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AZD-103, cyclohexane-1,2,3,4,5,6-hexol, myo-inositol , Scyllo-inositol
Mild to moderate Alzheimer Disease
Oral, small molecule
Block accumulation of Aβ oligomers; prevent Aβ oligomer formation
investigational in U.S.
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”.
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.”
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%).”
Transition Therapeutics, Inc.
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.
This record was updated September 8, 2010.
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
prevent and reverse Alzheimer phenotype in a mouse model.
Nat Med. 2006 Jul;12(7):801-8.