Therapy focus – Duchenne assets soar in the wake of Exondys 51 approval

The US FDA’s highly controversial approval of Sarepta’s Exondys 51 last month looks to have boosted valuations of clinical Duchenne muscular dystrophy assets. A case in point is the lucrative deal that Sarepta itself paid for European rights to Summit Therapeutics’ ezutromid on Tuesday.

It hardly matters whether the terms of that deal reflect the compound’s unrecognised potential, a possible paediatric disease priority review voucher, or – assuming that a regulatory precedent has been set – the possibility of early filings. A look at the DMD pipeline highlights several companies that could be knock-on beneficiaries (see table below).

The most obvious are PTC Therapeutics, Santhera and the private US firm Marathon Pharmaceuticals. However, while Summit climbed 70%, stock prices of the two quoted companies in this group have surprisingly not moved greatly since the Sarepta/Summit deal, though this likely reflects regulatory uncertainties.

Refuse to file

For instance, PTC holds a conditional EU approval for Translarna, but its application in the US got a refuse-to-file letter. The company is appealing, and hopes to finalise an agreement on a confirmatory study; to complicate matters, its EU conditional approval needs to be renewed annually – this is now overdue – with clearance seemingly also dependent on the design of this same study.

Santhera’s Raxone is under review in the EU, but plans to file in the US were knocked back when the FDA said data from a phase III trial in glucocorticoid-treated patients were necessary, potentially delaying filing by three years. The decision seemed to anticipate approval of Marathon’s deflazacort, which was accepted for priority review in August and given a February 2017 action date.

Deflazacort is a symptomatic therapy, but data from its 196-patient phase III study showed a significant improvement – versus placebo – in muscle strength at 12 weeks. Importantly, it is clear of the weight gain side effect associated with a more commonly used corticosteroid, prednisone.

The fact that it is available in several ex-US markets for autoimmune indications could cause Marathon pricing difficulties; the group’s IP comprises US orphan drug designation and rare paediatric disease status. Patent uncertainties will also dog Sarepta, even as it evolves into the dominant DMD player.

Sarepta is expected shortly to file Exondys 51 in the EU, a move that would undoubtedly escalate its legal battle against Biomarin over exon-skipping patents. Sarepta is appealing against an EU decision to uphold BioMarin’s IP on antisense oligonucleotides directed at exons 51 and 46.

Meanwhile, Biomarin wants to seek a review of a recent Patent Trial and Appeal Board ruling that denied its US composition of matter claims, but upheld method of use ones, on exon 51-skipping antisense oligonucleotides.

Paths diverge

The differing paths already taken by US and EU regulators look to widen next year, with the potential for an EMA OK for Raxone and US approval of deflazacort. Meanwhile, uncertainty remains over PTC’s ability to re-file Translarna in the US and Sarepta’s freedom to commercialise Exondys 51 in the EU.

No other candidates are on the immediate horizon for DMD. But data will come out in the next 12 months from the mid-stage cohort comprising five programmes in phase II and a further four in phase I/II.

The Duchenne muscular dystrophy pipeline
Company Project Amenable subset Status Trial ID Patient # Data 
PTC Therapeutics Translarna Nonsense mutation Approved EU n/a n/a n/a
Sarepta Exondys 51 Exon 51 skipping Approved US NCT02255552 160 Jan 2019
Marathon Deflazacort All  Filed US n/a n/a n/a
Santhera  Raxone  All  Filed EU NCT02814019 266 Jul 2019
Sarepta  SRP-4045/SPR-4053 Exon 45 & 53 skipping Phase III NCT02500381 99 Sep 2019
Italfarmaco Givinostat All  Phase III NCT02851797 213 Jun 2020
Otsuka TAS-205 All  Phase II NCT02752048 33 May 2017
Nippon Shinyaku NS-065 Exon 53 skipping Phase II NCT02740972 16 Dec 2017
Summit/Sarepta Ezutromid All  Phase II NCT02858362 40 Dec 2017
Pfizer Domagrozumab All  Phase II NCT02310763 105 May 2018
Fibrogen Pamrevlumab All  Phase II NCT02606136 22 Jun 2018
Catabasis Edasalonexent All  Phase I/II NCT02439216 30 Dec 2016
Capricor CAP-1002 All  Phase I/II NCT02485938 24 Aug 2017
Daiichi Sankyo DS-5141 All  Phase I/II NCT02667483 6 Sep 2017
Bristol-Myers Squibb Myostatin adnectin All  Phase I/II NCT02515669 40 Oct 2019

The next clinical readout looks to come from a phase I/II of edasalonexent from Catabasis, which given its modest market cap of less than $90m might suddenly find itself at the centre of the DMD investment community’s attention.

Edasalonexent is a small molecule inhibitor of NF-kB. Sarepta has just struck a collaboration with Catabasis to conduct preclinical tests on undisclosed combinations of exon-skipping molecules and NF-kB inhibitors, and it is a fair bet that the deal gives it first dibs on edasalonexent.

The relative absence of big pharma from the DMD pipeline is clearly evident, though Pfizer is the main exception. Its 105-patient study of domagrozumab is large for a phase II in this indication, but the group is using an unconventional measure of the four-stair climb as primary efficacy endpoint, while the more common six-minute walk test is one of many secondary endpoints.

Meanwhile, Biomarin remains the key unknown in DMD; it made a large investment to acquire Prosensa, only to see the FDA reject Kyndrisa in short order. It might not be easy, but re-entering this space is one thing that cannot be ruled out. 

To contact the writer of this story email Robin Davison at or follow @RobinDavison2 on Twitter

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