Name:	ELND005
Other Names:	AZD-103, cyclohexane-1,2,3,4,5,6-hexol, myo-inositol , Scyllo-inositol
Therapeutic Applications:	Mild to moderate Alzheimer Disease
Therapy Types:	Oral, small molecule
Mechanisms:	Block accumulation of Aβ oligomers; prevent Aβ oligomer formation
Development Status:	investigational in U.S.
FDA Phase:	Phase II/III
Role in Alzheimer's Disease:	Phase II testing of ELND005 was completed in August 2010. Primary outcome measures included cognition and function. Safety and tolerability were also tested. See related Alzforum News August 13, 2010 and Alzforum News Dec 16, 2009. Scyllo-inositol is a specific stereoisomer of the cyclic sugar alcohol inositol, occurring naturally in coconut palm, dogwood flowers and oak bark. McLaurin et al 2006 showed that scyllo-inositol can inhibit aggregation of Aβ in transgenic mice, improves many AD-like phenotypes and protects from cognitive decline. The Phase II trial completed the treatment of patients receiving 250 mg twice daily dosing. Elan has reported the study's cognitive (NTB) and functional (ADCS-ADL) co-primary endpoints did not achieve statistical significance. However, Elan reported that 250mg bid dose “demonstrated a biological effect” on Aβ in the cerebrospinal fluid (CSF), although no details have been provided. (See Elan press release). Twenty subjects total volunteered to provide CSF samples at beginning and end of trial. CSF analysis provided evidence that the 250 mg bid dose “achieved targeted drug levels in the CSF, and showed some effects on clinical endpoints in an exploratory analysis”.
Side Effects:	Phase II clinical trials of ELND-005 were adjusted mid-trial after nine deaths (approximately 5% high dose treated patients) and a higher rate of serious adverse effects were observed in the treatment groups receiving the two highest doses (1000 and 2000 mg twice daily). See Alzforum News Dec 16, 2009. No details have been provided by either Elan or Transition regarding specific adverse effects, although both companies maintain that “The study's independent safety monitoring committee reviewed the final safety results and continued to conclude that a causal relationship between the deaths and drug cannot be determined. The independent safety monitoring committee also concluded that the 250mg bid dose continued to have an acceptable safety and tolerability profile.” (See Elan press release). Of the treated subjects who received low dose 250 mg bid, Elan reports that “overall incidence of adverse events in the 250mg bid and placebo groups was 87.5% versus 91.6%; and the incidence of withdrawals due to adverse events was 10.2% versus 9.6%, respectively. The incidence of serious adverse events in the 250mg bid and placebo groups was 21.6% versus 13.3 %, but the incidence of serious adverse events that were considered drug related was 2.3% and 2.4%, respectively. The total number of deaths in the study was 5 and 4 in the 1000mg bid and 2000mg bid dose groups versus 1 and 0 in the 250mg bid and placebo groups, respectively. The most common adverse events in the 250mg bid group that were >5% in incidence and double the placebo rate were: falls (12.5% vs. placebo 6%), depression (11.4% vs. placebo 4.8%), and confusional state (8% vs. placebo 3.6%).”
Companies:	Transition Therapeutics, Inc.
Notes:	Elan and Transition Therapeutics intend to publish Phase 2 data in a peer-reviewed publication. Based on evidence from both biomarker and clinical data Elan and Transition Therapeutics intend to advance ELND005 into Phase 3 development. No specific details of the Phase 3 study design are available. A long term, open label, follow-up study is currently enrolling participants by invitation only, extending safety and tolerability data collection and analyses and is open only to subjects who have completed the week 78 visit in the completed Phase II trial NCT00568776. See NCT00934050. This record was updated September 8, 2010.

References

McLaurin J, Kierstead ME, Brown ME, Hawkes CA, Lambermon MH, Phinney AL, Darabie AA, Cousins JE, French JE, Lan MF, Chen F, Wong SS, Mount HT, Fraser PE, Westaway D, St George-Hyslop P. Cyclohexanehexol inhibitors of Abeta aggregation prevent and reverse Alzheimer phenotype in a mouse model. Nat Med. 2006 Jul;12(7):801-8. Abstract