FDA Approves 46 Novel Drugs in 2025, Small Molecules Lead with 31 Approvals

The FDA approved 46 novel drugs in 2025, a modest decline from 50 approvals in 2024 and below the 55 approvals granted in 2023. Small molecules again carried the year, accounting for 31 of the 46 approvals (67%) across multiple therapeutic areas, with a pronounced tilt toward precision oncology.

Large molecules contributed 15 approvals, making up 33% of the total. This set spanned multiple biological modalities—particularly antibody-drug conjugates and bispecific antibodies—and included practical advances in delivery, exemplified by pembrolizumab plus berahyaluronidase alfa-pmph (Keytruda Qlex), enabling subcutaneous injection.

Oncology dominated both small and large molecule innovation. Nine small molecule drugs were approved for oncology indications, with multiple approvals targeting genomically defined subtypes, particularly visible in treatments for non-small cell lung cancer. Five large molecules were approved for oncology indications, including approvals across solid tumors and hematologic malignancies, spanning PD-1 blockade, ADCs, and BCMA × CD3 engagement.

One of the most notable regulatory moments was a rare "novel–novel" combination approval: Verastem's avutometinib plus defactinib (Avmapki Fakzynja Co-Pack), which pairs a MEK-pathway inhibitor with a FAK (focal adhesion kinase) inhibitor for KRAS-mutated, recurrent, low-grade serous ovarian cancer. The FDA listed the co-pack as a single novel drug approval. Avutometinib is a "RAF/MEK clamp" that inhibits MEK kinase activity through the induced formation of dominant-negative RAF–MEK complexes, which limits paradoxical RAF-mediated phosphorylation of MEK1/2. Defactinib inhibits FAK and PYK2, providing complementary suppression of feedback loop reactivation of RAS/MAPK signaling. Approval was based on the Phase 2 RAMP-201 trial (NCT04625270) in 57 patients with measurable KRAS-mutated recurrent low-grade serous ovarian cancer, where the combination produced a confirmed objective response rate of 44% by blinded independent review (RECIST v1.1) with response duration lasting from 3.3 to 31.1 months. The regimen received Accelerated Approval.

Among small molecule oncology approvals, taletrectinib (Ibtrozi) was approved as an oral, CNS-penetrant ROS1 tyrosine kinase inhibitor for adults with locally advanced or metastatic ROS1-positive non-small cell lung cancer. While several ROS1 inhibitors have been approved based on demonstrated clinical benefit (beginning with crizotinib in 2016), durable disease control is frequently limited by acquired resistance. Taletrectinib's approval was supported by two multicenter, single-arm, open-label Phase 2 trials, TRUST-I (NCT04395677) and TRUST-II (NCT04919811), responses from which were assessed by blinded independent central review (RECIST v1.1). In treatment-naïve patients, objective response rate was 90% in TRUST-I and 85% in TRUST-II, with most responses lasting at least 12 months (72% and 63% of responders, respectively). In ROS1 TKI-pretreated patients, objective response rate remained substantial at 52% (TRUST-I) and 62% (TRUST-II), and responses were generally durable, with 74% and 83% of responders maintaining a duration of response of at least six months.

Treosulfan (Grafapex), a bifunctional DNA-alkylating agent, was approved for use with fludarabine as a conditioning regimen prior to allogeneic hematopoietic stem cell transplantation in patients ≥1 year of age with acute myeloid leukemia or myelodysplastic syndrome. US approval follows the 2019 EMA approval and was supported by an open-label Phase 3 trial (NCT00822393) comparing treosulfan/fludarabine with reduced-intensity busulfan/fludarabine in older/comorbid AML/MDS patients. Overall survival favored treosulfan/fludarabine versus busulfan/fludarabine, with stratified hazard ratios of 0.67 in the overall randomized population, 0.73 in AML, and 0.64 in MDS, notably due to improvements in non-relapse mortality. Treosulfan received Orphan Drug designation in 2015.

In large molecule oncology approvals, pembrolizumab and berahyaluronidase alfa-pmph (Keytruda QLex) represents a fixed-dose combination for subcutaneous injection consisting of the anti-PD-1 monoclonal antibody pembrolizumab plus a recombinant human hyaluronidase. This combination was FDA-approved for adult and pediatric patients across the solid-tumor indications already approved for IV pembrolizumab (Keytruda). Pembrolizumab blocks PD-1–mediated immune inhibition, enhancing anti-tumor immunity, while berahyaluronidase alfa enhances subcutaneous absorption of pembrolizumab. Pharmacokinetic comparability of the SC combination with IV pembrolizumab was evaluated in the MK-3475A-D77 trial (NCT05722015), a randomized, open-label trial in previously untreated metastatic non-small cell lung cancer. The trial met predefined criteria for comparability: the lower bounds of the geometric mean ratio for Cycle 1 AUC0–6 weeks and Cycle 3 steady-state Ctrough were both >0.8. Descriptive efficacy outcomes were similar between arms, with a confirmed objective response rate of 45% for subcutaneous Keytruda Qlex versus 42% for intravenous pembrolizumab, with no notable differences observed in PFS or OS. The drug was discovered by Merck & Co. and Organon Pharma and is currently marketed by MSD, with berahyaluronidase developed and manufactured by Alteogen.

Penpulimab-kcqx was approved as an intravenous anti-PD-1 monoclonal antibody to treat patients with recurrent or metastatic nasopharyngeal carcinoma in combination with chemotherapy or as a single agent. The 2025 FDA approval follows a 2021 approval for a variety of cancers in China. Penpulimab blocks PD-1–mediated immune inhibition, enhancing anti-tumor immunity; the molecule is also described as Fc-engineered to reduce FcγR-mediated effector functions, designed to limit immune-related adverse events. Penpulimab-kcqx was evaluated in two NPC studies. In AK105-304 (NCT04974398), penpulimab-kcqx plus cisplatin or carboplatin, and gemcitabine (followed by penpulimab maintenance) improved blinded independent review–assessed PFS versus placebo plus chemotherapy (median 9.6 vs. 7.0 months). In AK105-202 (NCT03866967), a study in patients with unresectable/metastatic non-keratinizing NPC, single-agent penpulimab-kcqx achieved an objective response rate of 28% with a median duration of response not reached. The application was granted Breakthrough Therapy, Fast Track, and Orphan Drug designations. Penpulimab-kcqx was discovered by Akeso Shanghai Biomed Tech, developed in partnership with Chia Tai Tianqing Pharmaceutical group, and marketed by Akeso Biopharma.

Datopotamab deruxtecan-dlnk (Datroway) was approved as an intravenous, TROP2-directed antibody–drug conjugate for adult patients with unresectable or metastatic HR+/HER2- breast cancer who have been previously treated with endocrine-based therapy and chemotherapy in the advanced setting. Datopotamab deruxtecan delivers a topoisomerase I inhibitor payload via a TROP2-binding antibody. Approval was supported by TROPION-Breast01 (NCT05104866), in which Datroway improved BICR-assessed PFS versus investigator's choice chemotherapy (median 6.9 vs. 4.9 months) with a confirmed objective response rate of 36%. The drug has also been granted accelerated approval for adults with locally advanced or metastatic EGFR-mutated non-small cell lung cancer after prior EGFR-directed therapy and platinum-based chemotherapy. This was based on a pooled efficacy analysis of 114 patients across the TROPION-Lung05 (NCT04484142) and TROPION-Lung01 (NCT04656652) studies.

Beyond oncology, 2025 small molecule approvals delivered first-in-class anti-infectives aimed at resistant pathogens, a first-in-class non-opioid NaV1.8 inhibitor for acute pain, and continued momentum for reversible covalent kinase inhibitors expanding beyond cancer, including BTK inhibitors in immunology. Among small molecule approvals, 29% were classified as first-in-class therapies, and 22% received approval through the accelerated approval pathway.

Large molecule approvals outside cancer advanced care across diverse therapeutic areas, spanning FcRn targeting in generalized myasthenia gravis, factor XII-pathway inhibition for hereditary angioedema prophylaxis, APRIL blockade in IgA nephropathy, IL-5 targeting in eosinophilic asthma, MASP2-directed complement modulation in transplant-associated thrombotic microangiopathy, and a PCSK9-directed recombinant fusion protein for LDL-C lowering.