Given anifrolumab’s failure in its first pivotal trial last year, and bearing in mind the poor track record of projects targeting lupus, expectations for the asset’s second phase III study, Tulip-2, must have been low. Yet today anifrolumab’s maker, Astrazeneca, heralded Tulip-2 a success.
With no numerical data to go on yet it is impossible to gauge the importance of the result, or of the chances of a filing based on just one successful pivotal trial. But it is clear that the positive hit owes much to Astra’s decision to overhaul Tulip-2 on the basis of what it had seen in Tulip-1, the trial that had failed.
Initially both pivotal studies had similar designs, testing as primary measures the proportion of patients achieving an SLE responder index score of 4 (SRI-4) or greater at week 52, versus standard of care. Tulip-1 tested 150mg or 300mg of anifrolumab, while 2 looked at just 300mg.
However, a year ago Tulip-1 failed, and Astra quietly set about overhauling the design of Tulip-2. According to the second study’s clinicaltrials.gov entry all the endpoints were amended – most importantly the primary, which was changed from SRI-4 to BICLA, a different measure of disease severity.
“The BICLA was chosen as the primary endpoint for Tulip-2 following a full evaluation of the previous phase III trial, which did not meet its primary endpoint of SRI-4,” an Astra spokesperson told Vantage today.
BICLA (British Isles Lupus Assessment Group-based Composite Lupus Assessment) requires only partial improvement to be seen but in all organs, whereas an SRI change will be registered only if there is full improvement in some lupus manifestations, but not necessarily in all organs. SRI is thought by some to indicate a targeted system response, while BICLA will show overall patient improvement.
|Study||Subjects||Design||Primary endpoint||Trial ID||Result|
|Tulip-1||460||150mg or 300mg q 4 weeks, vs placebo||SRI-4 response at 52 weeks||NCT02446912||Fail|
|Tulip-2||373||300mg q 4 weeks, vs placebo||BICLA response at 52 weeks||NCT02446899||Success|
What is still not known is whether BICLA is an approvable endpoint. Glaxosmithkline’s Benlysta, the only recently greelit lupus drug, got the thumbs-up on the basis of an improvement in 52-week SRI-4, which is presumably why Astra had initially looked at this measure; the approach was also backed by a mixed success in phase II.
However, US FDA guidance for developing lupus drugs does not mention BICLA specifically; EU guidance suggests that either SRI or BICLA is an acceptable endpoint. Astra said BICLA was a “more appropriate” measure to assess anifrolumab in Tulip-2.
Anifrolumab has a novel mechanism of action, binding to interferon type I receptors to downregulate cytokines thought to induce autoimmune response. The thinking is based on case reports of lupus appearing after interferon-α therapy, and findings that interferon-regulated gene expression is increased in the disease.
“Both the SRI and the BICLA are widely used for assessing disease activity,” the spokesperson said. “We will review the full dataset and explore pathways to bring this potential new treatment to patients.”
It is not clear whether the hit in Tulip-2 plus post-hoc analyses of Tulip-1 will suffice for a US filing, especially as the full Tulip-1 data have not been published. It is possible that Astra might have to run a third US phase III trial, but right now this represents the bear case.
It is fair to say that Benlysta has disappointed commercially, but it is still expected by the sellside to hit blockbuster revenues in 2023. The path is not straightforward, but anifrolumab now has a shot at becoming the second lupus approval of the modern pharmaceutical age.