Zeposia: New Drug for Ulcerative Colitis

Zeposia (ozanimod) is a new drug indicated for the treatment of moderate-to-severe active ulcerative colitis in adults.

Regulatory approval was granted by the U.S. Food and Drug Administration (FDA) in late May 2021.

A verdict from the European Medicines Agency (EMA) is expected in the second half of 2021.

Zeposia debuted in March 2020: for therapy of adult patients with relapsing-remitting forms of multiple sclerosis, including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS) in the active form.

Zeposia is being promoted by Bristol-Myers Squibb, which took over the drug in the Celgene takeover.

Ozanimod continues to undergo the final clinical review of its suitability for the treatment of Crohn’s disease.

 

Why Do We Need New Drugs for Ulcerative Colitis?

Ulcerative colitis is a chronic disease with a progressive and disabling course. Dysregulation of the immune response in genetically predisposed individuals is considered a key component of the development and progression of inflammatory bowel disease (IBD). This has led to the development of therapies targeting immune abnormalities. The first such drugs were tumor necrosis factor (TNF) blockers [infliximab, adalimumab, and golimumab], which achieved effective control of ulcerative colitis by suppressing systemic and intestinal inflammation. However, up to 30% of patients do not respond to TNF-blockers and up to 40% of patients lose response over time — due to immunogenicity, side effects, differences in gene expression, or inflammation not associated with TNF.

As a result, drugs targeting other mechanisms of immune disorders have been incorporated into clinical practice: for example, anti-integrin agents [vedolizumab], modulators of the interleukin 23 (IL-23) and T-helper 17 (T_h17) signaling pathway [ustekinumab], Janus kinase (JAK) inhibitors [tofacitinib].

But even here, long-term remission is not always achieved. Relapse of ulcerative colitis requires increasing the dose of the drug, switching to an alternative drug from the same class, or switching to a drug from a different class. As we can see, the drug armamentarium for the fight against ulcerative colitis is not rich at all.

 

Zeposia: Mechanism of Action of Ozanimod

Ozanimod (RPC1063) is an oral low-molecular-weight selective agonist of sphingosine-1-phosphate receptors 1 and 5 (S1PR₁ and S1PR₅). The immunomodulatory mechanism of action of ozanimod is due to internalization of S1P receptors with their subsequent degradation (functional antagonism) in the ubiquitin-proteasome pathway. This leads to inhibition of migration of a certain subtype of activated lymphocytes (T helpers CD4⁺ CCR7⁺ and T killers CD8⁺ CCR7⁺) from the lymphoid tissue to the sites of inflammation. The integrity of the immunological surveillance of infections and tumors is preserved because S1P signaling does not affect a subset of lymphocytes that do not migrate through the lymphoid tissue.

 

Zeposia: Efficacy of Ozanimod in Treating Ulcerative Colitis

The TRUE NORTH (NCT02435992) phase 3 clinical trial (randomized, double-blind, placebo-controlled, multicenter, international) enrolled adult patients (n=645) with an endoscopically confirmed diagnosis of active ulcerative colitis occurring with moderate to severe severity. The latter was defined as a three-component overall Mayo score ranging from 6 to 12, which included endoscopic subscore ≥2, rectal bleeding subscore ≥1, and stool frequency subscore ≥1.

Participants’ ulcerative colitis must have been characterized by inadequate response or intolerance to classes of medications such as oral aminosalicylates, corticosteroids, immunomodulators (e.g., 6-mercaptopurine and azathioprine), or a biologics (e.g., TNF blockers and/or vedolizumab).

Prior to enrollment in the study, participants were required to adhere to stable therapy with oral aminosalicylates and/or corticosteroids (prednisone at a maximum dose of 20 mg/day or multimatrix budesonide). These medications were discontinued at the start of the trial.

The study was divided into two periods: a 10-week induction therapy, at the end of which those who responded to treatment moved on to a blinded 42-week maintenance therapy (ozanimod or placebo). Patients with no response to treatment were transferred to an open maintenance therapy group, in which all were prescribed ozanimod alone.

The primary endpoint was the proportion of subjects who went into clinical remission, stated by a composite clinical and endoscopic score (based on the three-component Mayo score): no rectal bleeding, stool frequency subscore ≤1 (with ≥1 reduction in absolute number), endoscopic subscore ≤1 (without friability).

The secondary endpoints include:

• clinical response: reduction of the total three-component Mayo score by ≥2 and ≥35%, reduction of the rectal bleeding subscore by ≥1 or an absolute number to ≤1

• endoscopic improvement: endoscopic subscore ≤1 (without friability)

• mucosal healing: endoscopic improvement with the histologic improvement of colonic tissue: no neutrophils in epithelial crypts or lamina propria, no increase in eosinophils, no crypt destruction, no erosions, ulceration, or granulation tissue, i.e., Geboes <2.0

• histologic remission: ≤2.0 on the Geboes score, which is in 6 grades: 0 — structural changes only, 1 — chronic inflammatory infiltrate, 2A — eosinophils in mucosa, 2B — neutrophils in mucosa, 3 — neutrophils in epithelium, 4 — crypt destruction, 5 — erosion or ulceration.

 

Induction Period: 10 Weeks of Treatment

The ozanimod group outperformed the placebo group in the objective of reaching the primary endpoint of clinical remission of ulcerative colitis: this was evidenced for 18.4% of participants — versus 6.0% (p<0.0001). The difference was 12.4% (95% CI: 7.5–17.2); p<0.0001.

Therapeutic efficacy depended on whether patients had already been treated with tumor necrosis factor (TNF) blockers. The proportion who achieved clinical remission was higher among those who had not previously received this class of drugs (22.1% vs. 6.6%) than among those who had previously been treated with TNF blockers (10.0% vs. 4.6%; p=0.195).

A statistically significant difference in all secondary endpoints was confirmed in the ozanimod group:

• clinical response: 47.8% — versus 25.9% (p<0.0001)
• endoscopic improvement: 27.3% — vs. 11.6% (p<0.0001)
• mucosal healing: 12.6% — vs. 3.7% (p<0.001)
• histologic remission (p<0.001): 18.2% — vs. 7.4% [≤2.0 Geboes score], 34.7% — vs. 18.5% [≤3.1], 26.3% — vs. 11.1% [≤1.1].

In either case, ozanimod worked better among patients who had not previously received TNF blockers.

 

Maintenance Period: 52 Weeks of Treatment

Administration of ozanimod provided an exit to clinical remission of ulcerative colitis among 37.0% of subjects — versus 18.5% in the placebo group (p<0.0001).

At the same time, maintained clinical remission, the one that occurred after a 10-week course of treatment and then remained after another 42 weeks of therapy, was noted in 51.9% of patients — vs. 29.3% (p=0.0047).

Status of clinical remission of ulcerative colitis without concomitant use of corticosteroids (without their use for at least 12 weeks) was true for 31,7% of patients on therapy with ozanimod — vs. 16,7% of the control group (p<0,001).

Durable clinical remission of ulcerative colitis, remission after 10 and 52 weeks of treatment among all subjects who switched to maintenance therapy, was demonstrated in 17.8% — vs. 9.7% (p=0.003).

The ozanimod group confirmed exit to all secondary endpoints:

• clinical response: 60.0% — versus 41.0% (p<0.0001)
• endoscopic improvement: 45.7% — vs. 26.4% (p<0.001)
• mucosal healing: 29.6% — vs. 14.1% (p<0.001)
• histologic remission (p<0.001): 33.5% — vs. 16.3% [≤2.0 Geboes score], 49.1% — vs. 26.4% [≤3.1], 42.2% — vs. 22.5% [≤1.1].

In either setting, the success of treatment of ulcerative colitis with ozanimod depended on the status of prior prescription of TNF blockers: if such drugs were previously administered, the response to therapy was worse.

 

Zeposia: Safety of Ozanimod in Treatment of Ulcerative Colitis

In the induction period of ulcerative colitis treatment, the most common adverse reactions in response to the administration of ozanimod were: anemia (in 4.2% of patients versus 5.6% in the placebo group), nasopharyngitis (3.5% vs. 1.4%), and headache (3.3% vs. 1.9%).

In the maintenance period, the safety profile looked like this: elevated alanine aminotransferase (ALT) levels (4.8% vs. 0.4%; no serious events), headache (3.5% vs. 0.4%).

A combined analysis of the two periods revealed the following frequencies of adverse events: increased liver enzymes (11% vs. 2%), headache (5% vs. <1%), upper respiratory tract infections (5% vs. 4%), pyrexia (3% vs. 2%), nausea (3% vs. 2%), arthralgia (3% vs. 1%).

 

Zeposia: Efficacy and Safety of Ozanimod in Long-term Treatment of Ulcerative Colitis

Long-term follow-up of participants in the TOUCHSTONE (NCT01647516) phase 2 clinical trial (randomized, double-blind, placebo-controlled, multicenter, international) demonstrated that multi-year (200 weeks or nearly 4 years) continuous use of ozanimod during treatment of moderate-to-severe ulcerative colitis led, according to strict data analysis, to clinical response and clinical remission of 41.2% and 36.5% of patients, respectively.

Among the most frequent adverse events of long-term prescription of ozanimod were ulcerative colitis (in 6.5% of patients), hypertension (5.9%), upper respiratory tract infections (5.9%), increased gamma-glutamyltransferase levels (5.3%), anemia (4.7%), back pain (4.1%), nasopharyngitis (4.1%), and headache (4.1%).

 

Zeposia: Market Prospects for Ozanimod

Evaluate Pharma estimates that connecting patients with ulcerative colitis to ozanimod will allow Bristol-Myers Squibb to earn $1.4 billion in 2026. And, it is argued, sales of Zeposia for this indication will turn out to be about three times as large as for multiple sclerosis therapy.

Meanwhile, AbbVie is preparing to expand the list of indications for its drug Rinvoq (upadacitinib), a Janus kinase 1 (JAK1) inhibitor that debuted in August 2019 to treat moderate-to-severe rheumatoid arthritis. Upadacitinib is thought to become a blockbuster very quickly, taking the lead in ulcerative colitis therapy: demand will exceed $5 billion in 2026. This is understandable, because oral upadacitinib, judging by the data from the 8-week induction period of the U-ACHIEVE (NCT02819635) and U-ACCOMPLISH (NCT03653026) phase 3 clinical trials, showed decent treatment efficacy without any new safety signals.

Nevertheless, the prescription of any drugs from the class of JAK inhibitors is accompanied by toxicity, occasionally of a serious nature. And so the situation with upadacitinib will finally become clearer as the results of the long-term review of this drug under NCT03006068 become available. For nothing, Xeljanz/Jakvinus (tofacitinib), a Janus kinase 1, 2, and 3 (JAK1, JAK2, and JAK3) inhibitor by Pfizer, faced an FDA warning in February 2021 regarding an increased risk of serious cardiovascular problems and cancer.

AbbVie is betting on Rinvoq against ulcerative colitis largely because its best-selling TNF blocker Humira (adalimumab) is losing patent protection, which will disappear in the United States, the main market for any pharmaceutical product, in 2023. In Europe, adalimumab biosimilars started appearing back in 2017.

At the same time, there will be less interest in Entyvio (vedolizumab), a monoclonal antibody that binds α₄β₇ integrin, which Takeda Pharmaceutical is promoting. In contrast, sales of Stelara (ustekinumab), a monoclonal antibody against interleukin 12 (IL-12) and interleukin 23 (IL-23) marketed by Janssen, part of Johnson & Johnson, will increase.

In 2026, the global market for ulcerative colitis therapy will be $12.8 billion.

 

Zeposia: Ozanimod vs. Other Drugs in Treating Ulcerative Colitis

It should be understood that it is impossible to predict how well an individual patient will respond to treatment for ulcerative colitis with a particular drug. And therefore, it is not possible to compare the effectiveness of therapy for this disease with different drugs. For example, a direct comparison of vedolizumab with adalimumab found that the former led a higher proportion of patients to clinical remission than the latter. However, vedolizumab did worse in getting rid of oral corticosteroids.

Ozanimod is attractive because, first, it is made in a convenient oral formulation and, second, it belongs to a different class of drugs than all those that existed before it. If we talk about the effectiveness of treatment of ulcerative colitis with Zeposia, in the induction period of therapy it brought 12% of patients to clinical remission (relative to placebo, hereafter) — versus 10–13% in the case of Xeljanz/Jakvinus, 12% of Stelara, 12% of Entyvio, 7% of Humira. In the maintenance period, Zeposia provided clinical remission status not as good as other drugs: for 19% of patients — vs. 23–30% in the case of Xeljanz/Jakvinus, 19% of Stelara, 26% of Entyvio, 9% of Humira.

 

Extras

Zeposia (ozanimod). Prescribing information. U.S. [PDF]

P025 Ozanimod efficacy, safety, and histology in patients with moderate-to-severe ulcerative colitis during induction in the phase 3 True North study. Am J Gastroenterol. 2020 Dec 1;115(Suppl 1):S6-S7. [source]

P030 Ozanimod efficacy, safety, and histology in patients with moderate-to-severe ulcerative colitis during maintenance in the phase 3 True North study. Am J Gastroenterol. 2020 Dec 1;115(Suppl 1):S8. [source]

P012 Ozanimod reduced fecal calprotectin levels in patients with ulcerative colitis in the phase 3 True North study. Am J Gastroenterol. 2020 Dec 1;115(Suppl 1):S3. [source]

Long-term efficacy and safety of ozanimod in moderately to severely active ulcerative colitis: results from the open-label extension of the randomized, phase 2 TOUCHSTONE study. J Crohns Colitis. 2021 Jan 13;jjab012. [source]

Ozanimod induction and maintenance treatment for ulcerative colitis. N Engl J Med. 2016 May 5;374(18):1754-62. [source]

Small molecule drugs in the treatment of inflammatory bowel diseases: which one, when and why? — a systematic review. Eur J Gastroenterol Hepatol. 2020 Jun;32(6):669-677. [source]