FibroGen’s Roxadustat On The Rocks After Phase III Myelodysplastic Syndrome Failure
Executive Summary
MATTERHORN’s failure did not surprise analysts, but it’s likely the end of the road for roxadustat in the US market. The focus instead has shifted to FibroGen’s IPF asset pamrevlumab.
The failure of FibroGen, Inc.’s Phase III MATTERHORN trial of roxadustat in anemia among patients with transfusion-dependent lower-risk myelodysplastic syndrome (MDS) likely seals the drug’s fate in the US market, thereby shifting focus to pamrevlumab, FibroGen’s Phase III candidate for idiopathic pulmonary fibrosis (IPF). But IPF has been a challenging area of development.
FibroGen said 5 May that MATTERHORN, which enrolled 140 patients, did not met its primary endpoint measuring the proportion of patients achieving red blood cell transfusion independence in the first 28 weeks of the study. In the roxadustat arm, 47.5% of patients achieved transfusion independence, compared with 33.3% in the placebo arm, but the result was not statistically significant (p=0.217). Safety in the study was generally consistent with prior studies.
FibroGen sponsored and conducted MATTERHORN and has co-development partnerships for roxadustat with AstraZeneca PLC and Astellas Pharma, Inc. The company developed roxadustat for anemia in patients with chronic kidney disease (CKD), and the drug won approval for that indication in the European Economic Area under the brand name Evrenzo in August 2021, having already won approval in Japan and China in late 2018. (Also see "European Approval For Roxadustat Is Silver Lining For FibroGen" - Scrip, 23 Aug, 2021.)
Roxadustat’s Path To US Market Likely Closed
Despite Evrenzo’s European Commission approval, FibroGen had less luck with the US Food and Drug Administration, which in August 2021 sent FibroGen a complete response letter (CRL) raising concerns about roxadustat’s safety in comparison with erythropoietin-stimulating agents, especially the risk of thrombosis and major cardiovascular events. The CRL followed a negative FDA advisory committee vote and raised the possibility of a restructuring that even the EC approval could not head off, and in its third quarter 2021 earnings that November, FibroGen announced a cost-reduction plan to reduce expenses by $100m over the next three years. (Also see "Restructuring On The Table For FibroGen After Roxadustat Rejection" - Scrip, 11 Aug, 2021.)
Akebia Therapeutics, Inc.’s vadadustat – which, like roxadustat, is a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) – similarly received a CRL from the FDA over safety concerns in March 2022 for CKD anemia. (Also see "Akebia Could Face Long, Costly Effort To Overcome Vadadustat CRL" - Scrip, 31 Mar, 2022.)
Analysts were unsurprised at the MATTERHORN trial’s failure in anemia associated with MDS, given the drug’s history to date in the US, with Raymond James’s Danielle Brill dubbing it the “Doesn’t MATTERhorn” trial in a 5 May note.
“While this trial represented the best opportunity for roxa to establish a beachhead within the US market – our expectations for success were very low, and it was not incorporated into our model,” Brill said.
In a same-day note, William Blair analyst Andy Hsieh likewise said MATTERHORN’s failure eliminates the US market opportunity for roxadustat and called the negative outcome unsurprising and pointing to a “complicated path forward from both clinical and partnership perspectives.”
“Notably, even in the event of a success, FibroGen would have needed buy-in from partner AstraZeneca,” Hsieh said.
More Enthusiasm For IPF Program
With roxadustat out of the picture, analysts are instead shifting their attention to FibroGen’s next most advanced clinical asset, pamrevlumab, for which they have more confidence. The company said 3 April that it completed enrollment in the Phase III ZEPHYRUS-2 trial, which enrolled 372 patients and follows the 356-patient ZEPHYRUS-1 study. Both are randomized, double-blind, placebo-controlled trials.
“We continue to believe pamrevlumab in IPF is the key to future value creation for [FibroGen] – and we remain cautiously optimistic that the approaching pivotal Phase 3 (ZEPHYRUS-1) trial will be a success (data expected mid-year),” Raymond James’s Brill said.
William Blair’s Hsieh said investors have also been focused on pamrevlumab. “We remain bullish heading into the Phase III ZEPHYRUS-1 trial in IPF and reiterate our ‘Outperform’ rating on FibroGen shares,” he said.
IPF has been a challenging field in recent years. Biomedtracker lists three programs in active Phase III development – Boehringer Ingelheim GmbH’s BI-1015550, Grupo Ferrer Internacional, S.A.'s Tyvaso and Bellerophon Therapeutics Inc.'s INOpulse – but it lists 28 programs that are suspended.
The most recent FDA approvals in IPF were for BI’s Ofev (nintedanib) and Roche Holding AG’s Esbriet (pirfenidone), in October 2014. A potential tailwind came in February when Roche said in its fourth quarter 2022 earnings that it would discontinue development of the Phase III candidate PRM-151, which was the subject of its deal to acquire Promedior in 2019. (Also see "Harbingers For IPF Drug Development" - In Vivo, 24 Apr, 2023.)