Phase 2a Research Articles

LBA01-19 LONG-TERM EFFICACY AND SAFETY OF URO-902 (PVAX/ HSLO ) IN WOMEN WITH OVERACTIVE BLADDER AND URGE URINARY INCONTINENCE: FINAL RESULTS OF A PHASE 2A TRIAL

You have accessJournal of UrologyCME1 Apr 2023LBA01-19 LONG-TERM EFFICACY AND SAFETY OF URO-902 (PVAX/HSLO) IN WOMEN WITH OVERACTIVE BLADDER AND URGE URINARY INCONTINENCE: FINAL RESULTS OF A PHASE 2A TRIAL Kenneth M. Peters, Ekene A. Enemchukwu, Susan Kalota, Kaiser Robertson, Sijian Ge, Jingmei Lu, Hanh Badger, and Salim Mujais Kenneth M. PetersKenneth M. Peters More articles by this author , Ekene A. EnemchukwuEkene A. Enemchukwu More articles by this author , Susan KalotaSusan Kalota More articles by this author , Kaiser RobertsonKaiser Robertson More articles by this author , Sijian GeSijian Ge More articles by this author , Jingmei LuJingmei Lu More articles by this author , Hanh BadgerHanh Badger More articles by this author , and Salim MujaisSalim Mujais More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003360.19AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: URO-902 is an investigational gene therapy for overactive bladder (OAB) consisting of a plasmid vector expressing the large-conductance Ca2+-activated K+channel α subunit. URO-902 showed improved efficacy and quality of life (QoL) vs placebo in a 12-week interim analysis of a phase 2a trial. Here we report final safety and efficacy results from the trial. METHODS: This 48-week multicenter, double-blind, placebo-controlled, dose-escalation trial (NCT04211831) randomized women 40–79 years old with OAB, urge urinary incontinence (UUI), and inadequate pharmacologic OAB management to single-dose URO-902 24 or 48 mg or placebo administered by intradetrusor injection via cystoscopy under local anesthesia. Patients could request additional OAB treatments starting at week 24, after which they were not included in efficacy analyses. Exploratory efficacy endpoints were change from baseline (CFB) in mean daily micturitions, urgency episodes, and UUI episodes. Safety was assessed by adverse events (AEs) and postvoid residual (PVR) urine volume. RESULTS: Of 80 patients randomized, 74 were treated (intent-to-treat exposed [ITT-E] population), and 67 completed the trial. In the ITT-E population, mean age was 64.7 years; 13.5% had prior onabotulinumtoxinA treatment. URO-902 24 and 48 mg were associated with reductions from baseline starting at week 2 in daily micturitions, urgency episodes, and UUI episodes; reductions were durable through week 48. Overall, 45.5%, 53.8%, and 53.8% of patients receiving URO-902 24 mg, URO-902 48 mg, and placebo, respectively, experienced ≥1 treatment-emergent AE; the most commonly occurring (24 mg/48 mg/placebo) were urinary tract infection (0%/15.4%/3.8%) and hematuria (4.5%/7.7%/7.7%). One patient receiving URO-902 48 mg had asymptomatic elevated PVR urine volume, which resolved spontaneously without catheterization. CONCLUSIONS: URO-902 24 or 48 mg showed durable, meaningful improvements from baseline in micturitions, urgency episodes (dose dependent), and UUI episodes, consistent with previously reported QoL improvements at 12 weeks, and was safe and well tolerated in this phase 2a trial. Interpretation of efficacy vs placebo was limited by use of additional OAB treatments after week 24. Source of Funding: Urovant Sciences © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1184 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kenneth M. Peters More articles by this author Ekene A. Enemchukwu More articles by this author Susan Kalota More articles by this author Kaiser Robertson More articles by this author Sijian Ge More articles by this author Jingmei Lu More articles by this author Hanh Badger More articles by this author Salim Mujais More articles by this author Expand All Advertisement PDF downloadLoading ...

5612539 TRIAL IN PROGRESS: THE RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE 2A CROSSWALK-C TRIAL EVALUATING THE EFFICACY OF CROVALIMAB AS ADJUNCT TREATMENT IN THE PREVENTION OF VASO-OCCLUSIVE EPISODES (VOES) IN PATIENTS (PTS) WITH SICKLE CELL DISEASE (SCD)

Background: SCD is a group of autosomal recessive red blood cell (RBC) disorders caused by a single point mutation in the β-globin gene, with either homozygous inheritance or heterozygous co-inheritance with other pathogenic variants of the β-globin gene. Hemoglobin S, produced as a result of this point mutation, polymerizes within RBCs under certain conditions, distorting them and generating dense and sickle RBCs. These pathologic RBCs contribute to microvascular occlusions, which may present as acute painful episodes called VOEs. Pts with SCD may also have severe chronic anemia, chronic pain, immune dysfunction, and progressive multi-organ damage. Current therapies for SCD include hydroxyurea, as well as newer treatments such as L-glutamine, crizanlizumab, and voxelotor. Despite these treatments, considerable morbidity and mortality among pts with SCD represents a significant unmet medical need. Complement pathway activation has been reported in pts with SCD at baseline, in acute pain crises, and in delayed hemolytic transfusion reaction. Accumulating nonclinical data suggest the potential multimodal role for complement dysregulation in the pathophysiology of SCD, including vaso-occlusion, hemolysis, inflammation, thrombogenicity, endothelial activation, and end-organ damage.1 The complement pathway can be targeted with crovalimab, a novel anti-C5 monoclonal antibody that allows for small-volume subcutaneous (SC) self-injection. In a Phase 1/2 paroxysmal nocturnal hemoglobinuria (a complement-mediated disorder) study, crovalimab showed rapid and sustained complement inhibition with promising efficacy and safety.2 Aim: CROSSWALK-c (NCT05075824) is a randomized, double-blind, placebo-controlled, Phase 2a study evaluating the efficacy and safety of crovalimab as adjunct therapy in preventing VOEs in pts with SCD. Methods: Pts aged 12 to 55 years, weighing ≥40 kg, with a confirmed diagnosis of SCD, homozygous hemoglobin S (HbSS) or sickle cell β0 thalassemia (HbSβ0), and presenting with 2 to 10 VOEs are eligible, including pts on concurrent SCD-directed therapies. Vaccinations against Neisseria meningitidis, Haemophilus influenzae type B, and Streptococcus pneumoniae are required. Pts with a history of hematopoietic stem cell transplant will be excluded. Eligible pts will be randomized 1:1 to the crovalimab or placebo arms (Figure). An initial intravenous loading dose of crovalimab or placebo will be given on Week 1, Day 1, followed by SC dose on Week 1, Day 2, and then weekly SC doses on Weeks 2–4. Starting Week 5, a maintenance dose will be given every 4 weeks for 48 weeks. All study treatment will be given according to a weight-based tiered dosing schedule (pts weighing ≥ 40 kg to < 100 kg and pts ≥ 100 kg). The primary objective is to evaluate the efficacy of crovalimab vs placebo based on the annualized rate of medical facility VOEs. Key secondary efficacy objectives are the annualized rate of acute chest syndrome, the annualized rate of home VOE, and change in urinary albumin–creatinine ratio, tricuspid regurgitant jet velocity, and Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue score in adults, from baseline to Week 49. Safety, pharmacokinetic, immunogenicity, and exploratory biomarker objectives will also be evaluated. Protocol updates are in progress. Results: Primary results are expected in July 2024. Summary: CROSSWALK-c is enrolling pts with SCD and chronic VOEs in six countries.

Inaxaplin for Proteinuric Kidney Disease in Persons with Two APOL1 Variants

BackgroundPersons with toxic gain-of-function variants in the gene encoding apolipoprotein L1 (APOL1) are at greater risk for the development of rapidly progressive, proteinuric nephropathy. Despite the known genetic cause, therapies targeting proteinuric kidney disease in persons with two APOL1 variants (G1 or G2) are lacking.MethodsWe used tetracycline-inducible APOL1 human embryonic kidney (HEK293) cells to assess the ability of a small-molecule compound, inaxaplin, to inhibit APOL1 channel function. An APOL1 G2–homologous transgenic mouse model of proteinuric kidney disease was used to assess inaxaplin treatment for proteinuria. We then conducted a single-group, open-label, phase 2a clinical study in which inaxaplin was administered to participants who had two APOL1 variants, biopsy-proven focal segmental glomerulosclerosis, and proteinuria (urinary protein-to-creatinine ratio of ≥0.7 to <10 [with protein and creatinine both measured in grams] and an estimated glomerular filtration rate of ≥27 ml per minute per 1.73 m2 of body-surface area). Participants received inaxaplin daily for 13 weeks (15 mg for 2 weeks and 45 mg for 11 weeks) along with standard care. The primary outcome was the percent change from the baseline urinary protein-to-creatinine ratio at week 13 in participants who had at least 80% adherence to inaxaplin therapy. Safety was also assessed.ResultsIn preclinical studies, inaxaplin selectively inhibited APOL1 channel function in vitro and reduced proteinuria in the mouse model. Sixteen participants were enrolled in the phase 2a study. Among the 13 participants who were treated with inaxaplin and met the adherence threshold, the mean change from the baseline urinary protein-to-creatinine ratio at week 13 was −47.6% (95% confidence interval, −60.0 to −31.3). In an analysis that included all the participants regardless of adherence to inaxaplin therapy, reductions similar to those in the primary analysis were observed in all but 1 participant. Adverse events were mild or moderate in severity; none led to study discontinuation.ConclusionsTargeted inhibition of APOL1 channel function with inaxaplin reduced proteinuria in participants with two APOL1 variants and focal segmental glomerulosclerosis. (Funded by Vertex Pharmaceuticals; VX19-147-101 ClinicalTrials.gov number, NCT04340362.)

The D-amino acid oxidase inhibitor luvadaxistat improves mismatch negativity in patients with schizophrenia in a randomized trial

Several attempts have been made to enhance N-methyl-D-aspartate (NMDA) receptor function in schizophrenia, but they have yielded mixed results. Luvadaxistat, a D-amino acid oxidase (DAAO) inhibitor that increases the glutamate co-agonist D-serine levels, is being developed for the treatment of cognitive impairment associated with schizophrenia. We conducted a biomarker study in patients, assessing several endpoints related to physiological outcomes of NMDA receptor modulation to determine whether luvadaxistat affects neural circuitry biomarkers relevant to NMDA receptor function and schizophrenia. This was a randomized, placebo-controlled, double-blind, two-period crossover phase 2a study assessing luvadaxistat 50 mg and 500 mg for 8 days in 31 patients with schizophrenia. There were no treatment effects of luvadaxistat at either dose in eyeblink conditioning, a cerebellar-dependent learning measure, compared with placebo. We observed a nominally significant improvement in mismatch negativity (MMN) and a statistical trend to improvement for auditory steady-state response at 40 Hz, in both cases with 50 mg, but not with 500 mg, compared with placebo. Although the data should be interpreted cautiously owing to the small sample size, they suggest that luvadaxistat can improve an illness-related circuitry biomarker at doses associated with partial DAAO inhibition. These results are consistent with 50 mg, but not higher doses, showing a signal of efficacy in cognitive endpoints in a larger phase 2, 12-week study conducted in parallel. Thus, MMN responses after a short treatment period may predict cognitive function improvement. MMN and ASSR should be considered as biomarkers in early trials addressing NMDA receptor hypofunction.

Efficacy and Safety of Roflumilast Foam 0.3% in Patients With Seborrheic Dermatitis in a Phase 3 Trial

Introduction: Seborrheic dermatitis (SD) is a common, chronic, inflammatory dermatosis that affects patients of all ages with a global prevalence ≥5%. Treatments usually consist of topical therapies, including antifungals and low potency corticosteroids; however, current treatments have limitations such as side effects with long-term use and/or vehicles that can be difficult to use on both hair-bearing and non-hair-bearing areas. Roflumilast is a selective, nonsteroidal, highly potent phosphodiesterase-4 inhibitor once-daily foam under investigation for the treatment of SD. Efficacy, safety, and local tolerability of roflumilast foam 0.3% in patients with SD were demonstrated in a phase 2a and subsequent open-label trial (NCT04091646 and NCT04445987, respectively). Here, we present efficacy, safety, and local tolerability in a phase 3 trial of roflumilast foam 0.3% in patients with SD (NCT04973228). Methods: This phase 3 randomized, parallel group, double blind, vehicle-controlled trial was conducted in patients ≥9 years old with at least moderate SD affecting scalp and/or non-scalp areas. Patients were randomized 2:1 to apply once-daily roflumilast foam 0.3% (n=304) or vehicle (n=153) for 8 weeks. The primary efficacy endpoint was Investigator Global Assessment (IGA) Success (IGA of Clear or Almost Clear plus ≥2-grade improvement from baseline) at Week 8. Secondary efficacy endpoints included IGA score of Clear at Week 8, achievement of ≥4-point improvement from baseline in Worst Itch Numeric Rating Score (WI-NRS) among patients with baseline score ≥4 (WI-NRS Success), Overall Assessment of Erythema score of 0, and Overall Assessment of Scaling score of 0. Safety and local tolerability were also evaluated. Results: Overall, significantly more roflumilast-treated patients than vehicle-treated patients achieved the primary efficacy endpoint of IGA Success (79.5% vs. 58.0%; P&lt;0.0001) and IGA status of Clear (50.6% vs. 27.7%; P&lt;0.0001) at Week 8. Percentages of patients achieving IGA Success and IGA Clear at Weeks 2 and 4 were also greater with roflumilast. Significantly greater percentages of roflumilast- than vehicle-treated patients achieved secondary endpoints of WI-NRS success at Weeks 2, 4, and 8 (62.8% vs. 40.6%; P&lt;0.0001); Overall Assessment of Erythema score of 0 (57.8% vs. 32.0%; P&lt;0.0001) at Week 8; and Overall Assessment of Scaling score of 0 (58.1% vs. 36.5%; P&lt;0.0001) at Week 8. Local tolerability was favorable, with ≥98.9% of patients having no evidence of irritation at Weeks 4 and 8 on investigator-rated assessments and ≥92.3% of patients reporting a score of 0 (no sensation) or 1 (slight warm, tingling sensation; not really bothersome) after application on patient-rated tolerability. Overall incidence of treatment-emergent adverse events (TEAE), serious adverse events, and TEAEs leading to discontinuation were low, with similar rates between roflumilast and vehicle. Conclusion: Once-daily roflumilast foam provided improvement across multiple efficacy endpoints vs vehicle while demonstrating favorable safety and tolerability in patients ≥9 years old with SD affecting scalp and/or non-scalp body areas. Sponsored by Arcutis Biotherapeutics, Inc.

Efficacy and safety of vixarelimab, a human monoclonal oncostatin M receptor β antibody, in moderate-to-severe prurigo nodularis: a randomised, double-blind, placebo-controlled, phase 2a study.

Prurigo nodularis is a chronic skin disease characterised by intensely pruritic, hyperkeratotic nodules. Vixarelimab, a human monoclonal antibody, binds to the beta subunit of the oncostatin M receptor, inhibiting signalling of both interleukin 31 and oncostatin M, two cytokine pathways that contribute to pruritus and nodule formation in prurigo nodularis. This double-blind, placebo-controlled, phase 2a trial was done at both private and academic dermatology outpatient research clinics across the United States and Canada (n=40). Patient eligibility criteria included age 18-75 years, physician-documented diagnosis of prurigo nodularis minimum 6 months duration of prurigo nodularis, presence of at least 10 pruritic nodules approximately 0.5-2cm in size on at least two different anatomical locations (excluding face and scalp) and involving the extremities, and presence of normal-appearing skin between nodules; atopic dermatitis as a comorbidity was exclusionary. Patients were required to have moderate-to-severe pruritus, defined as Worst Itch-Numeric Rating Scale (WI-NRS) score ≥7at screening and LS-mean weekly WI-NRS score ≥5 for each of the 2 consecutive weeks immediately before randomisation. Participants were randomly assigned (1:1) to receive weekly subcutaneous vixarelimab 360mg (720mg loading dose) or placebo using stratification factors (sex and presence of atopy) and block size 4 through the IWRS system. Stratification by atopy status was based on the reported high prevalence of atopy in this population and the potential impact of atopy in the immunopathologic process in prurigo nodularis. Patients, investigators, study sponsor, and site staff were masked to study treatment. The primary efficacy endpoint was least squares (LS)-mean percent change from baseline (PCFB) at Week 8 in weekly average Worst Itch-Numeric Rating Scale (WI-NRS) score. The primary efficacy endpoint was analysed with ANCOVA including treatment as fixed effect, with baseline WI-NRS, and randomisation stratification factor as covariates. All randomised patients who had at least 1 dose of study drug or placebo were included in the Safety Analysis Set. This trial is registered at ClinicalTrials.gov, NCT03816891. Of 50 patients randomised between March 11, 2019 and January 31, 2020, 23 vixarelimab recipients and 26 placebo recipients comprised the modified intent-to-treat analysis population (baseline LS-mean [SD] WI-NRS score, 8.3 [1.05]). Outcomes at Week 8 for vixarelimab versus placebo included LS-mean PCFB in WI-NRS score,-50.6% versus-29.4% (LS-mean difference [95% CI],-21.2% [-40.82,-1.60]; p=0.03); ≥4-point reduction in WI-NRS score, 52.2% (12/23) versus 30.8% (8/26) (p=0.11); PN-IGA score of 0 or 1, 30.4% (7/23) versus 7.7% (2/26) (p=0.03); LS-mean PCFB in pruritus VAS score,-54.4% versus-32.6% (p=0.03); and LS-mean PCFB sleep loss reduction (improvement),-56.3% versus-30.0% (p=0.02). No deaths, serious TEAEs, or TEAEs leading to dose interruption were reported. The percentage of vixarelimab recipients reporting any TEAE was 91.3% (21/23) versus 76.9% (20/26) of placebo recipients; drug-related TEAEs generally were similar between the two groups (vixarelimab, 43.5% [10/23]; placebo, 38.5% [10/26]). Vixarelimab demonstrated rapid reduction of pruritus and achievement of clear/almost clear skin in one-thirdof the patients by Week 8. Relief of itch and clearing of skin nodules represent two important potential therapeutic advances in the management of patients suffering from the debilitating disease Prurigo Nodularis. Kiniksa Pharmaceuticals, Ltd.

Saroglitazar improves nonalcoholic fatty liver disease and metabolic health in liver transplant recipients.

NAFLD is common after liver transplantation (LT) and is associated with an increased metabolic burden. Currently, there is a paucity of investigations into the treatment of post-LT NAFLD. In the present study, we evaluated the safety and efficacy of saroglitazar, a novel dual peroxisome proliferator-associated receptor α/γ agonist, on the treatment of post-LT NAFLD and metabolic burden. This is a phase 2A, single-center, open-label, single-arm study in which patients with post-LT NAFLD received saroglitazar magnesium 4mg daily for 24 weeks. NAFLD was defined by a controlled attenuation parameter ≥264dB/m. The primary endpoint was the reduction in liver fat as measured by MRI proton density fat fraction (MRI-PDFF). Secondary MRI-based metabolic endpoints included visceral adipose tissue, abdominal subcutaneous adipose tissue volumes, muscle fat infiltration, and fat-free muscle volume. Saroglitazar treatment led to a reduction in MRI-PDFF from 10.3±10.5% at baseline to 8.1±7.6%. A relative 30% reduction from baseline MRI-PDFF value was noted in 47% of all patients and 63% of patients with baseline MRI-PDFF >5%. Reduction in serum alkaline phosphatase was an independent predictor of MRI-PDFF response. Saroglitazar did not decrease fat-free muscle volume nor increase muscle fat infiltration, but did lead to a mild increase in visceral adipose tissue and abdominal subcutaneous adipose tissue. The study drug was well tolerated and a mild nonsignificant increase in serum creatinine was noted. Saroglitazar did not affect the weight. The study provides preliminary data demonstrating the safety and metabolic benefits of saroglitazar in LT recipients and underscores the importance of future studies to establish its efficacy after LT.

First-in-class oral innate immune activator BXCL701 combined with pembrolizumab in patients with metastatic, castration-resistant prostate cancer (mCRPC) of small cell neuroendocrine (SCNC) phenotype: Phase 2a final results.

176 Background: BXCL701 (talabostat), oral small molecule inhibitor of dipeptidyl peptidases (DPP)—primarily DPP8/9 &amp; DPP4—triggers inflammasome to alert and prime immune cells, leading to induction of IL-18 &amp; IL-1ß, bridging innate &amp; adaptive immunity. BXCL701 is evaluated in a Phase 2 study in combination with pembrolizumab, in mCRPC patients with SCNC phenotype. SCNC is highly proliferative and aggressive with limited duration of response to platinum-based chemotherapy. Here are reported the results of the Phase 2a after enrollment of 32 patients for the SCNC cohort. The final results will be presented at the Symposium. Methods: Phase 2a patients with any SCNC histopathological features, either de novo or treatment-emergent including mixed SCNC, required to have progression by PCWG3 on ≥1 prior line of cytotoxic chemotherapy (patients who either have refused chemotherapy or are considered unsuitable for chemotherapy also permitted entry with prior approval by sponsor). Patients receive pembrolizumab (200 mg IV q3week) + BXCL701 0.2 mg BID on days 1-7 with step-up to 0.3 mg BID on days 8-14, and 0.3 mg BID on days 1-14 of subsequent cycles. Primary endpoint is Composite Response, either objective response by RECIST 1.1 or PSA50 or CTC count conversion from ≥5/7.5 mL to &lt;5/7.5 mL from baseline. Study uses a Simon 2-stage minimax design with 15 evaluable patients in stage 1 and 13 in stage 2. Baseline markers and changes in relevant immune effector cells also evaluated. Results: As of 10/11/2022, 32 patients have been accrued, 27 of which are evaluable. 16 patients (59%) are treatment-emergent SCNC and 11 (41%) are de novo SCNC. 19 patients (70%) received prior platinum chemotherapy. BXCL701 in combination with pembrolizumab continues to demonstrate acceptable tolerability without evidence of increased immune-related AEs compared to historic controls with checkpoint inhibitors. Adverse Events consistent with cytokine activation were observed (hypotension, fever, fatigue). In the previously reported 15 evaluable SCNC patients, 5 were composite responders, including 4 RECIST responders with a median duration of response of 39 weeks (range 9-45 weeks). 2/5 responders still actively receiving treatment and median duration of follow up is 48.3 weeks (range 1.9-88 weeks). All responders are MSS and/or low TMB. Enrollment is ongoing and 9 patients are actively receiving treatment at abstract submission. Final data for 28 evaluable patients will be presented at the Symposium. Conclusions: Oral BXCL701 in combination with pembrolizumab demonstrates encouraging anti-tumor activity with durability of response in late-line, refractory mCRPC SCNC for which there is currently no standard of care. BXCL701 BID dosing continues to demonstrate an acceptable safety profile. Clinical trial information: NCT03910660 .

Early dose escalation of LAVA-1207, a novel bispecific gamma-delta T-cell engager (Gammabody), in patients with metastatic castration-resistant prostate cancer (mCRPC).

153 Background: LAVA-1207 is a humanized bispecific antibody of 78 kDa comprised of two single domain antibody (VHH) fragments linked to a silenced fragment crystallizable immunoglobulin region. As shown pre-clinically, LAVA-1207 binds with high affinity to the Vδ2 chain of Vγ9Vδ2-T cells, a potent immune effector cell population, and to prostate specific membrane antigen (PSMA) expressed by prostate cancer cells to trigger robust (pM range EC50) Vγ9Vδ2-T cell mediated lysis of prostate cancer cells, whereas normal cells are relatively spared. Based on earlier clinical experience with systemic activation of Vγ9Vδ2-T cells through aminobisphosphonates and in vivo studies in non-human primates with cross-reactive surrogate bispecific γδ-T cell engagers, a low risk for cytokine release syndrome (CRS) is expected in the clinic. Methods: This is an open label, 3+3 design, phase 1/2a study in patients with therapy refractory metastatic castration resistant prostate cancer (NCT05369000; EudraCT Number: 2021-001789-39) to determine the safety of LAVA-1207 and its recommended Phase 2a dose (RP2D) and schedule. Secondary objectives include evaluation of PK, PD, immunogenicity, and preliminary antitumor activity. LAVA-1207 is administered IV every two weeks with an infusion duration of 2 hours for the first dose, 1 hour for the second dose, and 30 minutes for all subsequent doses. Results: As of September 23, 2022, a dose level of 40 µg (starting dose was 1.5 µg based on MABEL approach) has been reached without dose limiting toxicities (DLTs). A total of 16 patients have been treated with LAVA-1207 with treatment duration ranging from 1 to 25+ weeks. Treatment emergent AEs (TEAEs) that were suspected to be related were all grade 1-2, and included nausea (n=3), AST increase (n=2), fatigue (n=2), and infusion related reaction (n=2). Severity of TEAEs did not increase with escalating doses and no patient discontinued treatment due to an AE. PK data indicate increasing drug exposure in correlation with increasing doses of LAVA-1207. PD data show a consistent early reduction in Vγ9Vδ2-T cell frequencies at 2hrs after the first dose, which could be indicative of Vγ9Vδ2-T cell redistribution after treatment, often accompanied by an increase in Vγ9Vδ2-T cell activation markers. Vγ9Vδ2-T cell numbers are restored in the subsequent 3 to 5 days to at least pre-dose levels. Additionally, receptor occupancy of Vγ9Vδ2-T cells was detectable up to 5 days after first dosing. To date, stable disease at 8 weeks has been observed in 3 out of 8 evaluable patients. Conclusions: LAVA-1207 has been well tolerated early in dose escalation; further clinical activity including PSA results, response assessment, and pharmacodynamic data will clarify determination of an optimal biological active dose. Clinical trial information: NCT05369000 .

Safety and anti-tumor activity of lisavanbulin administered as 48-hour infusion in patients with ovarian cancer or recurrent glioblastoma: a phase 2a study

Purpose. Lisavanbulin (BAL101553) is the prodrug of avanbulin (BAL27862), a microtubule-destabilizing agent. The goal of this study (NCT02895360) was to characterize the safety, tolerability and antitumor activity of lisavanbulin administered as a 48-hour intravenous (IV) infusion at the recommended Phase 2 dose (RP2D) of 70 mg/m2. Results from the Phase 1 dose-escalation portion of the study identifying the RP2D have been previously reported. Here, we present the findings from the Phase 2a portion of this study. Methods. This multi-center, open-label study included patients with ovarian, fallopian-tube, or primary peritoneal cancer that was either platinum-resistant or refractory (11 patients), or with first recurrence of glioblastoma (12 patients). Lisavanbulin was administered as a 48-hour IV infusion on Days 1, 8, and 15 of a 28-day cycle. Results. Lisavanbulin was well tolerated in both patient cohorts. Thirteen patients (56.5%) developed 49 adverse events assessed as related to study treatment. The majority were mild or moderate; four were grade 3/4. Sixteen SAEs were reported in nine patients (39.1%), with none considered related to study treatment. No AEs led to permanent treatment discontinuation. Three patients in the ovarian cancer cohort had stable disease with lesion size reductions after two cycles of treatment; in the glioblastoma cohort, one patient showed partial response with a > 90% glioblastoma area reduction as best response, and one patient had stable disease after eight cycles of treatment. Conclusion. This study demonstrated a favorable safety and tolerability profile of 48-hour continuous IV infusion of lisavanbulin in patients with solid extracranial tumors or glioblastoma. Clinicaltrials.gov registration: NCT02895360.

Subanalysis of Subjective Cognitive Measures From a Phase 2, Double-Blind, Randomized Trial of REL-1017 in Patients With Major Depressive Disorder.

Objective: Improvement of cognitive function in patients with major depressive disorder (MDD) is an important treatment outcome. REL-1017 (esmethadone HCl) is a novel N-methyl-d-aspartate receptor (NMDAR) channel blocker and a potentially rapidly acting antidepressant. The objective of this study was to define the effects of REL-1017 on subjective cognitive measures in patients with MDD. Methods: Post hoc analysis was conducted of subjective cognitive measures from the Montgomery-Asberg Depression Rating Scale (MADRS) and the Symptoms of Depression Questionnaire (SDQ) from a randomized, double-blind, placebo-controlled, Phase 2a study. The study, designed to assess the safety, tolerability, and efficacy of 2 dosages (25 mg and 50 mg) of REL-1017 as an adjunctive treatment in patients with MDD unresponsive to standard antidepressants, included 62 patients. We analyzed subjective cognitive measures derived from the MADRS and SDQ scales at baseline and up to day 14, 7 days after the last dose of study drug. We developed 2 composite indexes that included subjective cognitive measures selected from the MADRS and SDQ. Results: The subanalysis of single measures and the 2 composite indexes derived from the MADRS and SDQ measures showed clinically meaningful and statistically significant improvements in cognitive function (P < .05). Conclusions: In a Phase 2a clinical trial, REL-1017 improved subjective measures of cognitive impairment, in addition to improving total MADRS and SDQ scores. These results need to be confirmed in larger and longer studies in MDD that include objective measures of cognitive function. Phase 3 studies of REL-1017 for MDD are currently underway. Clinical Trials Registration: ClinicalTrials.gov identifier: NCT03051256

The role of claudin 18.2 and HER-2 in pancreatic cancer outcomes.

To examine the prognostic value of claudin 18.2 (CLDN18.2) and human epidermal growth factor receptor-2 (HER-2) expression in patients with resected pancreatic ductal adenocarcinoma (PDAC). This study enrolled patients who underwent surgery and were diagnosed with PDAC at Suleyman Demirel University Hospital, Turkey between 2015 and 2019. Sixty-eight patients with resected PDAC treated at a medical oncology clinic were assessed. All patients were over the age of 18 years, underwent follow-up and treatment in our unit, and had pathology slides that we could access. Clinicopathological data were obtained from medical files, including the patients' age, sex, pathological parameters, and clinical stage according to the Eighth International Union against Cancer/American Joint Committee on Cancer. Patient survival and the period from the date of diagnosis to death were assessed in the follow-up data. There was no statistically significant difference between CLDN18.2 and HER-2 expression scores for samples and patient clinicopathological characteristics. No HER-2 expression scores of ≥2 were found in the samples. Only 25% (n = 17) of the samples had HER-2 expression scores of +1. CLDN18.2 expression was detected in 54.4% (n = 37) of the patient samples. CLDN18.2 expression scores were +1 in 30.8% (n = 21) of the patient samples, +2 in 16.2% (n = 11), and +3 in 7.4% (n = 5). When CLDN18.2 and HER-2 expression were compared, a statistically significant difference and moderate positive correlation were observed. No significant relationship between HER-2 expression and survival was observed in the survival analysis of PDAC patients; however, high CLDN18.2 expression was related to longer overall survival. Our study is the third to research CLDN18.2 expression in PDAC. HER-2 expression is low and CLDN18.2 expression is high in patients with PDAC. HER-2 expression is not related to overall survival but CLDN18.2 is related and may be used as a prognostic marker in patients with PDAC.

COVAC1 phase 2a expanded safety and immunogenicity study of a self-amplifying RNA vaccine against SARS-CoV-2.

Lipid nanoparticle (LNP) encapsulated self-amplifying RNA (saRNA) is well tolerated and immunogenic in SARS-CoV-2 seronegative and seropositive individuals aged 18-75. A phase 2a expanded safety and immunogenicity study of a saRNA SARS-CoV-2 vaccine candidate LNP-nCoVsaRNA, was conducted at participating centres in the UK between 10th August 2020 and 30th July 2021. Participants received 1μg then 10μg of LNP-nCoVsaRNA, ∼14 weeks apart. Solicited adverse events (AEs) were collected for one week post-each vaccine, and unsolicited AEs throughout. Binding and neutralisating anti-SARS-CoV-2 antibody raised in participant sera was measured by means of an anti-Spike (S) IgG ELISA, and SARS-CoV-2 pseudoneutralisation assay. (The trial is registered: ISRCTN17072692, EudraCT 2020-001646-20). 216 healthy individuals (median age 51 years) received 1.0μg followed by 10.0μg of the vaccine. 28/216 participants were either known to have previous SARS-CoV2 infection and/or were positive for anti-Spike (S) IgG at baseline. Reactogenicity was as expected based on the reactions following licensed COVID-19 vaccines, and there were no serious AEs related to vaccination. 80% of baseline SARS-CoV-2 naïve individuals (147/183) seroconverted two weeks post second immunization, irrespective of age (18-75); 56% (102/183) had detectable neutralising antibodies. Almost all (28/31) SARS-CoV-2 positive individuals had increased S IgG binding antibodies following their first 1.0μg dose with a ≥0.5log10 increase in 71% (22/31). Encapsulated saRNA was well tolerated and immunogenic in adults aged 18-75 years. Seroconversion rates in antigen naïve were higher than those reported in our dose-ranging study. Further work is required to determine if this difference is related to a longer dosing interval (14 vs. 4 weeks) or dosing with 1.0μg followed by 10.0μg. Boosting of S IgG antibodies was observed with a single 1.0μg injection in those with pre-existing immune responses. Grants and gifts from the Medical Research Council UKRI (MC_PC_19076), the National Institute for Health Research/Vaccine Task Force, Partners of Citadel and Citadel Securities, Sir Joseph Hotung Charitable Settlement, Jon Moulton Charity Trust, Pierre Andurand, and Restore the Earth.

Study protocol for Cognitive Behavioral Therapy for Insomnia in patients with primary brain tumor: A single-arm phase 2a proof-of-concept trial

BackgroundSleep disturbance is among the most common symptoms endorsed by patients with primary brain tumor (PwPBT), with many reporting clinically elevated insomnia and poor management of their sleep-related symptoms by their medical team. Though Cognitive Behavioral Therapy for Insomnia (CBT-I) remains the front-line treatment for sleep disturbance, CBT-I has yet to be evaluated in PwPBT. Thus, it is unknown whether CBT-I is feasible, acceptable, or safe for patients with primary brain tumors. MethodsPwPBT (N = 44) will enroll and participate in a six-week group-based CBT-I intervention delivered via telehealth. Feasibility will be based on pre-determined metrics of eligibility, rates and reasons for ineligibility, enrollment, and questionnaire completion. Acceptability will be measured by participant retention, session attendance, satisfaction ratings, and recommendation to others. Safety will be assessed by adverse event reporting. Sleep will be measured both objectively via wrist-worn actigraphy and subjectively via self-report. Participants will also complete psychosocial questionnaires at baseline, post-intervention, and three-month follow-up. ConclusionCBT-I, a non-pharmacological treatment option for insomnia, has the potential to be beneficial for an at-risk, underserved population: PwPBT. This trial will be the first to assess feasibility, acceptability, and safety of CBT-I in PwPBT. If successful, this protocol will be implemented in a more rigorous phase 2b randomized feasibility pilot with the aim of widespread implementation of CBT-I in neuro-oncology clinics.

Abstract TMP110: Elezanumab Decreases Neuronal Damage And Improves Functional Recovery In A Rabbit Model Of Permanent Middle Cerebral Artery Occlusion

Introduction: Current acute interventions for ischemic stroke aim to restore perfusion of affected tissue. There is an unmet need for therapies that protect neurons from ischemic damage and/or enhance natural repair processes to restore function. In humans, the neuronal growth and survival inhibitor RGMa (repulsive guidance molecule A) is upregulated following ischemic stroke. Elezanumab is a novel, humanized monoclonal antibody targeting RGMa. Preclinical evidence in traumatic and ischemic models of CNS damage suggest a protective and regenerative mechanisms for elezanumab following CNS damage. Methods: Elezanumab was evaluated in a rabbit permanent middle cerebral artery occlusion (MCAO) model of acute ischemic stroke by injection of an autologous blood clot. In replicate experiments, elezanumab (1, 10 and 40 mg/kg) or IgG control was administered 6 hours post occlusion or 24 hours post occlusion (10 mg/kg). Animals were dosed weekly through 28 days. Functional ability was assessed using the Neuromotor Score, a composite of sensorimotor performance tasks. Ex vivo MRI, histology, and fluid biomarker analyses were performed. Results: MCAO consistently reduced cerebral blood flow by ~60% and resulted in neuromotor dysfunction. All doses of elezanumab demonstrated statistically significantly improved neuromotor function and recovery rate versus controls when dosed 6 hours post occlusion. The 10 mg/kg group dosed 24 hours post occlusion did not show a statistically significant functional improvement versus controls. Infarct volumes, plasma neurofilament light chain levels, and histological evidence of microglial proliferation were all significantly reduced with elezanumab treatment versus controls, including in the delayed elezanumab treatment group. Conclusions: Elezanumab treatment was associated with improved functional recovery and reduced markers of neuronal damage. Collectively, these data support a neuroprotective role for elezanumab in this translational model of acute ischemic stroke. Elezanumab is now being tested in a Phase 2a clinical trial for acute ischemic stroke.

The Official Journal of ATTD Advanced Technologies &amp; Treatments for Diabetes Conference 22‐25 February 2023 I Berlin &amp; Online

The Official Journal of ATTD Advanced Technologies &amp; Treatments for Diabetes Conference 22‐25 February 2023 I Berlin &amp; Online

DOP87 The Anti-TL1A Antibody PRA023 Demonstrated Proof-of-Concept in Crohn’s Disease: Phase 2a APOLLO-CD Study Results

Abstract Background Tumor necrosis factor-like cytokine 1A (TL1A) is an upstream regulator of pro-inflammatory cytokines and fibrosis signals. PRA023 is an anti-TL1A monoclonal antibody in development for multiple inflammatory/fibrotic diseases with a precision medicine approach. This Phase 2a multi-center, open-label study aimed to assess the efficacy and safety of PRA023 as induction treatment in adults with moderately to severely active Crohn’s Disease (CD). Methods Key eligibility criteria included Crohn’s disease activity index ≥220 and ≤450 with centrally read [with adjudication] Simple Endoscopic Score (SES)-CD score of ≥6 (≥4 isolated ileal disease) and a history of insufficient/loss of response and/or intolerance to conventional and/or approved biologic therapies (≤4 biologic agents from ≤3 classes). Eligible patients were treated with intravenous PRA023 1000mg on Day 1, 500mg at Weeks 2, 6, and 10. The primary endpoint was endoscopic response (reduction in SES-CD score of ≥50%) at Week 12. Study design utilized historical placebo control rate estimates as a benchmark. Exploratory endpoints include efficacy assessment in a subpopulation identified by a genetics-based companion diagnostic test (CDx). Results Of the 55 patients in the full analysis data set, 53 (96.4%) completed the 12-week Induction Period. The patient population was notable for the high rate of prior biologic exposure (70.9%) and a mean (SD) disease duration of 10.3 (9.3) years (Table 1). A significantly greater proportion of patients receiving PRA023 achieved endoscopic response (26% PRA023 vs. 12% historical placebo estimate, p=0.002) and clinical remission (CDAI &amp;lt; 150 points; 49% PRA023 vs 16% historical placebo estimate, p&amp;lt; 0.001). Efficacy was observed in biologic-exposed patients (33% endoscopic response and 38.5% clinical remission) while concurrent steroid or immunosuppressant use did not impact efficacy. Significant reductions from baseline in C-reactive protein and fecal calprotectin were observed at all timepoints (Figure 1). Although the pre-specified CDx algorithm provided only limited additional benefit in clinical responses, an alternative CD-specific algorithm (not based on clinical trial data) using the same genetic markers demonstrated enhanced performance across both clinical (12/21 [57%] remission) and endoscopic (9/20 [45%] response) outcomes. No serious/severe AEs were deemed as study drug-related. Conclusion This Phase 2a study demonstrated robust proof-of-concept for PRA023’s efficacy in moderately to severely active CD with favorable tolerability. Patient selection using prespecified genetic markers showed promising results. Placebo-controlled clinical trials will be conducted to confirm these findings.

353 Amlitelimab reduces serum IL-13 in a phase 2a clinical trial in atopic dermatitis without impacting T-cell expansion in a T-cell recall assay

Abstract Amlitelimab (SAR445229), a fully human non-depleting, non-cytotoxic, monoclonal antibody, binds to OX40Ligand (OX40L) on antigen-presenting cells (APC) to block OX40-OX40L interactions. In a 16-week, double-blind, Phase 2a trial (NCT03754309), amlitelimab induced clinically meaningful disease activity improvement in patients with moderate-to-severe atopic dermatitis (AD). To assess the effects of amlitelimab on interleukin (IL)-13 and T-cell recall responses. In the trial, 89 patients were randomized to amlitelimab low dose (LD; 200 mg loading/100 mg maintenance every 4 weeks [Q4W]), high dose (HD; 500 mg loading/250 mg maintenance Q4W), or placebo. Serum IL-13 levels were assessed by single molecule immunoassay (259 samples). Using human peripheral blood mononuclear cells from five healthy donors, a T-cell recall assay was performed. At baseline in the trial, IL-13 levels significantly correlated with disease severity (Eczema Area and Severity Index; r = 0.4784, P &amp;lt; 0.0001). Week 16 IL-13 levels were significantly reduced with amlitelimab vs. baseline but not placebo (median fold change [95% confidence interval, CI] from baseline to week 16 with P-values based on two-way Analysis of Variance [ANOVA] of log10-transformed fold change for patients with a complete dataset at week 16: LD 0.345 [0.23–0.44], P &amp;lt; 0.0001; HD 0.390 [0.30–0.63], P = 0.0002; placebo 0.835 [0.34–1.12], P = 0.1544). In a T-cell recall assay, amlitelimab significantly reduced IL-13 protein levels at days 3 and 6 without negatively impacting T-cell expansion, based on the percentage of proliferating CD4+ T-cells vs. isotype control. Amlitelimab decreased IL-13 levels in patients with AD and in a T-cell recall assay without negative effects on T-cell expansion, thus reducing inflammation without blocking T-cell proliferation during recall responses.

345 Treatment with amlitelimab—a novel non-depleting, non-cytotoxic anti-OX40Ligand monoclonal antibody—reduces IL-22 serum levels in a phase 2a randomized, placebo-controlled trial in patients with moderate-to-severe atopic dermatitis

Abstract OX40Ligand (OX40L) upregulation on antigen-presenting cells (APCs) following antigen presentation contributes to the survival and functional activation of T helper (Th) 2 and Th1/17/22 cells, which are central to the inflammation and pathological outcomes in atopic dermatitis (AD). In a Phase 2a trial (NCT03754309), amlitelimab, a fully human, non-depleting, non-cytotoxic anti-OX40L monoclonal antibody, was effective in treating patients with moderate-to-severe AD. To assess the effects of amlitelimab on interleukin (IL)-22, an important Th22-associated disease mediator of AD. 89 patients with moderate-to-severe AD were enrolled in a Phase 2a randomized, double-blind, placebo-controlled, multicentre trial and randomized 1 : 1 : 1 to intravenous amlitelimab low dose (200 mg loading/100 mg maintenance every 4 weeks [Q4W]; n = 29), high dose (500 mg/250 mg Q4W; n = 30) or placebo (Q4W; n = 29) until week 12. The primary efficacy endpoint was the percentage change in Eczema Area and Severity Index (EASI) from baseline to week 16. Other disease severity measurements included SCORing of Atopic Dermatitis (SCORAD) and validated Investigator Global Assessment (vIGA). Serum was collected at baseline, week 4 and week 16, and further collected at week 24 and week 36 in responders, defined as patients who reached vIGA 0/1 at week 16. IL-22 levels were determined by ultrasensitive single-molecule immunoassay (Simoa). Of 88 subjects who received study treatment, 59 were evaluable at week 16. Amlitelimab was well tolerated with an unremarkable safety profile. The mean percentage change in EASI from baseline at week 16 was −80.12% for amlitelimab low dose and −69.97% for amlitelimab high dose vs. −49.37% for placebo (nominal P-values: 0.009 [amlitelimab low dose vs. placebo] and 0.072 [amlitelimab high dose vs. placebo]). Amlitelimab-treated patients who achieved vIGA 0/1 at week 16 had sustained clinical responses up to week 36. No difference in IL-22 serum levels was found between groups at baseline. IL-22 levels correlated with disease severity at baseline, as measured by EASI and SCORAD (r = 0.53, P &amp;lt; 0.0001; and r = 0.36, P = 0.001; respectively). A significant reduction in IL-22 levels was observed at week 16 in amlitelimab-treated patients (low dose P &amp;lt; 0.0001; high dose P = 0.001), but not in the placebo group (P = 0.381). The amlitelimab-induced decrease in IL-22 levels was maintained until week 36 in those defined as vIGA 0/1 responders at week 16. OX40L blockade on APCs represents a promising novel approach in the treatment of AD by effectively targeting underlying T-cell immune dysregulation. Amlitelimab monotherapy not only provided a sustained and clinically meaningful improvement in disease activity compared with placebo in patients with moderate-to-severe AD, but also significantly decreased serum levels of IL-22, a Th22 cell-associated cytokine involved in the underlying immunopathogenesis of AD.

Effects of half-dose spiomet treatment in girls with early puberty and accelerated bone maturation: a multicenter, randomized, placebo-controlled study protocol

BackgroundA “mismatch” sequence of less prenatal weight gain and more postnatal weight gain may lead to ectopic lipid accumulation, and trigger the development of early adrenarche/pubarche and the activation of the gonadotropic axis resulting in early puberty and ending up in full-blown adolescent polycystic ovary syndrome (PCOS). In the present study, we assess whether a low-dose combination of generics that collectively reduce ectopic fat through different pathways can slow down the accelerated maturation in “mismatch” girls with early puberty.MethodsRandomized, placebo-controlled, multicenter, phase 2a, study in 64 girls [age, 8.0–9.5 years; birthweight (BW) for gestational age: −2.5 < Z-score <0, body mass index (BMI): 0 < Z-score < +2.5 and early progressive puberty (Tanner B2 at 7.7–9.3 years)]. Pharmacological intervention will be with a half-dose version of SPIOMET (mini-spiomet), a combination that reverts the PCOS phenotype in “mismatch” adolescents; mini-spiomet will contain spironolactone (25 mg/day, to raise brown adipose tissue activity), pioglitazone (3.75 mg/day, to raise adiponectin and insulin sensitivity), and metformin (425 mg/day, to raise AMPK activity and GDF15). Recruitment: 1 year; double-blind treatment: 1 year; open follow-up: 1 year; analyses and reporting: 1 year. Interventions: randomization (1:1) for placebo vs mini-spiomet. Primary outcome: annualized bone age advancement (0–1 year) by BoneXpert; secondary outcomes: insulin, IGF-I, high-molecular-weight adiponectin (HMW-adip), sex hormone binding globulin (SHBG), ultra-sensitive C-reactive protein (usCRP), androgens, luteinizing hormone (LH), follicle-stimulating hormone (FSH), oestradiol, growth-and-differentiation factor 15 (GDF15), C-X-C motif chemokine ligand-14 (CXCL14), safety parameters, and quantification of hepato-visceral fat.DiscussionThe present study, if successful, may provide a first proof of the concept that the rapid maturation of girls with an upward mismatch between pre- and post-natal weight gain can be slowed down with a fixed low-dose combination of old and safe generics jointly targeting a reduction of ectopic fat without necessarily lowering body weight.Trial registrationEudraCT 2021-006766-21. Registered on May 30, 2022.