Michael E. Bozik

The effects of dexpramipexole (KNS-760704) in individuals with amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is characterized by upper and lower motor neuron dysfunction and loss, rapidly progressive muscle weakness, wasting and death. Many factors, including mitochondrial dysfunction, may contribute to ALS pathogenesis. Riluzole, which has shown only modest benefits in a measure of survival time without demonstrated effects on muscle strength or function, is the only approved treatment for ALS. We tested the putative mitochondrial modulator dexpramipexole (KNS-760704; (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine) in subjects with ALS in a two-part, double-blind safety and tolerability study, with a preliminary assessment of its effects on functional decline and mortality. In part 1, the effects of dexpramipexole (50, 150 or 300 mg d−1) versus placebo were assessed over 12 weeks. In part 2, after a 4-week, single-blind placebo washout, continuing subjects were re-randomized to dexpramipexole at 50 mg d−1 or 300 mg d−1 as double-blind active treatment for 24 weeks. Dexpramipexole was safe and well tolerated. Trends showing a dose-dependent attenuation of the slope of decline of the ALS Functional Rating Scale-Revised (ALSFRS-R) in part 1 and a statistically significant (P = 0.046) difference between groups in a joint rank test of change from baseline in ALSFRS-R and mortality in part 2 strongly support further testing of dexpramipexole in ALS.

Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): a randomised, double-blind, phase 3 trial

BACKGROUND In a phase 2 study, dexpramipexole (25-150 mg twice daily) was well tolerated for up to 9 months and showed a significant benefit at the high dose in a combined assessment of function and mortality in patients with amyotrophic lateral sclerosis. We aimed to assess efficacy and safety of dexpramipexole in a phase 3 trial of patients with familial or sporadic disease. METHODS In our randomised, double-blind, placebo-controlled phase 3 trial (EMPOWER), we enrolled participants aged 18-80 years (with first amyotrophic lateral sclerosis symptom onset 24 months or less before baseline) at 81 academic medical centres in 11 countries. We randomly allocated eligible participants (1:1) with a centralised voice-interactive online system to twice-daily dexpramipexole 150 mg or matched placebo for 12-18 months, stratified by trial site, area of disease onset (bulbar vs other areas), and previous use of riluzole. The primary endpoint was the combined assessment of function and survival (CAFS) score, based on changes in amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R) total scores and time to death up to 12 months. We assessed the primary endpoint in all participants who received at least one dose and had at least one post-dose ALSFRS-R measurement or died. We monitored adverse events in all participants. This study is registered with ClinicalTrials.gov, number NCT01281189. FINDINGS Between March 28, 2011, and Sept 30, 2011, we enrolled 943 participants (474 randomly allocated dexpramipexole, 468 randomly allocated placebo, and one withdrew). Least-square mean CAFS scores at 12 months did not differ between participants in the dexpramipexole group (score 441·76, 95% CI 415·43-468·08) and those in the placebo group (438·84, 412·81-464·88; p=0·86). At 12 months, we noted no differences in mean change from baseline in ALSFRS-R total score (-13·34 in the dexpramipexole group vs -13·42 in the placebo group; p=0·90) or time to death (74 [16%] vs 79 [17%]; hazard ratio 1·03 [0·75-1·43]; p=0·84). 37 (8%) participants in the dexpramipexole group developed neutropenia compared with eight (2%) participants in the placebo group, and incidence of other adverse events was similar between groups. INTERPRETATION Dexpramipexole was generally well tolerated but did not differ from placebo on any prespecified efficacy endpoint measurement. Our trial can inform the design of future clinical research strategies in amyotrophic lateral sclerosis. FUNDING Biogen Idec.

KNS-760704 [(6R)-4,5,6,7-tetrahydro-N6-propyl-2, 6-benzothiazole-diamine dihydrochloride monohydrate] for the treatment of amyotrophic lateral sclerosis.

Developing effective treatments for chronic neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) has proven extremely difficult. ALS is universally fatal, characterized by progressive weakness due to the degeneration of upper and lower motor neurons, and leads eventually to respiratory failure which is the usual cause of death. Only a single treatment has been approved, the modestly effective nonspecific neuroprotectant Rilutek® (riluzole; 2‐amino‐6‐(trifluoromethoxy)benzothiazole). KNS‐760704 [(6R)‐4,5,6,7‐tetrahydro‐N6‐propyl‐2,6‐benzothiazole‐diamine dihydrochloride, RPPX], a synthetic amino‐benzothiazole with demonstrated activity in maintaining mitochondrial function, is being developed as a treatment for ALS. It has proven to be effective in multiple in vitro and in vivo assays of neuroprotection, including the G93A‐SOD1 mutant mouse model; however, its specific mechanism of action remains unknown. The potential of KNS‐760604 as a treatment for ALS was first suggested by studies showing that its optical enantiomer, Mirapex®[(6S)‐4,5,6,7‐tetrahydro‐N6‐propyl‐2,6‐benzothiazole‐diamine; pramipexole dihydrochloride; PPX], a high‐affinity agonist at dopamine D2, D3, and D4 receptors, exhibits important neuroprotective properties independent of its dopamine receptor agonism. In cell‐based assays, both RPPX and PPX reduce the production of reactive oxygen species (ROS), attenuate the activation of apoptotic pathways, and increase cell survival in response to a variety of neurotoxins. However, PPX has limited utility as a clinical neuroprotective agent because the drug concentrations required for neuroprotection would likely produce unacceptable dopaminergic side effects. RPPX, on the other hand, while possessing the same neuroprotective potential as PPX, is a much lower‐affinity dopamine receptor agonist and may therefore be more useful in the treatment of ALS. This review will examine the data supporting the hypothesis that the RPPX may have therapeutic potential for the treatment of neurodegenerative disorders including ALS. In addition, we will briefly review recent preclinical data in support of RPPX, and discuss the current status of its clinical development.

Safety, Tolerability, and Pharmacokinetics of KNS-760704 (Dexpramipexole) in Healthy Adult Subjects

Dexpramipexole (KNS‐760704; [6R]‐4,5,6,7‐tetrahydro‐N6‐propyl‐2,6‐benzothiazole‐diamine) is a novel synthetic amino‐benzothiazole in development for the treatment of amyotrophic lateral sclerosis (ALS). Preclinical studies have shown that dexpramipexole is neuroprotective in vitro and in vivo, is highly orally bioavailable and water soluble, and rapidly achieves and maintains high central nervous system concentrations relative to plasma. Two phase 1 clinical studies were conducted to assess the safety, tolerability, and pharmacokinetics (PK) of single and multiple doses of dexpramipexole in 54 healthy male and female adults. The effect of food on the single‐dose PK of dexpramipexole was also evaluated. Single doses (50 mg, 150 mg, or 300 mg) and multiple doses (50 mg twice daily, 100 mg twice daily, or 150 mg twice daily) of dexpramipexole over 4.5 days were safe and well tolerated. Dexpramipexole was rapidly absorbed, with time to maximum plasma concentration ranging from 1.8 to 2.6 hours and half‐life ranging from 6.4 to 8.1 hours under fasted conditions, and was mostly eliminated in urine as unchanged parent drug (84%–90% of dose). Food had no effect on the single‐dose PK of dexpramipexole. These findings support the ongoing development of dexpramipexole for the treatment of ALS and further evaluation of the compounds therapeutic potential in other neurodegenerative diseases.

A post hoc analysis of subgroup outcomes and creatinine in the phase III clinical trial (EMPOWER) of dexpramipexole in ALS

Abstract Our objective was to compare the phase II and phase III (EMPOWER) studies of dexpramipexole in ALS and evaluate potential EMPOWER responder subgroups and biomarkers based on significant inter-study population differences. In a post hoc analysis, we compared the baseline population characteristics of both dexpramipexole studies and analyzed EMPOWER efficacy outcomes and laboratory measures in subgroups defined by significant inter-study differences. Results showed that, compared with phase II, the proportion of El Escorial criteria (EEC) definite participants decreased (p = 0.005), riluzole use increased (p = 0.002), and mean symptom duration increased (p = 0.037) significantly in EMPOWER. Baseline creatinine (p < 0.001) and on-study creatinine change (p < 0.001) correlated significantly with ALSFRS-R in EMPOWER. In the EMPOWER subgroup defined by EEC-definite ALS, riluzole use, and < median symptom duration (15.3 months), dexpramipexole-treated participants had reduced ALSFRS-R slope decline (p = 0.015), decreased mortality (p = 0.011), and reduced creatinine loss (p = 0.003). In conclusion, significant differences existed between the phase II and EMPOWER study populations in ALS clinical trials of dexpramipexole. In a post hoc analysis of EMPOWER subgroups defined by these differences, potential clinical benefits of dexpramipexole were identified in the subgroup of riluzole-treated, short-symptom duration, EEC-definite ALS participants. Creatinine loss correlated with disease progression and was reduced in dexpramipexole-treated participants, suggesting it as a candidate biomarker.

The targeted eosinophil-lowering effects of dexpramipexole in clinical studies

Dexpramipexole, an orally bioavailable small molecule previously under clinical development in amyotrophic lateral sclerosis, was observed during routine safety hematology monitoring to demonstrate pronounced, dose- and time-dependent eosinophil-lowering effects, with minor reductions on other leukocyte counts. Analysis of hematology lab values across two double-blind, randomized placebo-controlled clinical trials at total daily doses ranging from 50mg to 300mg demonstrated that dexpramipexole consistently and markedly lowered peripheral blood eosinophils. This effect developed after 1month on treatment, required 3-4months to reach its maximum, remained constant throughout treatment, and partially recovered to baseline levels upon drug withdrawal. All doses tested were well tolerated. The overall adverse event rate was similar for dexpramipexole and placebo, and notably with no increase in infection-related adverse events associated with eosinophil-lowering effects. Given the reliance on and insufficiency of off-label chronic corticosteroid therapy for hypereosinophilic syndromes and other eosinophilic-associated diseases (EADs), a need exists for less toxic, more effective, targeted therapeutic alternatives. Further clinical studies are underway to assess the eosinophil-lowering effect of dexpramipexole in the peripheral blood and target tissues of EAD patients and whether such reductions, if observed, produce clinically important benefits.

Association Between Decline in Slow Vital Capacity and Respiratory Insufficiency, Use of Assisted Ventilation, Tracheostomy, or Death in Patients With Amyotrophic Lateral Sclerosis

Importance The prognostic value of slow vital capacity (SVC) in relation to respiratory function decline and disease progression in patients with amyotrophic lateral sclerosis (ALS) is not well understood. Objective To investigate the rate of decline in percentage predicted SVC and its association with respiratory-related clinical events and mortality in patients with ALS. Design, Setting, and Participants This retrospective study included 893 placebo-treated patients from 2 large clinical trials (EMPOWER and BENEFIT-ALS, conducted from March 28, 2011, to November 1, 2012, and from October 23, 2012, to March 21, 2014, respectively) and an ALS trial database (PRO-ACT, containing studies completed between 1990 and 2010) to investigate the rate of decline in SVC. Data from the EMPOWER trial (which enrolled adults with possible, probable, or definite ALS; symptom onset within 24 months before screening; and upright SVC at least 65% of predicted value for age, height, and sex) were used to assess the relationship of SVC to respiratory-related clinical events; 456 patients randomized to placebo were used in this analysis. The 2 clinical trials included patients from North America, Australia, and Europe. Main Outcomes and Measures Clinical events included the earlier of time to death or time to decline in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) respiratory subdomain, time to onset of respiratory insufficiency, time to tracheostomy, and all-cause mortality. Results Among 893 placebo-treated patients with ALS, the mean (SD) patient age was 56.7 (11.2) years, and the mean (SD) SVC was 90.5% (17.1%) at baseline; 65.5% (585 of 893) were male, and 20.5% (183 of 893) had bulbar-onset ALS. In EMPOWER, average decline of SVC from baseline through 1.5-year follow-up was −2.7 percentage points per month. Steeper declines were found in patients older than 65 years (−3.6 percentage points per month [P = .005 vs <50 years and P = .007 vs 50-65 years) and in patients with an ALSFRS-R total score of 39 or less at baseline (−3.1 percentage points per month [P < .001 vs >39]). When the rate of decline of SVC was slower by 1.5 percentage points per month in the first 6 months, risk reductions for events after 6 months were 19% for decline in the ALSFRS-R respiratory subdomain or death after 6 months, 22% for first onset of respiratory insufficiency or death after 6 months, 23% for first occurrence of tracheostomy or death after 6 months, and 23% for death at any time after 6 months (P < .001 for all). Conclusions and Relevance The rate of decline in SVC is associated with meaningful clinical events in ALS, including respiratory failure, tracheostomy, or death, suggesting that it is an important indicator of clinical progression.

Dexpramipexole as an oral steroid-sparing agent in hypereosinophilic syndromes

Hypereosinophilic syndromes (HESs) are a heterogeneous group of disorders characterized by peripheral eosinophilia and eosinophil-related end organ damage. Whereas most patients respond to glucocorticoid (GC) therapy, high doses are often necessary, and side effects are common. Dexpramipexole (KNS-760704), an orally bioavailable synthetic aminobenzothiazole, showed an excellent safety profile and was coincidentally noted to significantly decrease absolute eosinophil counts (AECs) in a phase 3 trial for amyotrophic lateral sclerosis. This proof-of-concept study was designed to evaluate dexpramipexole (150 mg orally twice daily) as a GC-sparing agent in HESs. Dual primary end points were (1) the proportion of subjects with ≥50% decrease in the minimum effective GC dose (MED) to maintain AEC <1000/μL and control clinical symptoms, and (2) the MED after 12 weeks of dexpramipexole (MEDD) as a percentage of the MED at week 0. Out of 10 subjects, 40% (95% confidence interval [CI], 12%, 74%) achieved a ≥50% reduction in MED, and the MEDD/MED ratio was significantly <100% (median, 66%; 95% CI, 6%, 98%; P = .03). All adverse events were self-limited, and none led to drug discontinuation. Affected tissue biopsy samples in 2 subjects showed normalization of pathology and depletion of eosinophils on dexpramipexole. Bone marrow biopsy samples after 12 weeks of dexpramipexole showed selective absence of mature eosinophils in responders. Dexpramipexole appears promising as a GC-sparing agent without apparent toxicity in a subset of subjects with GC-responsive HESs. Although the exact mechanism of action is unknown, preliminary data suggest that dexpramipexole may affect eosinophil maturation in the bone marrow. This study was registered at www.clinicaltrials.gov as #NCT02101138.

Dexpramipexole depletes blood and tissue eosinophils in nasal polyps with no change in polyp size: Dexpramipexole Lowers Eosinophils

Chronic rhinosinusitis with nasal polyps (CRSwNP) and eosinophilia is a disease of the upper respiratory tract for which few therapies are available. Because the oral investigational drug dexpramipexole serendipitously decreased blood eosinophils in amyotrophic lateral sclerosis studies, we assessed its safety, eosinophil‐lowering activity, and preliminary clinical efficacy in patients with CRSwNP and eosinophilia.

Human Dopamine Receptor Affinity and Potency In Vitro and Dose Tolerability in Beagle Dogs In Vivo of Dexpramipexole and Pramipexole (P04.150)

Objective: To determine and quantify the relative dopamine receptor affinity and agonism of the optical enantiomers pramipexole and dexpramipexole. Background Dexpramipexole [(6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine dihydrochloride monohydrate (DEX)] is a new chemical entity now in Phase III development for ALS. It is the enantiomer of pramipexole (PPX), a high-affinity dopamine D2/D3 receptor agonist approved for use in Parkinson9s disease and restless legs syndrome. Design/Methods: We compared the in vitro receptor binding affinity and functional agonist potency of chirally pure DEX and PPX using human recombinant D2s and D3 dopamine receptors. To determine if observed differences in dopamine receptor affinities translated into differences in tolerability for the two enantiomers, both enantiomers were administered orally to beagle dogs in vivo, and the no-effect dose or the maximum tolerated dose were determined for each enantiomer. Results: PPX was a high-affinity ligand and a potent functional agonist at recombinant human D2s and D3 receptors, and produced multiple characteristic dopaminergic side effects in dogs at a dose of 0.0075 mg/kg. DEX was a much lower-affinity ligand and exhibited low potency agonism at each of these receptors. Further, dose tolerability of DEX was at least 10xE4 higher than that of PPX. The maximum tolerated dose of DEX was significantly reduced by spiking DEX drug substance with 0.5% PPX. Conclusions: While both enantiomers have been shown to have nonclinical neuroprotective properties independent of their dopamine receptor affinity, PPX9s use as a treatment for neurodegenerative disorders, including ALS, is restricted by dopamine-receptor mediated side effects. These data demonstrate that DEX, a candidate ALS therapeutic, has much lower functional dopamine activity than PPX, and should be tolerated at much higher clinical doses without titration; it is, therefore a valid candidate for the treatment of neurodegenerative disorders. The data furthermore underscore the importance of enantiomeric purity of DEX drug substance. Supported by: Knopp Biosciences LLC. Disclosure: Dr. Gribkoff has received personal compensation for activities with Knopp Biosciences LLC as an employee. Dr. Gribkoff holds stock and/or stock options in Knopp Biosciences, which sponsored research in which Dr. Gribkoff was involved as an investigator. Dr. Demady has received personal compensation for activities with Novartis Biologics as an employee. Dr. Ingersoll has received personal compensation for activities with Knopp Biosciences LLC as an employee. Dr. Ingersoll holds stock and/or stock options in Knopp Biosciences LLC, which sponsored research in which Dr. Ingersoll was involved as an investigator. Dr. Bozik has received personal compensation for activities with Knopp Biosciences LLC as an employee. Dr. Bozik holds stock and/or stock options in Knopp Biosciences LLC. Dr. Frantz has received personal compensation for activities with MPI Research Inc.