PharmaShots Interview: Janssen's Dr. Jan Wehkamp and Icahn School of Medicine's Dr. Bruce Sands Share Insights on the Data Presented at DDW 2021

In an interview with PharmaShots, Dr. Jan Wehkamp, M.D., Vice President, Gastroenterology Disease Area Leader at Janssen, and Bruce Sands, Dr. Burrill B. Crohn Professor of Medicine at the Icahn School of Medicine share their views on the data of Stelara and Tremfya presented at DDW 2021.

Shots:

Janssen presented the new data on Stelara (ustekinumab) and its impact on Crohn's disease and ulcerative colitis
Janssen unveils the data from the first head-to-head study in CD as well as 16 abstracts which showed safety & efficacy of Stelara in treating CD and UC
Additionally, the company presented new data on the efficacy of Tremfya (guselkumab) in CD.

Tuba: Summarize the 16 abstracts of STELARA presented at DDW in 3-5 lines each.

Dr. Jan Wehkamp:

Safety of Ustekinumab in IBD: Pooled Safety Analysis Through 5 Years in CD and 2 Years in UC (Presentation Number: 129)

Study Objective: This study presents an integrated analysis of the long-term 2020 IBD pooled safety dataset incorporating Phase 2/3 long-term safety data from IBD studies (T07, CERTIFI, UNITI, IM-UNITI, UNIFI) through up to five years in CD and two years in UC.
Study Conclusion: The safety profile of ustekinumab in the 2020 long-term IBD pooled safety dataset was favorable and consistent with the previously reported safety profile in IBD patients through one year and the well-established safety profile across all approved indications.

Safety of Ustekinumab in IBD: a Comprehensive Analysis of Major Cardiovascular Events (MACE) Through 5 Years in CD and 2 Years in UC (Presentation Number: 131)

Study Objective: This study reports the full MACE experience in ustekinumab Phase 2/3 IBD clinical studies to date, through 5 years in CD and 2 years in UC (2020 IBD pooled safety dataset).
Study Conclusion: Overall, MACE were infrequent in the long-term IBD dataset. Notably, IBD patients received higher doses than psoriasis patients, plus initial intravenous induction. The totality of available clinical trial data in IBD patients is consistent with previous results and suggests no significant difference in rates of MACE with ustekinumab treatment.

Pregnancy Outcomes in Women Exposed to Ustekinumab in the Crohn's Disease and Ulcerative Colitis Clinical Trials (Presentation Number: 178)

Study Objective: Pregnancy outcomes from ustekinumab in IBD clinical trials were presented, incorporating five years of treatment in CD and two in UC.
Study Conclusion: In the pregnancy cohort from ustekinumab IBD studies, no congenital anomalies were reported and rate of observed spontaneous abortions was generally comparable to the rate previously reported in psoriasis and the general US population. Additionally, birthweight, gestational age, and Apgar scores were within the reference ranges regardless of duration of ustekinumab exposure. The small number of pregnancies among women with IBD with prenatal exposure to ustekinumab precludes definitive interpretation of the data; thus, additional research is needed to determine the impact of ustekinumab exposure on pregnancy and newborn outcomes.

Long-term (5-year) Maintenance of Clinically Meaningful Improvement in Health-related Quality of Life in Patients with Moderate to Severe Crohns Disease Treated with Ustekinumab in the IM-UNITI Long-term Extension Study (Presentation Number Sa576)

Study Objective: Janssen presented the final Health-related Quality of Life (HRQoL) results for patients who received ustekinumab in the long-term extension study through five years (Week 252).
Study Conclusion: Long-term (five years) treatment with ustekinumab 90 mg every 12 weeks or 90 mg every 8 weeks was effective at maintaining improvements in HRQoL that were achieved during ustekinumab induction therapy in patients with CD.

The pharmacokinetics and immunogenicity of 5 years of treatment with ustekinumab: Results from the IM-UNITI long-term extension (Presentation Number Fr540)

Study Objective: The study evaluated the pharmacokinetics and immunogenicity of an additional four years of treatment with subcutaneous (SC) ustekinumab in patients with moderate to severe Crohn's disease who had completed the IM-UNITI maintenance study and continued treatment into the long-term extension (LTE).
Study Conclusion: Serum ustekinumab concentrations were maintained with SC ustekinumab treatment through week 252 and were generally consistent with those observed through week 44 of maintenance. Median serum trough ustekinumab concentrations were approximately 3 times higher in the every 8 weeks group than in the every 12 weeks group during the LTE. Use of 6-mercaptopurine, azathioprine, or methotrexate did not impact serum ustekinumab levels and did not reduce anti-drug antibodies (ADA) incidence. In general, no clear trend was observed for ustekinumab concentration and the proportions of patients in clinical remission or for safety events in the LTE. The overall incidence of ADA was low through 5 years of treatment and positive antibody status was usually transient.

Clinical Characteristics, Clinical Response, and Clinical Remission Status in Adults Treated with Ustekinumab in the Phase 3 UNITI Studies at Week 6 and Week 44 by Age at Crohn's Disease Onset (Presentation Number: 180)

Study Objective: The aim of this study was to describe clinical characteristics and treatment outcomes in adult participants with CD based on age at CD onset: pediatric/adolescent and adult.
Study Conclusion: Among adults with moderately to severely active CD treated with ustekinumab, response and remission rates were similar through Week 44 of the maintenance study in participants with Pediatric Onset CD and Adult Onset CD, despite having longer disease duration, higher C-reactive protein, and higher Crohn's Disease Activity Index scores at baseline in the Pediatric Onset group.

Clinical and Endoscopic Response to Treat-to-Target versus Standard of Care in Crohn's disease Patients Treated with Ustekinumab: Week 48 Results of the STARDUST Trial (Presentation Number 105)

Study Objective: This study describes week 48 endoscopic (primary endpoint) and clinical results.
Study Conclusion: After 48 weeks of maintenance therapy with ustekinumab, a numerically higher proportion of patients achieved primary endpoint in the treat-to-target (T2T) vs standard of care arm. T2T could be an additional tool for physicians to guide ustekinumab dosing decisions in CD. Overall, high clinical remission and biomarker responses with ustekinumab were achieved in both arms with ustekinumab at week 48.

Pharmacokinetics, Immunogenicity, and Exposure-response Relationship of Ustekinumab in Patients with Crohn's disease: Results from the Week 16 Interim Analysis of the STARDUST Study (Presentation Number: Su446)

Study Objective: This study compares ustekinumab treat-to-target with ustekinumab standard of care in achieving endoscopic response (a =50% reduction in Simple Endoscopic Score for CD [SES-CD] vs baseline) at week 48.
Study Conclusion: Serum ustekinumab concentration and low incidence of antibodies to ustekinumab were consistent with data from pivotal CD randomized controlled trials. Most patients attained clinical efficacy outcomes at ustekinumab concentrations derived from the approved dose regimen; however, patients with higher ustekinumab concentrations were more likely to achieve biomarker and endoscopic improvements.

Ustekinumab Improves Health-related Quality of Life in Patients with Moderate to Severe Crohn's disease: Results from a Week 16 Interim Analysis of the STARDUST Trial (Presentation Number: Sa073)

Study Objective: This study describes the health-related quality of life (HRQoL) response to ustekinumab induction at 16 weeks from the interim results of the STARDUST trial.
Study Conclusion: After 16 weeks of induction with ustekinumab, a statistically significant improvement of Inflammatory Bowel Disease Questionnaire (IBDQ) score, overall and for all domains, was noted, independent of previous biologic exposure, reflecting a meaningful improvement in IBD-specific HRQoL in patients with moderate-to-severe CD.

Feasibility of Using Real-World Data from the Improvecarenow Registry to Examine the Efficacy of Ustekinumab for Pediatric Crohn's Disease (Presentation Number: Sa581)

Study Objective: This study evaluated the capability of the registry of the ImproveCareNow (ICN), the worlds largest pediatric IBD network, to generate relevant, reliable, high-quality real-world evidence (RWE) on the use of ustekinumab in pediatric CD.
Study Conclusion: This study demonstrated the feasibility, reliability, and completeness of ICN data as a potentially suitable source of RWE to evaluate the effectiveness of ustekinumab treatment in children with CD.

The Real-World Effectiveness of Ustekinumab in the Treatment of Crohn's Disease (Presentation Number: 611)

Study Objective: This study evaluated the real-world effectiveness of ustekinumab in patients with CD.
Study Conclusion: In routine clinical practice, ustekinumab is an effective option for the treatment of CD, with 40% achieving clinical remission through 12 months in this largely biologic refractory population. Prior exposure to anti-TNF and vedolizumab therapy are associated a reduced probability for clinical and endoscopic remission, and an incremental reduction in effectiveness was observed for number of prior biologics used. The greatest treatment effect of ustekinumab was seen in bionaive patients with 63% and 55% of patients achieving clinical and endoscopic remission, respectively, by 12 months.

Shorter Disease Duration in Patients with Crohn's Disease is Associated with Higher Rates of Remission with Ustekinumab (Presentation Number: Su461)

Study Objective: This study evaluated the impact of disease duration on ustekinumab effectiveness in a real-world cohort of CD patients.
Study Conclusion: Patients with CD treated with ustekinumab earlier in their disease course had significantly improved outcomes with higher rates of clinical, steroid-free clinical, endoscopic and radiographic remission compared to those with longer disease duration.

Propensity Score Adjusted Quality of Life and Effectiveness of Ustekinumab Induction Therapy in Crohn's Disease: Results of the RUN-CD Study (Presentation Number: 526)

Study Objective: This study investigated the HRQoL and effectiveness, in terms of clinical and steroid-free remission at week 16, of ustekinumab induction therapy vs. other biologics in CD using propensity score adjustment.
Study Conclusion: In this prospective study, with propensity score weighted groups, the effectiveness of ustekinumab induction therapy was similar to that of other biologics therapies. The remarkably higher remission rates observed in this real-world setting, compared to those observed in approval studies, along with the significantly greater improvement in HRQoL at week 16 supports consideration of ustekinumab as a first-line targeted therapy for CD.

Performance of the Short Pediatric Crohn's Disease Activity Index (sPCDAI) as a Clinical Effectiveness Endpoint (Presentation Number: Sa469)

Study Objective: As few prospective studies have externally evaluated the sPCDAI, its use as an outcome measure is unexplored. This study compared performance of the sPCDAI and the full PCDAI in two pediatric Crohn's disease clinical trials.
Study Conclusion: The sPCDAI is highly correlated with PCDAI at baseline and when assessing change from baseline, with excellent concordance in categorization of remission. The sPCDAI omits the ESR and all other objective measures of inflammation. However, in the context of Real-World studies and pragmatic trials, sPCDAI may be a fit-for-purpose measure of clinical effectiveness, with fewer missing assessments from non-contributory labs and physical assessments. The pre-selected sPCDAI cutoff to indicate interventional success may vary depending upon aims of a particular study.

Treatment Patterns in Biologic-experienced Crohn's Disease Patients Using Three Large Commercial Claims Databases in the United States (Presentation Number: Su451)

Study Objective: This study examined biologic treatment patterns among bio-experienced CD patients that initiated treatment with adalimumab, certolizumab pegol, infliximab, ustekinumab, and vedolizumab.
Study Conclusion: Among CD patients, unadjusted persistence was high for ustekinumab, followed by vedolizumab, infliximab, and adalimumab. Adherence and dose reduction followed a similar trend. Further research is needed to examine treatment patterns after adjusting for confounders and baseline differences.

Tuba: The company also highlighted the RWE of Stelara at DDW. Please share the data with our readers.

Dr. Jan Wehkamp: In this real-world, retrospective, multicenter, consortium study, we evaluated the real-world effectiveness of STELARA in patients with Crohn's disease (CD), including cumulative rates of clinical and endoscopic remission of STELARA in a total of 1,113 patients with CD, the largest real-world cohort assessing STELARA effectiveness to date.* 90 percent of patients had prior anti-tumor necrosis factor (TNF) exposure and 64.5 percent had prior exposure to treatment with at least two prior biologics, and a median follow-up of 386 days.

Results showed 40 percent of patients achieved clinical remission through 12 months. Cumulative rates of steroid-free, endoscopic, and radiographic remission at 12 months were 32 percent, 39 percent, and 30 percent, respectively. Rates of clinical and endoscopic remission were lower with an increasing number of prior biologic exposures. Notably, the greatest treatment effect of STELARA was seen in biologic-naïve patients with 63 percent and 55 percent of patients achieving clinical and endoscopic remission, respectively, by 12 months.

*Note: RWE refers to data collected from diversified areas of daily life that are outside the scope of highly controlled randomized control trials (RCTs). RCT research, characterized as having the highest reliability, and RWE research, which reflects the actual clinical aspects, can have a mutually supplementary relationship. (SOURCE: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097073/)

Tuba: Highlight the Janssen efforts in the field of autoimmune diseases. Any more indications planned to be assessed for Tremfya and Stelara?

Dr. Jan Wehkamp: At Janssen, we will continue to build upon and reinforce the strength of Janssen's gastroenterology portfolio as part of our relentless focus on unmet patient needs. We are continuing to study STELARA in various clinical settings in the treatment of both ulcerative colitis and Crohn's disease. Additionally, since gaining approval in the U.S. in 2017 for psoriasis and 2020 for psoriatic arthritis, we continue to expand our research of TREMFYA, which is currently being studied in the Phase 2 GALAXI clinical trial in Crohn's disease, a Phase 2b/3 program in ulcerative colitis and two additional Phase 2 programs one exploring biologic combination therapy in ulcerative colitis and the other for the treatment of hidradenitis suppurativa. TREMFYA is also being studied in Phase 1 clinical trial in celiac disease.

Tuba: Highlight the key points of the head-to-head study of Stelara presented at DDW. Can we have a detailed view of the efficacy & safety findings of Stelara as it pertains to SEAVUE?

Dr. Bruce Sands: SEAVUE is the first head-to-head, blinded, randomized controlled trial of two biologic agents for the treatment of Crohn's disease. It compares the use of adalimumab, which is the most widely prescribed biologic agent anti-TNF for Crohn's disease, to ustekinumab, an anti-p40 antibody that blocks IL-12 and IL-23.

In this head-to-head comparison, the primary endpoint of the study was clinical remission at week 52. Although the study was designed for superiority, it was not demonstrated for ustekinumab, and the two agents appear to be roughly equally effective. However, it's important to note that these patients were naïve to biological therapies and also had a relatively short duration of disease, roughly about 2.58 years. Because of this, both treatment groups had very high clinical remission rates at the end of one year, approaching two-thirds of patients in each arm.

This study shows that both ustekinumab and adalimumab have similar efficacy and are effective treatments for patients with moderate to severe Crohn's disease and for patients who are biologic-naïve.

There are a number of other nuances in the results of this study that seemed to show, numerically, fewer patients dropping out of the study for lack of efficacy in the ustekinumab arm. Although this was not statistically different, this was numerically superior in the ustekinumab arm.

Additionally, there was a slightly greater trend numerically in this study of higher rates of infection and also of injection site reactions in the adalimumab arm. To contextualize these findings, it shows that both therapies are good options for the treatment of Crohn's disease, but the further context of the overall safety of these agents, as well as the convenience of dosing every eight weeks with ustekinumab as compared to every two weeks for adalimumab, would suggest that ustekinumab may be a superior choice to adalimumab, even though this study didn't hit its primary endpoint in demonstrating the superiority of clinical remission at week 52.

Both agents had similar efficacy with regard to endoscopic improvement, looking at the SES-CD score and clinical responses as well. Additionally, in terms of time to onset of effect, the drugs were similar.

Tuba: Discuss the impact of new SEAVUE data on the CD treatment landscape.

Dr. Bruce Sands: With regard to the Crohn's disease landscape, the results suggest that both of these agents, adalimumab, and ustekinumab, are excellent choices for first-line biologic therapy of Crohn's disease. Additionally, because of the safety and the convenience of dosing of ustekinumab, this may suggest that ustekinumab may be a more desirable choice for many patients.

Tuba: What is the new TREMFYA data presented at DDW?

Dr. Bruce Sands: The data presented at DDW was a further analysis looking at inflammatory biomarkers in the course of treatment patients with Crohn's disease in the GALAXI-1 study of guselkumab.

Patients were assigned to receive a placebo or 200, 600, or 1200 mg of guselkumab IV at weeks 0, 4, or 8, or the reference arm of ustekinumab according to the approved dosing regimen. Patients had analysis for change from baseline in their C-reactive protein (CRP), a blood biomarker fecal calprotectin (FeCal), and clinical-biomarker response which was defined as =a 100-point reduction from baseline in CDAI score or CDAI score <150 and =50% reduction from baseline in CRP or fecal calprotectin. This is a way of incorporating an objective outcome of a biomarker along with clinical response.

In this analysis, it was found that patients treated with guselkumab had significantly greater reductions in CRP and FeCal compared to placebo. In addition, the proportion of patients who normalized their CRP if they had an abnormal CRP at baseline was significantly higher in the guselkumab group compared to placebo at week 12 (35.4% versus 19.4%, respectively). Similarly, the proportion of patients who normalized their FeCal, if it was abnormal at baseline, was 33.3% with guselkumab versus 27.3% for placebo at week 12.

At week 12, a higher proportion of patients treated with guselkumab achieved clinical-biomarker response compared to placebo (48% versus 7.8%, respectively).

Similar results were achieved in patients who had the previous failure of biologic therapies at week 12; 46.1% of guselkumab-treated patients achieved clinical-biomarker responses versus 8.7% of patients on placebo. In the conventional treatment failure cohort, 50% of guselkumab-treated patients versus 7.1% of patients on placebo achieved clinical-biomarker response at week 12.

Overall, the study results concluded that guselkumab is effective in reducing inflammatory biomarkers CRP and FeCal during induction therapy as compared to placebo. This was accomplished regardless of prior treatment failure with biologic therapies or merely with conventional therapies. Importantly, these changes in the inflammatory biomarkers typically had been accomplished by week 4, concluding that it is not just that we see this effect, but that this effect also happens fairly quickly in the course of therapy, which is important for patients who are seeking more rapid relief of their Crohn's disease symptoms.

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About Dr. Jan Wehkamp:

Dr. Jan Wehkamp is the M.D., Vice President, Gastroenterology Disease Area Leader at Janssen.

About Dr. Bruce Sands:

Dr. Bruce Sands, MD, MS, is the Dr. Burrill B. Crohn Professor of Medicine at the Icahn School of Medicine. Dr. Sands was awarded his BA and MD from Boston University and trained in internal medicine at the University of Pennsylvania Hospital.