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Microtubule-targeting agentsIn useDerivative of an earlier drug

Ixabepilone

Also known as Ixempra, BMS-247550

A semisynthetic analogue of epothilone B, a product of a soil bacterium, given by infusion. Its US label lists metastatic or locally advanced breast cancer resistant to an anthracycline and a taxane, with capecitabine or, in later-line disease, alone.

From discovery to approval

  1. 2001 · Earliest report found

    Epothilones A and B were isolated from the myxobacterium Sorangium cellulosum. Ixabepilone, a semisynthetic analogue of epothilone B developed by Bristol-Myers Squibb, appears in the earliest paper found, a 2001 report of BMS-247550; no source read dates its first synthesis.[2][3][4][5][6][7][8][1][9]

  2. 2007-10-16 · FDA regular

    In combination with capecitabine, metastatic or locally advanced breast cancer resistant to an anthracycline and a taxane, or taxane-resistant where further anthracycline therapy is contraindicated; and as monotherapy, metastatic or locally advanced breast cancer resistant or refractory to anthracyclines, taxanes and capecitabine (NDA 22-065). The letter says the application was not taken to the Oncologic Drugs Advisory Committee. The type regular is an inference: no accelerated-approval wording was found.[9]

How it works

The label says ixabepilone binds directly to the beta-tubulin subunits of microtubules and suppresses microtubule dynamics, blocking cells in the mitotic phase and leading to cell death. It has low in vitro susceptibility to several tumour resistance mechanisms, including efflux transporters.[1]

Where it came from and why

Lee's 2008 review says natural epothilones A and B were potent in vitro but not in animal models, because of poor metabolic stability and pharmacokinetics, so analogues were made. Hunt's 2009 account adds that the parent compounds were inactivated by esterase cleavage, and that the lactam analogue was more stable and kept activity against paclitaxel-resistant cells.

Epothilones A and B were found as secondary metabolites of the soil myxobacterium Sorangium cellulosum, strain So ce90 [2]. A 1996 report describes antifungal activity against the zygomycete Mucor hiemalis in the culture broth, and high cytotoxicity for animal cells [3]. A 1995 study identified epothilones A and B as having all the biological effects of taxol on microtubules, and called them the first structural class described since taxol's discovery to mimic it [4].

Hunt's account describes an evaluation of the epothilones in collaboration with the Gesellschaft für Biotechnologische Forschung, with experiments at Bristol-Myers Squibb that confirmed their effects on tubulin [6]. Because the natural compounds were inactivated by esterase cleavage, semisynthetic analogues were prepared, and the lactam analogue of epothilone B, BMS-247550, now ixabepilone, was more metabolically stable and kept activity against paclitaxel-resistant cells [6]. A 2001 report presented BMS-247550 as a semisynthetic analogue of epothilone B [7].

The FDA approved ixabepilone on 16 October 2007 [9].

Cancers

  • Metastatic or locally advanced breast cancer

    The US label lists use with capecitabine in breast cancer resistant to an anthracycline and a taxane (or taxane resistant where further anthracycline is contraindicated), and as a single agent where tumours are resistant or refractory to anthracyclines, taxanes and capecitabine.[1]

  • Anthracycline- and taxane-resistant breast cancer (phase III)

    A phase III trial randomised patients with anthracycline-pretreated or -resistant and taxane-resistant breast cancer to ixabepilone plus capecitabine or capecitabine alone; the primary endpoint was progression-free survival.[10]

Worth knowing

  • In that phase III trial of 752 patients, median progression-free survival was 5.8 months with ixabepilone plus capecitabine against 4.2 months with capecitabine alone (hazard ratio 0.75, 95% CI 0.64 to 0.88; P = .0003), as reported by the authors.[10]
  • Bollag and colleagues described the epothilones in 1995 as retaining much greater toxicity than taxol against cells that express P-glycoprotein.[4]
  • The 1996 production report says the antifungal activity of Sorangium cellulosum strain So ce90 was excreted into the culture supernatant, and that adding an adsorber resin bound the active metabolites quantitatively.[3]
  • The label contraindicates ixabepilone with capecitabine in patients with AST or ALT above 2.5 times the upper limit of normal, or bilirubin above 1 times the upper limit, because of increased risk of toxicity and neutropenia-related death.[1]

References

  1. R-Pharm US Operating, LLC. Ixempra (ixabepilone) kit: prescribing information. DailyMed, set ID 241f0b1e-8b95-470d-876f-bf1804daaf18, published 5 December 2025. Source
  2. Reichenbach H, Höfle G. Discovery and development of the epothilones : a novel class of antineoplastic drugs. Drugs R D. 2008;9(1):1-10. PubMedDOI
  3. Gerth K, Bedorf N, Höfle G, Irschik H, Reichenbach H. Epothilons A and B: antifungal and cytotoxic compounds from Sorangium cellulosum (Myxobacteria). Production, physico-chemical and biological properties. J Antibiot (Tokyo). 1996;49(6):560-3. PubMedDOI
  4. Bollag DM, McQueney PA, Zhu J, Hensens O, Koupal L, Liesch J, et al. Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action. Cancer Res. 1995;55(11):2325-33. PubMed
  5. Höfle G, Bedorf N, Steinmetz H, Schomburg D, Gerth K, Reichenbach H. Epothilone A and B—Novel 16‐Membered Macrolides with Cytotoxic Activity: Isolation, Crystal Structure, and Conformation in Solution. Angewandte Chemie International Edition in English. 1996;35(13-14):1567-1569. DOI
  6. Hunt JT. Discovery of ixabepilone. Mol Cancer Ther. 2009;8(2):275-81. PubMedDOI
  7. Lee FY, Borzilleri R, Fairchild CR, Kim SH, Long BH, Reventos-Suarez C, et al. BMS-247550: a novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor efficacy. Clin Cancer Res. 2001;7(5):1429-37. PubMed
  8. Lee FY, Borzilleri R, Fairchild CR, Kamath A, Smykla R, Kramer R, et al. Preclinical discovery of ixabepilone, a highly active antineoplastic agent. Cancer Chemother Pharmacol. 2008;63(1):157-66. PubMedDOI
  9. U.S. Food and Drug Administration. NDA approval letter, Ixempra Kit (ixabepilone) for injection, NDA 22-065, Bristol-Myers Squibb Company; electronic signature dated 10/16/2007. Source
  10. Thomas ES, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, et al. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol. 2007;25(33):5210-7. PubMedDOI