dm+d

38925011000001101

New Medicines

DaurismoAcute myeloid leukaemia in adult patients who are not candidates for standard induction chemotherapy - first-line in combination with low dose cytarabine

Information

Daurismo
New molecular entity
Pfizer
Pfizer

Development and Regulatory status

Launched
Launched
Approved (Licensed)
October 2020
Yes
Yes
Oct 20Launched in the UK. Price: 25mg x 60 tablets=£10517.00; 100mg x 30 tablets=£10517.00 [11].
Jun 20Approved in EU [10].
Apr 20Recommended for EU approval by CHMP - the full indication is "in combination with low-dose cytarabine, for the treatment of newly diagnosed de novo or secondary acute myeloid leukaemia (AML) in adult patients who are not candidates for standard induction chemotherapy." It is proposed that the medicine be prescribed by physicians experienced in the use of anticancer products [9].
Jun 19Filed in EU, via centralised procedure [8].
Nov 18Approved in the US in combination with low-dose cytarabine for the treatment of newly-diagnosed AML in adults who are 75 years of age or older or who have other chronic health conditions or comorbidities that may preclude the use of intensive chemotherapy [5].
Jul 18Has been filed in the US, with priority review [4].
Aug 17PIII in EU & US. Will be filed in EU via centralised procedure [1].

Category

Oral small-molecule sonic hedgehog pathway inhibitor. The drug binds to and inhibits Smoothened (SMO), a transmembrane protein involved in hedgehog signal transduction, often over-expressed in cancer [3]
Incidence of AML in European adults is 5-8 cases per 100,000. AML can occur at any age but the incidence increases with age and the median age of onset is 67. Its significance has grown with an ageing population: of the 2,000 cases of AML diagnosed annually in the UK, 1,400 will be in the over-60s [2].
Acute myeloid leukaemia in adult patients who are not candidates for standard induction chemotherapy - first-line in combination with low dose cytarabine
Oral

Further information

Yes

Trial or other data

Nov 18PII BRIGHT 1003 trial = NCT01546038 [6].
Nov 18US approval was based on results of the pivotal, randomised, international PII BRIGHT 1003 trial (n=115). Median overall survival was 8.3 months (95% CI: 4.4 - 12.2) for patients treated with glasdegib plus low-dose cytarabine (LDAC) vs 4.3 months (95% CI: 1.9 - 5.7) for patients treated with LDAC alone. This difference represented a 54% reduction in the risk of death for patients treated with glasdegib plus LDAC (HR: 0.46, 95% CI: 0.30 - 0.71, p=0.0002). The U.S. labelling for glasdegib includes a boxed warning for embryo-fetal toxicity. The most frequently (≥20% of patients) reported adverse events (AEs) in the glasdegib arm were anaemia, fatigue, haemorrhage, febrile neutropenia, musculoskeletal pain, nausea, oedema, thrombocytopenia, dyspnoea, decreased appetite, dysgeusia, mucositis, constipation and rash. Serious adverse reactions were reported in 79% of patients treated in the glasdegib arm. The most common (≥5%) were febrile neutropenia, pneumonia, haemorrhage, anaemia and sepsis. PIII BRIGHT trials are ongoing [6].
Apr 18Two randomised, placebo-controlled PIII trials (BRIGHT AML 1019; NCT03416179) have started multinational recruitment (incl UK) to evaluate the addition of glasdegib to intensive or non-intensive chemotherapy in patients (n=720) with newly diagnosed AML. In the first study, patients with AML will be randomised to receive glasdegib plus cytarabine and daunorubicin, an intensive chemotherapy regimen, or placebo plus cytarabine and daunorubicin. In the second study, patients with AML for whom intensive chemotherapy is not an option will be randomised to receive glasdegib plus azacitidine, a hypomethylating agent, or placebo plus azacitidine. Primary outcome measure is overall survival. Estimated primary completion date is Jun 2021 [6,7].
Apr 12PI/II trial to investigate the effects of glasdegib in combination with either low-dose cytarabine or decitabine or daunorubicin and cytarabine in patients with AML or myelodysplastic syndromes (MDS), acute myeloid leukaemia (AML) and chronic myelomonocytic leukaemia starts (NCT01546038). The trial will recruit approximately 267 patients in the US, Canada, Germany, Italy, Poland and Spain [3].

Evidence based evaluations

DaurismoAcute myeloid leukaemia (AML) - first-line in combination with cytarabine and daunorubicin

Information

Daurismo
Licence extension / variation
Pfizer
Pfizer

Development and Regulatory status

Discontinued
Discontinued
Discontinued
Yes
Yes
Oct 20Development discontinued. Pfizer reports that the intensive cohort of the PIII BRIGHT AML 1019 trial evaluating DAURISMO (glasdegib) in combination with cytarabine and daunorubicin in adults with previously untreated acute myeloid leukemia (AML) is unlikely to show a statistically significant improvement in the primary endpoint of overall survival. Pfizer has accepted the independent Data Monitoring Committee recommendation to stop the intensive study cohort. The results continue to be analysed; however, no new safety signals have been observed. Pfizer will not be making HTA submissions for this combination in the UK [4,5].

Category

Oral small-molecule sonic hedgehog pathway inhibitor. The drug binds to and inhibits Smoothened (SMO), a transmembrane protein involved in hedgehog signal transduction, often over-expressed in cancer
Incidence of AML in European adults is 5-8 cases per 100,000. AML can occur at any age but the incidence increases with age and the median age of onset is 67. Its significance has grown with an ageing population: of the 2,000 cases of AML diagnosed annually in the UK, 1,400 will be in the over-60s [1].
Acute myeloid leukaemia (AML) - first-line in combination with cytarabine and daunorubicin
Oral