Upcoming events – Crucial data approach on zanubrutinib and filgotinib

Beigene seeks very good data in Waldenström's macroglobulinaemia, while Galapagos aims to extend filgotinib's reach.

Welcome to your weekly digest of approaching regulatory and clinical readouts. Beigene’s zanubrutinib is awaiting approval in China, but the key to cracking the US market is a phase III study reading out in the second half of this year.

This compares the BTK inhibitor against its market-leading rival, Abbvie/J&J’s Imbruvica, in a rare lymphoma known as Waldenström's macroglobulinaemia. The trial enrolled 210 subjects irrespective of therapy line, and as primary endpoint aims to show superiority over Imbruvica in terms of complete (CR) or very good partial (VGPR) remissions.

According to EvaluatePharma’s consensus estimates Waldenström's macroglobulinaemia is set to account for $201m of zanubrutinib’s $1.2bn 2024 sales. Imbruvica, meanwhile, posted $4.5bn in 2018 revenues, $414m of which were in Waldenström's, a use for which it was approved in 2015.

It is important to remember that zanubrutinib is, like Imbruvica, a covalent inhibitor, meaning that it has no potential in relapsed patients with the C481S mutation (EHA 2019 – turnaround puts Arqule in the takeover frame, June 14, 2019). Beigene’s claim is that it is more specific for BTK than Imbruvica, but to prove this it must beat the Abbvie/J&J drug head to head.

To back its case Beigene cites a phase I study in which VGPRs were seen in 41% of zanubrutinib-treated subjects. Imbruvica’s label, meanwhile, cites a VGPR rate of 17% as monotherapy, but a major caveat of this cross-study comparison is that the Imbruvica subjects were on average later-stage.

Zanubrutinib’s phase III trial is powered to show a doubling of the VGPR rate versus Imbruvica. If this can be achieved Beigene might then have a chance to beat Imbruvica in another phase III head-to-head study, in the much bigger use of chronic lymphocytic leukaemia.

Cross-study comparison in Waldenström's macroglobulinaemia 
Project Setting PR VGPR ORR
Zanubrutinib Ph I, 73 1st or 2nd-line subjects 51% 41% 92%
Imbruvica Ph II, 63 2nd-line subjects 51% 11% 62%
Imbruvica Ph III cohort, 31 2nd-line subjects 42% 29% 71%
Source: Beigene announcement & Imbruvica's US label.

Branching out with filgotinib

Much of the attention surrounding Galapagos’s filgotinib has focused on clinical success in rheumatoid arthritis. But later this year the Belgian group will unveil proof of concept data for the Jak inhibitor in the niche disorders cutaneous lupus erythematosus (CLE) and Sjögren’s syndrome.

The indications offer two very distinct opportunities for Galapagos to extend the filgotinib franchise. First to read out could be a 47-patient trial in CLE, a skin condition often associated with the more common systemic lupus erythematosus. Data in Sjögren's, a chronic, inflammatory autoimmune disease characterised by severe dryness of skin, eyes and mouth, ought to appear a few months later.

A dearth of CLE treatments could count in filgotinib’s favour, but Galapagos is not alone in looking at the opportunity. Biogen’s BIIB059 has posted encouraging phase I results and is being tested in a 320-patient phase II trial due to read out by the end of the year. The size of this study is in stark contrast to Galapagos’s efforts: the phase II trial design means that only 15-20 people with CLE are likely to be dosed with filgotinib.

If Galapagos does prevail analysts at Bernstein estimate the potential market opportunity at $500m. So far, though, lupus has proved notoriously tricky to treat.

In Sjögren's syndrome filgotinib’s prospects arguably look slightly brighter. Again, no approved treatment exists, and the unmet need is greater, with estimates of up to four million Sjögren’s patients in the US. Bernstein analysts have put the total market opportunity here at $1bn.

Filgotinib is being tested in a 48-week phase II trial in 152 adults with Sjögren’s, with a primary endpoint of a composite of biologic and patient-reported outcomes. However, this endpoint is not based on any measure recognised by the industry; secondary endpoints include the better-validated ESSDAI and ESSPRI scores.

While the CLE pipeline is relatively thin in Sjögren's there are substantially more projects in R&D many ahead of Galapagos's candidate. Bristol-Myers Squibb has an ongoing phase III trial with its rheumatoid arthritis product Orencia, but results so far have been mixed. Novartis is testing two projects in the disorder, the anti-CD40 MAb iscalimab and the BAFF MAb ianalumab. Both are in phase II.

Despite these challenges Galapagos is sensibly trying to differentiate its late-to-the-party drug from the other Jak inhibitors. While history has shown that success in lupus and its related conditions is elusive, if filgotinib does triumph it would provide very welcome revenue for both Galapagos and its partner Gilead.

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