Being private, Leo Pharma has managed to keep tralokinumab somewhat under wraps, making it an unknown in the Sanofi/Regeneron-dominated dermatitis space. When results of three pivotal studies of the anti-IL-13 MAb were toplined late last year, the lack of actual data prompted suspicions that they were less than knockout. So it has proved.
Efficacy data have now been released, and though the endpoints were hit the figures put tralo some way behind the competition. Indeed, on current clinical evidence, Pfizer’s Jak1 inhibitor abrocitinib is the one to beat.
The Ecztra-1 and 2 trials, comparing tralokinumbab with placebo, had twin endpoints: investigator global assessment (IGA) scores of 0 or 1, indicating clear or almost clear skin; and EASI-75, representing a reduction in eczema area and severity index of at least 75%. Ecztra-3 had the same endpoints, but active treatment and placebo were administered alongside steroids. Results were presented at the virtual annual meeting of the American Academy of Dermatology.
Comparing data from different trials is not ideal because of variables in design and severity of patients enrolled – as Kim Kjøller, Leo Pharma's executive vice-president of R&D pointed out to Evaluate Vantage. Nevertheless this is probably what doctors and payers will do, and the magnitude of the placebo-adjusted benefits on these endpoints suggests that tralokinumab has been outplayed by both Lilly’s lebrikizumab, which is also in phase III, and Sanofi/Regeneron’s blockbuster Dupixent.
Dupixent became the biggest-selling eczema drug in 2018, and is forecast to remain in this position until at least 2026; when sales are forecast to reach $5.8bn, according to sellside data compiled by EvaluatePharma.
And despite shareholders’ rapturous response to lebrikizumab phase IIb data earlier this year, the sellside appears to consider the product an also-ran, with revenue forecasts hovering at $140m for its fourth year on the market. This presumably reflects the difficulty of competing with Dupixent, though this clearly did not bother Lilly when it acquired the drug’s originator, Dermira, for $1.1bn earlier this year (Lilly jumps the gun with Dermira deal, January 10, 2020).
The real threat?
The other obvious conclusion from the chart above is that Pfizer’s abrocitinib is doing extremely well on efficacy – this could be down to its completely different mechanism. The agent inhibits Jak1, where tralo and lebri hit IL-13; Dupixent is slightly different in that it binds to the receptors for IL-13 and IL-4.
Moreover, abrocitinib is administered as two 100mg pills taken together once daily rather than a fortnightly subcutaneous jab like the IL-13-targeting therapies.
Abrocitinib’s Achilles heel is safety. The pivotal Jade-Mono-1 and 2 trials showed respective rates of 14% and 20% for nausea and 7% and 10% for headache for the 200mg dose, and there were signs of increased risk of thrombocytopenia and lipid disorders. Fortunately there was no pulmonary embolism, deep vein thrombosis, major cardiac events or malignancy – the main concerns for the Jak class.
But the Jade-mono trials read out at the three-month point where all the other trials lasted four; this has left unanswered questions around toxicity for longer-term use.
But Pfizer is deadly serious about taking on Dupixent, and has resorted to high stakes gamble of head-to-head trials. Toplining Jade-Compare, Pfizer stated that abrocitinib beat Dupixent on itching, but notably made no such claim on the co-primary endpoints of IGA 0 or 1 and Easi-75. Full data, and an FDA filing, should come this year.
Pfizer’s Jak could have a chance at slicing off a chunk of Dupixent’s sales but is unlikely to replace it as the bestseller unless the full Jade-Compare data do show a surprise superiority claim.
Leo Pharma’s tralokinumab would appear to have a less golden future. Mr Kjøller says that the drug could become the second biologic to treat adults with moderate-to-severe eczema, and the first biologic available to specifically neutralise IL-13 – a fair point, since it is ahead of Lilly’s lebrikizumab. He also suggests that tralo could offer a treatment option for patients whose disease is uncontrolled by, or who cannot tolerate, other therapies, suggesting that this could be a post-Dupixent treatment.
In its favour is a clean safety profile – there was little meaningful difference in adverse event rates between drug and placebo in the pivotal Ecztra trials. But this comes at the expense of efficacy, meaning that it will struggle to make a mark in dermatitis, particularly as it offers no convenience advantage over the market leader.
Perhaps Leo has a sales strategy that will allow it to make the most of its MAb should the asset gain approval. But any dream of displacing Dupixent, or even offering meaningful competition, has to have dissolved in the face of the Ecztra data.