Trials for JAK inhibitors in ulcerative colitis (UC) have faced, or still are challenged by, recruitment delays as already approved treatments have greater uptake, experts said.

In particular, experts said biologic-naïve patients, usually enrolled along with pretreated patients, are harder to recruit. This, in turn, has led to delays in results readouts. Furthermore, experts highlighted concerns about trials being able to prove adequate efficacy in pretreated patients, which is a more challenging population than treatment-naïve subjects.

As an example of the enrolment hurdles, Gilead Sciences’ Galapagos‘ filgotinib, whilst it has now completed patient accrual for its 1,351-patient Phase IIb/III SELECTION trial (NCT02914522), has data expected in 2020. Gilead expected enrolment completion in 4Q18 as per a 3Q earnings call. But recruitment was completed only in March 2019, according to the ClinicalTrials.gov website. A 250-patient Phase II (NCT03201445) MANTA filgotinib safety study had faced enrollment challenges as well, leading to an inclusion criteria modification to include Crohn’s disease patients, analysts have noted. MANTA was scheduled to complete data collection from the last enrolled patient in June 2019, but has since updated the target to January 2021 and is still enrolling patients, according to ClinicalTrials.gov.

As for AbbVie’s upadacitinib pivotal trials programme — the 844-patient Phase IIb/III U-ACHIEVE (NCT02819635), 462-patient Phase III U-ACCOMPLISH (NCT03653026) and 950-patient Phase III (NCT03006068)— the first two are still recruiting, according to ClinicalTrials.gov, while the third is a long-term efficacy and safety study meant for patients from the Phase IIb/III trial who fit certain criteria.

In terms of competition, experts support the potential of greater JAK1 selectivity with filgotinib and upadacitinib compared to Pfizer’s Xeljanz (tofacitinib)—the only approved JAK inhibitor for ulcerative colitis— but await clinical data to confirm an advantage. JAK inhibitors are a type of medication that functions by inhibiting the activity of one or more of the Janus kinase family of enzymes (JAK1, JAK2, JAK3, TYK2).

Safety issues recently highlighted with Xeljanz by the FDA further add to existing concerns about increased risks of infections and malignancies, which are noted on the drug’s label. Their alleged greater efficacy with better JAK1 selectivity is also yet unproven, experts said. Analysts have focused on Xeljanz’s anaemia risk, which filgotinib’s greater selectivity to JAK1 is supposed to abrogate. This, along with the advantage of an oral formulation and favourable efficacy, is driving analyst expectation for a successful launch in 2021 and peak sales of $800m. Analyst peak sales estimates for upadacitinib are $263m in 2026 in UC and total sales of $690m in UC and Crohn’s disease in 2030. AbbVie, Galapagos and Gilead did not respond to a request for comment.

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Treatment-naïve patients harder to recruit

It has been increasingly difficult in recent years following drug approvals in the UC space to find patients, and especially treatment-naïve patients, willing to participate in trials, said Dr John Marshall, director of the division of gastroenterology at McMaster University, Hamilton, Ontario. Moreover, there is good access to approved therapies in Canada, he added.

Moreover, many Phase III programs are competing for the same UC population, said Dr Gil Melmed, director of inflammatory bowel disease clinical research at Cedars-Sinai Medical Center in Los Angeles. In addition to JAK inhibitors, anti-IL23 antibodies and nonselective JAK inhibitors are also in development for UC, said Melmed. An approval for Johnson & Johnson’s Stelara (ustekinumab), which is expected to have an FDA decision later this year, will further limit the pool of eligible or interested patients for trials, said Melmed. Analysts have noted the impact of trial competition on even smaller companies with early studies like Immunic’s Phase II IMU-838, of which results (NCT03341962) were first expected in 2H20, while they are now expected in 1Q21.

Due to these enrolment challenges, sponsors are looking at other parts of the world where access to anti-TNF drugs is limited, said Melmed and Marshall. As a result, the majority of patients in UC trials are from Eastern European countries and Asia where access to first-line anti-TNF drugs may be problematic, said Dr Stephen Hanauer, professor of medicine at Northwestern University, Chicago. Among the upadacitinib trials, only 137 of 469 trial locations for U-ACHIEVE and 106 of 386 sites for U-ACCOMPLISH are in the US. A TNF inhibitor is a therapeutic that suppresses the physiologic response to tumour necrosis factor, which is part of the inflammatory response.

As UC trials tend to accrue patients that have failed other therapies, it’s more challenging to see an efficacy signal, said Marshall. The SELECTION filgotinib trial enrolled both biologic-naïve and experienced patients, while U-ACHIEVE and U-ACCOMPLISH are enrolling patients that demonstrated an inadequate response or loss of response to conventional therapy but have not failed biologics. Hanauer agreed that investigational JAK inhibitors that are being tested in patients that are least likely to respond — moderate-to-severe UC patients that have failed therapies — will mean a limited response in contrast to those with milder disease and those who are treatment-naïve.

JAK safety concerns and efficacy challenges not eliminated

Xeljanz, which became the first JAK inhibitor approved to treat moderate-to-severe UC in May 2018, has been used as a comparator by analysts in estimations of filgotinib and upadacitinib’s efficacy and uptake potential given their greater selectivity for JAK1. Both drugs are being evaluated in placebo-controlled studies. However, Xeljanz came under the spotlight in July when the FDA issued a safety warning for the 10mg dose used in UC due to an increased risk of blood clots and death. In response to a similar safety warning issued for the 10mg dose in rheumatoid arthritis (RA) earlier this year, UC experts told this news service on 30 May of their concerns on the possibility to exclude Xeljanz’s use in older UC patients at risk even without any official recommendation to do that.

In principle, filgotinib and upadacitinib may have a safety advantage over Xeljanz due to greater specificity for JAK1, but that still needs to be demonstrated, said Marshall and Hanauer. Most data showing greater selectivity toward JAK1 has been demonstrated in preclinical studies so it remains to be seen in the clinic, said Dr Brian Feagan, senior scientific director for Robarts Clinical Trials in London, Ontario, Canada.

Apart from Xeljanz’s risk of embolism and death, experts raised concerns about increased risk of infections like shingles and malignancies associated with JAK inhibitors. JAK inhibitors are known to be viral reactivators and this is a concern with filgotinib and upadacitinib as well, said Dr Michael Epstein, physician of Digestive Disorders Associates in Annapolis, Maryland. The next generation of JAK inhibitors will also likely have this burden, said Feagan.

In contrast, more selective UC agents like Takeda Pharmaceuticals’ Entyvio (vedolizumab) and Stelara have been effective and not had the same risk of systemic infections, said Feagan.

Experts also reserved forecasts for any significant efficacy advantage due to greater selectivity in the absence of detailed data. Gilead/Galapagos has not made the results from the Phase IIb portion of SELECTION filgotinib data public, but said the trial progressed in the Phase III portion following an interim futility analysis which allowed the trial to proceed at both 100mg and 200mg doses, as per a 22 October 2018 press release.

As JAK inhibitors are used at higher doses in IBD — which includes UC and Crohn’s disease — than RA or psoriasis, perhaps any selectivity advantage will fall by the wayside anyway, said Hanauer. Filgotinib has proven efficacy in Crohn’s disease but it is not clear if that means it would work in UC as well because even though both conditions attack the bowel, they are different diseases, said Epstein, pointing to the Xeljanz experience in Crohn’s disease. While approved for use in UC, Xeljanz’s development in Crohn’s disease was discontinued after primary efficacy endpoint measures were not differentiated from placebo in two studies (Panes et al.; Gut. 2017 Jun;66(6):1049-1059).

The biggest advantage remains that these are oral drugs, said Marshall and Epstein. Oral therapies also allow patients to be on intermittent therapy unlike biologics, wherein anti-drug antibodies may make that challenging, said Marshall and Hanauer.

by Manasi Vaidya in New York
Manasi Vaidya is a Senior Reporter for Pharmaceutical Technology parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.