Pharmacology
Fibrillex(TM) Preserves Kidney Function in Amyloidosis
By Neurochem
Jun 6, 2005, 09:57

Further analyses of the results of Neurochem's Phase II/III clinical study for Fibrillex(TM), an investigational product candidate for the treatment of Amyloid A (AA)Amyloidosis, were presented today at the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) meeting by Helen Lachmann, M.D., Senior Lecturer and Honorary Consultant Nephrologist and co-investigator
of the Phase II/III clinical trial, National Amyloidosis Centre, Royal Free and University College Medical School, Royal Free Hospital, London, UK.

AA Amyloidosis is a rare disease that frequently progresses to end-stage renal failure and death and for which no specific treatment is approved for use.

The most recent analysis of the primary endpoint using the pre-specified Cox proportional hazards regression model takes into account both the numberof events and the time to reach such an event.

This analysis indicates that Fibrillex(TM) reduces the risk of renal decline or all-cause mortality by 42% (p-value of 0.025, 95% CI 0.366 - 0.934).

"While Fibrillex(TM) did not achieve the study's pre-specified p-value of 0.01 on the primary endpoint, the analysis of the data suggest useful clinical effects of Fibrillex(TM)," said Dr. Lachmann. "This result supports the notion that Fibrillex(TM) may preserve kidney function in patients who face this very serious illness with no specific treatment to turn to" she added.

The Phase II/III trial enrolled 183 patients (89 on Fibrillex(TM), 94 on placebo) in 13 countries, and was a randomized, double-blind, placebo-controlled, and parallel-design study.

The primary analysis of the primary endpoint using the pre-specified Cochran-Mantel-Haenszel means row score test compares the number of events at the end of the study between the two treatment groups and was announced on
April 18, 2005. This analysis showed there were 13.4% fewer patients who worsened in the Fibrillex(TM) group as compared to placebo (p-value of 0.063, adjusted for renal status at baseline).

Secondary Endpoints

Analysis of secondary efficacy endpoints in Neurochem's trial, including progression to end-stage renal disease/dialysis and slope of decline of creatinine clearance, point in favor of Fibrillex(TM) reducing the risk of renal decline events in AA Amyloidosis patients.

Patients in the trial receiving Fibrillex(TM) experienced a slower decline in the mean slope of creatinine clearance of 4.7 ml/min/1.73 m2/year as compared to placebo (p-value of 0.025). This effect was corroborated by the analysis of another secondary endpoint being the slope of the reciprocal of serum creatinine.

During the course of the study, Fibrillex(TM) delayed by 3.6 months the time required to double serum creatinine (p-value of 0.081), delayed by 4.4 months the time to reach a 50% decrease in creatinine clearance (p-value of 0.029) and delayed by 5.3 months the time to progress to dialysis (p-value of 0.18), all as compared to placebo.

There was no statistically significant difference in the median time between the two groups to reach a 50% increase in creatinine clearance, time to death or median change in proteinuria.

Safety Data

The data suggest Fibrillex(TM) is well tolerated. The most frequent adverse events experienced by the patients in this study were of gastrointestinal origin and infections. The incidence of treatment-emergent adverse events (all causalities) in patients on Fibrillex(TM) was comparable
to placebo.

Additional data on the Phase II/III clinical trial will be presented at the European League Against Rheumatism (EULAR) conference, Vienna, Austria, on June 9, 2005.

About Fibrillex(TM)

Fibrillex(TM) is an oral investigational product candidate for the treatment of AA Amyloidosis through the prevention of amyloid fibril formation. It has received Orphan Drug Status designation in the United States and Orphan Medicinal Product designation in Europe.

Fibrillex(TM) also has been accorded "Fast Track Product" designation by the FDA and has been selected by the Cardio-Renal Drug Product Division of the FDA to be part of the Continuous Marketing Applications Pilot 2 program aimed
at further accelerating the development and eventual marketing of this product candidate. Under this Pilot 2 program, each FDA division is permitted to select only one product candidate.

About AA Amyloidosis

AA Amyloidosis is a progressive and fatal condition that occurs in a proportion of patients with chronic inflammatory diseases, including rheumatoid arthritis, ankylosing spondylitis, juvenile rheumatoid arthritis,
and Crohn's disease. The disease also occurs in patients suffering from many other conditions ranging from chronic infections to inherited inflammatory diseases such as Familial Mediterranean Fever. The most common clinical
presentation of AA Amyloidosis is renal dysfunction. Involvement of the gastrointestinal system is also frequent and is usually manifested as chronic diarrhea, gastrointestinal bleeding, abdominal pain and malabsorption.
Enlargement of the liver and the spleen may also occur in some patients. End-stage renal failure is the main cause of death in 40-60% of cases. The median survival time from diagnosis varies from 2 to 10 years depending on the stage
of the disease at the time of diagnosis.

No specific treatment is currently available for this orphan disease. The goal of the existing therapies is limited to the control of the underlying chronic inflammatory disease. The current therapeutic approaches are normally non-specific, and may be toxic, invasive or ineffective.

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