Acorda Therapeutics (United States)

3012 Background: VLS-1488 is an oral small molecule inhibitor of KIF18A, a mitotic kinesin protein important for successful division of cancer cells with chromosomal instability (CIN) but not required for mitosis in normal cells. Preclinical studies of VLS-1488 showed dose-dependent inhibition of tumor growth in CIN models. Methods: VLS-1488-2201 is a phase I/II study of patients (pts) with advanced solid tumors consisting of two parts, Dose Escalation and Dose Expansion. During Dose Escalation, a Bayesian Optimal Interval design was utilized to enroll pts to dose escalation cohorts with additional pts enrolled to backfill cohorts at dose levels (DLs) that did not meet de-escalation/elimination rules. Primary objective was to assess safety/tolerability of VLS-1488 at various DLs to determine the Maximum Tolerated Dose (MTD). Secondary objectives included evaluating preliminary efficacy and pharmacokinetics (PK). Eligible pts had exhausted standard of care treatments and had measurable disease per RECIST v1.1. Pts received VLS-1488 once daily, orally for 28-day cycles until disease progression, unacceptable toxicity or other stopping criteria. Results: 52 pts (ITT) were enrolled across 5 DLs including 50mg (n = 4), 100mg (n = 12), 200mg (n = 14), 400mg (n = 12) and 800mg (n = 10). Tumor types were high grade serous ovarian (HGSOC; n = 20), colorectal (n = 14), triple negative breast (n = 7), squamous lung (n = 3), endometrial (n = 3), ovarian carcinosarcoma (n = 2), esophageal (n = 2) and bladder (n = 1). The median number of prior lines was 4 (range 1-8). As of data cutoff, 52 pts (100%) received >1 dose of VLS-1488. No dose-limiting toxicities (as assessed during the first 28 days) were observed and MTD was not reached. Treatment-related AEs (TRAEs) occurred in 22 pts (42%), with fatigue (17.3%; G1 13.5%, G2 3.8%), aspartate aminotransferase increased (13.5%; G1 7.7%, G2 1.9%, G3 3.8%) and rash (11.5%; G1 3.8%, G2 1.9%, G3 5.8%) observed in >10% of pts. 6 pts (12%) experienced G3 TRAEs and no > G3 TRAEs were observed. Drug exposures exceeded preclinically defined efficacious thresholds and were approximately dose proportional at analyzed DLs. 41 pts (79%) were evaluable for response per RECIST v1.1. In the 16 HGSOC pts evaluable for response (where the median number of prior lines was 4.5; range 2-8), 3 partial responses (PRs; including 2 pts with sustained PR >24 weeks) and 6 with stable disease (SD; including 4 pts with tumor reductions) were observed across multiple DLs, with 5 pts continuing with study treatment. Conclusions: VLS-1488 was found to be safe and tolerable, with encouraging anti-tumor activity observed in heavily treated HGSOC pts. VLS-1488 will be evaluated further in the Dose Expansion phase of the study. Clinical trial information: NCT05902988 .

There is a need for improved approaches to rhythm control therapy of atrial fibrillation (AF). The effectiveness of flecainide (1.5 µmol/L) and ibutilide (20 nmol/L), alone and in combination, to cardiovert and prevent AF recurrence was studied in canine-isolated coronary-perfused right atrioventricular preparations. We also examined the safety of the combination of flecainide (1.5 µmol/L) and ibutilide (50 nmol/L) using canine left ventricular wedge preparations. Sustained AF (>1 hour) was inducible in 100%, 60%, 20%, and 0% of atria in the presence of acetylcholine alone, acetylcholine+ibutilide, acetylcholine+flecainide, and acetylcholine+ibutilide+flecainide, respectively. When used alone, flecainide and ibutilide cardioverted sustained AF in 40% and 20% of atria, respectively, but in 100% of atria when used in combination. Ibutilide prolonged atrial and ventricular effective refractory period by 15% and 8%, respectively, at a cycle length of 500 ms (P<0.05 for both). Flecainide increased the effective refractory period in atria by 27% (P<0.01) but by only 2% in the ventricles. The combination of the 2 drugs lengthened the effective refractory period by 42% in atria (P<0.01) but by only 7% (P<0.05) in the ventricles. In left ventricular wedges, ibutilide prolonged QT and Tpeak-Tend intervals by 25 and 55%, respectively (P<0.05 for both; cycle length, 2000 ms). The addition of flecainide (1.5 µmol/L) partially reversed these effects (P<0.05 for both parameters versus ibutilide alone). Torsades de Pointes score was relatively high with ibutilide alone and low with the drug combination. In our experimental model, a combination of flecainide and ibutilide significantly improves cardioversion and prevents the recurrence of AF compared with monotherapies with little to no risk for the development of long-QT-mediated ventricular proarrhythmia.

<h3>Objective:</h3> An analysis of the proportion of patients who turned ON after CVT-301 84mg treatment vs placebo, compared across patient subgroups with different baseline UPDRS-III scores when experiencing an OFF period in the Phase 3 SPAN-PD study. <h3>Background:</h3> SPAN-PD was an efficacy and safety study of CVT-301 in patients on a stable levodopa/dopa-decarboxylase inhibitor regimen experiencing ≥2h daily OFF periods. Patients were randomized to placebo/CVT-301 for OFF symptom treatment as needed ≤5 times/day. CVT-301 84mg significantly improved motor function at week 12, 30 min post-dose, as measured by lower UPDRS-III scores, with improvement recorded as early as 10 min post-dose. Proportion of patients achieving an ON state at week 12 also demonstrated significant superiority of CVT-301 over placebo (58% of CVT-301 84mg patients turned ON and remained ON at 60 min post-dose, vs 36% of placebo). <h3>Design/Methods:</h3> Analysis compared patients stratified by examiner-rated OFF UPDRS-III score at screening (median UPDRS-III score ≤33 “low” (range 8–33) vs &gt;33 “high” (range 34–75). Treatment differences were calculated between CVT-301 84mg and placebo for the proportion of patients who turned ON and remained ON at 60 min post-dose at week 12 (stratified by Hoehn &amp; Yahr stage, and screening spirometry). <h3>Results:</h3> In the low UPDRS-III group (≤33, n=104) at week 12, 30 (50.0%) CVT-301 patients turned ON post-dose and remained ON at 60 min compared with 11 (25.0%) placebo patients (odds ratio [OR] 3.0, <i>P</i>=0.011). In the high UPDRS group (&gt;33, n=90) at week 12, 26 (70.3%) CVT-301 patients turned ON post-dose vs 24 (45.3%) on placebo (OR 2.8, <i>P</i>=0.026). <h3>Conclusions:</h3> In SPAN-PD , CVT-301 84mg was significantly more effective than placebo in turning patients ON at week 12 in both subpopulations of PD patients experiencing, respectively, more or less severe OFF periods at screening. No substantive difference in drug response was observed between the more and less severe groups. <b>Disclosure:</b> Dr. Cohen has received personal compensation for serving as an employee of Acorda Therapeutics. Dr. Cohen has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for VBL Therapeutics. Dr. Cohen has stock in Acorda Therapeutics. Ping Zhao has received personal compensation for serving as an employee of Acorda Therapeutics Inc. Ping Zhao has received stock or an ownership interest from Acorda Therapeutics Inc.. Richard Marini has received personal compensation for serving as an employee of Acorda Therapeutics. Richard Marini has stock in Acorda Therapeutics. Burkhard Blank has received personal compensation for serving as an employee of Acorda Therapeutics. Burkhard Blank has received stock or an ownership interest from Acorda Therapeutics, Inc. Donald Grosset has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Glasgow Memory Clinic. Donald Grosset has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for IQVIA. Donald Grosset has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for AbbVie. Donald Grosset has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Britannia. Donald Grosset has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for GE Healthcare. The institution of Donald Grosset has received research support from Parkinson’s UK. Donald Grosset has received personal compensation in the range of $10,000-$49,999 for serving as a Clinical Director Excellence Network with Parkinson’s UK.

&lt;div&gt;AbstractPurpose:&lt;p&gt;To compare napabucasin (generator of reactive oxygen species) plus paclitaxel with paclitaxel only in patients with second-line advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma.&lt;/p&gt;Patients and Methods:&lt;p&gt;In the double-blind, phase III BRIGHTER study (NCT02178956), patients were randomized (1:1) to napabucasin (480 mg orally twice daily) plus paclitaxel (80 mg/m&lt;sup&gt;2&lt;/sup&gt; i.v. weekly for 3 of 4 weeks) or placebo plus paclitaxel. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety.&lt;/p&gt;Results:&lt;p&gt;Overall, 714 patients were randomized (napabucasin plus paclitaxel, &lt;i&gt;n&lt;/i&gt; = 357; placebo plus paclitaxel, &lt;i&gt;n&lt;/i&gt; = 357). 72.1% were male, 74.6% had gastric adenocarcinoma, and 46.2% had peritoneal metastases. The study was unblinded following an interim analysis at 380 deaths. The final efficacy analysis was performed on 565 deaths (median follow-up, 6.8 months). No significant differences were observed between napabucasin plus paclitaxel and placebo plus paclitaxel for OS (6.93 vs. 7.36 months), PFS (3.55 vs. 3.68 months), ORR (16% vs. 18%), or DCR (55% vs. 58%). Grade ≥3 adverse events occurred in 69.5% and 59.7% of patients administered napabucasin plus paclitaxel and placebo plus paclitaxel, respectively, with grade ≥3 diarrhea reported in 16.2% and 1.4%, respectively.&lt;/p&gt;Conclusions:&lt;p&gt;Adding napabucasin to paclitaxel did not improve survival in patients with pretreated advanced gastric or GEJ adenocarcinoma. Consistent with previous reports, the safety profile of napabucasin was driven by manageable gastrointestinal events; grade ≥3 diarrhea occurred at a higher frequency with napabucasin plus paclitaxel versus placebo plus paclitaxel.&lt;/p&gt;&lt;/div&gt;

Abstract Background Height, weight, and body mass index (BMI) are well established risk factors for atrial fibrillation (AF) but whether they are also predictors of successful pharmacological cardioversion of AF is unknown. Data from the open-label INSTANT study of flecainide acetate oral inhalation solution (FlecIH) for acute cardioversion of recent-onset symptomatic AF were examined to determine if these anthropometric measures are predictors of successful cardioversion of AF to sinus rhythm (SR) with FlecIH. Methods Logistic regression was performed on a broad array of patient and disease characteristics to identify predictors of cardioversion success at 90 minutes post-dose, and potential interactions were examined by boundary restriction analysis. Data are presented for patients receiving 120 mg FlecIH. Results Data from 81 patients (32.1% female) with a mean age of 59.8 years (range: 26.0, 84.0) were included in the analysis. This cohort had a mean weight of 87 kg (range: 57, 150), a mean height of 180 cm (range: 156, 199), and a mean BMI of 26.8 kg/m2 (range: 17.2, 37.9). A logistic regression model identified height, weight, and BMI as significant predictors of cardioversion success (p&amp;lt;0.01) and a boundary restriction analysis revealed a negative correlation between BMI and conversion rate across the entire dataset (see Figure 1). Clinically significant conversion rates were observed for patients with BMI values that were considered normal (BMI &amp;lt;25 kg/m2 = 53%; 95% CI: 36, 70), overweight (BMI ≥25 and &amp;lt;30 kg/m2 = 47%; 95% CI: 29, 64), and obese (BMI ≥30 and &amp;lt;35 kg/m2 = 43%; 95% CI: 17, 69); however, none of the severely obese patients (BMI ≥35 mg/m2) had their AF successfully converted to sinus rhythm (see Figure 2). Conclusions Successful cardioversion of recent onset AF with 120 mg FlecIH was observed in normal, overweight, and obese patients with BMI values &amp;lt;35 kg/m2; however, conversion rate decreases with increasing BMI. Further evaluation of FlecIH dosing in severely obese patients is warranted. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): InCarda Therapeutics

SummaryDNA-damage inducible 1 homolog 2 (DDI2) is a protease that activates the transcription factor NRF1. Cellular models have shown that this pathway contributes to cell-stress adaptation, for example, on proteasome inhibition. However, DDI2 physiological function is unknown. Ddi2 Knock-out (KO) mice were embryonic lethal. Therefore, we generated liver-specific Ddi2-KO animals and used comprehensive genetic analysis to identify the molecular pathways regulated by DDI2. Here, we demonstrate that DDI2 contributes to metallothionein (MT) expression in mouse and human hepatocytes at basal and upon cadmium (Cd) exposure. This transcriptional program is dependent on DDI2-mediated NRF1 proteolytic maturation. In contrast, NRF1 homolog NRF2 does not contribute to MT production. Mechanistically, we observed that Cd exposure inhibits proteasome activity, resulting in DDI2-mediated NRF1 proteolytic maturation. In line with these findings, DDI2 deficiency sensitizes cells to Cd toxicity. This study identifies a function for DDI2 that links proteasome homeostasis to heavy metal mediated toxicity.

UPDRS-III score (primary endpoint) and PGIC changes after levodopa inhalation powder (CVT-301) 84mg treatment were compared for baseline subgroups of patients in the phase 3, SPAN-PD study.

BackgroundRecombinant human immunoglobulin M22 (rHIgM22) has promoted remyelination in animal models and was well tolerated in people with clinically stable multiple sclerosis.ObjectiveSafety/tolerability of a single rHIgM22 dose was investigated following an acute relapse and to determine whether this enhanced CNS/CSF concentrations.MethodsAdults (N = 27) with acute relapse were assigned to rHIgM22 (0.5 or 2.0 mg/kg) or placebo. Study included screening/steroid administration periods and 10 study visits over 6 months. rHIgM22 CSF concentrations were assessed on days 2 and 29. Pharmacokinetic and safety samples were taken for up to 60 days. Assessments included adverse events and other clinical measures. Brain magnetic resonance imaging was performed with/without gadolinium.ResultsrHIgM22 CSF levels were consistent with dose-dependent concentration on both days 2 and 29. Infusion was generally well tolerated during an acute relapse. Immunogenicity was mild. Most adverse events did not appear to be dose dependent, were mild/moderate, and were events often associated with multiple sclerosis.ConclusionAlthough limited by high variability and small sample size, the data suggest enhanced CNS uptake associated with a drop in CSF levels. This study demonstrated safety of an antibody directed to myelin and oligodendrocytes in the course of active demyelinating disease. Further research into rHIgM22 is warranted.ClinicalTrials.gov: NCT02398461 https://clinicaltrials.gov/ct2/show/study/NCT02398461?term=M22&draw=2&rank=8

To investigate combined safety results from 3 trials of CVT-301 for the treatment of OFF episodes in PD patients on an oral dopa-decarboxylase inhibitor/levodopa (DDI/LD) regimen.