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#小分子/降解剂

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Oct 15Thu
  1. doi.org48

    Open-label extension study of leniolisib in activated PI3Kδ syndrome: Long-term efficacy and safety

    Long-term leniolisib was generally well tolerated in 37 patients with activated phosphoinositide 3-kinase delta syndrome treated for a median of 4.3 years. Annual infection rates (P = 0.0005), respiratory infection rates (P = 0.0017) and immunoglobulin replacement therapy use (P = 0.0095) all declined per year of treatment, with clinically meaningful gains in 36-Item Short Form Survey general health scores. This extends the efficacy and safety evidence for leniolisib in APDS well beyond the pivotal trials.

Oct 5Mon
  1. nature.com54

    Oral small-molecule GLP-1RA safiglipron versus dapagliflozin in type 2 diabetes: a randomized, double-blind, active-comparator-controlled phase 3 trial

    Once-daily oral safiglipron, a small-molecule GLP-1RA, was non-inferior to dapagliflozin for HbA1c reduction at all tested doses and superior at 90 mg in adults with type 2 diabetes in a randomized, double-blind, active-comparator-controlled phase 3 trial. Safiglipron gave greater improvements in glycemic control, similar modest weight loss, and an acceptable safety profile. It offers an oral alternative in the GLP-1 receptor agonist class.

    Why it matters: Phase 3 data show an oral GLP-1RA matching and at 90 mg beating dapagliflozin on HbA1c.

Oct 1Thu
  1. Nat Med60

    Werner helicase inhibitor for advanced microsatellite instability solid tumors: a phase 1 trial.

    RO7589831 (VVD-133214), a first-in-class covalent inhibitor of Werner syndrome helicase, showed manageable safety and early antitumor activity in 88 patients with MSI and/or mismatch repair-deficient advanced solid tumors in part 1 of a phase 1 trial. TEAEs were mostly grade 1-2, with no grade 5 events and discontinuation in 3.4% (3/88). In 66 MSI efficacy-evaluable patients, disease control rate was 74.2%, objective response rate 10.6% (7 partial responses), median PFS 6.7 months and median OS 17.6 months; 150 mg and 600 mg BID were selected as recommended phase 2 doses.

    Why it matters: First-in-human data on a WRN covalent inhibitor, a synthetic lethal target for MSI cancers.

  2. medrxiv.org46

    Axitinib in Progressive Metastatic Pheochromocytoma and Paraganglioma: Results of a Phase II Study

    Single-agent axitinib produced confirmed partial responses in 35.3% of 17 treated patients with progressive metastatic or unresectable pheochromocytoma and paraganglioma, with median progression-free survival of 7.9 months and median overall survival of 29 months. Hypertension occurred in 79% of patients but was managed with antihypertensive therapy and dose modification, and no patient stopped treatment for toxicity. The phase II trial's efficacy compares favorably with sunitinib in this rare disease.

    Why it matters: First prospective single-arm data on selective VEGFR inhibition with axitinib in a rare cancer with few systemic options.

Sep 29Tue
  1. nature.com54

    A synthetic lethal drug for microsatellite instability cancers

    Inhibition of the Werner syndrome helicase (WRN) enzyme exploits a new synthetic lethal vulnerability in cancers with microsatellite instability, a phase 1 trial shows. The approach offers a new way to target these tumors beyond immune checkpoint inhibition. No efficacy numbers are reported in the material.

    Why it matters: First clinical evidence that WRN inhibition can target microsatellite instability cancers beyond checkpoint inhibitors.

Sep 15Tue
  1. nature.com50

    Oral KRAS G12D inhibitor GFH375 for previously treated advanced solid tumors with KRASG12D mutations: a phase 1 trial

    The oral dual on-off binding KRAS G12D inhibitor GFH375 was evaluated in a phase 1 trial in patients with previously treated KRASG12D-mutated advanced solid tumors. Most treatment-related adverse events were low-grade, but there was one treatment-related death. Response rates were described as encouraging in non-small cell lung cancer and pancreatic cancer.

    Why it matters: First-in-human phase 1 data on an oral KRAS G12D inhibitor across KRASG12D-mutated solid tumors.

Sep 11Fri
  1. JAMA69

    Loberamisal for Acute Ischemic Stroke: The LAIS Randomized Clinical Trial.

    Intravenous loberamisal, given once daily for 10 days on top of standard care, improved functional recovery after acute ischemic stroke in the phase 3 LAIS trial. Among 997 treated adults in China with NIHSS scores of 7 to 20 within 48 hours of onset, 69.7% reached a 90-day mRS score of 0 to 1 versus 56.3% with placebo (RR, 1.24), with no increase in adverse events, serious adverse events, or mortality.

    Why it matters: Phase 3 evidence that a PSD-95 and α2-GABAA dual-target agent improves stroke outcomes, a field with few effective therapies.

Sep 3Thu
  1. N Engl J Med64

    Daraxonrasib for Previously Treated RAS-Mutant Non-Small-Cell Lung Cancer.

    Daraxonrasib (RMC-6236), an oral RAS(ON) multiselective inhibitor, showed antitumor activity in 136 previously treated patients with advanced RAS-mutant NSCLC: objective response occurred in 31% at doses of 120 mg or less, 34% at 160 to 220 mg, and 37% at 300 mg once daily. Adverse events of grade 3 or higher occurred in 54%, including four grade 5 events, with rash, diarrhea, nausea, vomiting, and mucositis or stomatitis each affecting at least 30% of patients.

    Why it matters: First safety and efficacy data for a pan-RAS inhibitor across multiple doses in previously treated RAS-mutant NSCLC.

Aug 31Mon
  1. Lancet73

    Switch to once-weekly, single-tablet islatravir-lenacapavir from daily standard of care for HIV-1 (ISLEND-2): a multicentre, randomised, open-label, active-controlled, phase 3 non-inferiority trial.

    Switching virologically suppressed adults with HIV-1 to a once-weekly, single-tablet regimen of islatravir (2 mg)-lenacapavir (300 mg) was non-inferior to continuing daily oral standard of care in the phase 3 ISLEND-2 trial. At week 48, HIV-1 RNA viral load of 50 copies per mL or higher occurred in 1 of 314 participants on islatravir-lenacapavir versus 4 of 312 on standard of care, meeting the non-inferiority margin of 4%. Treatment-related adverse events occurred in 18% of the islatravir-lenacapavir group versus fewer than 1% of the standard-of-care group, though discontinuations due to adverse events were rare in both groups.

    Why it matters: Phase 3 data support the first once-weekly complete oral single-tablet regimen for HIV-1 treatment.

Aug 29Sat
  1. N Engl J Med71

    First-Line Sunvozertinib in NSCLC with EGFR Exon 20 Insertion Mutations.

    First-line sunvozertinib extended median progression-free survival to 10.3 months versus 7.5 months with carboplatin-pemetrexed in advanced nonsquamous NSCLC with EGFR exon 20 insertion mutations (hazard ratio 0.65; P<0.001), in a phase 3 trial of 324 patients. Objective response was 58.9% versus 31.1%, with median duration of response of 11.2 versus 7.1 months. The findings support moving sunvozertinib, already accelerated-approved in later lines, into first-line use.

    Why it matters: Phase 3 evidence that sunvozertinib can replace platinum-pemetrexed as first-line therapy for EGFR exon 20 insertion NSCLC.

Aug 28Fri
  1. Lancet70

    Efficacy and safety of upadacitinib in adults and adolescents for treatment of non-segmental vitiligo (Viti-Up): results of two phase 3 randomised controlled studies.

    Upadacitinib 15 mg once daily produced clinically meaningful repigmentation in non-segmental vitiligo, a disease with no approved systemic therapies. In two phase 3 placebo-controlled trials, T-VASI 50 at week 48 was reached by 19% and 21% of patients on upadacitinib versus 6% on placebo in each study, and F-VASI 75 by 25% and 23% versus 6% and 7%; both coprimary endpoints met p<0·001. Safety was consistent with the known upadacitinib profile, with no new signals.

    Why it matters: First phase 3 data supporting a systemic therapy for non-segmental vitiligo, an approved-therapy gap.

CBACBA Frontier Insights (CFI)Chinese Biopharmaceutical Association (CBA)www.cba-usa.org