The deal sealed by Dermira yesterday for certain rights to Roche’s lebrikizumab echoes a transaction last year between Leo Pharma and Astrazeneca. That too was over an IL-13 targeting antibody and also saw the smaller partner buy into substantial dermatology indications, most notably atopic dermatitis.
Very strong results from Sanofi/Regeron's Dupixent, which is already on the market in this space, probably cooled these big pharma names to the opportunity; for a smaller company, a thinner slice of the pie can still be attractive. But it is also true that IL-13-targeting antibodies have a chequered clinical history – several have been abandoned – and the 13% drop in Dermira’s share price yesterday suggests that many remain to be convinced.
Despite a sound biological rationale for targeting IL-13 in many allergic or atopic conditions, clinical trials of various antibody approaches have yielded mixed results.
Tralokinumab, the subject of the Leo-Astra deal, failed its first phase III asthma trial earlier this year; lebrikizumab was abandoned by Roche in this respiratory disease after flunking one of two pivotal studies last year. Candidates from Pfizer and Novartis, anrukinzumab and dectrekumab respectively, were abandoned at phase II, while several earlier projects have also been scrapped over the past few years.
Still, atopic dermatitis is a much newer avenue of exploration for these projects. Progress in asthma, a very heterogeneous disease, has arguably been held back by lack of understanding around the most appropriate biomarkers needed to find patients most suited to these therapies, hence the turn to other uses.
Higher and longer
However, another concern for Dermira investors was probably the mixed phase IIa results generated by Roche with lebrikizumab in atopic dermatitis. The Treble study tested three different dosages, only one of which managed to hit the primary endpoint, registering a significant improvement on EASI-50 – a measure of eczema area and severity score.
Dermira believes that by using a loading dose – a strategy now widely employed with these IL-13 antibodies – higher doses and longer treatment durations, the real effectiveness of lebrikizumab will become apparent. This will be tested in a phase IIb trial designed to pin down the optimum regimen, which the company hopes will be once every four weeks.
This would put lebrikizumab at an advantage over Dupixent, which is dosed every two weeks, and possibly tralokinumab; Leo Pharma declined to describe to EP Vantage the dosing regimen being tested in the ongoing pivotal dermatitis programme, although previously two-weekly schedules have been used.
Clearly, lebrikizumab will have to perform strongly on efficacy and safety first. But it is not hard to appreciate why Dermira might have been tempted by the prospect of winning a convenience argument over a drug currently forecast to sell $4bn in atopic dermatitis by 2022.
|Targeting the IL-13 cytokine - selected approaches|
|Product||Company||Therapy area||Dosage||Key trials||Data|
|Dupixent||Sanofi/Regeneron||All||Loading dose then Q2W||Solo 1/2, Chronos (NCT02277743/NCT02277769/NCT02260986)||Published|
|Tralokinumab||AstraZeneca||Respiratory indications||Q2W||Stratos 2 (NCT02194699)||Late 2017|
|Leo Pharma (atopic dermatitis)||Dermatology indications||Not disclosed||Ecztra 1/2 in atopic dermatitis (NCT03131648/NCT03160885)||2020/2019|
|Lebrikizumab||Roche||Interstitial lung diseases (IPF)||Q4W||PII +/- Esbriet (NCT01872689)||Late 2017|
|Dermira||Atopic dermatitis, other indications||Loading dose then Q2W or Q4W||Phase IIb TBC||Late 2018?|
|RPC-4046||Celgene||Esophageal eosinophilia||Weekly tested in PII||TBC||?|
|Abandoned in phase II|
Dermira will pay $80m now and $55m next year for the lebrikizumab rights, as well as milestone payments that could total $1.2bn. It gains rights outside interstitial lung diseases like idiopathic pulmonary fibrosis, which Roche has retained.
The terms are very similar to those paid by Leo, which handed Astrazeneca $115m up front and committed to milestones of $1bn for tralokinumab, although the Danish firm only got dermatology rights. Results from its ongoing pivotal programme are due in a couple of years, putting it substantially ahead of its new US rival – the prospect of being third to market makes those convenience arguments even more important for Dermira to win.
Dupixent of course remains the one to beat, and it remains to be seen whether a different mechanism of action will allow it to retain an efficacy edge. While tralokinumab and lebrikizumab block signalling by binding to IL-13, Dupixent sits in the alpha subunit of the IL-4/IL-13 receptor, inhibiting both pathways. The activities of IL-13 and IL-4 are closely linked, but they also have distinct roles in TH2-mediated atopic and allergic diseases.
The exit of Astrazeneca and now Roche from this space is hardly a vote of confidence. But, assuming these IL-13 antibodies can compete on efficacy and safety, their new smaller owners should be able to carve a niche.