dm+d

40111311000001109

New Medicines

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

Information

Evrenzo
New molecular entity
Astellas
AstraZeneca

Development and Regulatory status

Launched
Launched
Not approved
September 2021
Nov 21Launched in EU [44].
Sep 21Available in the UK. Pricing 12x20mg tablets=£59.24, 12x50mg tablets=£148.11, 12x70mg tablets=£207.35, 12x100mg tablets=£296.21, 12x150mg tablets=£444.32 [42,43]
Aug 21Approved in the UK for the treatment of adult patients with symptomatic anaemia associated with chronic kidney disease (CKD) [41].
Aug 21Approved in the EU [40].
Aug 21The US FDA issued FibroGen a Complete Response Letter (CRL) for its New Drug Application (NDA) for roxadustat in which they state that it couldn’t be approved in its present form. They have asked for another clinical trial to be be run before the company reapplied. FibroGen and partner AstraZeneca plan to discuss next steps in the US FDA. [39]
Jul 21The FDA Cardiovascular and Renal Drugs Advisory Committee (CRDAC) has voted 13 to 1 that the benefit -risk profile of roxadustat does not support approval for the treatment of anaemia in chronic kidney disease (CKD) in non-dialysis dependent (NDD) adult patients, and 12 to 2 that the benefit-risk profile of roxadustat does not support approval for the treatment of anaemia in CKD in dialysis-dependent (DD) adult patients. The FDA will consider the vote, independent opinions and recommendations from experts as it reviews the new drug application (NDA) and is not bound by the Committee’s recommendation [38]
Jul 21FDA has scheduled a meeting of the Cardiovascular and Renal Drugs Advisory Committee for July 15 to discuss roxadustat tablets for treatment of anemia due to chronic kidney disease in adults not on dialysis and on dialysis. [37]
Jun 21Recommended for EU approval by CHMP – the full indication is “Evrenzo is indicated for treatment of adult patients with symptomatic anaemia associated with chronic kidney disease (CKD). Evrenzo will be available as 20mg, 50mg, 70mg, 100mg and 150mg film-coated tablets [37].
Apr 21FibroGen admits to manipulating safety data for roxadustat to enhance safety data. Parameters used to analyse heart safety were changed to yield more flattering data. Uncertainty now exists for approval of filing in US. Even if approved use may be restricted. The ongoing review of filing with EMA is unaffected [36].
Mar 21US FDA decide to put together an advisory committee of outside experts to review a New Drug Application (NDA) for roxadustat. This will likely delay an approval decision. [36]
Dec 20FDA has set a new PDUFA date of 20th March 2021 to review “further clarifying analyses of clinical data," which FibroGen and AstraZeneca will provide as soon as possible. This step does not indicate that the Agency considers that the drug would not be approvable [35].
May 20Currently pre-registration in EU [32].
Feb 20Application to US FDA will be filed on February 18, 2020. The FDA has set a Prescription Drug User Fee Act (PDUFA) date of December 20, 2020 [31].
Feb 20Analysts predict this will be one of the top 10 most-anticipated new US drug launches of 2020 based on estimated global sales in 2024 [30].
Nov 19According to the Q3 2019 Financial Results report from FibroGen, Astellas intends to submit an MAA to the EMA by the end of Q1 2020 [28].
Nov 19Data from the pooled efficacy and CV safety analyses, together with other statistical analyses, will form part of the regulatory submission in the US, which is anticipated in Q4 2019.[27]
Jun 19US filing planned for H2 19 [25].
Mar 19A new market research report identifies roxadustat as one of seven new drugs it believes will hit sales of $1 billion or more, the so-called “blockbuster” mark, by 2023 [23].
Dec 18Approved in China for dialysed patients with expedited review process. Launch anticipated H2 2019 [21]
Sep 18US filing acceptance expected H1 19 [17].
Mar 17Still listed as PIII in Astellas pipeline review Jan 17 [13].
Dec 15AstraZeneca plans for filing reported as unchanged - US 2018 [10].
Dec 15FibroGen has an agreement with AstraZeneca to collaborate on development in the US, China and all major markets except those that are covered by the agreement with Astellas. Astellas holds rights to develop and market roxadustat for treatment of anaemia in Europe, the Commonwealth of Independent States, the Middle East, and South Africa [11].
Mar 15Astellas is conducting three PIII studies in the Europe in patients on dialysis and not on dialysis [7]
Sep 14US filing planned for 2018; no plans reported for the EU [6].
Dec 12PIII study started [1].

Category

Hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor. HIF transcription factors play a key role in activating expression of genes that control body defence mechanisms against low levels of oxygen
NICE reports UK prevalence of stage 3-5 CKD is between 4.9% and 5.6% (4,900 to 5,600 per 100,000 people) in unselected populations: many of these will have been near end of life and referral to renal services inappropriate [14,15]. 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% [14].
Anaemia in chronic kidney disease in dialysed and non-dialysed patients
Oral

Further information

Yes

Trial or other data

May 22Astellas announces data from a pooled analysis of four phase 3 studies, in which there was no evidence of an increased risk of cardiovascular events or mortality with roxadustat vs. standard-of-care erythropoiesis-stimulating agents [45].
Apr 21Data from PIII programme recently stated that HR for three populations between roxadustat and Epogen/Procrit were 1.08, 0.96 and 0.7, respectively. These data were manipulated to improve the safety profile of roxadustat. It is now known that actual numbers by pre-specified standards were 1.1, 1.02 and 0.83 respectively, suggest higher relative risks for roxadustat [36].
Oct 20Data from two pooled analyses from PIII development program analysed data from 6 trials (3 in non-dialysis-dependent pts and 3 in DD patients). This showed that that roxadustat is effective in increasing and maintaining Hb levels in pts with anemia with CKD. Major Adverse Cardiovascular Events (MACE; all-cause mortality, myocardial infarction, and stroke) and MACE+ (MACE plus heart failure or unstable angina requiring hospitalization) rates were highest when Hb was 10 g/dL. These data will support regulatory filing with a PDUFA expected Dec 20.[34]
Jun 20Data from the PIII DOLOMITES trial comparing roxadustat with Aranesp (darbepoetin alfa) for anemia in non-dialysis dependent (NDD) adults with stage 3-5 chronic kidney disease (CKD) showed non-inferiority between the two treatments in the correction of hemoglobin levels during the first 24 weeks of treatment (89.5% vs 78.0%; difference 11.51% [95% Cl: 5.66%, 17.36%]), meeting the study´s primary endpoint. Regarding safety, the overall incidence of adverse events was comparable between roxadustat and Aranesp (91.6% and 92.5%, respectively).[33]
Dec 19Primary endpoint met in PIII PYRENEES study [29].
Nov 19FibroGen presented pooled efficacy and cardiovascular safety analyses from the pivotal PIII program of roxadustat for anemia from CKD. Roxadustat demonstrated a mean increase from baseline in Hb levels, regardless of iron repletion, averaged over weeks 28 to 52 of 1.85 g/dL in pts treated with roxadustat vs. 0.13 g/dL with placebo (p<0.001). Roxadustat did not increase the risk of MACE (HR 1.08, 95% CI 0.94 to 1.24), MACE+ (HR 1.04, 95% CI 0.91 to 1.18) and all-cause mortality (HR 1.06, 95% CI 0.91 to 1.23) in non-dialysis-dependent (NDD) compared to placebo and dialysis-dependent (DD) pts compared vs. epoetin alfa.[27]
Nov 19Phase III trial OLYMPUS found Hb levels rose from baseline, with a mean increase of 1.75g/dL averaged over weeks 28 to 52, compared to 0.40g/dL with placebo (primary efficacy endpoint). In the ROCKIES trial, Hb levels in dialysis-dependent patients increased by a mean of 0.77g/dL from baseline averaged over weeks 28 to 52, compared to 0.68g/dL with epoetin alfa [26].
May 19Top line results from pooled analysis of PIII safety data found that roxadustat was non-inferior to opoetin alfa in terms of major adverse cardiac events in chronic kidney disease patients. Full data have not yet been released in order to determine clinical significance of these findings [24].
Dec 18Primary endpoint met in PIII ANDES, OLYMPUS, ROCKIES & SIERRAS studies [22].
Sep 18Roxadustat met its objectives in the PIII randomised, double-blind, placebo-controlled ALPS study (NCT01887600) in 597 CKD pts with Anemia not on Dialysis. Topline results were announced demonstrating superiority in efficacy vs. placebo in both Hb response rate in the 1st 24 weeks and Hb change from baseline at Weeks 28 to 52.[18,19]
Sep 18Roxadustat commissioned by CCGs for non-dialysed patients, and by NHS England for dialysed patients [20].
Dec 17Four global trials are ongoing in patients receiving dialysis with data due in either 2017 or 2018. ROCKIES (NCT02174731) vs. epoetin alfa in 2,100 patients, SIERRAS (NCT02273726) vs. epoetin alfa in 820 patients, PYRENEES (NCT02278341) vs. darbepoetin alfa or an erythropoeisis stimulating agent in 838 patients, and HIMALAYAS (NCT02052310) vs. epoetin alfa in 750 patients. There is also another PIII trial assessing roxadustat in patients not receiving dialysis - the placebo-controlled OLYMPUS trial (NCT02174627) in 2,700 patients [16].
Jan 17FibroGen announces positive phase 3 data on its AstraZeneca-partnered anaemia drug. Both trials in the Chinese phase 3 program met their primary endpoints, moving FibroGen closer to filing for approval of a drug that enjoys fast-track status in the country. The first of the phase 3 trials enrolled 151 anaemia patients and randomized them to receive either FibroGen’s oral HIF-PH inhibitor roxadustat or a placebo. Hemoglobin levels in the treatment arm increased by 1.9 g/dL over the course of the eight-week trial. Levels fell by 0.4 g/dL in the placebo cohort, resulting in the study meeting its primary endpoint. The trial also hit a secondary endpoint that looked at the proportion of patients whose hemoglobin levels increased by 1 g/dL or more. In the second phase 3 trial, which gave roxadustat or epoetin alfa (EPO) to 271 hemodialysis and 33 peritoneal dialysis patients. FibroGen matched up to EPO in terms of change in hemoglobin from baseline and, as such, the study met its primary endpoint [12].
Aug 15Nephrology Dialysis Transplantation has published detailed efficacy results and safety data from a PIIa multicentre, randomised, placebo-controlled trial (n=116, NCT00761657) that was conducted in non-dialysis pts with anemia associated with stage 3 or 4 CKD. Roxadustat produced dose-dependent increases in haemoglobin (Hb) within 14 to 25 days. Roxadustat 0.7, 1.0, 1.5, or 2.0 mg/kg, increased Hb levels in a dose-related manner. Hb responder rates ranged from 30% with roxadustat 0.7 mg/kg to 100% with 2 mg/kg. The median time to response ranged from 42 days (1 mg/kg) to 14 days (2 mg/kg). Roxadustat transiently and moderately increased endogenous erythropoietin and reduced hepcidin levels. Adverse events were similar in the roxadustat and placebo groups. Most common adverse events associated with roxadustat were diarrhea (9.1%), headache (6.8%), back pain (4.5%), fatigue (4.5%) and hyperkalemia (4.5%). Detailed results and safety data from the trial were published in Nephrology Dialysis Transplantation [8,9].
Mar 14Astellas report that the first European patients have been enrolled into the global ALPINE study programme of roxadustat. In Europe, Astellas will conduct three PIII studies as part of this programme, ALPS, DOLOMITES and PYRENEES. NCT02278341(Pyrennees) started Nov 14 and will enrol 750 patients with anaemia of ESRD on stable dialysis and compare roxadustat vs epoetin alfa and darbepoetin alfa; NCT02021318 (Dolomites) started in Feb 14 and will compare roxadustat vs darbepoetin alfa in 570 patients with anaemia of CKD not on dialysis; and NCT01887600 is a placebo controlled trial started in May 13 in 600 patients with anaemia of CKD not on dialysis [7].
Dec 13NCT02021318 is a PIII, randomized, open-label, active-controlled study of FG-4592 in the treatment of anaemia in 570 patients with chronic kidney disease *stage 3,4 or 5) not on dialysis. The primary outcome is Hb response to treatment without the use of rescue therapy to week 24. The study starts Feb 14 and is due to complete Jul 17 [5].
Nov 13PII subgroup analysis comparing treatment response to roxadustat (FG-4592), in incident peritoneal dialysis (PD) pts and incident hemodialysis (HD) pts for the treatment of anemia in end stage renal disease (ESRD) presented in an oral session at the 2013 American Society of Nephrology (ASN) Kidney Week in Atlanta, Georgia. A Hb increase of 3.3 g/dL in PD pts (from baseline Hb = 8.8 g/dL) and 3.5 g/dL increase in HD pts (from baseline Hb = 8.5 g/dL) was observed over 12 weeks, with 100% of PD and 93% of HD pts achieving a Hb response (Hb increased by ≥1 g/dL from baseline). Roxadustat achieved a comparable and significant correction of anemia with average Hb increases of over 3 g/dL when supplemented with only oral iron in both incident PD pts and incident HD pts, regardless of dialysis modality. [5]
Jul 13NCT01887600 is a PIII, randomized, double-blind, placebo controlled study of FG-4592 for the treatment of anaemia in 600 chronic kidney disease patients not on dialysis. The primary outcome is Hb response to treatment to Week 24. The study started May 13 and is due to complete Aug 15 [4].
Mar 13An open-label extension (NCT01630889) study to evaluate long-term efficacy & safety of FG-4592 in maintaining hemoglobin in dialysis and non-dialysis CKD pts who have completed the treatment period of the NCT01750190 study. 150 pts will be followed for up to 2 yrs. The study is expected to complete in Oct 15 [3].
Mar 13Pivotal PIII (NCT01750190) study will enrol 450 pts from the US, Australia, Hong Kong & Korea. FG-4592 will be dosed three times weekly (TIW), twice weekly (BIW) or weekly. It is expected to compete in Mar 15 [3].
Dec 12FibroGen, and Astellas has started the first study in the PIII clinical development programme of FG-4592/ASP1517 to support approval in the EU and US. In PII studies FG-4592/ASP1517 met its primary objective of correcting anaemia in treatment-naïve CKD patients not on dialysis as well as maintenance of haemoglobin in CKD patients on dialysis and not on dialysis [1].

Evidence based evaluations

Evrenzo Lower risk myelodysplastic syndromes (MDS)

Information

Evrenzo
Licence extension / variation
Astellas
AstraZeneca

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials

Category

Hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor. HIF transcription factors play a key role in activating expression of genes that control body defence mechanisms against low levels of oxygen.
The incidence of MDS is approximately 4 in 100,000 population/year. It is predominantly a disease of the elderly with an incidence of over 30 in 100,000/year in those over the age of 70 years. The overall prevalence of the syndromes appears to be increasing due to an ageing population and better diagnosis [1].
Lower risk myelodysplastic syndromes (MDS)
Oral