The development of therapeutics for the treatment of ALS is an area of significant interest for CytRx. ALS is a deadly and debilitating disease. According to the ALS Survival Guide, 50% of ALS patients die within 18 months of diagnosis and 80% of ALS patients die within five years of diagnosis. According to the ALS Association, in the United States alone, approximately 30,000 people are living with ALS and nearly 6,000 new cases are diagnosed each year.

In September 2006, CytRx announced that arimoclomol was shown to be safe and well tolerated at all three doses tested in its Phase IIa clinical trial in patients with ALS. 

In the 10-center, double-blind, placebo-controlled Phase IIa trial, ALS patients received placebo or arimoclomol in one of three dose levels (25 mg, 50 mg or 100 mg) three times daily for 12 weeks and then were studied for an additional four weeks without treatment.  Eighty-four patients with ALS entered the clinical trial with only seven withdrawing prior to completion of dosing.  No statistically significant treatment-related increases in adverse events were reported, and encouragingly, arimoclomol-treated patients reported fewer asthenia (weakness) adverse events than the patients receiving placebo.  The minor treatment-related changes in laboratory results that reached statistical significance were well within the normal safety range and did not change with time or dose, and therefore were considered to be clinically unimportant.  No treatment-related effects on vital signs, electrocardiogram or body weight were observed. Based on these results, CytRx plans to proceed with activities associated with initiating a Phase IIb clinical trial with arimoclomol for the treatment of ALS in the first half of 2007, subject to FDA approval.

One of the secondary endpoints of the trial included an analysis of pharmacokinetics (drug oral absorption, distribution, and removal). While full analysis of these data is not yet complete, tests indicate that arimoclomol effectively entered the cerebral spinal fluid, demonstrating that the drug passed the "blood:brain barrier," overcoming a potential impediment for the development of drugs like arimoclomol that are intended to treat neurodegenerative diseases.  The average amount of drug detected in the cerebral spinal fluid was similar to the amounts present in blood and increased with increasing doses.

Additional secondary endpoints of the trial included a preliminary evaluation of the disease progression markers, the Revised ALS Functional Rating Scale (ALSFRS-R) and vital capacity (VC).  The ALSFRS-R is used to determine a patient's capacity and independence in 13 functional activities and VC is an assessment of a patient's breathing capacity. As previously announced the Phase IIa clinical trial was designed with a scale and scope to show statistical significance with respect to safety and tolerability, with the planned monitoring of the rate of disease progression using ALSFRS-R and VC designed to show statistical significance only in the case of extreme responses to drug treatment.  While disease progression was measured as a secondary endpoint, the primary purpose of the trial was to generate sufficient data regarding safety and tolerability to determine whether to proceed with a significantly larger Phase IIb clinical trial designed primarily to detect efficacy.  As was expected by CytRx due to the limited size and duration of the trial, arimoclomol did not show a statistically significant change in disease progression as measured by these markers.  However, the average decrease in ALSFRS-R score for those patients receiving the highest dose of arimoclomol was higher than the placebo group at all time points except week 12 after dose initiation (i.e. it was higher at weeks 4, 8 and 16 and substantially the same at week 12). This trend of higher ALSFRS-R scores in the high dose group relative to the placebo was not observed with VC as the indicator of disease progression.

In January 2006, CytRx initiated an open-label extension of this Phase IIa trial allowing patients who complete the trial to continue treatment with arimoclomol at the highest dose level three times daily for up to an additional six months.  The open-label extension is designed to provide additional safety and tolerability data in combination with the previous Phase IIa trial. Approximately 99% of the patients who completed the Phase IIa trial elected to enroll in the open-label extension trial. It is anticipated that the open-label extension trial will be completed in January 2007.

Based on the results of the Phase IIa trial, CytRx plans to initiate a subsequent Phase IIb trial that will be powered to detect more subtle efficacy responses. Although this second trial is still in the planning stages and will be subject to FDA approval, it is currently expected to include approximately 400 ALS patients recruited from approximately 30 clinical sites, and will take approximately 18 months after initiation to complete. Given the severity of ALS and the lack of therapeutic treatment options, CytRx believes that positive efficacy and safety results from the Phase IIb clinical trial could be sufficient for arimoclomol product registration for this indication.