Therapy focus – Atopic dermatitis competition Jaks up

The launch of Sanofi and Regeneron’s atopic dermatitis therapy Dupixent has been slower than some had expected, but hopes are still high for the product. However, several mid-stage assets could start putting some unwelcome pressure on the anti-IL-4 & IL-13 MAb in the not-too-distant future (see table below).

One of these potential rivals is Abbvie’s Jak inhibitor upadacitinib, which last week posted phase IIb data that were impressive enough to hit Regeneron’s share price. But thrombotic events are a worry with Jaks, and upadacitinib has not escaped these issues – this could throw a spanner in the works for Abbvie and play in Sanofi and Regeneron’s favour.

Until Dupixent’s approval in March there were few options available for the more severe end of the atopic dermatitis spectrum, which explains the enthusiasm from the sellside. Still, the product has a lot of catching up to do to meet its $181m sales forecast this year, with second-quarter revenues of €26m ($31m) falling short of analyst expectations and leaving it needing to ramp up significantly in the second half. 

Top five eczema/dermatitis products in 2022
Indication sales ($m)
Product Company Mechanism Delivery 2016 2018 2020 2022
Dupixent Sanofi Anti-IL-4 & IL-13 MAb Injected - 620 2,256 3,625
Eucrisa Pfizer PDE4 inhibitor Topical - 264 720 1,118
Bepanthen Bayer Vitamin B5 Topical 400 428 472 496
Temovate GlaxoSmithKline Corticosteroid Topical 102 95 95 95
Cormax Akorn Corticosteroid Topical 70 49 48 47
Source: EvaluatePharma.

Upadacitinib is being tested in a similar population to Dupixent’s approved indication: patients with moderate to severe disease who have an inadequate response to topical steroids. If it can sidestep the safety issues it has a chance to grab a chunk of this market.

There are not too many late-stage candidates to challenge Dupixent in the near term: the only novel projects in phase III, according to an EP Vantage analysis, are the similarly acting anti-IL-13 MAb tralokinumab – which Astrazeneca licensed to Leo Pharma in dermatology indications – Amorepacific’s transient receptor potential vanilloid (TRPV) 1 antagonist PAC-14028, and Japan Tobacco's topical Jak inhibitor JTE-052, which is in trials in Japan.

However there are nine active projects in phase II. Lilly's Olumiant, which has been knocked back by the FDA in rheumatoid arthritis, has just posted positive phase II results, but only at the higher dose studied. Lilly says it plans to start phase III development in atopic dermatitis later this year.

Atopic dermatitis candidates in active clinical trials
Project Company Description Enrolment Trial ID Primary completion date
Phase III
PAC-14028 Amorepacific TRPV 1 antagonist 240 NCT02965118 Aug 2017
Tralokinumab Astrazeneca/Leo Pharma Anti-IL-13 MAb 780/780 NCT03160885/NCT03131648 Nov 2019/Feb 2020
JTE-052 Japan Tobacco/Torii Pharmaceutical Topical Jak inhibitor 150/330 JapicCTI-173554/JapicCTI-173555 Unknown
Phase II
ABT-494/upadacitinib  Abbvie Jak 1 inhibitor 167 NCT02925117 Reported
Olumiant Lilly/Incyte Jak 1& 2 inhibitor 124 NCT02576938 Reported
Lebrikizumab Dermira Anti-IL-13 MAb N/A N/A Phase IIb to start
INCB018424 Phosphate Cream Incyte Topical Jak 1 & 2 inhibitor 300 NCT03011892 Jul 2017
DMT210 Dermata Therapeutics GPCR antagonist 25 NCT02949960 Aug 2017
FURESTEM-AD Kang Stem Biotech Stem cell therapy 206 NCT03269773 Dec 2017
ALX-101 Ralexar Therapeutics LXR agonist 203 NCT03175354 Dec 2017
Cosentyx Novartis Anti-IL-17 MAb 44 NCT02594098 Apr 2018
Nemolizumab Chugai Pharmaceutical/Roche Anti-IL-31 MAb 250 NCT03100344 Jun 2018
Source: clinicaltrials.gov; EvaluatePharma.

Another project no longer in the hands of big pharma is the anti-IL-13 MAb lebrikizumab, developed by Roche but licensed to Dermira for dermatology indications. A Roche-sponsored study is listed as completed, and Dermira has said it plans to start a phase IIb trial in the near future.

It is interesting that both Astra and Roche have opted to leave this sector – this might have something to do with failures with both lebrikizumab and tralokinumab in asthma, an indication where Dupixent is still active (Regeneron and Sanofi breathe easier on Dupixent, September 11, 2017). 

Or perhaps they want to avoid a fight with Dupixent, which by then will have had plenty of time to establish itself. Smaller players, meanwhile, might believe that they can still find a relatively lucrative niche.

Risk-benefit

However, Abbvie is unlikely to be satisfied with upadacitinib being an also-ran, even in one of its follow-on indications. Expectations for the project, also known as ABT-494, in atopic dermatitis are low; its entire $1.2bn 2022 EvaluatePharma sellside consensus forecast comes from its lead indication, rheumatoid arthritis.

This could change after the Jak inhibitor posted a phase IIb win last week. The trial met its primary endpoint of mean percentage change in eczema area and severity index (EASI) score at 16 weeks at all doses studied, with a clear dose response.

The data appear to put the higher doses of upadacitinib in line with Dupixent in terms of efficacy, although the usual caveats about across-trial comparisons apply.

Upadacitinib vs Dupixent
Upadacitinib phase IIb Phase III – Solo 1  Phase III – Solo 2
Placebo 7.5mg  15mg  30mg Placebo Dupixent every other week Placebo Dupixent every other week
# of patients 41 42 42 42 224 224 236 233
Mean percentage change in EASI score† 23% 39%*** 62%*  74%* 38% 72%* 31% 67%*
IGA score of 0 or 1‡ 2% 14%*** 31%*  50%* 10% 38%* 8% 38%*
†Primary endpoint in upadacitinib trial; ‡Primary endpoint in Solo 1 & 2: proportion of patients with both IGA 0-1 and a reduction from baseline of ≥2 points at week 16; *p<0.001 **p<0.01 ***p<0.05; Source: Leerink note September 7, 2017.

Abbvie will advance upadacitinib into phase III studies in atopic dermatitis in 2018. However, safety will be closely watched, following concerns about thrombotic events with other Jak inhibitors including Lilly’s Olumiant and Pfizer’s Xeljanz (Olumiant clot signal echoes Xeljanz experience, July 26, 2017). 

These did not appear to be a problem with upadacitinib in the atopic dermatitis trial: according to Abbvie there were no new safety signals and no cases of pulmonary embolism or deep vein thrombosis.

However, this week the company reported two deaths in a phase III trial in RA, Select-Beyond: one due to an unknown cause, and the other due to heart failure presumed related to pulmonary embolism. There was also a non-fatal case of pulmonary embolism, but no episodes of deep vein thrombosis. Its first pivotal RA study, Select-Next, did not raise any serious safety concerns and Abbvie maintains that the rate of pulmonary embolism seen with upadacitinib is consistent with the background rate in the RA patient population. But the issue will no doubt be closely watched in the several ongoing phase III RA trials, as well as the pivotal atopic dermatitis study.

Whatever happens with upadacitinib, the potential seen in atopic dermatitis means other rivals will emerge. Sanofi in particular is heavily reliant on Dupixent; the product’s net present value accounts for 16% of the French group’s market cap.

Last week’s wobble – when Regeneron’s shares fell 6% on the upadacitinib data – shows just how important it is that Dupixent delivers. With so much at stake, the companies will hope that competition holds off for a little longer.

Project Study Trial ID Data
Upadacitinib Phase IIb trial in atopic dermatitis NCT02925117 Reported
Upadacitinib Select-Next (RA) NCT02675426 Reported
Upadacitinib Select-Beyond (RA) NCT02706847 Reported
Upadacitinib Select-Compare (RA) NCT02629159 Primary completion Aug 2017
Upadacitinib Select-Monotherapy (RA) NCT02706951 Primary completion Oct 2017
Upadacitinib Select-Early (RA) NCT02706873 Primary completion Jul 2018
Upadacitinib Select-Choice (RA) NCT03086343 Primary completion Jul 2019

To contact the writer of this story email Madeleine Armstrong or Edwin Elmhirst in London at news@epvantage.com or follow @ByMadeleineA or @EdwinElmhirst on Twitter

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