Big hitters eye Sjögren’s syndrome white space

Orencia’s late-stage failure in Sjögren’s has dashed hopes of a therapy soon, but the mid-stage pipeline is crowded, with Novartis, Glaxosmithkline and Galapagos all interested.

Sjögren’s syndrome might not be the best-known autoimmune disease out there, but the potential market is large enough to have attracted plenty of biopharma’s big players.

The likes of Novartis and Glaxosmithkline have no doubt been tempted by the fact there are no approved therapies for the disorder. But the causes of the disease are not well understood, which could make drug development tricky. And a look at the pipeline shows a wide variety of mechanisms being tested, not all of which can be expected to succeed.

Sjögren’s syndrome clinical pipeline
Project Company Description Trial details
Phase III
Orencia Bristol-Myers Squibb Selective T-cell co-stimulation modulator NCT02915159, failed 
Phase II 
RSLV-132 Resolve Therapeutics Interferon alpha pathway inhibitor NCT03247686, reported at Eular 2019
Filgotinib + lanraplenib (GS-9876) + tirabrutinib (GS-4059) Galapagos/Gilead/Ono Jak1 inhibitor/Syk inhibitor/BTK inhibitor NCT03100942, data due H2 2019
Benlysta Glaxosmithkline Anti-BAFF MAb NCT02631538, primary completion Aug 2019
INCB50465/parsaclisib Incyte PI3K delta inhibitor NCT03627065, primary completion Aug 2019
VAY736/ianalumab Novartis Anti-BAFF MAb NCT02962895, primary completion Jun 2020
CFZ533/iscalimab Novartis Anti-CD40 MAb NCT02291029, completed                      NCT03905525, starting Q3 2019
Phase I
LY3090106/tibulizumab Lilly Anti-BAFF & IL-17 bispecific NCT02614716, completed
VIB7734 Viela Bio Anti-ILT 7 MAb NCT03817424, primary completion Sep 2019
Source: EvaluatePharma, Bernstein note June 3, 2019.

One approach, at least, does not seem to work: Bristol-Myers Squibb’s rheumatoid arthritis drug Orencia failed to show a benefit on clinical symptoms in a phase III trial in Sjögren’s, which was presented at last week’s Eular meeting in Madrid.

Still, plenty of other projects are still in play. At the same meeting, Resolve Therapeutics said it had seen enough with its mid-stage contender, RSLV-132, to press into phase III.

Galapagos could be the next to report in Sjögren’s, with results from a phase II trial of its Jak inhibitor filgotinib expected in the second half of this year (Upcoming events – Crucial data approach on zanubrutinib and filgotinib, June 14, 2019).

Other projects with phase II data due soon include Glaxosmithkline’s lupus therapy Benlysta, which is being tested in Sjögren’s in combination with Rituxan, and Incyte’s parsaclisib.

Drying out

Sjögren’s syndrome involves the autoimmune destruction of patients’ saliva and tear glands, leading to the disease’s characteristic symptoms of dry mouth and dry eyes. Patients can also suffer systemic symptoms including fatigue and chronic pain. There are no disease-modifying therapies, and patients are managed largely using eye drops and painkillers.

The disorder affects around four million patients in the US, and the market could be worth as much as $1bn, Bernstein analysts estimate.

However, diagnosing the disease can be difficult as Sjögren’s is associated with a broad range of symptoms, and also because other autoimmune diseases are often present – around 20% of Sjögren’s patients also have rheumatoid arthritis, according to Bernstein.

Many of the approaches outlined above aim to damp down the immune system, including Galapagos’s filgotinib, which is primarily being developed for rheumatoid arthritis. There do not appear to be any other Jak inhibitors in active trials for Sjögren’s; however, a phase II study of Pfizer’s Xeljanz in dry eye was previously withdrawn.

One worry with the Jak inhibitors is their side effects, and in Sjögren’s their link with malignancies is particularly troubling, as the disease is associated with an increased incidence of lymphoma.

Other Sjögren’s hopefuls are taking a different tack, the most common of which is inhibiting B-cell activating factor (BAFF) – the rationale being that B cells are thought to play an important role in the disorder.

The biggest ongoing trial, due to complete next year, involves Novartis’s VAY736. An earlier phase II study only showed a trend towards improvement on the primary endpoint, the ESSDAI score. However, this was a small, 27-patient trial, and Novartis must have thought the data encouraging enough to continue.

The Swiss company has two shots at Sjögren’s: the other, iscalimab, targets CD40, which has a role in T-cell activation. Still, with a second large phase II study yet to begin it will be a while until full data are available.

Meanwhile, Incyte’s parsaclisib is a PI3K inhibitor, a mechanism more commonly associated with cancer therapies; indeed, parsaclisib is also being tested in lymphomas and myelofibrosis.

Not a dry eye in the house

The private company Resolve Therapeutics is looking at another mechanism again with its contender, RSLV-132.

The group’s chief executive, Jim Posada, told Vantage: “Most of other drugs in development for Sjögren’s are pretty potent immunosuppressants. Our approach is completely different: we’re trying to remove inflammatory nucleic acids from the circulation and prevent the activation of the immune system in the first place.”

The company presented data at Eular last week from a 28-patient phase II trial, testing RSLV-132 dosed at 10mg/kg versus placebo.

The study primarily evaluated changes in expression levels of inflammatory markers in patients’ blood, but also had various clinical measures as secondary endpoints. The company claimed to have found a significant improvement in PRO-F, a measure of fatigue, as well as a clinically meaningful improvement in another measure of Sjögren’s severity, the ESSPRI score, which did not hit significance.

Mr Posada insisted that he had not expected to see a significant benefit on these outcomes in such a small trial. Resolve is encouraged enough to push into a pivotal study, in which ESSPRI will be the primary endpoint – the chief exec believes that this score is a more accurate measure of Sjögren’s than the commonly used ESSDAI.

Other details have not been hammered out, but the trial will likely enrol 150-200 patients, and could also test a lower dose of RSLV-132 alongside 10mg/kg, Mr Posada said.

Tinkering with dosing at this late stage seems risky. Furthermore, Resolve will not start its second phase III until it has finished the first one, to allow it to select the most effective dose, the chief exec added.

He conceded that this would push back the timelines for Resolve’s pivotal programme, but argued that enrolment in the studies would still be quick as the company would include all comers, rather than focusing on more severely affected patients as other trials have done.

Still, Resolve is already up against some fearsome competitors in Sjögren’s. Any delay will only make things tougher for the smaller group.

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