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Anthracyclines and anthracenedionesAuthorisation expiredRational designNeeds review

Pixantrone

Also known as Pixuvri, BBR 2778

A synthetic aza-anthracenedione given by injection and designed to reduce anthracycline-related heart toxicity. The EU authorised it in 2012 for multiply relapsed or refractory aggressive B-cell non-Hodgkin lymphoma; that authorisation expired in June 2024.

From discovery to approval

  1. 1995 · Earliest report found

    A 1995 Biochemical Pharmacology paper by Hazlehurst, Krapcho and Hacker, the earliest report found naming BBR 2778, compared it with two other aza-anthracenediones for DNA damage and cytotoxicity. A 2001 paper says BBR 2778 emerged from screening many new nitrogen-containing molecules made as second-generation anthracenedione analogues.[2][3][4][5][6]

  2. 2012-05-10 · EMA conditional

    Conditional marketing authorisation granted by the European Commission for Pixuvri as monotherapy in adults with multiply relapsed or refractory aggressive non-Hodgkin B-cell lymphoma, with a study in patients previously treated with rituximab awaited (EPAR summary; the CHMP opinion was adopted 16 February 2012 per the EPAR page).[7]

  3. 2019-06-06 · EMA converted

    Commission decision on the renewal of the authorisation (R/0046; CHMP opinion 28 March 2019): the CHMP considered that all specific obligations had been fulfilled and recommended the marketing authorisation no longer subject to specific obligations. The procedural-steps table does not use the word converted; the EPAR page says the conditional authorisation was subsequently converted to a full marketing authorisation. The authorisation expired on 12 June 2024.[8]

How it works

EMA's assessment report describes it as related to doxorubicin and mitoxantrone, classes whose activity is linked to topoisomerase II inhibition and DNA intercalation. Its interaction with DNA and topoisomerase II was qualitatively similar to mitoxantrone's but caused fewer DNA breaks in L1210 cells, so other mechanisms probably contribute.[1]

Where it came from and why

The 2001 paper aimed to provide anthracenedione analogues with reduced side effects and a wider spectrum than mitoxantrone and doxorubicin. A 2012 phase 3 report says pixantrone was synthesised to reduce anthracycline-related cardiotoxicity without compromising antitumour efficacy. A 1994 paper described a related class; its abstract does not name BBR 2778.

Cancers

  • Aggressive B-cell non-Hodgkin lymphoma, multiply relapsed or refractory

    The EU indication was monotherapy in adults with multiply relapsed or refractory aggressive non-Hodgkin B-cell lymphoma; EMA's page states that the benefit has not been established when used as fifth-line or greater chemotherapy in patients refractory to last therapy.[9]

  • Aggressive non-Hodgkin lymphoma, phase 3 trial

    In a 140-patient randomised trial against investigator's choice of a single agent, a complete or unconfirmed complete response at end of treatment occurred in 14 of 70 patients (20.0%) given pixantrone and 4 of 70 (5.7%) given the comparator (p = 0.021).[6]

Worth knowing

  • In mice pretreated with doxorubicin, pixantrone did not worsen pre-existing cardiomyopathy, while further doxorubicin or mitoxantrone did.[5]
  • The EU authorisation (10 May 2012) was conditional and, according to EMA's page, was later converted to a full marketing authorisation in 2019; the page states that it expired on 12 June 2024 because the holder, Les Laboratoires Servier, did not apply for renewal, and gives the holder's reason as lack of demand.[9]
  • In the phase 3 trial, grade 3 or 4 neutropenia occurred in 28 of 68 patients (41.2%) given pixantrone and 13 of 67 (19.4%) given the comparator.[6]
  • The EPAR summary says the main study compared pixantrone with other chemotherapy in 140 adults and notes that more data were needed on benefit in patients previously treated with rituximab.[7]

References

  1. European Medicines Agency. Pixuvri: CHMP assessment report (public assessment report), EMEA/H/C/002055. Source
  2. Hazlehurst LA, Krapcho AP, Hacker MP. Comparison of aza-anthracenedione-induced DNA damage and cytotoxicity in experimental tumor cells. Biochem Pharmacol. 1995;50(7):1087-94. PubMedDOI
  3. Beggiolin G, Crippa L, Menta E, Manzotti C, Cavalletti E, Pezzoni G, et al. Bbr 2778, an aza-anthracenedione endowed with preclinical anticancer activity and lack of delayed cardiotoxicity. Tumori. 2001;87(6):407-16. PubMedDOI
  4. Krapcho AP, Petry ME, Getahun Z, Landi JJ Jr, Stallman J, Polsenberg JF, et al. 6,9-Bis[(aminoalkyl)amino]benzo[g]isoquinoline-5,10-diones. A novel class of chromophore-modified antitumor anthracene-9,10-diones: synthesis and antitumor evaluations. J Med Chem. 1994;37(6):828-37. PubMedDOI
  5. Cavalletti E, Crippa L, Mainardi P, Oggioni N, Cavagnoli R, Bellini O, et al. Pixantrone (BBR 2778) has reduced cardiotoxic potential in mice pretreated with doxorubicin: comparative studies against doxorubicin and mitoxantrone. Invest New Drugs. 2007;25(3):187-95. PubMedDOI
  6. Pettengell R, Coiffier B, Narayanan G, de Mendoza FH, Digumarti R, Gomez H, et al. Pixantrone dimaleate versus other chemotherapeutic agents as a single-agent salvage treatment in patients with relapsed or refractory aggressive non-Hodgkin lymphoma: a phase 3, multicentre, open-label, randomised trial. Lancet Oncol. 2012;13(7):696-706. PubMedDOI
  7. European Medicines Agency. Pixuvri: EPAR summary for the public, EMA/299783/2012, EMEA/H/C/002055 (last updated 03-2012). Source
  8. European Medicines Agency. Pixuvri: procedural steps taken and scientific information after the authorisation (renewal R/0046, CHMP opinion 28 March 2019, Commission decision 6 June 2019). Source
  9. European Medicines Agency. Pixuvri (pixantrone): European public assessment report page, status expired, marketing authorisation issued 10 May 2012, expiry 12 June 2024. Page read 2026-10-29. Source
  10. Minotti G, Han H, Cattan V, Egorov A, Bertoni F. Pixantrone: novel mode of action and clinical readouts. Expert Rev Hematol. 2018;11(7):587-596. PubMedDOI