Spotlight – scratching the surface of the urticaria pipeline

Catalysts from several late-stage projects including those from Astrazeneca, Sanofi, Allakos and Celldex aim to shake up the market.

Novartis and Roche’s Xolair has had a monopoly on the chronic spontaneous urticaria market for some time, but this is expected to change this year with the approval of Sanofi and Regeneron’s Dupixent for the skin disorder. 

And several late-stage projects are due to report clinical data in the next six to 12 months, including BTK inhibitors from Novartis and Sanofi. Amgen, Astrazeneca and the smaller players Allakos and Celldex are all also vying for a piece of the market. 

Xolair sets the bar 

Urticaria is an inflammatory skin condition characterised by itchy hives and swelling. First-line treatment for chronic spontaneous urticaria (CSU) is H1-antihistamines but many patients remain symptomatic even on treatment.  

Novartis and Roche’s Xolair was approved in 2014 as an add-on therapy to antihistamines but responses can be inconsistent and the anti-IgE antibody also comes with a black boxed warning of anaphylaxis. 

Xolair is also approved for moderate to severe asthma and nasal polyps and racked up $3.7bn in total sales last year. However, there are several biosimilars to the drug in development, and total 2028 forecasts sit at $1.4bn according to Evaluate Pharma consensus.

Berenberg estimates that CSU could potentially become a $2bn market in the US, and a $7-8bn market worldwide, though they gave no date for when this might happen.

Another option is nearing, with Sanofi and Regeneron’s Dupixent expected to gain FDA approval in CSU by its October Pdufa date. In terms of efficacy the IgG4 antibody, which inhibits IL-4 and IL-13 signalling, looks as good as Xolair’s lower dose. Also, currently without a black boxed warning Dupixent could have the edge on safety. 

Hoping to widen the patient pool Sanofi and Regeneron had tested Dupixent in CSU patients refractory to Xolair, but the study failed

Here comes BTK 

Given the impending threat from Xolair biosimilars, Novartis has a BTK inhibitor called remibrutininb in phase 3 and the convenience of its oral delivery sets it apart from Dupixent. Two phase 3 studies, Remix-1 and Remix-2, are expected to report 12-week data in the second half of the year. Final 52-week data and submission is expected next year. 

Efficacy in phase 2b puts the project on a par with Xolair and Dupixent, with the caveat about cross-trial comparisons. Safety in the phase 2b study also looks manageable, with 2.6% of patients discontinuing remibrutininb due to adverse events, versus none on placebo. The most common adverse events included headache, nausea, diarrhoea and respiratory tract infections. 

Cross-trial comparison of urticaria projects
  Xolair* (Roche/Novartis) Dupixent (Sanofi/Regeneron) Remibrutinib (Novartis)
  Asteria I/Asteria II Liberty Cupid study A  Ph2b
Dose 150mg 300mg 200 or 300mg Various
Placebo-adjusted reduction in UAS7 (% points)  22/24 40/41 25 25-40
Time point 12wk 24wk 12wk
Regimen SubQ every 4 weeks SubQ every 2 weeks Oral, once or twice daily
*Xolair is FDA approved as 150 or 300 mg subcutaneously every 4 weeks. UAS7: weekly urticaria activity score. All tested as add-on therapies to H1-antihistamines. Source: analyst notes, company releases, published papers.

Safety appears to have scuppered a different BTK inhibitor in CSU. Roche’s fenebrutinib showed efficacy but also grade 3 liver toxicities in phase 2

Another BTK inhibitor, Sanofi’s rilzabrutinib, is still in play, with phase 2 data due by the end of the third quarter. The RileCSU study includes patients who are Xolair naïve or incomplete responders to Xolair and a win in the latter population would be needed to set rilzabrutinib apart from competitors. However, a previous failure in pemphigus, an autoimmune skin condition that causes blisters and sores, has dampened sentiment. 

Getting in on the act 

BTK blockade aside, there are several other mechanisms being tested. Amgen and Astra’s Tezspire is a thymic stromal lymphopoietin (TSLP) blocker and is already approved as an add-on therapy for severe asthma. The action of TSLP is said to be upstream of IL-4 and IL-13, which Dupixent targets. 

Tezspire’s phase 2 Inception trial is complete and data are expected soon. The study includes a Xolair comparator arm and there are also separate Tezspire arms to include and exclude patients who have previously been treated with Xolair. The primary endpoint is the change from baseline in urticaria activity score over seven days (UAS7) at week 16. 

Also, Allakos is testing its siglec-8 antibody lirentelimab. Siglec-8 is highly expressed on eosinophils, but it is uncertain whether eosinophil depletion is clinically meaningful, as is evident from two previous clinical failures in rare inflammatory gastrointestinal disorders

Lirentelimab's phase 2 CSU study, Maverick, is due to report in the second half and includes patients who have previously been on Xolair. 

Late and mid-stage chronic spontaneous urticaria pipeline
Product Company Mechanism  RoA Upcoming catalyst
Dupixent Sanofi/Regeneron IL-13 antagonist; IL-4 alpha antagonist SC Pdufa 22 Oct 2023
Phase 3
Remibrutinib Novartis BTK inhibitor Oral Primary 12wk data from Remix-1 & Remix-2 due H2 2023; final 52wk data & submission 2024
Phase 2
Tezspire Amgen/Astrazeneca Thymic stromal lymphopoietin antibody SC Inception, data mid-2023
Rilzabrutinib Sanofi BTK inhibitor Oral RileCSU, data Q3 2023
Lirentelimab (AK002) Allakos Siglec-8 antibody SC Maverick, topline data H2 2023 
Barzolvolimab (CDX-0159) Celldex Therapeutics Proto-oncogene c-Kit antibody SC NCT05368285, data YE
UB-221 United Biopharma (private) Immunoglobulin E antibody IV infusion NCT05298215, taking place in Taiwan, PCD: Dec 2023
TAS5315 Otsuka Holdings (Taiho) BTK inhibitor Oral NCT05335499, PCD Mar 2024
Sources: company releases, analyst notes,

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