Amyotrophic Lateral Sclerosis (ALS)

August 1, 2016

BrainStorm Cell Therapeutics reported results of a phase II study of NurOwn in patients with amyotrophic lateral sclerosis (ALS). The trial was a randomized, double-blind, placebo-controlled, multicenter study. Patients were randomized to receive NurOwn cells administered via combined intramuscular and intrathecal injection (n= 36) or placebo (n=12). The pre-specified efficacy analyses were change in the slope of Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score, change in Slow Vital Capacity (SVC) and muscle strength, responder analysis (the percentage of subjects who improved post-treatment compared with pre-treatment), and a subgroup analysis excluding slowly progressing patients who are less likely to have a detectable benefit from NurOwn. Given the exploratory nature of this study, statistical significance was defined as a one-sided p<0.1 using Fisher’s exact test. Given that NurOwn is thought to slow disease progression, a pre-specified subgroup was defined in order to exclude subjects whose disease was progressing slowly (defined by an ALSFRS-R slope of -0.7 or higher during the pre-treatment phase). These subjects would be less likely to have a detectable benefit from NurOwn. The more rapidly progressing subgroup, comprising approximately half of the subjects in the study, showed a marked benefit from NurOwn treatment: 94% of those treated with NurOwn (n=18) achieved 100% improvement in slope at two weeks, compared to only 20% in the placebo (n=5) group (p=0.0027). At four, eight, 12, 16 and 24 weeks the proportion of responders in the active treatment group compared to placebo were 78% vs. 20%, 44% vs. 20%, 39% v. 17%, 33% v. 0% and 22% v. 0%. NurOwn was found to be safe and well tolerated with the majority of adverse events being mild or moderate.

January 12, 2015

BrainStorm Cell Therapeutics released results of a phase IIa study of NurOwn in amyotrophic lateral sclerosis (ALS) patients. The single-arm, dose-escalating study enrolled 14 early-stage ALS patients into three ascending dose cohorts; each subject received NurOwn cells via IT and IM administration after a threemonth run-in period, and was then followed for six additional months after treatment. The study achieved its primary endpoint in demonstrating that NurOwn is safe and well-tolerated at doses up to 2 million cells per kilogram administered intrathecally and 48 million cells administered intramuscularly. Importantly, nearly all subjects in this study experienced clinical benefit from treatment with NurOwn. Of the 12 subjects with three or more months of follow up, 92% experienced an improvement in the rate disease progression for the three-month period after administration of NurOwn, as measured by ALS Functional Rating Score-Revised (ALSFRS) or forced vital capacity (FVC). Fifty percent had an improvement in the slope of the ALSFRS score, and 67% had an improvement in the slope of the percent-predicted FVC.

November 5, 2012

Neuraltus Pharmaceuticals released results from a phase II trial of NP001 for the treatment of amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease). This multi-center, double-blind, placebo-controlled study enrolled 136 patients. Subjects received 1mg/kg NP001 or 2mg/kg NP001 intravenously, or placebo, over a period of six months, followed by a six-month follow-up period. Study efficacy results demonstrated positive trends in slowing the rate of disease progression, ranging from 13% to 19% in multiple parameters of clinical benefit, although these pre-defined endpoints did not reach statistical significance. Importantly, according to a post hoc analysis, 27% of patients in the 2mg/kg NP00l arm had no progression of their disease during the six-month dosing period. The drug was well tolerated. Based on these results, and after a meeting with the FDA, Neuraltus is planning a phase III clinical trial, expected to begin in 2013.

April 16, 2012

Neuralstem reported interim results from a phase I trial evaluating spinal cord stem cells for the treatment of Amyotrophic Lateral Sclerosis. The trial plans to enroll 18 subjects with varying degrees of the disease. The first stage of the trial enrolled 12 subjects received five-to-ten stem cell injections in the lumbar area of the spinal cord. Of the 12 subjects, the first six (cohort 1) were non-ambulatory and the second six (cohort 2) were ambulatory. The subjects were examined at regular intervals post-surgery. At 18 months post-transplant none of the subjects experienced any long-term complications related to either the surgical procedure or the implantation of stem cells, or showed signs of rejecting the cells. In the months following the surgery to inject the cells, none of the subjects showed evidence that their ALS progression was accelerating. The FDA has granted approval for the trial to advance to the final two groups of subjects, all of who will be transplanted in the cervical region of the spinal cord.

December 5, 2011

Adeona Pharmaceuticals reported results from a phase I/II trial of AEN-100, their oral high dose zinc therapy for the treatment of Amyotrophic Lateral Sclerosis. This open label trial enrolled 10 subjects with sporadic ALS and on stable doses of Rilutek. The subjects were administered AEN-100 tablets containing 90mg of elemental zinc per day, as well as 2 mg of copper every other day to prevent potential copper depletion, for three months. The rate of disease progression was measured by the ALS Functional Rating Scale-Revised (ALSFRS-R) and was compared to historical controls. Eight subjects completed the trial. On average, the eight subjects who completed the study lost 0.37 ALSFRS-R points per month during the three months of therapy. This represents a lower rate of monthly disease progression compared to the average 0.89 ALSFRS-R monthly rate of disease progression in ALS based on historical controls. No safety issues were reported.

Cytokinetics released interim results from a phase II trial of CK-2017357 for the treatment of Amyotrophic Lateral Sclerosis. Part A of this double-blind, randomized, placebo-controlled trial enrolled 24 subjects who were not taking riluzole. The subjects received daily oral doses of placebo or 125 mg, 250 mg, or 375 mg of CK-2017357 for two weeks. CK-2017357 was well-tolerated at all dose levels. In the combined dose groups receiving CK-2017357, the most common and dose-related side effect reported was dizziness. No serious adverse events were reported. Plasma concentrations of CK-2017357 increased with escalating doses. While this portion of the trial was not designed to show significant differences in clinical outcome measures, a trend towards improvement was observed, especially at the highest CK-2017357 dose of 375 mg daily. Four of five subjects who completed treatment in this dose group reported improvement in their Global Assessments and three of these five subjects improved at least 1 point on the ALS Functional Rating Scale-Revised (ALSFRS-R).

December 10, 2007

Avicena released positive results from a phase II trial of AL-08 for the treatment of Amyotrophic Lateral Sclerosis (ALS). This randomized, double-blind, selection trial enrolled one hundred and twenty subjects who received AL-08 in combination with minocycline or AL-08 in combination with celecoxib. The primary objective was to determine treatment selection based on which drug combination appeared to slow deterioration in the ALS-Functional Score. Results showed subjects treated with AL-08/celcoxib showed a smaller mean functional decline versus AL-08/minocycline. At the end of the trial, the decline in ALS-Functional Score in both treatment arms was compared separately to the mean historical control group at a 0.05 significance level. The mean decline in ALS-Functional Score was 5.27 in the celecoxib/creatine arm, compared to 6.47 in the minocycline/creatine arm, and 5.82 in the historical control group. Based on the results, Avicena plans to move forward with phase III trials.

August 6, 2007

Intellect Neurosciences reported positive results from a phase I trial of OXIGON for the treatment of neurological disorders. This double-blind, randomized, placebo-controlled, single-escalating dose study enrolled 54 healthy elderly subjects. The trial was designed to determine the safety, tolerability and pharmacokinetics of OXIGON with and without food interactions. Treatment was shown to be safe and well tolerated, with no serious adverse events reported up to the highest single dose of 1.2 grams. Data from a phase Ib trial were expected shortly.

Phytopharm announced positive results from a phase Ib trial of Myogane for the treatment of Amyotrophic Lateral Sclerosis (ALS). This randomized, double blind, placebo-controlled, trial enrolled healthy subjects in the UK. Subjects received single escalating oral doses of Myogane. The study demonstrated good safety, tolerability and pharmacokinetic profiles, as well as an excellent absorption profile. The highest dose administered (640 mg) was well tolerated with no adverse events. Based on the results, Phytopharm plans to advance Myogane into phase II trials.

Targacept issued positive results from a phase II trial of mecamylamine HCL as add-on therapy for the treatment of depression. This trial, dubbed STAR*D (Sequenced Treatment Alternatives to Relieve Depression), enrolled 192 subjects in the US and India. All subjects were inadequate responders to first-line citalopram therapy. After a 3 to 5 day washout period, subjects were started on citalopram in an open label phase. . Citalopram therapy started at 20 mg once daily and was increased at week 2 to 40 mg once daily. This monotherapy lasted 6 weeks. After evaluation, those subjects considered inadequate responders were randomized in a double-blind fashion to receive either placebo or mecamylamine as an add-on to continued citalopram therapy, a combination known as TRIDMAC. Mecamylamine was started at 5 mg daily and could be increased to 7.5 mg after 2 weeks of treatment. After a further 2 weeks, medication could be increased to 10 mg. Results showed mecamylamine was superior to placebo, when added to subjects who were inadequate responders to first-line treatment with citalopram. Mecamylamine was also superior to placebo in treating symptoms of irritability. The treatment combination was generally well tolerated.

April 2, 2007

Aeolus announced positive results from a phase I trial of AEOL10150 for the treatment of Amyotrophic Lateral Sclerosis (ALS). Thisdouble-blind, randomized, placebo-controlled trial enrolled 18 subjects whowere placed into three groups of six subjects, with four receiving AEOL 10150and two receiving placebo. Each subject in the first two cohorts receivedsubcutaneous (SC) injections of AEOL 10150 or placebo for six days, followed bya single SC injection on the seventh day, for a total of 13 injections. In thefirst cohort, each injection was 40 mg and in the second cohort each injectionwas 60 mg. In the third cohort subjects received a daily dose of 2 mg/kgdelivered by osmotic infusion pump over 24 hours for 6.5 days. Treatment wasgenerally well tolerated, with injection/infusion site reactions the mostcommon adverse event. Pharmacokinetic analyses showed a dose related increasein plasma concentrations between 40 and 60 mg bid. The continuous infusion ofAEOL 10150 2 mg/kg/day resulted in lower, but sustained, plasma levels ofapproximately 1,500 ng/ml. The maximum tolerated dose was not reached. Based onthe results Aeolus plans to move forward with the development of AEOL 10150.

Alexza released positive results from a phase IIb trial of AZ-001for the treatment of migraine headaches. This randomized, double blind,placebo-controlled trial enrolled 400 migraine subjects with and without aura.Subjects received one of three doses of AZ-001 (5 mg, 7. 5 mg or 10 mg) orplacebo. The primary endpoint, pain relief at 2-hours post-dose using theInternational Headache Society (HIS) 4-point scale, was met for all three dosesof AZ-001 compared to placebo. Statistical significance in pain response wasobserved in 66% of subjects at the 10 mg dose (p=0.0013), 63.7% of those at the7.5 mg dose (p=0.0046) and 60.2% of subjects at the 5 mg dose (p=0. 0076),compared to 40.8% of subjects receiving placebo. Secondary endpoints were metas well in pain-free response at 2 hours for AZ-001 compared to placebo.Statistical significance was observed in the 10 mg AZ-001 group, with 35% ofsubjects achieving pain-free status (p=0.0019) and in the 7. 5 mg dose group,with 29.7% of the subjects achieving pain-free status (p=0.0226) versus 15. 3%of those on placebo. Statistical significance was also seen in sustained painfree response for up to 24 hours in the 10 mg group (30.1% of the subjects) and7.5 mg group (23.1% of the subjects) versus the placebo group (10. 2% of thesubjects). In addition, AZ-001 had a rapid onset of pain relief. At 30 minutes,all three doses of AZ-001 showed statistically significant pain response,compared to placebo; 10 mg (p=0.0056), 7.5 mg (p=0.0003) and 5 mg (p=0. 0056).Based on the results, Alexza plans to move forward with the development ofAZ-001.

MediciNova reported positive results from a phase II trial ofMN-166 for the treatment of multiple sclerosis. This randomized, double-blind,placebo-controlled trial enrolled 297 subjects who received placebo or MN-166in a 30 or 60 mg per day dose, for 12 months. The primary endpoint, efficacybased on the evaluation of the cumulative number of active(gadolinium-enhancing (T1) and non-enhancing new/enlarging (T2)) cranial MRIlesions, was not met. No reduction in active lesions was observed. However,when compared to the placebo group, a significantly higher proportion of thesubjects who received 60 mg per day of MN-166 remained relapse free over 12months (p=0.03) and had a significant increase in the time to first relapse(p=0.04). In addition, a significant reduction in brain volume loss wasobserved in the 60 mg dose group when compared to placebo (p=0. 04). Based onthe results, MediciNova plans to continue the trial beyond the first year oftreatment in order to gather and evaluate data to support a phase III trial.

October 2, 2006

Acorda released positive results from a phase III trial of Fampridine-SR for the treatment of walking in subjects with multiple sclerosis. This double-blind, placebo-controlled trial enrolled 301 subjects in the US and Canada who had a definite diagnosis of MS and some degree of walking disability. Subjects were randomized receive Fampridine-SR (n=229) or placebo (n=72), for 14 weeks. Treatment was well tolerated with falls and urinary tract infections the most commonly reported adverse events. Efficacy data revealed that the trial met the primary endpoint of improvement in walking speed, as measured by the Timed 25-Foot Walk, with 34.8% of the Fampridine-SR group showing improvement versus 8.3% of the placebo group (p less than 0.001). This improvement was maintained throughout the length of the treatment. In addition, after 14 weeks the average increase in walking speed compared to baseline was 25.2% for the treated group versus 4.7% for the placebo group. Based on this data Acorda plans to move Fampridine-SR into further development.

CytRx issued positive results from a phase IIa trial of arimoclomol for the treatment of amyotrophic lateral sclerosis (ALS). This multi-center, double-blind, placebo-controlled trial enrolled 84 subjects with ALS, who received arimoclomol, or placebo, in one of three dose levels (25 mg, 50 mg or 100 mg) three times daily for 12 weeks. They were then studied for an additional four weeks without treatment. Treatment was shown to be safe and well tolerated across all dose ranges, with no statistically significant adverse events reported. Pharmacokinetic data indicated that arimoclomol effectively entered the cerebral spinal fluid. The amount of the drug in the cerebral spinal fluid was similar to the amount in the blood and increased as the dose increased. Based on these results a phase IIb efficacy trial, using arimoclomol at the highest dose level, is planned for H1 2007.

Medivation issued positive results from a phase II trial of Dimebon for the treatment of Alzheimer's disease. This six-month randomized, double-blinded, placebo-controlled trial enrolled 183 subjects at 11 sites in Russia, who received treatment for 26 weeks. Treatment was well tolerated with the most commonly reported adverse event dry mouth. Efficacy data revealed that all endpoints were met. Subjects receiving Dimebon demonstrated a statistically significant improvement on the study's primary efficacy endpoint, the Alzheimer's Disease Assessment Scale-cognition, with a 4.0 point improvement in the mean change from baseline to week 26 as compared to placebo (p less than 0.0001). The secondary key endpoint, mean change in Clinical Global Impression of Change, was met as well, with a 0.6 point improvement from baseline to week 26 as compared to placebo (p less than 0.0001). Additional phase II trials are ongoing, with results expected in Q2 2007.

September 12, 2005

Aeolus Pharmaceuticals reported positive results from a phase I trial of AEOL 10150 for the treatment of amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease). Pharmacokinetic analysis demonstrated linear dose response and dose proportionality, and found a mean elimination half-life ranging from 2.6 hours for the lowest-dose cohort to 6.4 hours for the highest. These data suggest little likelihood of drug accumulation following multiple doses. Safety data were generally positive, with no clinically meaningful changes in laboratory values, ECG data, vital signs or functional assessments. The most frequent overall adverse events were injection site reactions, dizziness and headache. This multi-center, double-blind, randomized, placebo-controlled study enrolled 32 ALS patients, who received one of 7 single ascending doses of the drug (3 mg, 12 mg, 30 mg, 45 mg, 60 mg and 75 mg) or placebo. Based on these results, the company announced plans to initiate a multiple dose phase I trial of the drug in Q4 2005.

April 4, 2005

Aeolus Pharmaceuticals reported interim results from a phase I trial investigating AEOL 10150, a antioxidant neuroprotectant under development for the treatment of amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease). Interim data demonstrated that was well tolerated compared to placebo. Results showed that plasma AUC values ranged from 354.2 ng*hr/mL in the 3 mg group to 4579.9 ng*hr/mL in the 30 mg group. Cmax ranged from 114.8 ng/mL to 733.4 ng/mL, and mean Tmax ranged from 0.5 to 1.3 hours in these same groups. The half-life of AEOL 10150 ranged from 2.61 to 5.25 hours. The most frequently reported adverse events were injection site reactions, dizziness and headache. No serious adverse events were reported. The multi-center, double-blind, randomized, placebo-controlled escalating single dose study is enrolling up to 5 subjects with ALS. The study is designed to evaluate the safety, tolerability and pharmacokinetics of the drug administered by subcutaneous injection. Single doses of up to six levels of AEOL 10150(3, 12, 30, 45, 60, and 75 mg) are being administered.

November 1, 2004

Avanir Pharmaceuticals reported positive results of its first phase III trial of their drug Neurodex (dextromethorphan/quinidine), for the treatment of pseudobulbar affect in patients with amyotrophic lateral sclerosis. Trial data indicated that the drug met its primary efficacy endpoint of emotional lability, producing significant improvement in CNS-LS diagnostic scale symptom severity score, compared with either of its component drugs (3.3 points greater vs. dextromethorphan, p=0.001; 3.7 points greater vs. quinidine, p<0.001). The drug also met all secondary endpoints, including reduction in affect episode incidence and improving quality of life and quality of relationship score significantly vs. the component drugs (p<0.01). Discontinuation due to adverse events with Neurodex occurred at four times the rate of dextromethorphan and three times the rate of quinidine, though adverse events were generally mild to moderate. The multicenter, randomized, double-blind, controlled, parallel, three-arm study enrolled a total of 140 ALS patients demonstrating pseudobulbar affect across 17 American sites.

Newron Pharmaceuticals has reported preliminary results of a phase II trial of ralfinamide, their non-opioid sodium-channel blocker for the treatment of neuropathic pain. Study results indicated that the drug was successful in meeting its efficacy primary endpoint, a significant improvement in score on the Visual Analogue Scale, a standard diagnostic tool, versus baseline. Secondary efficacy measures, including provoked allodynia, pin-prick test, clinical global impression and patient global impression, supported the primary finding. The primary safety endpoint was also met, with no consistent pattern of clinically relevant serious adverse events at any dosing regimen. This observer-blinded tolerability and efficacy pilot study enrolled a total of 18 patients with neuropathic pain, who received ascending oral doses of ralfinamide for 4 weeks; the trial was conducted at a single center in Austria. Newron announced plans to use these results to support future trials.

July 1, 2002

Phase II/III trial results indicate that Avanir Pharmaceuticals' Neurodex is effective in the treatment of pseudobulbar affect (emotional lability) in subjects with amyotrophic lateral sclerosis. The double-blind, controlled trial compared Neurodex to each of its two active components: dextromethorphan and an enzyme inhibitor. The primary efficacy variable, change from baseline in CNS-Lability Scale score, was statistically significant in favor of Neurodex in the intent-to-treat population.