Boehringer Ingelheim (China) Investment Co., Ltd.

We report phase I results for obrixtamig (BI 764532), a delta-like ligand 3 (DLL3)/CD3 IgG-like T-cell engager, in patients with previously treated DLL3-positive small cell lung cancer (SCLC), extrapulmonary neuroendocrine carcinomas (epNECs), or large cell neuroendocrine carcinoma of the lung (LCNEC-L).

Patients received escalating intravenous obrixtamig doses using four regimens: a fixed dose once every 3 weeks (A); a fixed dose once weekly (B1); a step-up dose once weekly for two weeks and target dose once weekly (B2); and a step-up dose once weekly for 3 weeks, target dose once weekly for 3 weeks, and once every 3 weeks thereafter (B3). The primary objective was maximum tolerated dose (MTD). Secondary objectives included safety, pharmacokinetics, and tumor response (RECIST v1.1).

As of February 21, 2024, 168 patients received obrixtamig, 72% received ≥2 lines of previous anticancer therapy, and 51% received previous anti–PD-1/PD-L1 therapy. Seven dose-limiting toxicities occurred during MTD evaluation (Regimen A, n = 1; Regimen B2, n = 6). MTD was not reached. The most common treatment-related adverse event was cytokine release syndrome (any grade: 57%; grade ≥3: 3%); most cases occurred early and were reversible. Across all doses, regimens, and tumor types, the overall response rate (ORR) was 23% (95% CI, 17.4% to 30.2%), the median duration of response (DoR) was 8.5 months (95% CI, 6.2 to not reached), and the 6-month DoR rate was 70% (95% CI, 53% to 88%). All patients in Regimens B2/B3 received the minimum effective dose (≥90 μg/kg once weekly or once every 3 weeks), achieving an ORR of 28% (95% CI, 20.7% to 35.9%). With Regimens B2/B3, ORRs were 21% (95% CI, 12.9% to 33.1%), 27% (95% CI, 17.4% to 39.6%), and 70% (95% CI, 39.7% to 89.2%) for SCLC, epNECs, and LCNEC-L, respectively.

The demonstrated tolerability and efficacy of obrixtamig regimens, administered as step-up followed by target doses of 90-1,080 μg/kg (once weekly or once every 3 weeks), in patients with heavily pretreated DLL3-positive tumors support further exploration in SCLC, epNEC, and LCNEC-L.

To the Editor: Generalized pustular psoriasis (GPP) is a chronic, systemic, neutrophilic inflammatory disease that is distinct from plaque psoriasis.[1] Flares are a hallmark of GPP and although the severity, frequency, and length of flares varies widely between patients, significant flares are often accompanied by systemic symptoms. Life-threatening complications of GPP include sepsis and renal, hepatic, respiratory, and heart failure. Reported GPP mortality rates range from 2% to 16%.[1] Spesolimab, a selective humanized monoclonal antibody targeting the interleukin-36 (IL-36) receptor, is approved in around 40 countries including China, the United States, European Union, and Japan for the treatment of GPP flares in adults.[2] We report safety and efficacy data for spesolimab from an expanded access program (EAP) that was conducted in Chinese patients with GPP who could not participate in clinical trials and to provide real-world evidence of spesolimab treatment. This was a multicenter, single-arm, open-label EAP of intravenous spesolimab 900 mg in patients with GPP presenting with a flare. The EAP was conducted at 12 sites in China from May 23, 2022, to July 17, 2023 (Trial registration: ClinicalTrials.gov, No. NCT05239039). The EAP was conducted and reported in accordance with the Declaration of Helsinki, guidelines for good clinical practice, and local regulations. All local ethics committees were informed and approved the study. All patients provided written informed consent. A schematic of the study design is shown in Supplementary Figure 1, https://links-lww-com.libproxy1.nus.edu.sg/CM9/C578. After screening and enrolment, eligible patients received a single dose of spesolimab. If deemed necessary by the treating physician and if the flare symptoms persisted, patients could receive a second dose of spesolimab 1 week after the first dose. Each patient's study participation ended after conclusion of the 16-week follow-up period following the last administration of spesolimab. Patient enrolment in the EAP stopped when spesolimab became commercially available in China (May 2023). Inclusion and exclusion criteria are documented in Supplementary Materials and Methods, https://links-lww-com.libproxy1.nus.edu.sg/CM9/C578. The primary endpoint was the occurrence of any treatment-emergent adverse events (TEAEs). Secondary endpoints were the occurrence of treatment-emergent serious adverse events (SAEs) and treatment-emergent adverse events of special interest (AESIs). Efficacy endpoints were Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) total scores at week 1 after the administration of spesolimab. The GPPGA total score assesses the average severity of pustulation, erythema, and scaling, with scores ranging from 0 (clear) to 4 (severe). Forty-four patients were screened; 39 entered the EAP and received spesolimab. All patients completed the trial, except for 1 patient (premature discontinuation from the trial by his/her own decision). Baseline demographic and characteristics of patients are summarized in Supplementary Table 1, https://links-lww-com.libproxy1.nus.edu.sg/CM9/C578. All patients were Chinese with a mean (standard deviation [SD]) age of 39.3 (14.6) years and more were female than male (23 [59.0%] vs. 16 [41.0%]). Thirteen (33.3%) patients were diagnosed with GPP >10 years ago; 28 (71.8%) reported using at least one previous medication to treat GPP. Evaluation of common pathogenic mutations in GPP was conducted in 7 (17.9%) patients; no mutations in IL36RN, CARD14, and AP1S3 genes were detected. All patients presented with one GPP flare and none were treated with spesolimab for a recurrent flare after administration in the EAP. Of patients in the treated analysis set, 24 received one dose of spesolimab 900 mg and 15 received the second dose of spesolimab 900 mg 1 week apart. A summary of TEAEs reported during the flare treatment period, and their corresponding incidence rates (rate/100 patient-years), is presented in Table 1. Table 1 - Overall summary of the safety of spesolimab and treatment-emergent AEs during the GPP flare treatment period. Items Values Rate/100 pt-yrs Number of patients 39 Time at risk (pt-yrs) 12.2 Patients with any AE 30 (76.9) 629.0 Patients with severe AEs (RCTC Grade 3 or 4) 4 (10.3) 35.9 Patients with investigator-defined drug-related AEs 14 (35.9) 175.1 Patients with AEs leading to discontinuation of trial drug 0 0 Patients with investigator-defined AESIs 2 (5.1) 17.0 Patients with SAEs* 3 (7.7) 26.2 Resulting in death 0 0 Patients with other significant AEs† (according to project definition) 0 0 Values were shown as n or n (%). *Pneumonia and respiratory failure (1 patient), COVID-19 and pneumonia (1 patient), pustular psoriasis (1 patient); all SAEs recovered. †Significant AEs are those non-serious AEs which were reported with "action taken = drug withdrawn" or "action taken = dose reduced." AE: Adverse event; AESI: Adverse event of special interest; pt-yrs: Patient-years; GPP: Generalized pustular psoriasis; RCTC: Rheumatology Common Toxicity Criteria; SAE: Serious adverse event. Thirty patients (76.9%) experienced one or more TEAEs during the EAP (primary endpoint). The majority of TEAEs were of mild or moderate intensity. The frequency and incidence rate (per 100 patient-years) of adverse events (AEs) by system organ class (SOC) and preferred term (PT) during the GPP flare treatment period are shown in Supplementary Table 2, https://links-lww-com.libproxy1.nus.edu.sg/CM9/C578. At the SOC level, the most frequently reported AEs were infections and infestations (19 patients, 48.7%). At the PT level, the most frequently reported AEs were coronavirus disease 2019 (COVID-19) (10 patients, 25.6%) and pyrexia (6 patients, 15.4%). Investigator-defined drug-related AEs were reported in 14 patients (35.9%). By SOC, the most frequently reported drug-related AEs were infections and infestations, investigations, and general disorders and administration site conditions (each 5 patients). Coding by PT, the most frequently reported drug-related AE was pyrexia (5 patients, 12.8%). In 4 out of 5 patients who experienced drug-related pyrexia, the event occurred in a timeframe close to the GPP flare; in the other patient, pyrexia was reported to be temporally close to a pneumonia event. Severe AEs were experienced by four patients (10.3%): pneumonia (n = 2, 5.1%), COVID-19 (n = 1, 2.6%), pustular psoriasis (n = 1, 2.6%), pyrexia (n = 1, 2.6%), all Grade 3; and Grade 4 respiratory failure (n = 1, 2.6%). All severe AEs were resolved. No AEs resulted in premature discontinuation in this study. Three patients (7.7%) experienced SAEs (which were also classified as severe AEs), comprising pneumonia and respiratory failure (1 patient), COVID-19 and pneumonia (1 patient), and pustular psoriasis (1 patient) [Table 1]. Reported AESIs were severe infections, namely, pneumonia (2 patients) and COVID-19 (1 patient). No AEs resulted in death during the study. Drug-related SAEs were reported in 2 patients (5.1%). One patient experienced pneumonia and non-serious dyspnea 3 days after spesolimab administration. On day 7, respiratory failure was reported, which required respiratory support with oxygen (3–5 L/min). These events were reported as temporally close to the GPP flare. The second patient experienced pustular psoriasis. All events recovered. Pregnant women were not allowed in the EAP. However, one event of spesolimab exposure during pregnancy was reported during the study. A 27-year-old female reported the pregnancy after receiving one dose of spesolimab 900 mg, and a healthy female newborn was delivered successfully. A total of 12 patients had recorded GPPGA scores at baseline. At week 1 after spesolimab administration, 9/12 patients achieved a GPPGA pustulation subscore of 0 and 6/12 patients achieved a GPPGA total score of 0 or 1 [Supplementary Table 3, https://links-lww-com.libproxy1.nus.edu.sg/CM9/C578]. In addition, a total of 6 patients (6/12) were followed up over 16 weeks, of which 5 had a GPPGA pustulation subscore of 0 at each visit after the administration of spesolimab on day 1 until the end of the study visit. The current EAP, conducted in China, allowed patients with GPP flares early access to spesolimab and provides supportive data for the safety profile and efficacy of spesolimab in Asian patients. TEAEs were reported in 30 patients (76.9%) receiving spesolimab. There were no deaths, other significant AEs, or AEs leading to premature discontinuation in this study. The majority of TEAEs were of mild or moderate intensity and in line with expectations from the Effisayil® 1 and 2 clinical trials of spesolimab in GPP.[3,4] The most commonly reported AE was COVID-19 (10 patients, 25.6%), consistent with the fact that this trial was conducted in the context of the COVID-19 pandemic. For the AEs of pyrexia, occurring in 6 patients (15.4%), the association with the GPP flare itself cannot be excluded based on the onset date of the event (mostly 1 or 2 days after the initiation of GPP flare treatment with spesolimab). The frequency of SAEs was generally low (3 patients, 7.7%). All reported SAEs were resolved, including pneumonia (5.1%), COVID-19 (2.6%), respiratory failure (2.6%), and pustular psoriasis (2.6%). Overall, the EAP showed that intravenous spesolimab was associated with improvement of skin manifestations at week 1 compared with baseline. These results are consistent with those reported in Effisayil® 1,[3] although it should be noted that one-third of patients in the EAP had a baseline GPPGA total score of 2 whereas all patients in Effisayil® 1 had a baseline GPPGA total score of 3 or 4 (indicating more severe GPP); similarly, 2 patients in the EAP had a baseline GPPGA pustulation subscore of 1 whereas all patients in Effisayil® 1 had a baseline GPPGA pustulation subscore >1. In summary, to the best of our knowledge, this EAP conducted in China represents the largest real-world study of spesolimab in patients with GPP presenting with a flare and provides important safety evidence regarding the use of spesolimab for future clinical practice. Overall, spesolimab was safe and well tolerated. The improvements from baseline in skin manifestations are consistent with those reported in Effisayil® 1. Conflicts of interest This study was supported by Boehringer Ingelheim. Nichiren Pillai, Fan Chen, Yijun Zhou, and Yuexiao Xu are employees of Boehringer Ingelheim. All other authors have nothing to disclose. Data availability statement Datasets generated during and/or analyzed during the current study are available upon request via the link https://trials.boehringer-ingelheim.com/. Acknowledgements The authors thank Nora Pöntynen for her contributions to study design and conception and program implementation. Medical writing support, under the guidance of the authors, was provided by David P. Figgitt and Robert A.

Traditional methods for developing modified-release (MR) formulations involve numerous iterations and large quantities of drug substances, which pose considerable challenges in exploration settings. Given the growing necessity for modified-release (MR) formulations in the pharmaceutical industry, particularly during the preclinical research and development phase, modified-release strategies may serve as attractive alternatives to discontinuing clinical development and could mitigate the costs and time associated with identifying new drug candidates. This study specifically explores the application of melt extrusion deposition (MED) 3D printing technology as a rapid prototyping platform for creating extended-release (ER) oral dosage forms tailored for the preclinical phase. Using the model compound BI 894416, the study demonstrated that MED 3D printing enables precise control over drug release profiles through both structural and compositional designs. The physicochemical analysis conducted during the 3D printing process revealed no degradation or compatibility issues. In vivo pharmacokinetic (PK) studies in rats and dogs validated the extended-release (ER) performance of BI 894416, with t_max values of 2-4 h in rats and 5 h in dogs. The ER tablets achieved prolonged plasma exposure and reduced peak-to-trough fluctuations compared to those of immediate-release (IR) formulations (ER: 144 versus IR: 929 in dogs). A Level A in vitro-in vivo correlation (IVIVC) was established, demonstrating strong alignment between in vitro dissolution and in vivo absorption up to 4 h, with a minor lag time observed. These results further confirmed the likely absorption of BI 894416 in the upper gastrointestinal (GI) tract and the potentially ascending colon. These findings highlight the potential of MED 3D printing to streamline the development of MR formulations in preclinical settings, offering a flexible, efficient, and material-sparing alternative to conventional approaches.