Lilly at ACG 2024: Anabela Cardoso and Mark Genovese in Conversation with PharmaShots

Shots:

Lilly presented results from two long-term studies evaluating sustained efficacy in patients treated with mirikizumab for both moderately to severely active Ulcerative Colitis and Crohn’s Disease at ACG 2024

At three years, more than 80 percent of patients with moderately to severely active ulcerative colitis who were on remission sustained long-term remission and relief

In a stimulating discussion with PharmaShots, Anabela Cardoso and Mark Genovese from Lilly share key findings from the studies

Saurabh: Would you like to share the study design of LUCENT-3 and VIVID-2?

Anabela: Ulcerative Colitis:

Mirikizumab was studied in two, Phase 3 clinical trials which evaluated the efficacy and safety of mirikizumab in adults with moderately to severely active ulcerative colitis (UC) and included 60% patients who had never tried a biologic (biologic-naïve) and 40% harder-to-treat patients who had previously taken a biologic.

The induction LUCENT-1 and maintenance LUCENT-2 studies were randomized, double-blind, and placebo-controlled and included those who had inadequate response, loss of response, or failed to tolerate any of the following: corticosteroids, immunomodulators (6-mercaptopurine and azathioprine), biologic therapy (TNF blocker, vedolizumab) or Janus kinase inhibitors (JAKi, tofacitinib). Patients randomized to mirikizumab received induction with 300 mg intravenously at Weeks 0, 4 and 8 in LUCENT-1. At 12 weeks, those who entered LUCENT-2 and were treated with mirikizumab received 200 mg subcutaneously every four weeks, up to 52 weeks. Both at induction and maintenance, mirikizumab demonstrated statistically significant and clinically meaningful improvement in clinical remission, endoscopic remission, mucosal healing and bowel urgency – one of the most common and bothersome symptoms for people living with UC.

After 52 weeks, patients entered LUCENT-3, the ongoing long-term Phase 3 extension of LUCENT-1 and LUCENT-2, which evaluated the efficacy and safety of mirikizumab 200 mg subcutaneous every four weeks in patients with UC for up to three years.

Crohn’s Disease:

SERENITY, the Phase 2, multi-center, randomized, parallel-arm, double-blind, placebo-controlled trial was designed to assess the safety and efficacy of mirikizumab in patients with moderately to severely active Crohn's disease. At baseline, participants were randomized with a 2:1:1:2 allocation across four treatment arms (placebo, mirikizumab 200 mg, mirikizumab 600 mg and mirikizumab 1000 mg). The primary endpoint, endoscopic response as determined by the proportion of participants achieving at least 50% reduction from baseline on the Simple Endoscopic Score for Crohn's Disease (SES-CD) at Week 12, was achieved as well as key secondary endpoints.

VIVID-1 was a Phase 3, randomized, double-blind study that evaluated the safety and efficacy of mirikizumab compared with placebo and an active control (ustekinumab) in adults with moderately to severely active Crohn's disease. Patients randomized to mirikizumab were administered 900 mg of mirikizumab intravenously every four weeks at Weeks 0, 4 and 8, followed by 300 mg subcutaneously every four weeks from Weeks 12-52. In this study, 49% of patients taking mirikizumab or placebo had experienced a prior biologic failure while 51% had not been treated with a biologic before.

Mirikizumab demonstrated statistically significant and clinically meaningful improvements versus placebo in clinical remission, endoscopic remission, histological healing, bowel urgency and other key secondary endpoints in both induction and maintenance periods.

VIVID-2 is the ongoing long-term Phase 3 extension of SERENITY and the VIVID-1 study, evaluating the efficacy and safety of mirikizumab 300 mg subcutaneous every four weeks in patients with Crohn's disease for up to five years.

Saurabh: How does Mirikizumab's ability to induce histological healing place it with other IL23p19 antagonists in the market?

Anabela: Histologic inflammation is important to understand as it persists in up to one-quarter of patients with Crohn’s disease despite evidence of endoscopic mucosal healing. For this reason, treatment strategies for Crohn’s disease must evolve beyond traditional measures of clinical remission and endoscopy.

Multi-year data presented at both UEG Week and ACG show mirikizumab is a targeted therapy that can provide intestinal healing over time and improvement in key symptoms that matter most to patients, including those with prior biologic experience.

At UEG Week, Lilly was the first company to report rigorous histologic and endo-histologic outcomes in Crohn's disease that align with a recent ECCO position statement, including more ambitious targets of mucosal healing. Applying these more ambitious targets, data show more patients treated with mirikizumab achieved histologic response at Week 52 compared to ustekinumab, regardless of prior biologic experience.

The resulting data show that mirikizumab achieved statistically significant improvements across all histologic and histologic-endoscopic endpoints versus placebo at Weeks 12 and 52, and nominally statistically significant improvements versus ustekinumab on the following endpoints:

A greater number of patients that achieved histologic response were observed with mirikizumab at Week 52 in the overall population.
In patients with active histologic disease at baseline and with at least one prior biologic failure, mirikizumab also showed a greater histologic response and endoscopic-histologic response at Week 52.

These data build on the growing body of evidence for mirikizumab and may provide evidence of a greater depth of mucosal healing over existing treatments for those living with this chronic, progressive disease.

At ACG, Lilly presented long-term data in UC from LUCENT-3, which showed mirikizumab helped patients with moderately to severely active UC achieve long-term outcomes, including histologic-endoscopic mucosal remission, defined as mucosal healing. Mirikizumab also provided sustained benefit across symptomatic, clinical, endoscopic and histologic endpoints for up to three years, regardless of previous failure to TNF inhibitors, tofacitinib or other biologics.

Saurabh: The result of both studies looks promising. Would you like to share the outcomes of both studies observed so far?

Anabela: Mirikizumab is the first and only IL23p19 antagonist to report long-term, multi-year, sustained efficacy and safety data in both UC and Crohn's disease, demonstrating that mirikizumab can provide intestinal healing over time and improvement in key symptoms that matter most to patients.

This is important because current therapies to treat UC and Crohn’s disease fail to achieve remission for a majority of patients, and of the patients who do achieve remission, a substantial proportion lose it within the first year. Despite continued advances, people living with UC and Crohn’s disease are still seeking treatments that can address difficult-to-manage symptoms, such as bowel urgency, and provide lasting results over time.

UC:

In LUCENT-3, mirikizumab helped patients with moderately to severely active UC achieve long-term outcomes, including histologic-endoscopic mucosal remission, defined as mucosal healing. Mirikizumab also provided sustained benefit across symptomatic, clinical, endoscopic and histologic endpoints for up to three years, regardless of previous failure to TNF inhibitors, tofacitinib or other biologics.

Among those who achieved clinical remission with mirikizumab at one year in the LUCENT-2 study, the following results were achieved based upon observed case analysis after an additional two years of treatment (up to three years total):

81% of patients maintained long-term clinical remission

82% achieved long-term endoscopic remission

72% had mucosal healing

79% achieved corticosteroid-free clinical remission

Patients demonstrated a sustained clinically meaningful improvement in symptom score reduction for bowel urgency (-4.72)

Crohn’s disease:

New data from patients in the Phase 2 program who enrolled into the VIVID-2 long-term extension study showed that patients with moderately to severely active Crohn’s disease treated with mirikizumab maintained high rates of clinical and endoscopic remission over time. The following results were achieved based upon observed case analysis after an additional three years of treatment (up to five years total):

96% of patients had clinical response as measured by the Crohn’s Disease Activity Index (CDAI)

87% were in clinical remission as measured by CDAI

76% had endoscopic response

54% of patients were in endoscopic remission

Saurabh: During the studies, did you observe any new safety signal associated with Mirikizumab?

Anabela: In both studies, the long-term safety profiles in patients with moderately to severely active UC and Crohn’s disease were consistent with the known safety profile of mirikizumab.

Among patients receiving mirikizumab in the LUCENT-3 study, 7.4% reported a serious adverse event (AE), while 5.3% discontinued treatment due to an AE.

Among patients who enrolled into the VIVID-2 long-term extension study, 8.5% reported a serious AE and 1.9% discontinued treatment due to an AE.

Saurabh: Mirikizumab is being studied as a combination therapy with Eltrekibart for the treatment of Ulcerative Colitis. Can you shed some light on the aforementioned trial?

Mark: Lilly has a combination study underway in UC with mirikizumab and eltrekibart, a humanized monoclonal antibody that binds to the seven ligands that signal through the CXCR1 and CXCR2 chemokine receptors involved in neutrophil movement to sites of inflammation (NCT06598943).

This is a Phase 2, randomized, double-blind, placebo-controlled study that will evaluate the safety and efficacy of eltrekibart and mirikizumab in adult participants with moderately to severely active UC. Participants will receive eltrekibart and mirikizumab in combination or separately as monotherapy.

Saurabh: MORF-057 is another candidate in your pipeline which is targeting Crohn’s disease and Ulcerative Colitis. Is MORF-057 an extension product to Mirikizumab as an LCM strategy or does it target different patient segments in UC?

Mark: MORF-057 is an oral, small molecule, selective alpha-4/beta-7 integrin inhibitor that may improve outcomes and expand treatment options for people with inflammatory bowel disease.

Oral therapies are an important part of Lilly’s strategy in immunology, as they could open up new possibilities for earlier intervention in diseases like UC and offer potential for combination therapy to help patients with more severe disease.

Phase 2 trials currently underway in UC and Crohn’s disease will help us better understand the potential for MORF-057.

Image Source: Canva

About the Author:

Anabela Cardoso

Anabela Cardoso, MD, MBA is the Senior Vice President of Global and US Immunology Medical Affairs at Lilly. She got her medical degree and rheumatology training in Oporto, Portugal, where she did clinical trials (ph2-4) and taught rheumatology. She has an MBA from Lisbon, Portugal and an innovation certificate from What If company London, UK. She has worked in the pharma industry for 20 years at Merck& Co, AbbVie and Lilly, where she led large ph4 trials and had various medical affairs roles in Europe, Global and US in immunology and diabetes. At Lilly, she also led baricitinib development including Covid19 and the early phase research team for ph1 trials across Lilly’s portfolio before returning to Medical Affairs in Immunology. Anabela is curious, eager to learn and passionate about connecting science with impacting patients’ lives. She is Portuguese, married, has a daughter, lives in Indianapolis and enjoys traveling to places with beaches and sailing.

Mark Genovese

Mark C. Genovese, MD, is the SVP for Immunology Development at Eli Lilly overseeing all development endeavors in the areas of Rheumatology, Gastroenterology, Dermatology and Allergy. Prior to joining Lilly, he served as the SVP for Clinical Development for Inflammation and Fibrosis at Gilead Sciences. Before joining industry, he was the James W. Raitt Professor of Medicine and Clinical Chief of the Division of Immunology and Rheumatology at Stanford University. He remained at Stanford as a fellow in the Division of Immunology and Rheumatology before joining the faculty in the same division. Dr. Genovese led a clinical research program focused on translational medicine in autoimmune diseases. He designed and led numerous investigator-initiated studies and international multi-center trials investigating novel therapies and therapeutic strategies for the treatment of autoimmune disease.