Fibrogen has a lot riding on pivotal data for roxadustat, its project for anaemia in chronic kidney disease. Today's win in the European Alps trial will help its cause – but a safety analysis of the global pivotal programme, due in early 2019, is what investors are really waiting for.
Astellas, which has partnered the project in Europe and Japan, did not give many details about the Alps study, except to say it had met its primary endpoints, haemoglobin response rate in the first 24 weeks and haemoglobin change from baseline at weeks 28 to 52. Crucially, there did not appear to be any safety signals.
Leerink analysts noted that roxadustat’s efficacy now looked “more or less certain”. Trials in China and Japan have already read out positively, and an approval decision in China is expected by the end of the year. But the main questions over the asset now involve its side-effect profile.
The current standard of care for anaemia in chronic kidney disease is erythropoiesis-stimulating agents (ESAs), synthetic versions of erythropoietin that spur the patient’s bone marrow to produce red blood cells. However, these drugs are linked with thromboses and cardiovascular events.
HIF-PH inhibitors like roxadustat are designed to stabilise the HIF complex and stimulate endogenous erythropoietin production, effectively mimicking the body’s reaction to high altitude. It is thought that, compared with ESAs, they could lead to lower but more consistent blood erythropoietin levels, thus having better cardiovascular safety.
This theory will be put to the test when the full phase III programme for roxadustat reads out. Two more European trials are set to report, while five trials are ongoing in the US, where the project is partnered with Astrazeneca.
|Roxadustat's pivotal programme|
|Dolomites||Non-dialysis dependent||Europe||NCT02021318||616||Year end 2018|
|Pyrenees||Dialysis dependent||Europe||NCT02278341||838||Year end 2018|
|Himalayas||Dialysis dependent||US & ROW||NCT02052310||900||Year end 2018|
|Sierras||Dialysis dependent||US||NCT02273726||820||Year end 2018|
|Rockies||Dialysis dependent||US & ROW||NCT02174731||2,133||Year end 2018|
|Andes||Non-dialysis dependent||US & ROW||NCT01750190||922||Year end 2018|
|Olympus||Non-dialysis dependent||US & ROW||NCT02174627||2,781||Year end 2018|
|Source: EvaluatePharma, Clinicaltrials.gov.|
Initial data from the rest of the pivotal programme are expected by the end of the year, while a pooled safety analysis on major adverse cardiovascular events (MACE) is due in early 2019. Readout was delayed earlier this year (More patience needed for novel anaemia class’s biggest test, February 28, 2018).
Getting a clean safety label will be particularly important if roxadustat is to be used in the less sick non-dialysis-dependent kidney disease population, which the Leerink analysts forecast will account for 45% of the drug’s sales. They put peak roxadustat revenues at $5.8-8.1bn, depending on the drug’s performance on MACE.
If roxadustat ends up with a similar label to the ESAs, the former's greater convenience as an oral drug could help it gain market share in the non-dialysis population, Bernstein analysts believe. Still, the emergence of biosimilar ESAs would make this tough. Realistically, roxadustat needs to show a better safety profile to have a chance of meeting the high expectations set by the sellside.
Roxadustat is not the only HIF-PH inhibitor in town. Akebia’s vadadustat and Glaxosmithkline’s daprodustat are also in phase III trials, but data are not due until the end of next year at the earliest. This should give Fibrogen and its partners a chance to make the most of their first-mover advantage – if they can get a good safety result.
|Other HIF-PH inhibitor pivotal trials|
|Vadadustat (Akebia) trials|
|Inno2vate-Conversion||Dialysis dependent||US & ROW||NCT02892149||2,800||Q4 2019/Q1 2020|
|Inno2vate-Correction/Conversion||Dialysis dependent||US & ROW||NCT02865850||400||Q4 2019/Q1 2020|
|Pro2tect-Conversion||Non-dialysis dependent||US & ROW||NCT02680574||2,100||Mid-2020|
|Pro2tect-Correction||Non-dialysis dependent||US & ROW||NCT02648347||1,600||Mid-2020|
|Daprodustat (Glaxosmithkline) trials|
|Ascend-D||Dialysis dependent||US & ROW||NCT02879305||3,000||2020|
|Ascend-TD||Dialysis dependent||US & ROW||NCT03400033||402||2020|
|Ascend-ID||Patients initiating dialysis||US & ROW||NCT03029208||300||2020|
|Ascend-ND||Non-dialysis dependent||US & ROW||NCT02876835||4,500||2020|
|Ascend-NHQ||Non-dialysis dependent||US & ROW||NCT03409107||600||2020|
|Source: EvaluatePharma, Clinicaltrials.gov.|