Vorasidenib

Vorasidenib
6-(6-chloropyridin-2-yl)-N2,N4-bis[(2R)-1,1,1-trifluoropropan-2-yl]-1,3,5-triazine-2,4-diamine

CAS 1644545-52-7, C₁₄H₁₃ClF₆N₆, 414.74

FDA APPROVED, 8/6/2024, Voranigo, To treat Grade 2 astrocytoma or oligodendroglioma

UNII 789Q85GA8P

• AG 881
• AG-881
• AG881

Vorasidenib, sold under the brand name Voranigo, is an anti-cancer medication used for the treatment of certain forms of glioma.^[1][2] Vorasidenib acts to inhibit the enzymes isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2).^[1][2]

The most common adverse reactions include fatigue, headache, increased risk of COVID-19 infection, musculoskeletal pain, diarrhea, nausea, and seizures.^[2]

Vorasidenib was approved for medical use in the United States in August 2024.^[2][3] It is the first approval by the US Food and Drug Administration (FDA) of a systemic therapy for people with grade 2 astrocytoma or oligodendroglioma with a susceptible isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 mutation.^[2]

Medical uses

Vorasidenib is indicated for the treatment of people aged twelve years of age and older with grade 2 astrocytoma or oligodendroglioma with a susceptible isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 mutation, following surgery including biopsy, sub-total resection, or gross total resection.^[2]

Side effects

The most common adverse reactions include fatigue, headache, increased risk of COVID-19 infection, musculoskeletal pain, diarrhea, nausea, and seizures.^[2] The most common grade 3 or 4 laboratory abnormalities include increased alanine aminotransferase, increased aspartate aminotransferase, GGT increased, and decreased neutrophils.^[2]

History

Efficacy was evaluated in 331 participants with grade 2 astrocytoma or oligodendroglioma with a susceptible isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 mutation following surgery enrolled in INDIGO (NCT04164901), a randomized, multicenter, double-blind, placebo-controlled trial.^[2] Participants were randomized 1:1 to receive vorasidenib 40 mg orally once daily or placebo orally once daily until disease progression or unacceptable toxicity.^[2] Isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 mutation status was prospectively determined by the Life Technologies Corporation Oncomine Dx Target Test.^[2] Participants randomized to placebo were allowed to cross over to vorasidenib after documented radiographic disease progression.^[2] Participants who received prior anti-cancer treatment, including chemotherapy or radiation therapy, were excluded.^[2]

Society and culture

Legal status

Vorasidenib was approved for medical use in the United States in August 2024.^[2]

The FDA granted the application for vorasidenib priority review, fast track, breakthrough therapy, and orphan drug designations.^[2]

SYN

WO/2024/161041NOVEL COMPOUNDS THAT CAN BE USED AS THERAPEUTIC AGENTS

20240254118PRMT5 INHIBITORS AND USES THEREOF

118359585共晶体、其药物组合物以及涉及其的治疗方法

WO/2024/148437USE OF PCLX-001 OR PCLX-002 AS A RADIOSENSITIZER

20240238424HETEROBIFUNCTIONAL COMPOUNDS AND METHODS OF TREATING DISEASE

1020240097895CD73 화합물

WO/2024/137852PRMT5 INHIBITORS AND USES THEREOF

2024057088THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE

20240116928CD73 COMPOUNDS

117586228Preparation method of triazine medicine

20240041892THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE

117529323Therapeutically active compounds and methods of use thereof

WO/2024/006929CD73 COMPOUNDS

PATENT

US10028961, Compound 101

https://patents.google.com/patent/US10028961B2/en

Step 3: Preparation of 6-(6-chloropyridin-2-yl)-N²,N⁴-bis((R)-1,1,1-trifluoro propan-2-yl)-1,3,5-triazine-2,4-diamine

A mixture of 2,4-dichloro-6-(6-chloro-pyridin-2-yl)-1,3,5-triazine (0.27 g, 1.04 mol), (R)-1,1,1-trifluoropropan-2-amine hydrochloride (0.39 g, 2.6 mol), and potassium carbonate (0.43 g, 3.1 mol) in dry 1,4-dioxane (2.5 mL) was stirred under the atmosphere of N₂ at 50° C. for 36 hr then at 100° C. for another 36 hr until the reaction was complete. The resulting mixture was filtered through Celite and the cake was washed with EtOAc. The filtrate was concentrated and the residue was purified by standard methods to give the desired product.

¹H NMR (400 MHz, CDCl₃) δ 8.32 (m, 1H), 7.80 (m, 1H), 7.48 (d, J=7.9 Hz, 1H), 5.61 (m, 1.5H), 5.25 (m, 0.5H), 5.09 (m, 0.5H), 4.88 (m, 1.5H), 1.54-1.26 (m, 6H). LC-MS: m/z 415 (M+H)⁺.

The procedure set forth in Example 10 was used to produce the following compounds using the appropriate starting materials.Compound 6-(6-Chloropyridin-2-yl)-N²,N⁴-bis((S)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (400 MHz, CDCl₃) δ 8.29-8.16 (m, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.41 (d, J=7.9 Hz, 1H), 5.70-5.13 (m, 2H), 5.09-4.71 (m, 2H), 1.34 (m, 6H). LC-MS: m/z 415 (M+H)⁺.Compound 6-(6-Chloropyridin-2-yl)-N²—((R)-1,1,1-trifluoropropan-2-yl)-N⁴—((S)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (400 MHz, CDCl₃) δ 8.41-8.23 (m, 1H), 7.83 (s, 1H), 7.51 (d, J=6.2 Hz, 1H), 5.68-5.20 (m, 2H), 5.18-4.81 (m, 2H), 1.48-1.39 (m, 6H). LC-MS: m/z 415 (M+H)⁺.Compound 6-(6-Chloropyridin-2-yl)-N²,N⁴-bis(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine

¹H NMR (400 MHz, CDCl₃) δ 8.29-8.16 (m, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.41 (d, J=7.9 Hz, 1H), 5.70-5.13 (m, 2H), 5.09-4.71 (m, 2H), 1.34 (m, 6H). LC-MS: m/z 415 (M+H)⁺.

References

^ Jump up to:^a b c “Voranigo- vorasidenib citrate tablet, film coated”. DailyMed. 9 August 2024. Retrieved 15 August 2024.

1. ^ Jump up to:^{a b c d e f g h i j k l m n o} “FDA approves vorasidenib for Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation”. U.S. Food and Drug Administration (FDA). 6 August 2024. Archived from the original on 7 August 2024. Retrieved 7 August 2024.  This article incorporates text from this source, which is in the public domain.
2. ^ “Servier’s Voranigo (vorasidenib) Tablets Receives FDA Approval as First Targeted Therapy for Grade 2 IDH-mutant Glioma” (Press release). Servier Pharmaceuticals. 6 August 2024. Archived from the original on 7 August 2024. Retrieved 7 August 2024 – via PR Newswire.

Further reading

• Mellinghoff IK, Lu M, Wen PY, Taylor JW, Maher EA, Arrillaga-Romany I, et al. (March 2023). “Vorasidenib and ivosidenib in IDH1-mutant low-grade glioma: a randomized, perioperative phase 1 trial”. Nature Medicine. 29 (3): 615–622. doi:10.1038/s41591-022-02141-2. PMC 10313524. PMID 36823302.
• Mellinghoff IK, Penas-Prado M, Peters KB, Burris HA, Maher EA, Janku F, et al. (August 2021). “Vorasidenib, a Dual Inhibitor of Mutant IDH1/2, in Recurrent or Progressive Glioma; Results of a First-in-Human Phase I Trial”. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research. 27 (16): 4491–4499. doi:10.1158/1078-0432.CCR-21-0611. PMC 8364866. PMID 34078652.
• Mellinghoff IK, van den Bent MJ, Blumenthal DT, Touat M, Peters KB, Clarke J, et al. (August 2023). “Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma”. The New England Journal of Medicine. 389 (7): 589–601. doi:10.1056/NEJMoa2304194. PMID 37272516.
• Popovici-Muller J, Lemieux RM, Artin E, Saunders JO, Salituro FG, Travins J, et al. (April 2018). “Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers”. ACS Medicinal Chemistry Letters. 9 (4): 300–305. doi:10.1021/acsmedchemlett.7b00421. PMC 5900343. PMID 29670690.

External links

Clinical trial number NCT04164901 for “Study of Vorasidenib (AG-881) in Participants With Residual or Recurrent Grade 2 Glioma With an IDH1 or IDH2 Mutation (INDIGO)” at ClinicalTrials.gov

• Clinical trial number NCT02481154 for “Study of Orally Administered AG-881 in Patients With Advanced Solid Tumors, Including Gliomas, With an IDH1 and/or IDH2 Mutation” at ClinicalTrials.gov
• Clinical trial number NCT03343197 for “Study of AG-120 and AG-881 in Subjects With Low Grade Glioma” at ClinicalTrials.gov

////////Vorasidenib, Voranigo, FDA 2024, APPROVALS 2024, AG 881, AG-881, AG881