What is the future of inflammatory bowel disease (IBD) treatment?

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Inflammatory bowel disease (IBD) is often the result of an overactive immune system that causes severe tummy pain and diarrhea. While there are quite a few treatments in the market to treat IBD, patients face a number of unmet needs and managing symptoms can still be a struggle. New drugs aim to address these concerns but how promising are they?

How does IBD manifest in patients?

The main types of IBD are Crohn’s disease and ulcerative colitis. Ulcerative colitis occurs when the colon in the intestine becomes inflamed causing symptoms like diarrhea, rectal bleeding, and stomach cramps. With an incidence of around nine to 20 cases per 100,000 people every year, patients who don’t respond well to anti-inflammatory drugs have unmet needs. Similarly, people with Crohn’s disease, a condition where the gut becomes inflamed, have unmet needs too, and the prevalence is estimated between 2.4 and 3.1 million in the U.S.

Inflammation is typically due to cytokines that are released in the gut that go on to damage the cells and inflame the tissues. This attracts T cells to the site, aggravating inflammation. These T cells exit the bloodstream and enter the gut with the help of proteins on the surface of these cells called α4β7. This protein binds to a receptor that allows the cells to get through to the gut. α4β7 is overexpressed in people with IBD, and has been validated as a drug target since the anti-inflammatory drug vedolizumab was approved by the U.S. Food and Drug Administration (FDA) a decade ago. Currently, this target is the focus of Morphic’s MORF-057.

Morphic’s MORF-057: a promising treatment for IBD

Massachusetts-based Morphic’s pipeline is dedicated to treating IBD. If we believe the interest of pharma giant Eli Lilly – which recently sealed a $3.2 billion acquisition deal to get its hands on the drug – MORF-057 could be a strong candidate for the treatment of IBD.

MORF-057 is a small molecule that is orally administered, and binds to α4β7, thus disabling its ability to bind to the receptor that takes the cells into the gut. Thanks to this inhibition, T cells can stay in the bloodstream without causing damage to the gut.

MORF-057 is currently in phase 2 for ulcerative colitis and Crohn’s disease and could challenge Takeda’s injectable drug Entyvio, which has a similar mechanism to MORF-057, but doesn’t have the advantage of being an oral drug like MORF-057. However, MORF-057 didn’t seem as strong a contender last year due to lackluster phase 2 results that saw the company’s share prices plummet.

The investigational drug demonstrated a statistically significant reduction of 6.4 points from baseline after 12 weeks in the Robarts Histopathology Index (RHI) score, an IBD measure that assesses disease activity in phase 2a studies. It also achieved 26% remission of the disease. These scores weren’t much of an improvement next to Takeda’s Entyvio. Nevertheless, phase 2b drug results for MORF-057, which will soon belong to Lilly, will be out next year.

AbbVie strengthens position in IBD research

MORF-057 isn’t the only treatment looking to tackle IBD. One therapy that has been on a clinical upswing is American multinational AbbVie’s Skyrizi. Following the drugmaker’s prior commercial success – but currently dipping sales – with arthritis medicine Humira, Skyrizi seems to be the next blockbuster in line as it was approved to treat ulcerative colitis last month.

The drug targets a protein called IL-23, which is a key driver of inflammation, to mitigate ulcerative colitis symptoms. Skyrizi beat multinational Johnson & Johnson’s (J&J’s) monoclonal antibody Stelara, which has long been a treatment for Crohn’s disease and ulcerative colitis. Phase 3 results from late last year showed that the drug led to more patients in remission than Stelara after 48 weeks. To be exact, 59% of those who took Skyrizi and 40% of those who took Stelara reached remission after 24 weeks.

The formidable Skyrizi isn’t AbbVie’s only prized possession when it comes to IBD treatments. The JAK inhibitor Rinvoq, which targets the enzyme janus kinase that causes inflammation, was greenlit by the FDA to treat Crohn’s disease last year following its ulcerative colitis approval in 2022. It first garnered attention when it was given the go-ahead to treat rheumatoid arthritis, an autoimmune disease that causes swelling of the joints, back in 2019.

AbbVie’s interest in IBD treatments isn’t waning. Last month, it bought up a preclinical candidate from Chinese biopharma FutureGen Biopharmaceutical for $150 million. The candidate FG-M701 inhibits TL1A, another key driver of inflammation. This class of drugs rose to fame when phase 2 data of Prometheus’ IBD drug PRA023 – now owned by pharma giant Merck – met primary endpoints and sent stocks soaring in late 2022.

Now a crowded therapeutic space, last year saw AstraZeneca drop its IBD candidate brazikumab owing to a “competitive landscape,” poised to be dominated by pharma giants like AbbVie and J&J. In fact, J&J’s other IBD drug Tremfya has overtaken Stelara in Crohn’s disease, just as Stelara’s patent draws to a close. Contrary to Stelara, which blocks IL-12 and IL-23, Tremfya only binds to IL-23 to minimize inflammation.

A phase 3 study found that 37.2% and 33.2% of patients who were given Tremfya at 200mg every four weeks and 100mg every eight weeks, achieved endoscopic remission – when no inflammation is seen during an endoscopy or colonoscopy – after 28 weeks when compared to 24.7% for Stelara. Tremfya also had a slight edge over Stelara in clinical remission rates.

α4β7 inhibitors: players battle it out in clinic

Meanwhile, Japanese multinational Eisai’s gastrointestinal wing has launched Ensho Therapeutics with its phase 2-ready α4β7 inhibitor NSHO-101, which was found to be safe in phase 1 studies. Moreover, California-based Palisade Bio’s PDE4 inhibitor has seen encouraging preclinical results. The prodrug PALI-2108 prevented colon length reduction in mice models with colitis, and improved body weight and stool scores. Palisade is advancing towards Investigational New Drug (IND)-enabling studies with hopes of initiating a first-in-human trial next year.

Yesterday, French biotech OSE Immunotherapeutics lusvertikimab reported marked improvements in patients with ulcerative colitis in a phase 2 study testing lusvertikimab. These patients had previously been failed by steroid drugs, immunosuppressants, and biologics. A high dose regimen (850 mg) saw a 0.82 difference in Modified Mayo Score (MMS) – a measure for stool frequency and rectal bleeding – between the drug and placebo groups, with lusvertikimab coming out on top at 10 weeks.

The dose was actually upped from 450 mg when investigators interrupted the initial study claiming a “risk of futility,” according to a press release. Lusvertikimab was found to have a favorable safety profile.

Genetic link to IBD found, bacterial pills that target the microbiome gather support in clinic

While IBD clinical trials are ongoing, scientists have uncovered a major cause for IBD. Researchers at the Francis Crick Institute in the U.K. found that a part of the genetic code present in immune cells called macrophages, boosts a gene called ETS2, which is linked to inflammation. While currently available medicines don’t block ETS2, anti-ETS2 prescribed for other conditions do exist. Now, it’s up to researchers to find a way to redirect these drugs to act on the gut while limiting side effects.

Besides these advancements, the Crohn’s & Colitis Foundation in the U.S. is supporting a few clinical projects that are addressing IBD, one of which is an oral bacterial pill developed by Paris-based Exeliom. It has just begun a first-in-human trial in patients who are on steroid treatment. EXL01 contains a single species of bacteria called F. prausnitzii, which has anti-inflammatory properties and is said to improve gut health.

Massachusetts-based Seres Therapeutics is trying something similar with its pill made of a consortium of gut bacteria. SER-301 is currently undergoing phase 2 studies.

Another study the Crohn’s & Colitis Foundation is tied to is run by American biotech Allonix, which has designed a drug that targets a protein called LRH-1, which stimulates steroid production in the gut to reduce inflammation and heal damaged gut tissue. Essentially, the drug aims to encourage the production of the body’s natural steroids to treat IBD.

However, there have been a few flops as well. California-based Surrozen binned its antibody SZN-1326 after dosing concerns came to light amid burgeoning competition in the IBD research and development (R&D) space. Swedish biotech InDex also abandoned a phase 3 trial starring TLR9 agonist cobitolimod as it was unlikely the drug would reap positive results last year.

Although a number of drugs have missed the mark in recent times, many clinical trials seem to be going strong at the moment. As different classes of drugs are being tested, this could offer more options to patients, especially those who have been failed by therapies that are currently on the market.