CytRx believes arimoclomol represents a potentially powerful breakthrough in the treatment of multiple neurological disorders including Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's disease), Alzheimer's, Huntington's and Parkinson's diseases, and stroke. Arimoclomol is believed to function by amplifying "molecular chaperone" proteins, normally found in all cells of the body and thought to enhance the cell's natural ability to, in essence, mend damaged, misfolded proteins. Arimoclomol may thus provide cellular protection from misfolded, toxic proteins, repairing those that are believed to cause many diseases, including ALS. Arimoclomol has demonstrated the ability to protect motor nerves subjected to physical trauma and to accelerate the regeneration of previously damaged nerves in animals. These observations provide additional evidence that, in addition to ALS, it is possible that the drug may have a much broader application profile in the area of neurodegenerative diseases. Arimoclomol is an orally available small molecule compound that has been shown to be well tolerated in seven previous Phase I clinical trials with healthy human subjects.
ALS Program
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.
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 June 2007, CytRx reported promising data from the six-month, open-label extension of its Phase 2a clinical trial with arimoclomol in ALS volunteers. Arimoclomol at the 100 mg dose level administered orally three times daily appeared to be safe and well-tolerated throughout the extended period. Further, the rate of decline of the ALSFRS-R and vital capacity in the arimoclomol-treated group compared favorably to a matched historical control. While difficult to draw definitive conclusions without a concurrent placebo control group, CytRx observed a decrease in the rate of decline of 21% for ALSFRS-R, 8.0% for vital capacity, 23% for total body weight and 20% for body mass index when compared with an historical control.
Further Clinical Development
In December 2009, CytRx announced that the FDA lifted its clinical hold on the Company’s arimoclomol Phase 2 ALS clinical study, and CytRx has announced plans to resume the clinical trial in parallel with its discussions with potential partners.
In addition, in February 2009, a Phase II/III adaptive clinical trial commenced to study arimoclomol in a subset of patients with the inherited or familial form ALS. Patients with familial ALS (fALS) who harbor certain mutations in the superoxide dismutase-1 (SOD1) gene suffer from a rapidly progressing form of the disease. The clinical trial is being financially supported by grants from the ALS Association and the U.S. Food and Drug Administration’s (FDA’s) Office of Orphan Products Development (OOPD), and CytRx is supplying the drug and allowing the sponsor to reference the Company's Investigational New Drug Application for regulatory purposes.
Stroke Program
Stroke results from an acute loss of normal blood flow to the brain caused most often by a blockage in a blood vessel (ischemic) or due to leaking of blood from a vessel (hemorrhagic). According to the American Heart Association: stroke is thethird leading cause of death and the number one cause of long-term disability in the U.S.; between 50% and 70% of stroke survivors regain functional independence, but between 15% and 30% are permanently disabled and 20% require institutional care within three months after stroke; and the direct and indirect stroke cost in the U.S. totaled approximately $58 billion in 2006.
After the normal flow of blood is restored to the brain after the initial event, post-stroke neurological function continues to decline. CytRx believes that this continuing decline in neurological function is the consequence of mis-folded protein aggregates generated as a result of oxygen deprivation during the original event.
Preclinical efficacy studies completed by the Company in April 2007 indicated that arimoclomol accelerated the time to recovery, and improved recovery, in experimental animal models of stroke. These results were obtained even when arimoclomol was administered as long as 48 hours after onset.
By comparison, tissue plasminogen activator, or t-PA, the only treatment currently approved in the U.S. for acute ischemic stroke, must be administered within three hours of stroke, which substantially limits the number of patients who qualify for this treatment.
In light of these preclinical data, CytRx plans to seek a partner for the development of arimoclomol for stroke recovery and other indications. 
