Ivosidenib

Published

dm+d

Unassigned

New Medicines

TibsovoBile duct cancer (cholangiocarcinoma) in patients with an isocitrate dehydrogenase 1 (IDH1) mutation, whose disease has progressed after one or two systemic therapies

Information

Tibsovo
New molecular entity
Servier
Servier

Development and Regulatory status

Phase III Clinical Trials
Pre-registration (Filed)
Launched
Mar 22Filed in EU for treatment of previously treated, locally advanced or metastatic IDH1-mutated cholangiocarcinoma [12].
Aug 21Approved in US for adult patients with previously treated, locally advanced or metastatic cholangiocarcinoma with an isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test [10].
Nov 20Agios agrees to sell its commercial, clinical and research-stage oncology portfolio to Servier. Plans for progressing EU/UK development of Tibsovo unknown at this time [7,8].
Sep 20Agios announce plans to file sNDA Q1 21 [5].
Dec 19No plans for filing in EU discussed in latest company annual report [3].
May 19Company plan to file a NDA with US FDA for this indication at the end of the year [2].

Category

First-in-class inhibitor of mutated IDH1 protein
Cholangiocarcinoma is a carcinoma arising in any part of the biliary tree from the small intrahepatic bile ducts to the ampulla of Vater at the distal end of the common bile duct. Can also occur (least commonly) as an intrahepatic tumour. The incidence of intrahepatic cholangiocarcinoma is increasing and the incidence is estimated as 0.9-1.3/100,000 for males and 0.4-0.7/100,000 for females. Intrahepatic cholangiocarcinoma accounts for 10-15% of primary liver cancer [1].
Bile duct cancer (cholangiocarcinoma) in patients with an isocitrate dehydrogenase 1 (IDH1) mutation, whose disease has progressed after one or two systemic therapies
Oral

Trial or other data

Sep 21PIII ClarlDHy RCT (n=187) found ivosidenib was associated with a higher overall survival versus placebo, when adjusted for crossover (median 10.3 v 5.1 months; HR 0.49; 95% CI 0.34-0.70; P <0.001) [11].
Dec 20PIII ClarIDHy trial is ongoing but has finished recruitment. Collection of primary outcome data completed in Jan 19 and the study itself is due to end in Aug 21 [6].
Sep 20Agios announces results of the final overall survival (OS) analysis from its global Phase 3 ClarIDHy trial. A consistent trend in improved OS was observed in patients treated with Tibsovo vs. those randomised to placebo, but was not statistically significant. The OS endpoint can be affected by crossover, so these results should be taken in the context of the large proportion (70%) of patients in the placebo arm who crossed over to receive Tibsovo following radiographic disease progression; additional analyses performed to take crossover into account further support that Tibsovo may improve OS. The estimated PFS rate was 32% at six months and 22% at 12 months for patients randomised to Tibsovo, while no patients randomised to placebo were free from progression or death beyond six months as of the data cut-off [9].
May 20PIII NCT02989857 RCT (n=185) reported improved progression-free survival with ivosidenib, a small-molecule targeted inhibitor of mutated IDH1, compared with placebo, (median 2.7 vs 1.4 months; HR 0.37; 95% CI 0.25–0.54; p<0.0001) in patients with IDH1-mutant cholangiocarcinoma [4].
May 19Agios Pharma report positive results from PIII ClarIDHy trial (NCT02989857). Study (n

TibsovoNewly diagnosed acute myeloid leukaemia (AML) with an isocitrate dehydrogenase-1 (IDH1) mutation, combination with azacitidine

Information

Tibsovo
New molecular entity
Agios Pharmaceuticals
Agios Pharmaceuticals

Development and Regulatory status

Phase III Clinical Trials
Pre-registration (Filed)
Launched
Yes
Yes
May 22Approved in the US for first-line use in combination with azacitidine in patients aged 75 and older or those who have comorbidities that preclude the use of induction chemotherapy [10].
Mar 22Filed in EU for use in combination with azacitidine, in patients with previously untreated IDH1-mutated acute myeloid leukaemia (AML) not eligible for intensive chemotherapy [8].
Mar 22Filed in the US for first-line treatment of AML, with Priority Review [7].
Dec 21Servier is in discussions with regulatory health authorities regarding submissions to expand the currently approved indications for Tibsovo [6].

Category

First-in-class inhibitor of mutated IDH1 protein
AML affects < 1.2 in 10,000 people in the EU (equivalent to not more than 61,000 people).
Newly diagnosed acute myeloid leukaemia (AML) with an isocitrate dehydrogenase-1 (IDH1) mutation, combination with azacitidine
Oral

Trial or other data

Apr 22Company announces PIII AGILE trial results are published in the New England Journal of Medicine [9]
Dec 21Servier presents data from PIII AGILE study showing ivosidenib in combination with azacitidine significantly improved event-free survival (EFS) and overall survival (OS) compared to azacitidine plus placebo in adults with previously untreated IDH1-mutated acute myeloid leukemia (AML) who are not candidates for intensive chemotherapy. Treatment with TIBSOVO in combination with azacitidine demonstrated a statistically significant improvement in EFS (hazard ratio [HR] = 0.33, 95% CI 0.16, 0.69, 1-sided P = 0.0011 1,2). In addition, the combination of TIBSOVO with azacitidine showed a statistically significant improvement in OS (HR = 0.44 [95% CI 0.27, 0.73]; 1-sided P = 0.0005), with a median OS of 24.0 months in the ivosidenib + azacitidine arm vs 7.9 months in the placebo + azacitidine arm. Complete remission (CR) rate was 47.2% (n=34/72) for TIBSOVO in combination with azacitidine vs. 14.9% (n=11/74) for placebo plus azacitidine (p < 0.0001). CR + complete remission with partial hematologic recovery rate (CR + CRh rate) was 52.8% (n=38/72) for TIBSOVO in combination with azacitidine vs. 17.6% (n=13/74) for placebo plus azacitidine (p < 0.0001). Objective response rate (ORR) was 62.5% (n=45/72) for TIBSOVO in combination with azacitidine vs. 18.9% (n=14/74) for placebo plus azacitidine (p < 0.0001). The AGILE study has halted further enrollment due to compelling efficacy data for TIBSOVO [6].
Aug 21Servier announce PIII AGILE study met primary endpoint of event-free survival (EFS) and all secondary key endpoints. Ivosidenib with azacitidine demonstrated a statistically significant improvement in EFS vs azacitidine with placebo [5].
Dec 20PIII AGILE study continues to recruit [4].
Dec 19PIII AGILE study is recruiting; timescales unchanged [3].
Nov 18Based on regulatory discussions with the FDA the company is accelerating development in IDH1m AML including a shorter enrollment timeline for the AGILE trial [2].
Jun 17NCT03173248 (AGILE) is a PIII study of ivosidenib + azacitidine vs placebo + azacitidine in 392 adult subjects with previously untreated IDH1m AML who are considered appropriate candidates for non-intensive therapy. The primary endpoint is overall survival. The estimated date for primary completion is Apr 22 and for study completion Jun 22 [1].

TibsovoRelapsed or refractory isocitrate dehydrogenase-1 (IDH-1) mutation-positive acute myeloid leukaemia

Information

Tibsovo
New molecular entity
Servier
Servier

Development and Regulatory status

Filing withdrawn
Filing withdrawn
Launched
Yes
Yes
Dec 20Agios agrees to sell its commercial, clinical and research-stage oncology portfolio to Servier. Plans for progressing EU/UK development of Tibsovo unknown at this time [13,14].
Oct 20Withdrawal announced of EU Marketing Application for ivosidenib tablets for the treatment of adult patients with relapsed or refractory AML with an IDH1 mutation. The decision is based on feedback from the CHMP that the available clinical data from the single arm, uncontrolled Phase 1 study do not sufficiently support a positive benefit-risk balance for the proposed indication [12].
Dec 19Tibsovo has been available in the US since Jul 18 [10].
Feb 19Filed in EU [9].
Jan 19Company state that filing in EU for adults with RR AML with IDH1 mutation planned by year end 2018 [7].
Jul 18Approved by the FDA [6].
Dec 17Agios has submitted a NDA to the FDA for ivosidenib for oral treatment for patients with relapsed or refractory acute myeloid leukemia (R/R AML) and an isocitrate dehydrogenase-1 (IDH1) mutation [5].
Dec 16Granted orphan drug status in EU (EU/3/16/1802) [8].
May 15FDA grant fast track designation [1].

Category

First-in-class inhibitor of mutated IDH1 protein
AML affects < 1.2 in 10,000 people in the EU (equivalent to not more than 61,000 people).
Relapsed or refractory isocitrate dehydrogenase-1 (IDH-1) mutation-positive acute myeloid leukaemia
Oral

Further information

Yes

Trial or other data

Jun 18Results of PI study (NCT02074839) published. Overall, 258 patients received ivosidenib and had safety outcomes assessed. Among patients with relapsed or refractory AML (179 patients), treatment-related adverse events of grade 3 or higher that occurred in at least 3 patients were prolongation of the QT interval (in 7.8% of the patients), the IDH differentiation syndrome (in 3.9%), anemia (in 2.2%), thrombocytopenia or a decrease in the platelet count (in 3.4%), and leukocytosis (in 1.7%). In the primary efficacy population (125 patients), the rate of complete remission or complete remission with partial hematologic recovery was 30.4% (95% confidence interval [CI], 22.5 to 39.3), the rate of complete remission was 21.6% (95% CI, 14.7 to 29.8), and the overall response rate was 41.6% (95% CI, 32.9 to 50.8). The median durations of these responses were 8.2 months (95% CI, 5.5 to 12.0), 9.3 months (95% CI, 5.6 to 18.3), and 6.5 months (95% CI, 4.6 to 9.3), respectively. Transfusion independence was attained in 29 of 84 patients (35%), and patients who had a response had fewer infections and febrile neutropenia episodes than those who did not have a response. Among 34 patients who had a complete remission or complete remission with partial hematologic recovery, 7 (21%) had no residual detectable IDH1 mutations on digital polymerase-chain-reaction assay. No preexisting co-occurring single gene mutation predicted clinical response or resistance to treatment [11].
Mar 14Agios Pharmaceuticals initiate PI open-label, dose-escalation (NCT02074839) trial in patients with relapsed/ refractory AML or recurrent/refractory myelodysplastic syndrome, to assess safety, pharmacokinetics, pharacodynamic and clinical activity of AG120 when administered continuously to participants on days 1 through 28 or a 28-day cycle. The co-primary end-points are incidence of adverse events and maximum tolerated dose or recommended PII dose. Results are expected in late 2014 [2].

Evidence based evaluations