BIOM30002 Study Guide - Final Guide: Amyloid, Beta-Secretase 1, Bapineuzumab
Drug name
Drug class
Molecular
target
Mechanism
Issues/notes
Clinical
trials
Semagacestat
(Eli Lilly)
Gamma
secretase
inhibitor
Gamma
secretase
Dose
-
dependently lower plasma, CSF and
brain Abeta in animals
Change both Abeta40/42 lv
D
id not slow AD
progression
Worsen cognition and motor ability
Due to non-selectivity (many substrates including NOTCH)
AE: increase risk of skin cancers and infections
III
Merck drug
MK-8931
(Verubecestat)
Beta
secretase
inhibitor/
Peptide-
based BACE1
inhibitor
Beta
secretase
Bind to BACE1 active site and inhibit
enzymatic activity
Low oral bio
-
a
va
ilability
Low serum half-life
Do not cross blood-brain barrier (BBB)
Difficult to make non-peptic BACE1 inhibitor that
1. large enough to bind to active site
2. but small enough to cross BBB and for PK properties
Knocking out both BACE1 & 2 is lethal
No clinical benefit
Suggesting worsening AD
II/III
AN1792
Active
(antigen)
anti-Abeta
vaccines
Abeta
Redu
ce amyloid plaques and Abeta lv
AN1792 is aggregated Abeta peptide
antigen
Ab need to cross the BBB
No significant improvement in mild-to-moderate AD
Interrupted due to meningoencephalitis due to T cell activation
No evidence of improved survival or improvement in time to
severe dementia
No effect on ND progression
IIa
Bapineuzumab
Passive
(antibody)
anti-Abeta
vaccines (3)
Abeta
1
-
5
Bapineuzumab is
humanized mAb to
epitope Abeta 1-5
Binds both soluble and fibrillar Abeta
Reduce amyloid burden in Tg mice
No effect in human
Phase III: failed in AD patients with/without ApoE4 allele
III
Solanezumab
Passive
(antibody)
anti-Abeta
vaccines (3)
Abeta16
-
24
Solanezumab is humanized mAb to
Abeta16-24
Preferentially binds to soluble Abeta
Reverse memory deficits without affecting
brain Abeta load in mice
Phase II: increase plasma and CSF
Abeta40/42, indicating reduction plaque
load in brain (reverse aggregation)
No effect on behavioral
(cognitive and functional) outcomes
Expedition III trial – changed protocol to now look at cognitive
performance as the main readout
Small treatment benefit and short of statistical significance
III
Stopped
Aducanumab
Passive
(antibody)
anti-Abeta
vaccines (3)
Abeta
3
-
7
mAb that targets linear epitope in Abeta
residue 3-7 in aggregated forms of beta
amyloid
Including soluble oligomers and insoluble
fibrils
Not powered to determine effects on cognition
1b
Document Summary
Dose-depe(cid:374)de(cid:374)tl(cid:455) lo(cid:449)e(cid:396) plas(cid:373)a, csf a(cid:374)d (cid:271)(cid:396)ai(cid:374) a(cid:271)eta i(cid:374) a(cid:374)i(cid:373)als. Bi(cid:374)d to bace(cid:1005) a(cid:272)ti(cid:448)e site a(cid:374)d i(cid:374)hi(cid:271)it e(cid:374)z(cid:455)(cid:373)ati(cid:272) a(cid:272)ti(cid:448)it(cid:455) Bapi(cid:374)euzu(cid:373)a(cid:271) is hu(cid:373)a(cid:374)ized (cid:373)a(cid:271) to epitope a(cid:271)eta (cid:1005)-(cid:1009) Ae: i(cid:374)(cid:272)(cid:396)ease (cid:396)isk of ski(cid:374) (cid:272)a(cid:374)(cid:272)e(cid:396)s a(cid:374)d i(cid:374)fe(cid:272)tio(cid:374)s. Diffi(cid:272)ult to (cid:373)ake (cid:374)o(cid:374)-pepti(cid:272) bace(cid:1005) i(cid:374)hi(cid:271)ito(cid:396) that (cid:1005). la(cid:396)ge e(cid:374)ough to (cid:271)i(cid:374)d to a(cid:272)ti(cid:448)e site (cid:1006). (cid:271)ut s(cid:373)all e(cid:374)ough to (cid:272)(cid:396)oss bbb a(cid:374)d fo(cid:396) pk p(cid:396)ope(cid:396)ties. K(cid:374)o(cid:272)ki(cid:374)g out (cid:271)oth bace(cid:1005) & (cid:1006) is lethal. I(cid:374)te(cid:396)(cid:396)upted due to (cid:373)e(cid:374)i(cid:374)goe(cid:374)(cid:272)ephalitis due to t (cid:272)ell a(cid:272)ti(cid:448)atio(cid:374) No e(cid:448)ide(cid:374)(cid:272)e of i(cid:373)p(cid:396)o(cid:448)ed su(cid:396)(cid:448)i(cid:448)al o(cid:396) i(cid:373)p(cid:396)o(cid:448)e(cid:373)e(cid:374)t i(cid:374) ti(cid:373)e to se(cid:448)e(cid:396)e de(cid:373)e(cid:374)tia. Phase iii: failed i(cid:374) ad patie(cid:374)ts (cid:449)ith/(cid:449)ithout apoe(cid:1008) allele. Re(cid:448)e(cid:396)se (cid:373)e(cid:373)o(cid:396)(cid:455) defi(cid:272)its (cid:449)ithout affe(cid:272)ti(cid:374)g (cid:271)(cid:396)ai(cid:374) a(cid:271)eta load i(cid:374) (cid:373)i(cid:272)e. A(cid:271)eta(cid:1008)(cid:1004)/(cid:1008)(cid:1006), i(cid:374)di(cid:272)ati(cid:374)g (cid:396)edu(cid:272)tio(cid:374) pla(cid:395)ue load i(cid:374) (cid:271)(cid:396)ai(cid:374) (cid:894)(cid:396)e(cid:448)e(cid:396)se agg(cid:396)egatio(cid:374)(cid:895) (cid:373)a(cid:271) that ta(cid:396)gets li(cid:374)ea(cid:396) epitope i(cid:374) a(cid:271)eta (cid:396)esidue (cid:1007)-(cid:1011) i(cid:374) agg(cid:396)egated fo(cid:396)(cid:373)s of (cid:271)eta a(cid:373)(cid:455)loid. No effe(cid:272)t o(cid:374) (cid:271)eha(cid:448)io(cid:396)al (cid:894)(cid:272)og(cid:374)iti(cid:448)e a(cid:374)d fu(cid:374)(cid:272)tio(cid:374)al(cid:895) out(cid:272)o(cid:373)es. E(cid:454)peditio(cid:374) iii t(cid:396)ial (cid:272)ha(cid:374)ged p(cid:396)oto(cid:272)ol to (cid:374)o(cid:449) look at (cid:272)og(cid:374)iti(cid:448)e pe(cid:396)fo(cid:396)(cid:373)a(cid:374)(cid:272)e as the (cid:373)ai(cid:374) (cid:396)eadout.