoints, and the trial showed mixed results. Still, other companies are pushing ahead with their own takes on IPF drugs.
For example, taladegib, also known as ENV-101, is a hedgehog signaling pathway inhibitor being developed by Endeavor BioMedicines. The hopeful treatment is currently in Phase IIB clinical trials.
“The most positive thing about it is that it shows reversal of lung fibrosis,” says Eramangalath. “So far, all of the drugs on the market reduce symptoms; in Phase IIA, this drug showed reversal of lung fibrosis and improved lung function, which is very positive.”
Eramangalath also points to products by Insilico Medicine and Blade Therapeutics, which are designed to slow the advancement of IPF. However, it’s still too early to determine if these drugs improve lung capacity.
Across Phases I, II, and III, Eramangalath says there are about 15 IPF drugs currently in development.
One emerging IPF drug in the pipeline is showing promise in Phase III trials. In September 2024, Boehringer Ingelheim announced late-stage results of the company’s PDE4B inhibitor, nerandomilast. Topline data showed that the agent successfully improved forced vital capacity in IPF patients after 52 weeks. Ioannis Sapountzis, head of global therapeutic areas at Boehringer Ingelheim, said in a press release that this is the first IPF Phase III trial in a decade to meet its primary endpoint.6 Eramangalath says that the study has shown significant positive results, and Boehringer Ingelheim is on track to file for regulatory submission this year.
Slightly further back in the pipeline, Bristol Myers Squibb’s investigational drug, BMS-986278, posted Phase II results in September 2023.The drug, a lysophosphatidic acid receptor 1 agonist, was found to reduce the rate of decline in forced vital capacity among IPF patients by 69% relative to placebo.7
Meanwhile, United Therapeutics’ inhaled treprostinil is in Phase III development; Eramangalath says the drug has shown great results so far. The TETON 2 trial, a Phase III clinical study on treprostinil for IPF, is currently underway, with topline data expected in the second half of 2025.8
The GLP-1 train rolls on
GLP-1s, short for glucagon-like peptide-1 receptor agonists, have gained significant popularity among patients and a great deal of attention from the media. Originally designed as medications for type 2 diabetes, GLP-1 drugs, such as Novo Nordisk’s Wegovy and Ozempic (semaglutide) and Eli Lilly’s Mounjaro (tirzepatide), have since been found to be highly effective at treating obesity (with tirzepatide branded as Zepbound for weight loss).
Sara Mallatt Stahl, director of healthcare research at AlphaSense in New York City, says now that GLP-1s have been proven in the obesity sphere, companies in the market are creating different combinations of weight loss drugs to better treat obesity. Roche, Viking Therapeutics, and Amgen, for instance, are all working on a GLP-1/GIP combination drug, while Zealand Pharma is developing a GLP-1/glucagon agonist drug. Lilly, meanwhile, is pursuing a triple agonist drug that targets GLP-1, GIP, and glucagon all in a single medication.
Mallatt Stahl also notes that there’s significant interest among biopharma manufacturers in expanding the indications that GLP-1s can treat. She explains that in order to get insurers on board, it’s important to provide research around other indications beyond obesity.
“We already had diabetes and obesity indications,” says Mallatt Stah. “In March 2024, Novo’s Wegovy was approved for cardiovascular disease. The other indications that are being pursued are fatty liver disease, chronic kidney disease, obstructive sleep apnea, and Alzheimer’s disease. Beyond those, there’s speculation that GLP-1s could be used for substance abuse disorders and arthritis.”
Overall, according to projections from Towards Healthcare, theGLP-1 receptor agonist market will total $62.86 billion in 2025, a figure it predicts will skyrocket to $268.37 billion by 2034 (a compound annual growth rate of 17.5 % during that period).9
In December, the FDA approved Zepbound for the treatment of moderate-to-severe obstructive sleep apnea in adults with obesity.The approval was based on two randomized, double-blind, placebo-controlled studies of 469 adults without type 2 diabetes.10 According to the results, Zepbound was about five times more effective than placebo in reducing breathing disruptions in adults not on positive airway pressure (PAP) therapy, leading to 25 fewer breathing disruptions per hour with Zepbound and five with placebo. In adults on PAP therapy, Zepbound led to 29 fewer breathing disruptions per hour compared to six with placebo.
Back on the cardiovascular front, one 2024 systematic review and meta-analysis examined the results of 13 randomized clinical trials of GLP-1 receptor agonists and tirzepatide. In total, 65,878 patients with type 2 diabetes mellitus were included in the meta-analysis. The review found that relative to placebo, GLP-1s reduced incidents of major adverse cardiovascular events, all-cause mortality, and cardiovascular mortality while simultaneously reducing the risk of a stroke.11
Meanwhile, other studies are underway to examine the effects of GLP-1s on Parkinson’s disease, Alzheimer’s disease, drug and alcohol addiction, and sleep apnea. Novo Nordisk is currently running two Phase III clinical trials, the evoke and evoke+ studies, to assess the safety and efficacy of oral semaglutide in managing the symptoms of Alzheimer’s disease. Readouts of the two trials are expected in 2025.12
Last month, results of an observational study conducted by Washington University in St. Louis, published in Nature Medicine, found that the use of semaglutide and tirzepatide may reduce the risk of Alzheimer’s disease and substance abuse disorders.13 At the same time, the study, which is based on health records from the US Department of Veterans Affairs (covering 215,970 diabetes patients taking the new drugs), also reported a spike in the risk of digestive issues and arthritis.
Other biopharma companies active in R&D and expansion pursuits in the GLP-1 space include Pfizer, AstraZeneca,Boehringer Ingelheim, Merck,Sanofi, Amneal Pharmaceuticals, Ascendis Pharma,Hansoh Pharma, Innovent Biologics, and Metsera, Inc.
ATMPS offer breakthroughs for autoimmune diseases
ATMPs are medical products that are made from cells, tissues, or genes. These products typically fall into one of three categories: gene therapies, somatic-cell therapies, and tissue-engineered medicines.14 While ATMPs have historically been studied for their oncological applications,15 Mallatt Stahl says there’s now significant investment in CAR T-cell therapy for autoimmune indications.
“There was a breakthrough study from a group in Germany in February 2024,” notes Mallatt Stahl. “They had results from a case series in which 15 patients with various autoimmune conditions all achieved complete remission after receiving a single infusion of CAR T. It was also found that after infusion, patients could stop taking their immunosuppressants.”
Mallatt Stahl says that since then, other studies have confirmed the benefits of ATMPs in treating autoimmune conditions, leading to significant interest and enthusiasm. She notes that as of December 2023, there are over 30 companies pursuing or planning to pursue drugs in this area; as of May 2024, there were over 50 clinical trials for ATMPs for autoimmune diseases listed on ClinicalTrials.gov. While the results of these trials are still pending, companies such as Novartis have published encouraging updates.
“CAR T researchers are focusing on B-cell-mediated diseases,” explains Mallatt Stahl. “That includes lupus, rheumatoid arthritis, and multiple sclerosis. In this disease group, B-cells start attacking healthy cells. These B-cells contain a specific surface protein that CAR T can recognize and target. B-cell targets employed in autoimmune CAR T-cell therapy happen to be the same targets employed in CAR T-cell therapy for blood cancers.”
Mallatt Stahl says that there is significant interest in CAR T for autoimmune disease treatment; she points to AstraZeneca’s acquisition of Graycell Biotech and Regeneron’s purchase of 272 Bio as evidence of the growing focus in that area.
In just the UK alone, there were over 175 clinical trials for ATMPs in 2023. Oncology remains the largest therapeutic area being investigated, with 41% of clinical trials studying ATMPs for cancer. Meanwhile, hematological conditions account for 10% of clinical trials, and ophthalmological conditions account for 9%.16
One ATMP in development, axicabtagene ciloleucel (axi-cel), was studied as a second-line treatment in a Phase III trial published in 2023. In this trial, 359 patients were randomly assigned to receive either axi-cel or standard care for refractory large B-cell lymphoma. The study found that axi-cel administration increased four-year survival rates by 8% relative to standard care.17
Other ATMPs in development include RNA- and mRNA-based drugs and vaccines such as CTX001 and rhBMP-2. An investigational CRISPR gene-edited stem cell therapy for sickle cell disease under development by CRISPR Therapeutics and Vertex Pharmaceuticals, CTX001 works by genetically modifying stem cells to increase fetal hemoglobin production. A Phase III clinical trial published in the New England Journal of Medicine in April 2024 found that out of 30 patients who were evaluated, 29 patients were free from vaso-occlusive crises for at least 12 consecutive months. Furthermore, all 30 patients stayed out of the hospital for vaso-occlusive crises for at least 12 consecutive months.18
Meanwhile, recombinant human bone morphogenetic protein-2 (rhBMP-2) is a growth factor that potentiates stem cells to become osteocytes. rhBMP-2’s potential applications include treating open tibia fractures, tibia shaft nonunions, and other orthopedic trauma.19 A 2024 in vitro/in vivo study examined the effects of rhBMP-2 and human bone marrow mesenchymal stromal cell (hBM-MSC) administration on bone formation and differentiation. The clinical study found that when combined with other differentiation signals, rhBMP-2 potentiates multilineage differentiation of osteogenesis, adipogenesis, and chondrogenesis.20
Next-generation antibiotics overcome resistance
Antibacterial resistance is a significant problem facing not only the pharmaceutical industry, but also the world. The World Health Organization (WHO) has deemed antimicrobial resistance to be a top global public health threat, estimating that it was directly responsible for 1.27 million global deaths in 2019.21 Thus, developing novel antibiotics to overcome antibiotic resistance is imperative.
Thankfully, pharma manufacturers are bypassing resistance by creating a variety of new, first-in-class antibiotics through the power of artificial intelligence (AI). AI drug discovery works by predicting the types of molecules that will have a particular biological effect and then designing those molecules from the ground up.22
In March 2024, researchers at McMaster University in Hamilton, Canada, and Stanford University in Stanford, CA, invented a generative AI model called SyntheMol that can design new antibiotics. SyntheMol is capable of even designing antibiotics that work against Acinetobacter baumannii, a bacterium that the WHO has determined to be one of the world’s most dangerous antibiotic-resistance bacteria.23
Earlier work in AI by a team of MIT researchers identified a new antibiotic called halicin. In 2020, engineers at the MIT Institute for Medical Engineering and Science created a computer platform that could identify drugs with antibacterial properties. The research team tested the platform on the Broad Institute’s Drug Repurposing Hub, which contains 6,000 drug formulas. The model predicted that one particular formula would be a strong antibacterial compound; one different from any existing antibiotic. Researchers called the compound halicin, named after H.A.L. from 2001: A Space Odyssey. Halicin had previously been investigated as a potential diabetes treatment. During testing, the researchers discovered that halicin could kill many treatment-resistant species of bacteria, including C. difficile, A. baumannii, and M. tuberculosis. The only species of bacteria that the drug failed to treat was P. aeruginosa.24
Halicin has since entered in vitro and animal testing. In one 2024 animal trial, halicin was found to successfully treat respiratory A. pleuropneumoniae infections in mice. The drug also showed low toxicity and good tolerability.25
Rich in Innovations
The drug development pipeline is showing a great deal of promise, even for difficult-to-treat conditions such as IPF and antibiotic resistance. Cutting-edge therapeutics are also making inroads in oncology, autoimmune disease, and cardiovascular disease, among other areas. As pharma companies continue to innovate, expect treatments for these indications to proceed through clinical trials and, eventually, to the market.
About the author
Mike Straus is a freelance writer based in British Columbia, Canada. His work has appeared in Nutritional Outlook, Hoist, and Massage Therapy Canada, among other publications.
References
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2. BioNTech and DualityBio Initiate Pivotal Phase III Trial of Antibody-Drug Conjugate Candidate BNT323/DB-1303 in Metastatic Breast Cancer. BioSpace. January 22, 2024. https://www.biospace.com/biontech-and-dualitybio-initiate-pivotal-phase-3-trial-of-antibody-drug-conjugate-candidate-bnt323-db-1303-in-metastatic-breast-cancer
3. A Study of DB-1303/BNT323 vs Investigator’s Choice Chemotherapy in HER2-Low, Hormone Receptor Positive Metastatic Breast Cancer (DYNASTY-Breast02). ClinicalTrials.gov.Last updated November 26, 2024. https://clinicaltrials.gov/study/NCT06018337
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5. Datopotamab Deruxtecan New BLA Submitted for Accelerated Approval in the US for Patients with Previously Treated Advanced EGFR-Mutated Non-Small Cell Lung Cancer. AstraZeneca press release. November 12, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/dato-dxd-new-bla-submitted-nsq-bla-withdrawn.html
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7. Bristol Myers Squibb’s Investigational LPA1 Antagonist Reduces Rate of Lung Function Decline in Progressive Pulmonary Fibrosis Cohort of Phase II Study. Bristol Myers Squibb press release. September 9, 2023. https://news.bms.com/news/details/2023/Bristol-Myers-Squibbs-Investigational-LPA1-Antagonist-Reduces-Rate-of-Lung-Function-Decline-in-Progressive-Pulmonary-Fibrosis-Cohort-of-Phase-2-Study/default.aspx
8. United Therapeutics Corporation Announces Full Enrollment of the TETON 2 Study of Inhaled Treprostinil for the Treatment of Idiopathic Pulmonary Fibrosis. United Therapeutics press release. July 10, 2024. https://business.times-online.com/times-online/article/bizwire-2024-7-10-united-therapeutics-corporation-announces-full-enrollment-of-the-teton-2-study-of-inhaled-treprostinil-for-the-treatment-of-idiopathic-pulmonary-fibrosis
9. GLP-1 Receptor Agonist Market Size & Worldwide Demand 2023-34. Towards Healthcare. https://www.towardshealthcare.com/insights/glp-1-receptor-agonist-market-sizing
10. FDA Approves Zepbound® (Tirzepatide) as the First and Only Prescription Medicine for Moderate-to-Severe Obstructive Sleep Apnea in Adults with Obesity. Eli Lilly press release. December 20, 2024. https://investor.lilly.com/news-releases/news-release-details/fda-approves-zepboundr-tirzepatide-first-and-only-prescription
11. Stefanou, M.I.; Theodorou, A.; Malhotra, K; et al. Risk of Major Adverse Cardiovascular Events and Stroke Associated with Treatment with GLP-1 or the Dual GIP/GLP-1 Receptor Agonist Tirzepatide for Type 2 Diabetes: A Systematic Review and Meta-Analysis. Eur. Stroke J. 2024. 9 (3), 530-539. https://pubmed.ncbi.nlm.nih.gov/38400569/
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13. Dunleavy, K. Large Study of Novo, Lilly Weight Loss Drugs Shows Decrease in Risk of Alzheimer’s. Fierce Pharma. January 21, 2025. https://www.fiercepharma.com/pharma/large-study-novo-lilly-weight-loss-drugs-show-decrease-risk-alzheimers
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20. Kathami, N.; Moreno-Vicente, C.; Martin, P.; et al. rhBMP-2 Induces Terminal Differentiation of Human Bone Marrow Mesenchymal Stromal Cells Only by Synergizing with Other Signals. 2024. Stem cell res. Ther. 15 (124). https://stemcellres.biomedcentral.com/articles/10.1186/s13287-024-03735-y
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22. Chun, M. How Artificial Intelligence is Revolutionizing Drug Discovery. Bill of Health. March 20, 2023. https://www.scribd.com/document/698297989/How-Artificial-Intelligence-is-Revolutionizing-Drug-Discovery-Bill-of-Health
23. Researchers Invent Artificial Intelligence Model to Design New Superbug-Fighting Antibiotics. McMaster University. March 22, 2024. https://brighterworld.mcmaster.ca/articles/artificial-intelligence-model-synthemol-superbug-fighting-antibiotics/
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Key Findings of the NIAGARA and HIMALAYA Trials
November 8th 2024In this episode of the Pharmaceutical Executive podcast, Shubh Goel, head of immuno-oncology, gastrointestinal tumors, US oncology business unit, AstraZeneca, discusses the findings of the NIAGARA trial in bladder cancer and the significance of the five-year overall survival data from the HIMALAYA trial, particularly the long-term efficacy of the STRIDE regimen for unresectable liver cancer.
Cell and Gene Therapy Check-in 2024
January 18th 2024Fran Gregory, VP of Emerging Therapies, Cardinal Health discusses her career, how both CAR-T therapies and personalization have been gaining momentum and what kind of progress we expect to see from them, some of the biggest hurdles facing their section of the industry, the importance of patient advocacy and so much more.
