Eli Lilly (United Kingdom)

Injuries to the trigeminal nerve, responsible for sensory innervation to the face, may occur during routine dental procedures, resulting in the formation of a neuroma accompanied by loss of sensation and/or symptoms of pain. To gain insight into the molecular mechanisms underpinning the sensory changes, single nuclei RNA sequencing and spatial transcriptomics were used to profile the transcriptional landscape at single cell resolution of human trigeminal nerves and neuromas. Cellular and transcriptional changes were identified that correlated with the presence of pain, including an expansion of endothelial cells with a proinflammatory phenotype and overexpression of HLA-A , CXCL2 , and CXCL8 . Interactome analysis highlighted signaling changes linked with the presence of pain. HLA-A protein expression was confirmed in neuromas and positively correlated with symptoms of pain. Our data provide a detailed spatial overview of the cell types that populate human peripheral trigeminal nerves, in health and injury, and their transcriptional profile. The comparison of painful and nonpainful samples highlights several changes in cellular composition, transcriptome and inferred molecular signaling linked specifically with the presence of pain, and also a novel role for HLA-A in neuropathic pain. Our findings represent a valuable resource for pain research, highlighting the role of inflammation, endothelial cell dysfunction, and chemokine signaling in neuropathic pain.

Abstract Background Traditional Crohn’s disease (CD) trials used a re-randomisation design, but more recent trials, including trials with the interleukin (IL)-23p19 inhibitors mirikizumab, guselkumab, and risankizumab, used a treat-through design vs a direct comparator ustekinumab; however, there were clinically relevant different trial settings. The U.S. Food and Drug Administration raised concerns on the reliability of network meta-analysis (NMA) results with such limitations. This study developed an adjustment method to address the heterogeneity of these trials using the imbalanced discontinuation rates and to test the impact of the proposed bias adjustments in NMA. Methods The studies VIVID-1, GALAXI 2-3, and SEQUENCE were identified for this NMA and only patients with a previous failure of a biologic were considered. While VIVID-1 and GALAXI 2-3 had a similar design, SEQUENCE was open label and presented an uncommon heterogeneous discontinuation rate between the study arms (9.8% for risankizumab vs 27.2% for ustekinumab). We developed a method and applied in 3 scenarios to adjust the risk difference based on a clinical assumption about the outcomes of the excess discontinuers in the ustekinumab arm and incorporated it into an NMA. Scenario one assumed that the higher amount of non-completers in the ustekinumab arm would respond like the completers, if they had not discontinued the study. For the second and third scenarios, different downgrade factors were applied to mitigate the strength of the assumption. The outcomes presented are clinical remission and endoscopic remission at 48/52 weeks. Results The data included only bio-failed patients that presented comparable values regarding age, sex, SES-CD, and CDAI across the studies. After the three adjustments, clinical remission achievement rates for ustekinumab in the study SEQUENCE were 50.5%, 49.5%, and 47.8%, respectively, compared to the unadjusted 40.8%. Endoscopic remission achievement rates for ustekinumab in the study SEQUENCE were 20.1%, 19.7%, and 19.0% compared to the unadjusted 16.2%. The NMA showed comparable efficacy across the IL-23s in all three situations. Conclusion Across different approaches, this study explored the impact of different adjustments for discontinuation bias in an NMA of CD IL-23p19 treat-through trials. Consistent results were observed across adjusted approaches compared to the unadjusted NMA. No difference in remission efficacy was observed across mirikizumab, guselkumab, and risankizumab. Conflict of interest: Dr. Mckenzie, Robert: I work full time for Eli Lilly and a shareholder Sands, Bruce E: Grant: Janssen Personal Fees: Abivax SA Abbvie Adiso Therapeutics Agomab Therapeutics Alimentiv Amgen AnaptysBio AstraZeneca Biora Therapeutics Boehringer-Ingeleim Bristol Myers Squibb Celltrion, Inc. ClostraBio Cytoki Pharma EcoR1 Capital Eli Lilly and Company Enthera Equilium, Inc. Ensho Therapeutics Evommune Ferring Galapagos Genentech, Inc. Gilead Sciences GlaxoSmithKline Gossamer Bio Imhotex Immunyx Pharma Ltd. Index Pharmaceuticals Innovation Pharmaceuticals Janssen Janssen Biotech Janssen Pharmaceutica NV Janssen Research & Development, LLC Janssen Scientific Affairs, LLC Janssen-Cilag PTY, Ltd. Johnson & Johnson Kaleido Kallyope Kyowa Kirin, Inc. Merck & Co. Microba Microbiotica Limited Mirador Therapeutics Morphic Therapeutic MRM Health NV Palisade Therapeutics Pfizer, Inc. Prometheus Biosciences Prometheus Laboratories Protagonist Therapeutics, Inc. Q32 Bio Sanofi Sorriso Therapeutics Surrozen Takeda Target RWE Teva TLL Pharmaceutical Tr1x Union Therapeutics Ventyx Biosciences Non-financial Support: Janssen, Pfizer, Lilly, Takeda, Bristol Myers Squibb Other: Stock/Stock Options from Ventyx Biosciences Dignass, Axel: Personal Fees: AbbVie, Alfasigma, CED Service GmbH, Celltrion, Dr. Falk Pharma, Falk Foundation, Ferring, Fresenius Kabi, Gilead, High5MD, J & J, Lilly, Materia Prima, MSD, Pfizer, Pharmacosmos, Sandoz, Stada, Streamed-Up, Takeda, Tillotts, Vifor Pharma Grant Abbvie, J & J, Takeda Non-financial support Abbvie, J & J, Takeda Other: Abivax, AbbVie, Alfasigma, Dr Falk Pharma, Fewrring, J & J, Pfizer Hisamatsu, Tadakazu: Grant support: Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., AbbVie GK, JIMRO Co. Ltd., Zeria Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Pfizer Inc., Mochida Pharmaceutical Co. Ltd., Boston Scientific Corporation, Kissei Pharmaceutical Co. Ltd. Consulting: Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., AbbVie GK, Janssen Pharmaceutical K.K., Pfizer Inc., Eli Lilly, Gilead Sciences, Bristol Myers Squibb, Abivax, MSD, Chugai. Lecture fee: Mitsubishi Tanabe Pharma Corporation, AbbVie GK, EA pharma Co. Ltd., Kyorin Pharmaceutical Co. Ltd., JIMRO Co., Janssen Pharmaceutical K.K., Mochida Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. Ltd., Pfizer Inc., Kissei Pharmaceutical Co. Ltd. Panni, Tommaso: I am a full time employee by Eli Lilly and a shareholder tarafder, abdul_masud: I am a full time employee at Eli Lilly and a shareholder Richards, Melissa: work for Eli Lilly and Co, pharmaceutical company De La Torre Ortega, Inmaculada: Lilly employee Fewster, Harriet: No conflict of interest Moss, Joe: No conflict of interest

BackgroundWe aimed to describe the diagnostic journey, current treatment, caregiving needs, and burden of patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia in China.MethodData were drawn from the Adelphi Real World AD Disease Specific Programme™, a cross‐sectional survey of neurologists and their patients with MCI/AD across China, between 2024/02–2024/05. Neurologists completed patient record forms for their next (up to) nine consecutively consulting MCI/AD patients, capturing the diagnostic journey, current treatment, and caregiver support. Patients were invited to provide a self‐completion questionnaire, reporting on delays to first seeing a doctor and quality of life via the EQ‐5D visual analogue scale. Disease severity was defined using Mini Mental State Examination (MMSE) score: MCI/mild AD (20‐28) or moderate/severe AD (0‐19). Analyses were descriptive.ResultNinety‐three neurologists reported data on 774 patients (mean±standard deviation age 69.2±8.3 years, body weight 64.2±11.4 kg, 49.1% female), of whom 192 self‐completed a patient survey. Of 699 patients with an available MMSE, 52.5% were currently MCI/mild AD and 47.5% moderate/severe AD. Median (interquartile range [IQR]) time between symptom onset and first consultation was 18.1 (8.4, 40.3) weeks, with 34.7% of patients experiencing moderate/severe AD by their initial consultation. Most patients (80.0%) were not diagnosed at initial consultation, with median (IQR) time from first consultation to diagnosis taking 4.4 (1.9, 12.9) weeks. Few patients (18.8%) had a biomarker confirmed diagnosis (mainly cerebral spinal fluid [11.2%] and amyloid positron emission tomography [7.7%]). Acetylcholinesterase Inhibitors (66.0%), N‐methyl‐D‐aspartate antagonist (33.5%), and nootropics (26.4%) were the most common current treatments, and long‐lasting effect was the top (37.1%) identified area for improvement. Among those with MCI/mild AD, 79.4% received non‐professional care (NPC) and 2.7% required professional care (95.2% and 15.7% for moderate/severe AD, respectively). On average, NPC partners spent 36.7±39.5 hours/week for MCI/mild AD and 47.3±39.6 hours/week for moderate/severe AD, and spouse/partner was the most frequent NPC partner. Mean EQ‐5D‐VAS score was 71.9±11.1 for those with current MCI/mild AD and 63.7±16.6 for moderate/severe AD.ConclusionFurther improvement is needed in early detection and accurate diagnosis of MCI/AD to lessen the burden to patients, care partners, and society.

INTRODUCTIONDonanemab is an immunoglobulin G1 antibody that targets an N‐terminal truncated form of amyloid beta present in mature plaques. Treatment‐emergent (TE) anti‐drug antibodies (ADAs) were quantified in donanemab‐treated participants from two pivotal clinical trials, and effects of TE ADAs on donanemab pharmacokinetics, efficacy, and safety were assessed.METHODSData were pooled from the phase 2 TRAILBLAZER‐ALZ (NCT03367403) and phase 3 TRAILBLAZER‐ALZ 2 trials (NCT04437511). Eligible participants were randomized 1:1 to donanemab (700 mg for the first three doses, 1400 mg thereafter) or placebo intravenously every 4 weeks up to 72 weeks. TE ADA‐evaluable participants had a non‐missing baseline ADA result and ≥ 1 non‐missing post‐baseline ADA result. TE ADA incidence and effect of titer on pharmacokinetics, amyloid plaque reduction, clinical efficacy (measured by change from baseline of integrated Alzheimer's Disease Rating Scale [iADRS] score and Clinical Dementia Rating Scale Sum of Boxes [CDR‐SB]), and safety were assessed.RESULTSOf 922 TE ADA‐evaluable donanemab‐treated participants, 56 (6.1%) had ADAs detected at baseline, and 812 (88.1%) were TE ADA positive. Donanemab clearance increased linearly with logarithm of ADA titer; however, titer did not affect maximum donanemab concentration. Amyloid plaque level was significantly reduced with donanemab versus placebo, irrespective of titer (P < 0.001 for all). No association was found between ADA presence or titer and donanemab efficacy by iADRS or CDR‐SB. Eighty‐four of 984 (8.5%) donanemab‐treated participants and 4 of 999 (0.4%) placebo‐treated participants reported infusion‐related reactions (IRRs). All donanemab‐treated participants reporting immediate IRRs developed ADAs at some point during the study; however, 90.5% of TE ADA‐positive participants did not experience IRRs.DISCUSSIONMost participants were TE ADA positive. TE ADAs increased donanemab clearance but did not have clinically meaningful impact on plaque reduction or efficacy. While all participants reporting IRRs developed ADAs at some point during the study, the majority of participants with ADAs did not experience IRRs.HighlightsIn pivotal trials, most donanemab‐treated participants were treatment‐emergent anti‐drug antibody (TE ADA) positive.TE ADAs increased donanemab clearance but did not impact plaque reduction/efficacy.All participants reporting infusion‐related reactions (IRRs) developed ADAs at some point during the study.However, the majority of participants with ADAs did not experience IRRs.

Background: Parkinson Disease (PD) is a progressive neurodegenerative disorder. Current therapeutic trials investigate treatments that can potentially modify the disease course. Testing their efficiency requires outcome assessments that are relevant to patients' daily lives, which include gait and balance. Home-based examinations may enhance patient compliance and, in addition, produce more reliable results by assessing patients more regularly in their familiar surroundings. Objective: The objective of this pilot study was to assess the feasibility of a home-based outcome assessment designed to video record the Timed up and Go (vTUG) test via a study-specific smartphone app for patients with PD. Methods: 28 patients were recruited and asked to perform at home each week a set of three consecutive vTUG tests, over a period of 12 weeks using an app. The videos were subjected to a manual review to ascertain the durations of the individual vTUG phases, as well as to identify any errors or deviations in the setup that might have influenced the result. To evaluate the usability and user-friendliness of the vTUG and app, the System Usability Scale (SUS) and User Experience Questionnaire (UEQ) were administered to patients at the study end. Results: 19 patients completed the 12-week study, 17 of which recorded 10 videos or more. A total of 706 vTUGs with complete timings were recorded. Random Forest Regression yielded "time to walk up" as the most important segment of the vTUG for predicting the total time. Variance of vTUG total time was significantly higher between weeks than it was between the three consecutive vTUGs at one time point [F(254,23) = 6.50, p < 0.001]. The correlation between vTUG total time and UPDRS III total score was weak (r = 0.24). The correlation between vTUG and a derived gait subscore (UPDRS III items 9-13) was moderate (r = 0.59). A linear mixed-effects model revealed a significant effect of patient-reported motion status on vTUG total time. Including additional variables such as UPDRS III gait subscore, footwear and chairs used further improved the model fit. Conclusions: Assessment of gait and balance by home-based vTUG is feasible. Factors influencing the read-out were identified and could be better controlled for future use and longitudinal trials.

ABSTRACTSelpercatinib is a first‐in‐class, highly selective, RET kinase inhibitor with CNS activity, approved for the treatment of RET‐altered lung, thyroid, and other cancers. We report pharmacokinetic analyses to identify factors affecting selpercatinib steady‐state exposure and support posology in pediatric patients. Population pharmacokinetic analyses using nonlinear mixed‐effects modeling were performed on data from two ongoing, open‐label, Phase 1/2 studies in adult and pediatric patients with advanced solid tumors. In LIBRETTO‐001 (NCT03157128) patients (≥ 12 years) received oral selpercatinib from 20 mg once daily through 240 mg twice daily (BID) during phase 1 and 160 mg BID in phase 2. In LIBRETTO‐121 (NCT03899792), patients (6 months–21 years) received doses based on body surface area (BSA), starting at a dose expected to match adult exposure of 160 mg BID. Overall, 8024 selpercatinib plasma concentration measurements from 830 patients were included in the pharmacokinetic analysis. The final model, a 2‐compartment disposition model with sequential zero‐ and first‐order absorption, was similar to a previously developed adult model, which identified weight, dose, and Asian race as covariates. Simulations performed using the final model suggested the following dose regimen as appropriate for patients aged 2–17 years: 40 mg three times a day for pediatric patients with a BSA of 0.33–0.65 m2; BSA‐based dosing (92 mg/m2 rounded for 40 and 80 mg capsules) for pediatric patients 2 to < 12 years, and BSA ≥ 0.66 m2; and weight‐based dosing (120 mg BID < 50 kg and 160 mg BID ≥ 50 kg) for adolescent patients ≥ 12 years.

To understand the trade-offs that patients with episodic migraine are willing to make between attributes of self-injectable calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) and oral small-molecule calcitonin gene-related peptide receptor antagonists (gepants). This was an online discrete choice experiment survey among adults with episodic migraine (≥4 and <15 migraine headache days and <15headache days per month over 3 months) in the United States. Hypothetical treatments were characterized by five attributes: chance of ≥50% migraine reduction, impact on daily activities, onset of treatment effect, reduction in number of acute medications, and treatment administration. The attributes were selected based on insights gained from a previously conducted literature review and focus group study and aligned with the primary and secondary outcome measures in the double-blind Phase IV head-to-head clinical trial of a CGRP mAb versus gepant. 601 patients (mean age: 44.8 years) completed the survey. Treatment preferences differed significantly between patients. However, for all patients, the most important driver of treatment preferences was the chance of a ≥50% reduction in monthly migraine headache days (relative attribute importance: 38.3%), followed by the impact on daily activities (23.5%), the onset of treatment effect (19.5%), the reduction in need for acute medication (15.4%), and finally the route of administration (3.4%). Patients were willing to consider a one-week delayed onset of treatment effect or one-day increased need for acute medication for a higher chance (by 2.06% and 2.65% respectively) of a ≥50% reduction in monthly migraine headache days. Patients would trade a reduction of migraine's impact on daily activities from "extreme" to "moderate" or "minimal" with a lower chance (17.09%, 12.06% respectively) of halving the number of monthly migraine headache days. A ≥50% reduction in monthly migraine headache days was the most important treatment attribute for which participants were willing to trade against other attributes. The variation in treatment preferences between patients emphasizes the importance to align decision-making with individual patients' preferences.