dm+d

Unassigned

New Medicines

Anaemia in chronic kidney disease in dialysed and non-dialysed patients

Information

New molecular entity
Otsuka
Akebia

Development and Regulatory status

Pre-registration (Filed)
Pre-registration (Filed)
Not approved
May 22Otsuka will terminate its licensing deals with Akebia that cover vadadustat for CKD anaemia for the US, Europe and other regions, even as applications for the drug have been submitted to multiple drug agencies, including the European Medicines Agency and regulators in the UK, Switzerland and Australia. The ex-US agreement will end in 12 months; for the US deal, Otsuka is alleging material breaches by Akebia (which it disputes) and is therefore demanding an early termination on June 12, 2022 [23].
Mar 22FDA reject NDA due to safety concerns, including thromboembolic events and risk of drug-induced liver injury, also because the data did not support a favourable benefit-risk assessment of vadadustat for dialysis and non-dialysis patients. The CRL states Akebia could explore ways to potentially demonstrate a favourable benefit-risk assessment through new clinical trials; Akebia plan to request a meeting with the FDA [20].
Mar 22A decision from FDA is expected March 29th and vadadustat could be the first in its class of HIF-PH oral inhibitors to reach the market with sales expected to generate $532million in 2026 [19].
Oct 21Filed in EU for treatment of anaemia associated with chronic kidney disease in adults [18].
Mar 21NDA submitted to the FDA for vadadustat for anaemia due to CKD in adult patients on dialysis and not on dialysis. Otsuka also plan to file MAA with EMA this year [16].
Sep 20FDA NDA expected early 2021 both for dialysis dependent and non-dialysis dependent patients. EMA application in development, but no timeline given [15].
Jul 18primary completion dates for pivotal trials NCT02648347 and NCT02680574 updated to August 2020 for both [13].
Mar 18pivotal PIII trials (NCT02648347 and NCT02680574) in progress and recruiting, with estimated completion date of September 2019 for both [10].
Apr 17collaboration with Otsuka Pharmaceuticals expanded to cover Europe, China and other territories [7].
Dec 16Akebia has announced a collaboration with Otsuka Pharmaceuticals to commercialise vadadustat jointly in the US; this will provide funding for the PIII trial programme and marketing. Akebia is still in discussions with potential partners for marketing in the EU [5].
Aug 16Company intends to file in US and EU by the end of 2019 [7].
Oct 15Akebia intends to file for approval of vadadustat in the US by 2018 [2].
Oct 15Akebia Therapeutics announces successful completion of the End-of-Phase 2 Meeting process with the FDA and the Scientific Advice Process with the EMA for vadadustat for patients with anaemia related to non-dialysis dependent chronic kidney disease (NDD-CKD). The company has reached agreement with both the FDA and EMA regarding key elements of the Phase 3 program, known as the PRO2TECT™ program, and expects to launch the program later this year [1].

Category

Hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor. Hypoxia-inducible factors are transcription factors which play a key role in activating the expression of genes that control body defence mechanisms against low levels of oxygen. Taken once daily.
UK prevalence of stage 3-5 CKD is about 8.5% (8,500 per 100,000 people). Prevalence of anaemia in CKD (defined as a haemoglobin level less than 12 g/dL in men and postmenopausal women and less than 11 g/dL in premenopausal women) is about 12% [3].
Anaemia in chronic kidney disease in dialysed and non-dialysed patients
Oral

Further information

Yes

Trial or other data

Apr 21Pooled analysis of data from 2 PIII INNO2VATE RCTs (NCT02865850 and NCT02892149, n=3923) found vadadustat noninferior to darbepoetin alfa with respect to CV safety (first major adverse CV event in 18.2% and 19.3%, respectively; HR 0.96; 95% CI, 0.83 to 1.11) and correction and maintenance of haemoglobin levels [22].
Apr 21Pooled analysis of data from 2 PIII PRO2TECT RCTs (NCT02648347and NCT02680574 n=3476) found vadadustat noninferior to darbepoetin alfa with respect to haematologic efficacy (met prespecified noninferiority margin of −0.75g/dl) but not prespecified noninferiority margin (1.25) for CV safety (HR 1.17; 95% CI, 1.01- 1.36) [17].
Sep 20Vadadustat failed to achieve the primary safety endpoint (non-inferiority of vadadustat to darbepoetin alfa in time to first major adverse cardiovascular event) in the PRO2TECT study programme [15].
Jun 20Collection of primary outcome data completes in PIII studies PRO2TECT-CORRECTION (NCT02648347) and PRO2TECT-CONVERSION (NCT02680574) [14].
May 20Vadadustat achieved the primary and key secondary efficacy endpoint in each of the two INNO2VATE studies. In INNO2VATE´s Correction/Conversion study of incident dialysis patients (n=369), vadadustat was non-inferior to darbepoetin alfa with a mean difference in Hb of -0.31 g/dL (95% CI: -0.53 to -0.10) between gps. The mean (SD) Hb level at week 24 to week 36 was 10.36g/dL for vadadustat-treated pts vs. 10.61g/dL for darbepoetin alfa-treated pts. In INNO2VATE´s Conversion study of dialysis patients (n=3,554), vadadustat was also non-inferior to darbepoetin alfa with similar results between gps. Vadadustat achieved the INNO2VATE program´s primary safety endpoint of non-inferiority for Major Adverse Cardiovascular Events (MACE) and vadadustat was non-inferior to darbepoetin alfa (HR 0.96, 95% CI: 0.83, 1.11). The incidence of treatment emergent adverse events in vadadustat treated pts was 83.8% and 85.5% in darbepoetin alfa treated pts [21].
Mar 19Vadadustat hit its primary endpoint in two Japanese PIII trials in patients with anaemia due to chronic kidney disease. Differences between Japanese CKD patients compared to American and European CKD patients may mean that these data cannot be translated to general population, and may not reflect what is found in the PROTECT and INNOVATE studies; Japanese patients with CKD tend to have diabetes less often and are usually healthier. Topline data at week 24 from two other PIII trials show that vadadustat is non-inferior to darbepoeitin alfa at maintaining haemoglobin in both dialysis-dependent and non-dialysis dependent patients [12].
Sep 18Vadadustat commissioned by CCGs for non-dialysed patients, and by NHS England for dialysed patients [11].
Sep 16The multi-national PIII trial programme involves four trials addressing correction and maintenance therapy in dialysis-dependent (DD) and non-dialysis-dependent (NDD) patients: the PRO2TECT studies in NDD patients (NCT02648347 correction, NCT02680574 maintenance), and the INNO2VATE studies in DD patients (NCT02865850 correction, NCT02892149 maintenance). Estimated study populations are 3,100 for PRO2TECT and 2,600 for INNO2VATE, with estimated primary completion dates of October 2018 and August 2019 respectively [6].
Sep 16Akebia publish data for phase 2b RCT of Vadadustat treatment in non-dialysis patients with anaemia related to CKD. Results (n=210) showed that 54.9% of patients on vadadustat achieved the primary endpoint (percentage of patients who during the last 2 weeks of treatment, achieved a mean Hb level of ≥11.0g/dl or an increase in Hb of ≥1.2g/dl) vs 10.3% on placebo (P<0.0001) [4].
Oct 15The PRO2TECT™ program includes two separate studies and will collectively enrol approximately 3,100 NDD-CKD patients across 500 sites globally. The correction study will address anaemia patients not currently being treated with recombinant erythropoiesis stimulating agents (rESAs). The conversion study includes patients currently receiving rESA who will be converted to either vadadustat or the active control with the goal of maintaining their baseline hemoglobin levels. Both studies will include a 1:1 randomisation and an open label, active-control, non-inferiority design. Primary endpoints include an efficacy assessment of the hemoglobin response and an assessment of cardiovascular safety measured by major adverse cardiovascular events [1].