A Phase 1 study of GDC-0134, a dual leucine zipper kinase inhibitor, in ALS.

OBJECTIVE: Dual leucine zipper kinase (DLK), which regulates the c-Jun N-terminal kinase pathway involved in axon degeneration and apoptosis following neuronal injury, is a potential therapeutic target in amyotrophic lateral sclerosis (ALS). This first-in-human study investigated safety, tolerability, and pharmacokinetics (PK) of oral GDC-0134, a small-molecule DLK inhibitor. Plasma neurofilament light chain (NFL) levels were explored in GDC-0134-treated ALS patients and DLK conditional knockout (cKO) mice. METHODS: The study included placebo-controlled, single and multiple ascending-dose (SAD; MAD) stages, and an open-label safety expansion (OLE) with adaptive dosing for up to 48 weeks. RESULTS: Forty-nine patients were enrolled. GDC-0134 (up to 1200 mg daily) was well tolerated in the SAD and MAD stages, with no serious adverse events (SAEs). In the OLE, three study drug-related SAEs occurred: thrombocytopenia, dysesthesia (both Grade 3), and optic ischemic neuropathy (Grade 4); Grade ≤2 sensory neurological AEs led to dose reductions/discontinuations. GDC-0134 exposure was dose-proportional (median half-life = 84 h). Patients showed GDC-0134 exposure-dependent plasma NFL elevations; DLK cKO mice also exhibited plasma NFL compared to wild-type littermates. INTERPRETATION: This trial characterized GDC-0134 safety and PK, but no adequately tolerated dose was identified. NFL elevations in GDC-0134-treated patients and DLK cKO mice raised questions about interpretation of biomarkers affected by both disease and on-target drug effects. The safety profile of GDC-0134 was considered unacceptable and led to discontinuation of further drug development for ALS. Further work is necessary to understand relationships between neuroprotective and potentially therapeutic effects of DLK knockout/inhibition and NFL changes in patients with ALS.

A randomized placebo-controlled phase 3 study of mesenchymal stem cells induced to secrete high levels of neurotrophic factors in amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative illness with great unmet patient need. We aimed to evaluate whether mesenchymal stem cells induced to secrete high levels of neurotrophic factors (MSC-NTF), a novel autologous cell-therapy capable of targeting multiple pathways, could safely slow ALS disease progression. METHODS: This randomized, double-blind, placebo-controlled study enrolled ALS participants meeting revised El Escorial criteria, revised ALS Functional Rating Scale (ALSFRS-R) ≥25 (screening) and ≥3 ALSFRS-R points decline prior to randomization. Participants received three treatments of MSC-NTF or placebo intrathecally. The primary endpoint evaluated efficacy of MSC-NTF through a responder analysis and safety. A change in disease progression post-treatment of ≥1.25 points/mo defines a clinical response. A pre-specified analysis leveraged baseline ALSFRS-R of 35 as a subgroup threshold. RESULTS: Overall, MSC-NTF treatment was well tolerated; there were no safety concerns. Thirty-three percent of MSC-NTF and 28% of placebo participants met clinical response criteria at 28 wk (odds ratio [OR] = 1.33, P = .45); thus, the primary endpoint was not met. A pre-specified analysis of participants with baseline ALSFRS-R ≥ 35 (n = 58) showed a clinical response rate at 28 wk of 35% MSC-NTF and 16% placebo (OR = 2.6, P = .29). Significant improvements in cerebrospinal biomarkers of neuroinflammation, neurodegeneration, and neurotrophic factor support were observed with MSC-NTF, with placebo unchanged. DISCUSSION: The study did not reach statistical significance on the primary endpoint. However, a pre-specified subgroup suggests that MSC-NTF participants with less severe disease may have retained more function compared to placebo. Given the unmet patient need, the results of this trial warrant further investigation.

Plasma creatinine and oxidative stress biomarkers in amyotrophic lateral sclerosis.

Objective: To determine the associations between plasma creatinine (PCr), plasma uric acid (PUA), and urinary oxidative stress (OS) biomarkers with the ALSFRS-R at baseline and survival in a large epidemiological cohort study (ALS COSMOS) with a well-phenotyped patient population (N = 355).Methods: Fasting plasma and first void urine samples were obtained. PCr, PUA, urinary 8-oxo-deoxy guanosine (8-oxodG), and 15-F2t-isoprostane (IsoP) were analyzed at baseline, near the midpoint of follow-up, and at the final blood draw (before death or withdrawal from study). We estimated associations between these biomarkers and the ALSFRS-R at baseline and survival.Results: At baseline, PCr correlated with ALSFRS-R (Spearman r = 0.30), percent (%) FVC (r = 0.20), PUA (r = 0.37), and 8-oxodG (r = -0.13, all p < 0.05). Baseline PCr significantly predicted survival (adjusted hazard ratio 0.28, p < 0.001). Time to death from baseline was shortest for those in the lowest two PCr quartiles relative to the highest two quartiles. PCr and ALSFRS-R values were significantly correlated at all three time points (baseline: r = 0.29, midpoint: r = 0.23, final: r = 0.38, all p < 0.001). PCr and PUA significantly declined over time, whereas OS biomarkers significantly increased over time.Conclusions: To date, PCr predicted survival the best, compared to PUA, 8-oxodG, and IsoP. Although PCr represents the degree of muscle mass, it may also represent complex biochemical changes in ALS. Because the field has no reliable prognostic biomarkers, the importance of PCr warrants further investigation through clinical studies in ALS.

Review process for IVIg treatment: Lessons learned from INSIGHTS neuropathy study.

BACKGROUND: This project is an effort to understand how orders for IV immunoglobulin (IVIg) are documented and prescribed by physicians, and subsequently, how they are reviewed by insurance companies for the treatment of immune neuropathies. METHODS: A panel of neuromuscular specialists reviewed case records from 248 IVIg-naive patients whose in-home IVIg infusion treatment was submitted to insurance for authorization. After reviewing a case record, 1 panelist was asked to make a diagnosis and to answer several questions about the treatment. A second panelist reviewed the original record and follow-up records that were obtained for reauthorization of additional treatments and was asked to determine whether the patient had responded to the treatment. RESULTS: Our specialists believed that only 32.2% of 248 patients had an immune neuropathy and were appropriate candidates for IVIg therapy, whereas 46.4% had neuropathies that were not immune mediated. Only 15.3% of cases met electrodiagnostic criteria for a demyelinating neuropathy. Our specialists believed that 36.7% of 128 cases with follow-up records had responded to therapy. In cases in which the initial reviewer had predicted that there would be a response to IVIg, the second reviewer found that 54% had responded. This is compared with a 27% response rate when the first reviewer predicted that there would be no response (p = 0.019). CONCLUSIONS: Our expert review finds that the diagnosis of immune neuropathies made by providers, and subsequently approved for IVIg therapy by payers, is incorrect in a large percentage of cases. If payers include an expert in their review process, it would improve patient selection, appropriate use, and continuation of treatment with this expensive therapeutic agent.

Phase I clinical trial of safety of L-serine for ALS patients.

We performed a randomized, double-blind phase I clinical trial for six months on the effects of oral L-serine in patients with ALS. The protocol called for enrollment of patients with a diagnosis of probable or definite ALS, age 18-85 years, disease duration of less than three years and forced vital capacity (FVC) ≥ 60%. Patients were randomly assigned to four different oral twice-daily dose regimens (0.5, 2.5, 7.5, or 15 g/dose). Blood, urine and CSF samples, ALS Functional Rating Scale-Revised (ALSFRS-R) scores and forced vital capacity (FVC) were obtained throughout the trial. Disease progression was compared with matched historical placebo controls from five previous ALS therapeutic trials. Of 20 patients enrolled, one withdrew before receiving study drug and two withdrew with gastro-intestinal problems. Three patients died during the trial. L-serine was generally well tolerated by the patients and L-serine did not appear to accelerate functional decline of patients as measured by slope of their ALSFRS-R scores. Based on this small study, L-serine appears to be generally safe for patients with ALS.

Cognitive-behavioral screening reveals prevalent impairment in a large multicenter ALS cohort.

OBJECTIVES: To characterize the prevalence of cognitive and behavioral symptoms using a cognitive/behavioral screening battery in a large prospective multicenter study of amyotrophic lateral sclerosis (ALS). METHODS: Two hundred seventy-four patients with ALS completed 2 validated cognitive screening tests and 2 validated behavioral interviews with accompanying caregivers. We examined the associations between cognitive and behavioral performance, demographic and clinical data, and C9orf72 mutation data. RESULTS: Based on the ALS Cognitive Behavioral Screen cognitive score, 6.5% of the sample scored below the cutoff score for frontotemporal lobar dementia, 54.2% scored in a range consistent with ALS with mild cognitive impairment, and 39.2% scored in the normal range. The ALS Cognitive Behavioral Screen behavioral subscale identified 16.5% of the sample scoring below the dementia cutoff score, with an additional 14.1% scoring in the ALS behavioral impairment range, and 69.4% scoring in the normal range. CONCLUSIONS: This investigation revealed high levels of cognitive and behavioral impairment in patients with ALS within 18 months of symptom onset, comparable to prior investigations. This investigation illustrates the successful use and scientific value of adding a cognitive-behavioral screening tool in studies of motor neuron diseases, to provide neurologists with an efficient method to measure these common deficits and to understand how they relate to key clinical variables, when extensive neuropsychological examinations are unavailable. These tools, developed specifically for patients with motor impairment, may be particularly useful in patient populations with multiple sclerosis and Parkinson disease, who are known to have comorbid cognitive decline.

Echocardiography and Cardiac Rupture: Is Contrast Extravasation an Indication for Surgery?

Contrast echocardiography demonstrating microbubbles in the pericardial space has often been cited as evidence of ventricular rupture requiring emergent surgical intervention. We report a case where no myocardial perforation was found during post-myocardial infarction surgery despite prior echocardiographic evidence of contrast extravasation into the pericardial effusion. Clinical decision making requires balancing imaging evidence with clinical circumstances to determine the optimal timing for surgical intervention.

Phrenic nerve conduction studies as a biomarker of respiratory insufficiency in amyotrophic lateral sclerosis.

Our objective was to examine the value of phrenic nerve conduction studies (PNCS) in quantifying diaphragm dysfunction in ALS, as no ideal test of respiratory insufficiency exists in ALS. We prospectively recorded bilateral PNCS, forced vital capacity (FVC), maximum inspiratory pressure (MIP), sniff nasal inspiratory pressure (SNIP), respiratory rate, ALSFRS-R, and respiratory symptoms in 100 ALS patients attending our clinic over a nine-month period. Survival data were collected for two years. Results showed that PNCS were reproducible and well tolerated. When the Pamp was abnormal (<0.3 mV), the relative risk of a respiratory rate >18 was 7.2 (95% CI 2.2-37.2, p <0.01) compared with a Pamp ≥0.3 mV. Similarly, the relative risk of orthopnea was 3.5 (95% CI 1.6-8.7, p <0.01) and dyspnea 2.4 (95% CI 1.4-4.0, p <0.01). FVC had the strongest correlation with Pamp (R(2) = 0.48 (p <0.001)). Fourteen of 15 patients with a FVC <50% had a Pamp <0.3 mV. However, eight with a Pamp <0.3 had a FVC >80%. The median survival was 1.07 years when the Pamp was <0.3 mV and >2 years when the Pamp was >0.3 mV (p <0.001). In conclusion, the phrenic Pamp correlated closely with multiple symptoms, signs, and laboratory measures of respiratory insufficiency and may prove to be a useful biomarker of respiratory dysfunction in ALS.

Amyotrophic Lateral Sclerosis: A Historical Perspective.

This article looks back in time to see where the foundational basis for the understanding of amyotrophic lateral sclerosis originated. This foundation was created primarily in France by Jean-Martin Charcot and his fellow countrymen and disciples, along with key contributions from early clinicians in England and Germany. The early work on amyotrophic lateral sclerosis provides a useful foundation for today's clinicians with respect to tying together genetic and biologic aspects of the disorder that have been discovered over the past few decades.

Patterns of Weakness, Classification of Motor Neuron Disease, and Clinical Diagnosis of Sporadic Amyotrophic Lateral Sclerosis.

When approaching a patient with suspected motor neuron disease (MND), the pattern of weakness on examination helps distinguish MND from other diseases of peripheral nerves, the neuromuscular junction, or muscle. MND is a clinical diagnosis supported by findings on electrodiagnostic testing. MNDs exist on a spectrum, from a pure lower motor neuron to mixed upper and lower motor neuron to a pure upper motor neuron variant. Amyotrophic lateral sclerosis (ALS) is a progressive mixed upper and lower motor neuron disorder, most commonly sporadic, which is invariably fatal. This article describes a pattern approach to identifying MND and clinical features of sporadic ALS.

The Dilemma of the Clinical Trialist in Amyotrophic Lateral Sclerosis: The Hurdles to Finding a Cure.

Amyotrophic lateral sclerosis can be described as a disease with a poorly understood pathophysiologic mechanism and no treatment that dramatically impacts the course of the disease. Clinical trialists are faced with finding small treatment effects against a background of multiple potential treatments, a past history of failed trials, and heterogenous clinical outcomes. This article summarizes this environment and provides a rationale for drug development going forward.

Amyotrophic Lateral Sclerosis Regional Variants (Brachial Amyotrophic Diplegia, Leg Amyotrophic Diplegia, and Isolated Bulbar Amyotrophic Lateral Sclerosis).

Amyotrophic lateral sclerosis (ALS), a rapidly progressive, invariably fatal disease, involves mixed upper and lower motor neurons in different spinal cord regions. Patients with bulbar onset progress more rapidly than patients with limb onset or with a lower motor neuron presentation. Recent descriptions of regional variants suggest some patients have ALS isolated to a single spinal region for many years, including brachial amyotrophic diplegia, leg amyotrophic diplegia, and isolated bulbar palsy. Clearer definitions of regional variants will have implications for prognosis, understanding the pathophysiology of ALS, identifying genetic factors related to slower disease progression, and future planning of clinical trials.

Randomized phase 2 trial of NP001-a novel immune regulator: Safety and early efficacy in ALS.

OBJECTIVE: To assess the safety, tolerability, and preliminary efficacy of NP001, a novel immune regulator of inflammatory monocytes/macrophages, for slowing progression of amyotrophic lateral sclerosis (ALS). METHODS: This was a phase 2 randomized, double-blind, placebo-controlled trial of NP001 in 136 patients with ALS of <3 years' duration and forced vital capacity ≥70%. Participants received NP001 2 mg/kg, NP001 1 mg/kg, or placebo for 6 months. Safety, tolerability, and inflammatory biomarkers were assessed throughout the study. Preliminary efficacy was evaluated using the ALS Functional Rating Scale-Revised (ALSFRS-R) slope and change from baseline, with and without matched historical placebo controls, after 6 months of treatment. A post hoc analysis of the percentage of patients ("responders") whose ALSFRS-R did not change from baseline was also conducted. RESULTS: NP001 was generally safe and well-tolerated, except for infusion site pain and dizziness. No significant slowing of decline in the primary or secondary measures was observed. However, slowing of progression was observed in the high-dose group in patients with greater inflammation (wide range C-reactive protein). Moreover, NP001 may have dose dependently halted symptom progression in a subset of patients. More than 2 times as many patients on high-dose NP001 (25%) did not progress during 6 months of treatment compared with those on placebo (11%). Most "responders" had an elevated biomarker of inflammation, interleukin-18, and were positive for lipopolysaccharide at baseline, which decreased after treatment with NP001. CONCLUSION: The arresting of progression of ALS symptoms by NP001 in a subset of patients with marked neuroinflammation, as observed here, will represent a novel therapeutic approach for patients with ALS, if confirmed. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with ALS, NP001 is safe and did not significantly slow progression of the disease (difference in slope of the ALSFRS-R/month 0.12 favoring NP001, p = 0.55). The study lacks the precision to exclude an important effect of NP001.

ALS Multicenter Cohort Study of Oxidative Stress (ALS COSMOS): study methodology, recruitment, and baseline demographic and disease characteristics.

Abstract In a multicenter study of newly diagnosed ALS patients without a reported family history of ALS, we are prospectively investigating whether markers of oxidative stress (OS) are associated with disease progression. Methods utilize an extensive structured telephone interview ascertaining environmental, lifestyle, dietary and psychological risk factors associated with OS. Detailed assessments were performed at baseline and at 3-6 month intervals during the ensuing 30 months. Our biorepository includes DNA, plasma, urine, and skin. Three hundred and fifty-five patients were recruited. Subjects were enrolled over a 36-month period at 16 sites. To meet the target number of subjects, the recruitment period was prolonged and additional sites were included. Results showed that demographic and disease characteristics were similar between 477 eligible/non-enrolled and enrolled patients, the only difference being type of health insurance among enrolled patients. Sites were divided into three groups by the number of enrolled subjects. Comparing these three groups, the Columbia site had fewer 'definite ALS' diagnoses. This is the first prospective, interdisciplinary, in-depth, multicenter epidemiological investigation of OS related to ALS progression and has been accomplished by an aggressive recruitment process. The baseline demographic and disease features of the study sample are now fully characterized.

Genetic CJD with a novel E200G mutation in the prion protein gene and comparison with E200K mutation cases.

A novel point mutation resulting in a glutamate-to-glycine substitution in PRNP at codon 200, E200G with codon 129 MV polymorphism (cis valine) and type 2 PrPSc was identified in a patient with a prolonged disease course leading to pathology-proven Jakob-Creutzfeldt disease. Despite the same codon as the most common genetic form of human PRNP mutation, E200K, this novel mutation (E200G) presented with a different clinical and pathological phenotype, including prolonged duration, large vacuoles, no vacuolation in the hippocampus, severe neuronal loss in the thalamus, mild cerebellar involvement, and abundant punctate linear and curvilinear deposition of PrPSc in synaptic boutons and axonal terminals along the dendrites.

Leg amyotrophic diplegia: prevalence and pattern of weakness at US neuromuscular centers.

OBJECTIVE: To identify the frequency of leg amyotrophic diplegia (LAD) at a US academic center, describe the pattern of weakness, and provide comparative data from 8 additional major US academic institutions. BACKGROUND: LAD is a leg onset variant of progressive muscular atrophy (PMA). LAD weakness is confined to the legs for at least 2 years, and there are no upper motor neuron signs. DESIGN/METHODS: We present a retrospective chart review of 24 patients with the LAD presentation from the University of Kansas Medical Center ( n = 8 cases) and from 8 US academic institutions (n = 16 cases). RESULTS: Of the 318 subjects identified in the University of Kansas Medical Center Neuromuscular Research Database, 82% (260 subjects) had amyotrophic lateral sclerosis (ALS), 1.9% (6) had familial ALS, 6.6% (21) had primary lateral sclerosis, and 9.2% (29) had lower motor neuron (LMN) disease. Of these 29 cases, 16 had PMA, 5 had brachial amyotrophic diplegia, while 8 had LAD. The mean LAD age of onset was 58 years with a male/female ratio of 3/1. Onset was asymmetric in 7/8. We identified a pelviperoneal pattern of weakness (sparing of knee extension and/or ankle plantar flexion) in 4 cases and distal predominant weakness in 3 cases. All patients had electrodiagnostic findings consistent with motor neuron disease confined to the lower extremities. We present LAD disease duration and survival data from 8 major academic neuromuscular centers. At last follow-up, weakness progressed to involve the arms in 6/24 LAD cases and of these 6 cases, 2 patients died from progression to typical ALS. From onset of symptoms, mean survival in LAD is 87 months, with 92% of cases being alive. CONCLUSIONS/RELEVANCE: The natural history of LAD differs from typical forms of ALS and PMA. LAD is a slowly progressive disorder that accounts for a fourth of LMN disease cases. An asymmetric pelviperoneal pattern of weakness should heighten the suspicion for LAD.

Effects of noninvasive ventilation on sleep outcomes in amyotrophic lateral sclerosis.

STUDY OBJECTIVES: The objective was to study the effects on noninvasive ventilation on sleep outcomes in patient with ALS, specifically oxygenation and overall sleep quality. METHODS: Patients with ALS who met criteria for initiation of NIV were studied with a series of 2 home PSG studies, one without NIV and a follow-up study while using NIV. Primary outcome was a change in the maximum overnight oxygen saturation; secondary outcomes included change in mean overnight oxygen saturation, apnea and hypopnea indexes, sleep latency, sleep efficiency, sleep arousals, and sleep architecture. RESULTS: A total of 94 patients with ALS were screened for eligibility; 15 were enrolled; and 12 completed study procedures. Maximum overnight oxygen saturation improved by 7.0% (p = 0.01) and by 6.7% during REM sleep (p = 0.02) with NIV. Time spent below 90% oxygen saturation was also significant-ly better with NIV (30% vs 19%, p < 0.01), and there was trend for improvement in mean overnight saturation (1.5%, p = 0.06). Apnea index (3.7 to 0.7), hypopnea index (6.2 to 5.7), and apnea hypopnea index (9.8 to 6.3) did not significantly improve after introducing NIV. NIV had no effect on sleep efficiency (mean change 10%), arousal index (7 to 12), or sleep stage distribution (Friedman chi-squared = 0.40). CONCLUSIONS: NIV improved oxygenation but showed no significant effects on sleep efficiency, sleep arousals, restful sleep, or sleep architecture. The net impact of these changes for patients deserves further study in a larger group of ALS patients.

Combined fulminant frontotemporal dementia and amyotrophic lateral sclerosis associated with an I113T SOD1 mutation.

Mutations in the gene for superoxide dismutase type 1 cause amyotrophic lateral sclerosis (ALS), but are not thought to be associated with frontotemporal dementia (FTD). A lack of detailed case reports is one reason, among others, for this skepticism. This case report comments on a patient with familial ALS caused by I113T mutation in the SOD1 gene presenting with progressive cognitive and behavioral decline two years before developing progressive motor degeneration. In conclusion, this case provides evidence that SOD1 mutations can be associated with FTD.

Progression of white matter degeneration in amyotrophic lateral sclerosis: A diffusion tensor imaging study.

Whether longitudinal diffusion tensor MRI imaging (DTI) can capture disease progression in patients with amyotrophic lateral sclerosis (ALS) is unclear. The primary goal of this study was to determine if DTI detects progression of the corticospinal tracts (CST) degeneration in ALS. Seventeen ALS patients and 19 age- and gender-matched healthy controls were scanned with DTI at baseline for cross-sectional analyses. For longitudinal analyses, the ALS patients had repeat DTI scans after eight months. Tractography of the CST was used to guide regions-of-interest (ROI) analysis and complemented by a voxelwise analysis. Cross-sectional study found that baseline FA of the right superior CST was markedly reduced in ALS patients compared to controls. The FA reductions in this region correlated with the disease severity in ALS patients. Longitudinal study found that FA change rate of the right superior CST significantly declined over time. In conclusion, longitudinal DTI study captures progression of upper motor fiber degeneration in ALS. DTI can be useful for monitoring ALS progression and efficacy of treatment interventions.