Roxadustat shows the latest regulatory fault line split

 The reception roxadustat received from drug regulators on the two sides of the Atlantic could not have been much different. In the US Fibrogen’s novel anaemia pill was savaged by an advisory committee and then sent back for more trials by the FDA, while Europe’s CHMP has recommended use in a surprisingly broad patient population.

The EU backing was rubber-stamped by the European Commission this week, although the full label and prescribing information have yet to emerge. While it is fairly rare for the FDA and EMA to take such stridently different positions this does happen, a look back at diverging decisions shows.

Other notable examples include Viviant, an osteoporosis product that the FDA rejected three times on the grounds of stroke and clotting risks, but one that Wyeth and then Pfizer have been selling in Europe for more than a decade.

Replagal, a treatment for the rare enzyme deficiency disease Fabry disease, never satisfied the US regulator, despite repeated attempts by the therapy’s originator, Tranksaryotic Therapies, and then Shire, which bought TKT in 2005. EU regulators approved the drug in 2001, and Shire gave up trying to appease the FDA in around 2012.

Galapagos’s Jyseleca could yet join this club, with the FDA  last year refusing to approve a dose high enough to be commercially competitive in rheumatoid arthritis. The company and its partner Gilead are still exploring options in ulcerative colitis and Crohn’s disease, but with ongoing FDA scrutiny of the Jak class, to which Jyseleca belongs, it would not be too surprising if this product never makes it to the US market.

The cross-Atlantic regulatory fault lines
Product	Company	EMA approval	US status	2026e sales
Leqvio	Novartis	2020	Pdufa date Jan 2022 (delayed by manufacturing concerns)	$2bn (assumes US approval)
Zynteglo	Bluebird	2019	Clinical hold lifted Jun 2021; BLA in beta-thal to complete Q3 2021	$723m (consensus predates decision to exit Europe)
Viviant	Pfizer	2009	Abandoned after three rejections	$638m
Jyseleca	Galapagos/Gilead	2020	Abandoned in arthritic conditions, inflammatory bowel diseases under review	$623m
Zynquista	Lexicon	2019	Filing in type 2 diabetes with heart failure planned in 2021 (EU approval is in type 1 diabetes)	$476m
Priorix	Glaxosmithkline	1997	Filed Aug 2021	$387m
Replagal	Takeda	2001	Abandoned	$385m
Hepcludex	Gilead	2020	Filing planned 2021	$364m
Libmeldy	Orchard Therapeutics	2020	Filing planned 2022/23	$360m
Source: Evaluate Pharma.

Bluebird’s ability to win speedy EU approval for Zynteglo, also known as Lentiglobin, turns out not to have mattered much. The company failed to negotiate an acceptable price with reimbursement gatekeepers and last month said it would wind down operations on the continent.

The US had always wanted to see longer-term data on the gene therapy for beta-thalassemia, evidence that could well have helped the company in its talks with EU payers.  

Others still hoping to convince the FDA include PTC Therapeutics, which has been trying to get its Duchenne muscular dystrophy project Translarna to the US market for almost a decade, having been turned down three times already.

A small study designed to support accelerated approval yielded disappointing results earlier this year, and it seems likely that the regulator will want to see data from an ongoing placebo-controlled trial. That is unlikely to yield results until late 2023 at the earliest, however, meaning that PTC’s wait looks set to continue.  

One of the most curious examples here is Glaxosmithkline’s MMR vaccine Priorix, which protects children against mumps, measles and rubella in one shot, but which has never been filed in the US. This live vaccine was first registered in Germany in 1997 and is authorised in more than 100 countries worldwide.            

Glaxo filed Priorix with the FDA a few weeks back, and approval would make the jab only the second measles-containing vaccine available in the US, where currently Merck’s MMR II is the only option.

Several projects highlighted here seem likely to receive FDA approval at some point, including Gilead's recently acquired hepatitis D treatment Hepcludex and Novartis's cholesterol-lower Leqvio. But should Fibrogen’s US partner, Astrazeneca, decide to walk away from roxadustat it seems likely that the drug will join the small group of products destined never to reach the US market.

https://www.evaluate.com/vantage/articles/news/policy-and-regulation/roxadustat-shows-latest-regulatory-fault-line-split