Introduction ND0612 is being investigated as a continuous, subcutaneous levodopa/carbidopa infusion, in combination with oral levodopa/carbidopa, for motor fluctuations in Parkinson's disease (PD). One-year data from the ongoing BeyoND study (NCT02726386) showed that the ND0612 regimen was safe and well tolerated and provided a sustained ≥2-h improvement in daily Good ON-time through 12 months of treatment. Methods We describe 3-year safety and efficacy outcomes for participants who completed 12 months of ND0612 treatment in the core study period and entered the extension phase. Results Of the 214 enrolled participants, 120 completed the core 1-year period, and 114 participants continued into the extension phase. Of these, 95/114 (83.3 %) completed 2 years and 77/114 (67.5 %) completed 3 years of study treatment. Key reasons for discontinuation were treatment-emergent adverse events (TEAEs) (n = 5 and n = 11 after 2 and 3 years, respectively) and withdrawal of consent (n = 9 and n = 5, respectively). TEAEs were reported by 105/114 (92.1 %) participants in Year 1, 77/114 (67.5 %) in Year 2, and 73/95 (76.8 %) in Year 3. While most participants experienced infusion site reactions, these led to discontinuation in only five participants during this extension. At Month 36, the mean reduction in OFF-time from baseline was 2.81 h and the increase in Good ON-time was 2.79 h. Conclusions Three-year results from this open-label study support the long-term safety, tolerability, and efficacy of ND0612. For participants who entered the extension phase, the high rate of retention supports a favorable benefit-risk ratio of the ND0612 regimen for patients with PD experiencing motor fluctuations.

Abstract The tumor-associated antigen STEAP1 is a potential therapeutic target that is expressed in most prostate tumors and at increased levels in metastatic castration-resistant prostate cancer (mCRPC). We developed a STEAP1-targeted XmAb 2+1 T-cell engager (TCE) molecule, AMG 509 (also designated xaluritamig), that is designed to redirect T cells to kill prostate cancer cells that express STEAP1. AMG 509 mediates potent T cell–dependent cytotoxicity of prostate cancer cell lines in vitro and promotes tumor regression in xenograft and syngeneic mouse models of prostate cancer in vivo. The avidity-driven activity of AMG 509 enables selectivity for tumor cells with high STEAP1 expression compared with normal cells. AMG 509 is the first STEAP1 TCE to advance to clinical testing, and we report a case study of a patient with mCRPC who achieved an objective response on AMG 509 treatment. Significance: Immunotherapy in prostate cancer has met with limited success due to the immunosuppressive microenvironment and lack of tumor-specific targets. AMG 509 provides a targeted immunotherapy approach to engage a patient's T cells to kill STEAP1-expressing tumor cells and represents a new treatment option for mCRPC and potentially more broadly for prostate cancer. See related commentary by Hage Chehade et al., p. 20. See related article by Kelly et al., p. 76. This article is featured in Selected Articles from This Issue, p. 5

To confirm target engagement of hits from our high-throughput screening efforts, we ran biophysical assays on several hundreds of hits from 15 different high-throughput screening campaigns. Analyzing the biophysical assay results from these screening campaigns led us to conclude that we could be more strategic in our biophysical analysis of hits by first confirming activity in a thermal shift assay (TSA) and then confirming activity in either a surface plasmon resonance (SPR) assay or a temperature-related intensity change (TRIC) assay. To understand how this new workflow shapes the quality of the final hits, we compared TSA/SPR or TSA/TRIC confirmed and unconfirmed hits to one another using four measures of compound quality: quantitative estimate of drug-likeness (QED), Pan-Assay Interference Compounds (PAINS), promiscuity, and aqueous solubility. In general, we found that the biophysically confirmed hits performed better in the compound quality metrics than the unconfirmed hits, demonstrating that our workflow not only confirmed target engagement of the hits but also enriched for higher quality hits.

BackgroundConventional oral levodopa therapy for the treatment of Parkinson's disease can be associated with variations in plasma concentrations. Levodopa infusion strategies might provide more consistent drug delivery and fewer motor fluctuations. We aimed to assess the safety and efficacy of a continuous 24 h/day subcutaneous infusion of ND0612 (a levodopa–carbidopa solution) compared with oral immediate-release levodopa–carbidopa for the treatment of motor fluctuations in people with Parkinson's disease.MethodsWe conducted a phase 3, randomised, double-blind, double-dummy, active-controlled, multicentre trial at 117 academic and community neurology sites in 16 countries, including in Europe, Israel, and the USA. Eligible participants were men and women aged 30 years or older with a diagnosis of Parkinson's disease (Hoehn and Yahr stage ≤3 in the on state) who experienced at least 2·5 h/day of off time. Participants underwent an open-label run-in phase (<12 weeks), during which time optimal regimens were established for both oral immediate-release levodopa–carbidopa and for 24 h/day subcutaneous ND0612 infusion (levodopa–carbidopa 60·0/7·5 mg/mL), with supplemental oral levodopa–carbidopa if needed. Participants were then randomly assigned (1:1) to 12 weeks of double-blind treatment with their optimised regimen of either subcutaneous ND0612 or oral levodopa–carbidopa, with matching oral or subcutaneous placebo given as required to maintain blinding. Randomisation was done via an interactive web response system, stratified by region, using a permuted block schedule. Participants, study partners, treating investigators, study site personnel, and the sponsor were masked to treatment group allocation. The primary efficacy endpoint was the change from baseline (ie, time of randomisation, when all patients were receiving an optimised open-label ND0612 regimen) to end of the double-blind phase in total daily on time without troublesome dyskinesia, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, NCT04006210, and is complete.FindingsBetween Sept 30, 2019, and April 8, 2022, 381 participants were enrolled, of whom 259 (68%) were randomly assigned, 128 (49%) to subcutaneous ND0612 and 131 (51%) to oral levodopa–carbidopa. 243 (94%) participants completed the study. Treatment with subcutaneous ND0612 provided an additional 1·72 h (95% CI 1·08 to 2·36) of on time without troublesome dyskinesia compared with oral levodopa–carbidopa (change from baseline of –0·48 h [–0·94 to –0·02] with subcutaneous ND0612 vs –2·20 h [–2·65 to –1·74] with oral levodopa–carbidopa; p<0·0001). Significant treatment differences favouring subcutaneous ND0612 were also found in the first four of nine prespecified hierarchical outcomes of daily off time (–1·40 h [95% CI –1·99 to –0·80]), Movement Disorders Society-Unified Parkinson's Disease Rating Scale part II scores (–3·05 [–4·28 to –1·81]), Patients Global Impression of Change (odds ratio [OR] 5·31 [2·67 to 10·58]), and Clinical Global Impression of Improvement (OR 7·23 [3·57 to 14·64]). Hierarchical testing ended after the fourth secondary endpoint. Adverse events were reported by 287 (89%) of 322 participants during open-label ND0612 optimisation, and by 103 (80%) of 128 in the ND0612 group and 97 (74%) of 131 in the oral levodopa–carbidopa group during the double-blind phase. The most common adverse events were infusion-site reactions (266 [83%] participants during open-label ND0612, and 73 [57%] in the ND0612 group vs 56 [43%] in the oral levodopa–carbidopa group during the double-blind phase), most of which were mild. Serious adverse events in four participants in the ND0612 group were related to study treatment (infusion-site cellulitis [n=2], infusion-site abscess and infusion-site ulcer [n=1]; and paraesthesia and peripheral sensorimotor neuropathy [n=1]). One participant in the ND0612 group died during the double-blind phase, but the death was not related to study treatment (fall leading to traumatic brain injury).InterpretationResults of this phase 3 study showed that subcutaneous ND0612 used in combination with oral immediate-release levodopa–carbidopa increased on time without troublesome dyskinesia and reduced off time, with a favourable benefit–risk profile. ND0612 might offer a safe and efficacious subcutaneous levodopa infusion approach to managing motor fluctuations in people with Parkinson's disease. The ongoing open-label extension phase will provide further information on the long-term efficacy and safety of treatment.FundingNeuroDerm.

STEAP1 plasmid constructs used for alanine-scanning mutagenesis.

This file contains Methods for Supplementary Data.

Objective: Evaluate three-year outcomes from the ND0612 BeyoND study. Background: ND0612 is in development as a continuous, subcutaneous levodopa/carbidopa delivery system for PD patients experiencing motor fluctuations. One year data showed that ND0612 was safe and well-tolerated and provided a sustained ≥2-hour improvement in daily 'Good' ON-time without troublesome dyskinesia and a corresponding reduction in OFF-time through 12 months of treatment. Design/Methods: The BeyoND study is an ongoing international, open-label study (NCT02726386) evaluating the long-term safety of ND0612 in PD patients experiencing ≥2 hours daily OFF-time. The primary endpoint was assessed at 12 months followed by an extension (OLE) of up to 108 months. Results: Of the 114 patients who continued into the OLE, 94 (82.5%) completed ≥2 years and 76 (66.7%) completed ≥3 years of ND0612 treatment; main reasons for discontinuation were withdrawal of consent in the 2nd (n=8) and 3rd (n=5) years, and adverse events (AEs) (n=4 and n=10, respectively). Of those patients who started the OLE, treatment-related AEs were reported by 73.7% of patients in Yr1, decreasing to 36.9% in Yr2 and 39.4% in Yr3. While most patients experienced infusion-site reactions (ISRs), these led to early discontinuation in only 4.4% of patients. The incidence of infusion-site infection decreased from 19.3% in Yr1 to 9.9% in Yr2, and 11.7% in Yr3, while incidence of other ISRs decreased from 60.5% in Y1 to 26.1% in Yr2, and 27.7% in Yr3. Dyskinesia was reported in 3.5% of patients in Yr1, none in Yr2, and 1.1% in Yr3. At Month 36, the mean reduction in OFF-time was −2.81h and the increase in Good ON-time was 2.79h. Conclusions: Three-year data from this open-label study support the long-term safety, tolerability, and efficacy of ND0612. For patients who entered the OLE, the high rate of retention supports a favorable benefit-risk ratio of ND0612. Disclosure: Dr. Ellenbogen has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for allergan. Dr. Ellenbogen has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for allergan. Dr. Ellenbogen has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Teva. Dr. Ellenbogen has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Supernus. Dr. Ellenbogen has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for ipsen. Dr. Ellenbogen has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Acorda. Liat Adar has received personal compensation for serving as an employee of Neuroderm. Laurence Salin has received personal compensation for serving as an employee of NeuroDerm. Dr. Case has received personal compensation for serving as an employee of NeuroDerm. Tamar Yardeni has received personal compensation for serving as an employee of NeuroDerm. Dr. Espay has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Neuroderm. Dr. Espay has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Avion. Dr. Espay has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Amneal. Dr. Espay has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Acadia. Dr. Espay has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Acorda. Dr. Espay has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Kyowa Kirin. Dr. Espay has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sunovion. Dr. Espay has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Herantis Pharma. Dr. Espay has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Supernus (formerly USWorldMeds). Dr. Espay has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Acadia. Dr. Espay has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AskBio. Dr. Espay has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Supernus (formerly, USWorldMeds). Dr. Espay has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Amneal. Dr. Espay has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Avion Pharmaceuticals. The institution of Dr. Espay has received research support from NIH. The institution of Dr. Espay has received research support from Michael J Fox Foundation for Parkinson's Research. Dr. Espay has received intellectual property interests from a discovery or technology relating to health care. Dr. Espay has received publishing royalties from a publication relating to health care. Dr. Espay has received publishing royalties from a publication relating to health care. Dr. Espay has received publishing royalties from a publication relating to health care.

Supplementary Methods. Supplementary Table 1 - Key Resources Including Sources of Biological Samples, Antibodies, and Key Reagents. Supplementary Table 2 -Correlation of FLT3 Expression Levels With Disease Characteristics at Initial Diagnosis. Supplementary Table 3 - Summary of Human Nonimmune Tissues Positive for FLT3 mRNA and/or Protein Expression in At Least One Platform. Supplementary Table 4. Cerebellum FLT3 RNA Analysis. Supplementary Table 5 - Binding Affinities of Experimental FLT3 BiTE® Molecule and AMG 427. Supplementary Table 6 - Cell Line Characterization, Cytotoxicity, and T-Cell Activation (Human). Supplementary Table 7 - Cynomolgus Monkey Pharmacokinetics for Experimental FLT3 BiTE® Molecule. Supplementary Table 8 - Cynomolgus Monkey Pharmacokinetics for AMG 427. Supplementary Table 9 - Cynomolgus Monkey FLT3 Primer and Probe Sequences. Supplementary Table 10 - Patient Characteristics. Supplementary Table 11 - Mass Spectrometry Results. Supplementary Figure 1 - Additional flow cytometry expression analysis for acute myeloid leukemia (AML) and healthy donor (HD) bone marrow (BM). Supplementary Figure 2 - Analysis of FLT3 expression on normal human bone marrow. Supplementary Figure 3 - Analysis of FLT3 transcript and protein in cerebellum revealed truncated transcripts. Supplementary Figure 4 - In vitro characterization of FLT3 BiTE® molecules. Supplementary Figure 5 - Experimental FLT3 BiTE® molecule activity in vivo. Supplementary Figure 6 - FLT3 BiTE® molecule in vitro activity with cynomolgus monkey effector cells. Supplementary Figure 7 - FLT3 expression in cynomolgus monkey blood and bone marrow. Supplementary Figure 8 - AMG 427 pharmacodynamics in cynomolgus monkey. Supplementary Figure 9 - (A) Representative populations of T cells (CD2+) and AML cells (CD33+) over time from a responder (Patient 4; Figure 6A). (B) PD-1 expression on CD3+ cells from a T-cell-dependent cellular cytotoxicity (TDCC) of human pan T cells co-cultured 5:1 with MV4-11 cells for 48 hours assessed by flow cytometry.

To evaluate the pharmacokinetic–pharmacodynamic relationships between levodopa plasma exposure and motor treatment response in patients with Parkinson's disease (PD) treated with ND0612 and adjunct oral PD medication.

Background While treatment with levodopa remains the cornerstone of Parkinson's disease (PD) management, chronic oral therapy is often associated with the development of motor complications, that correlate to fluctuating levodopa plasma concentrations, limiting its clinical utility. Continuous infusion is considered to be the optimal delivery route for treating PD patients with motor fluctuations, but current infusion systems require invasive surgery. Subcutaneous infusion of (SC) levodopa has the potential to provide a better tolerated and more convenient route of continuous levodopa delivery. ND0612 is in development as a combination product providing continuous levodopa/carbidopa via a minimally invasive, subcutaneous delivery system for PD patients experiencing motor response fluctuations. We present pharmacokinetic results from a series of studies that analyzed plasma concentrations after SC levodopa delivery with ND0612 to inform the clinical development program. Methods We performed a series of six Phase I and II studies to characterize the pharmacokinetics of levodopa and carbidopa derived from ND0612 infusion with/without adjunct oral therapy of the same ingredients. These studies were conducted in healthy volunteers and in PD patients experiencing motor response fluctuations while on their current levodopa therapy regimen. Results Taken together, the results demonstrate dose-proportionality dependent on rate of subcutaneous levodopa infusion leading to stable and sustained plasma concentrations of levodopa. Subcutaneous infusion of ND0612 administered with oral levodopa/carbidopa maintained near-constant, therapeutic levodopa plasma concentrations, thereby avoiding the troughs in levodopa plasma concentrations that are associated with OFF time in PD. The data generated in this series of studies also confirmed that a levodopa/carbidopa dose ratio of 8:1 would be the most reasonable choice for ND0612 development. Conclusions This series of clinical pharmacokinetic studies have demonstrated that ND0612, administered continuously with a levodopa concentration of 60 mg/ml combined with carbidopa 7.5 mg/ml, and complemented with oral levodopa/carbidopa, is suitable for 24 h continuous administration in patients with PD. The stable plasma concentrations of levodopa achieved predict utility of ND0612 as a parenteral formulation for achieving clinically useful delivery of levodopa for PD patients.

To report cumulative data from the ongoing BeyoND study (NCT02726386) beyond 1 year.

ABSTRACTBackgroundContinuous, subcutaneous (SC) levodopa/carbidopa infusion with ND0612 is under development as a treatment for patients with Parkinson's disease (PD) and motor fluctuations.ObjectiveEvaluate 1‐year safety data.MethodsBeyoND is an open‐label study evaluating the long‐term safety of two ND0612 dosing regimens.ResultsOf the 214 enrolled patients (24‐hour SC infusion: n = 90; 16‐hour SC infusion: n = 124), 120 (56%) completed 12 months of treatment. Leading causes for study discontinuation were consent withdrawal (19.6%) and adverse events (17.3%). Rates of discontinuation were reduced from 49% to 29% after a protocol revision and retraining. Systemic safety was typical for PD patients treated with levodopa/carbidopa. Most patients experienced infusion site reactions, particularly nodules (30.8%) and hematoma (25.2%), which were judged mostly mild to moderate and led to discontinuation in only 10.3% of the participants.ConclusionsSubcutaneous levodopa/carbidopa continuous infusion with ND0612 is generally safe, with typical infusion site reactions for SC delivery as the main adverse event. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Significance Alzheimer’s disease (AD) is the most common dementia; no therapy halts its progression. AD pathology, including amyloid-β (Aβ) plaques, neurofibrillary tangles, and synapse loss, triggers microglial responses that modulate disease course. The TREM2 receptor promotes microglia responses to pathology and a variant, TREM2 R47H , impairs ligand binding and increases AD risk. Employing scRNA-seq, we asked: can an anti-TREM2 antibody, acting as a surrogate ligand, stimulate microglia in mice that accumulate Aβ and express either the common TREM2 variant ( TREM2 CV ) or TREM2 R47H ? One systemic injection of anti-TREM2 restored microglia activation in TREM2 R47H mice but promoted limited activation in mice carrying TREM2 CV , which binds endogenous ligands. Thus, anti-TREM2 can strengthen microglial responses during AD, contingent on preexisting TREM2 engagement and basal activation.

INTRODUCTION:ND0612 is a continuous, subcutaneous levodopa/carbidopa delivery system under development for patients with Parkinson's disease (PD) and motor fluctuations. METHODS:This was a randomized, placebo-controlled, double-blind, 2-period study evaluating the safety and pharmacokinetics of ND0612 in PD patients on an optimized oral levodopa regimen and experiencing ≥2 h/day of OFF time. During Period-1, patients received their current standard of care (SoC) levodopa/carbidopa and were randomized (2:1) to 14 days treatment with adjunct ND0612 (daily levodopa/carbidopa dose of 270/63 mg) or placebo infusion +SoC. During Period-2, 16 patients were randomized to receive 7 days treatment with ND0612 or ND0612 plus oral entacapone. Reduction in OFF time was analyzed as an exploratory measure using a futility design with a predefined margin of 1.6 h. RESULTS:ND0612 was well-tolerated; most patients experienced infusion site nodules (95% vs. 56% with placebo), which all resolved without sequelae. Patients treated with adjunct ND0612 during Period-1 avoided deep troughs in levodopa plasma levels and had a decreased fluctuation index versus placebo (1.6 ± 0.5 vs 3.1 ± 1.6 at end of Period-1, respectively). In Period-2, the coadministration of entacapone with continuous ND0612 SC infusion translated to an increase in mean levodopa AUC0-10h compared to baseline. Exploratory efficacy analysis of Period 1 showed mean ± SD OFF time reductions of -2.13 ± 2.24 [90%CI: -2.8, ∞] hours (p = 0.84 using H0 of μ0 ≤-1.6). CONCLUSION:Levodopa/carbidopa infusion with ND0612 was generally well-tolerated and resulted in reduced fluctuations in plasma levodopa concentrations when given with SoC oral levodopa. ND0612 met the efficacy endpoint for the futility design.

Background: ND0612 is a continuous, subcutaneous levodopa/carbidopa delivery system in development for patients with Parkinson’s disease (PD) experiencing motor fluctuations Objective: Evaluate the efficacy and safety of two ND0612 dosing regimens in patients with PD. Methods: This was a 28-day open-label study (NCT02577523) in PD patients with ≥2.5 hours/day of OFF time despite optimized treatment. Patients were randomized to treatment with either a 24-hour infusion (levodopa/carbidopa dose of 720/90 mg) or a 14-hour ‘waking-day’ infusion (levodopa/carbidopa dose of 538/68 mg plus a morning oral dose of 150/15 mg). Supplemental oral doses of levodopa were permitted for patients in both groups if required. In-clinic assessments of OFF time (primary endpoint) and ON time with or without dyskinesia were determined by a blinded rater over 8 hours (normalized to 16 hours). Results: A total of 38 patients were randomized and 33 (87%) completed the study. Compared to baseline, OFF time for the overall population was reduced by a least squares (LS) mean[95% CI] of 2.0[– 3.3, – 0.7] hours (p = 0.003). ON time with no/mild dyskinesia (no troublesome dyskinesia) was increased from baseline by a LS mean of 3.3[2.0, 4.6] hours (p < 0.0001), and ON time with moderate/severe dyskinesia was reduced by a LS mean of 1.2[– 1.8, – 0.5] hours (p≤0.001). Reduction in OFF time was larger in the 24-hour group (– 2.8[– 4.6, – 0.9] hours; p = 0.004) than in the 14-hour group (– 1.3[– 3.1, 0.5] hours; p = 0.16). Complete resolution of OFF time was observed in 42% (n = 8) of patients in the 24-hour group. Infusion site reactions were the most common adverse event. Conclusion: This study demonstrates the feasibility and safety of continuous subcutaneous delivery of levodopa as a treatment for PD and provides preliminary evidence of efficacy.

Bettina Brauchle 1,2,† , Rebecca L. Goldstein 3,† , Christine M. Karbowski 4 , Anja Henn 5 , Chi-Ming Li 3 , Veit L. Bücklein 1,2 , Christina Krupka 1,2 , Michael C. Boyle 4 , Priya Koppikar 4 , Sascha Haubner 1,2 , Joachim Wahl 5 , Christoph Dahlhoff 5 , Tobias Raum 5 , Matthew J. Rardin 3 , Christine Sastri 3 , Dan A. Rock 3 , Michael von Bergwelt-Baildon 1,2,6 , Brendon Frank 3 , Klaus H. Metzeler 2,6 , Ryan Case 3 , Matthias Friedrich 5 , Mercedesz Balazs 3 , Karsten Spiekermann 2,6,7 , Angela Coxon 5 , Marion Subklewe 1,2,6,* , Tara Arvedson 3,*

Tuesday, April 28April 14, 2020Free AccessThe BouNDless Study: An Active-Controlled, Randomized, Double-Blind, Double-Dummy Phase 3 Study of Continuous ND0612 Infusion in Patients with Parkinson’s Disease Experiencing Motor Fluctuations (4474)Alberto Espay, Olivier Rascol, Tamar Yardeni, Liat Adar, Olivia Rosenfeld, Ryan Case, and C. Warren OlanowAuthors Info & AffiliationsApril 14, 2020 issue94 (15_supplement)https://doi.org/10.1212/WNL.94.15_supplement.4474 Letters to the Editor