Initial thoughts from DDW 2022: IBD therapies
What's new, what's hot and what's falling flat in IBD therapies
The IBD therapeutic landscape is shifting fast (read my latest post here).
But not everything is turning out as expected. A number of key data from exciting new molecules was presented, along with helpful additional controlled observations with existing drugs.
Let’s take an initial look at highlights from DDW 2022.
Etrasimod for UC - ELEVATE (phase 3)
Etrasimod is an oral selective S1p1, S1p4 and S1p5 modulator.
All key primary and secondary outcomes were met in the phase 3 trial programme. This was a treat-through study design, somewhat unusual in IBD where most studies re-randomise responders after induction.
Clinical remission was achieved at week 12 in 27.0% of patients taking etrasimod 2mg vs 7.4% on placebo (delta 19.8%) and at week 52 this rose to 26.6% vs 8.1% (delta 25.4%). The rates of mucosal healing at week 52 were 26.6% in the etrasimod group versus 8.1% placebo. The safety profile was as expected for this class, with 4 patients stopping due to bradycardia.
Etrasimod was developed by Arena pharmaceuticals, who were acquired by Pfizer earlier this year.
Mirikizumab for UC - LUCENT-1 (phase 3)
Mirikizumab is a humanised IgG4 antibody from Eli Lily that binds to the p19 subunit of IL-23.
The induction data for mirikizumab in UC met key endpoints demonstrating superiority over placebo at week 12 for clinical response, clinical remission, endoscopic remission and histologic-endoscopic mucosal improvement. Of note, in bio-experienced patients there was a significant delta in clinical response over placebo, but not with clinical remission. A novel bowel urgency score was included in this study.
The safety profile of the p19 inhibitor class continues to look excellent.
Guselkumab for Crohn’s disease - GALAXI (phase 2)
Guselkumab is a humanised IgG1 antibody from Janssen targeting the p19 subunit of IL-23.
The maintenance data of the GALAXI study in Crohn’s disease were presented. Guselkumab demonstrated high rates of clinical and endoscopic response and remission at week 48 with no concerning safety signals. There was no clear dose response in this phase 2 study. Ustekinumab, which was included as a reference arm, also demonstrated high rates of clinical and endoscopic response at week 48.
Guselkumab (Tremfya) continues clinical development with an ambitious phase 3 programme.
The SPARE study
Withdrawal of infliximab or immunomodulator in patients on combination therapy.
Stopping of infliximab resulted in a significantly increased number of flares versus stopping of immunomodulator or continuing with combo therapy over 2 years follow-up. However, nearly all patients rapidly regained remission on restarting infliximab with no observable increase in immunogenicity. The mean time in remission was not significantly different between the three groups.
Meaningful predictors of relapse were:
withdrawal of infliximab
young age at diagnosis (<17 years)
faecal calprotectin >300mcg/g at withdrawal
Note this patient population had stable disease in long-term remission on combo therapy.
VEGA - combination therapy in UC (phase 2)
VEGA is the first controlled trial combining two biologics in IBD.
Golimumab (anti-TNF) and guselkumab (anti-p19) used in combination were compared with either therapy alone. The primary outcome of clinical response at week 12 was achieved by 83.1% on combination therapy, 74.6% on guselkumab and 61.1% on golimumab. Combo therapy was significantly better than either monotherapy at clinical remission and endoscopic improvement at week 12. No concerning safety signals were observed during induction.
The longer term outcomes are eagerly awaited.
LATTICE - Deucravacitinib in UC (phase 2)
Duecravacitinib is an oral small molecule from BMS targeting TYK2.
The induction data at week 12 did not meet the primary endpoint of clinical remission comparing 6mg twice daily and placebo (14.8% versus 16.3%). Endoscopic improvement was seen in 19.3% of patients taking deucravacitinib versus 27.9% taking placebo.
TYK2 remains an exciting potential target given strong genetic and mechanistic data supporting a role in IBD pathogenesis.
IDEAL - PN-943 in UC (phase 2)
This is an orally active anti-a4b7 integrin molecule (the same target as vedolizumab) from Protagonist.
This study did not demonstrate evidence of efficacy of this molecule at week 12.
EXPLORER - adalimumab + vedolizumab + methotrexate in Crohn’s disease
Another interesting combination approach, but difficult to interpret with no control arm.
This study examined patients with high-risk Crohn’s disease. 34.5% of all enrolled participants and 42.2% of observed cases met the primary endpoint of endoscopic remission at week 26. Clinical remission were achieved in 61.8% at week 10 and 54.5% at week 26.
Upadacitinib in ulcerative colitis
Upadacitinib is an oral selective JAK1 inhibitor from Abbvie.
Two post-hoc analyses from the phase 3 upadacitinib programme were presented. Similar to other drugs in this class the rapidity of onset is impressively fast with reduction in stool frequency by day 1 and both abdominal pain and bowel urgency by day 3.
Extended induction to 16 weeks of 45mg upadacinitib once daily was beneficial in almost half of patients who failed to achieve clinical response at week 8.
Upadacitinib (Rinvoq) has just this week received EMA approval for UC (press release).
ENTERPRET trial of vedolizumab in UC
This study examined the benefit of vedolizumab dose escalation in patients with high drug clearance during induction in UC.
Drug levels were measured at Patients who had drug levels of 30-50 were given twice the normal dose (300mg every 4 weeks). Thos how had drug levels of <30 were given four times the normal dose (600mg every 4 weeks). The primary endpoint was endoscopic mucosal healing at week 30. There was no difference in the different treatment arms.
Vedolizumab in an effective drug in UC. These data suggest that dose escalation is of no value in patients who have high drug clearance and poor initial response.
What are my initial thoughts about these new data?
Etrasimod for UC and combination therapy in both UC and Crohn’s disease. Upadacitanib continues to look like a highly effective molecule which just yesterday received EMA approval in UC.
Mirakizumab looks solid in UC, although there are positioning questions given the data in bio-experienced patients. Guselkumab needs the phase 3 readouts to determine positioning versus ustekinumab. Deucravacitinib data are disappointing - this molecule will be explored at a high dose and other TYK2 inhibitors are in development.
The promise of combination therapy for IBD
Combination therapy continues to look like the most exciting avenue to break the therapeutic ceiling in IBD.
I look forward to ambitious studies targeting multiple inflammatory pathways - using both new molecules (eg anti-p19 and JAK1 inhibitors) and biosimilars (eg anti-TNF and anti-p40). We need data on efficacy and safety for induction and maintenance - in early severe disease and late refractory disease.
Combining for induction with monotherapy for maintenance is an attractive strategy.
And finally …
There was an emotional moment at the end of the last clinical trials session. An impromptu standing ovation for Bill Sandborn as he gave his last academic talk. He is now president and chief medical officer at Ventyx biosciences.
Good luck Bill.