Drugs in Clinical Pipeline: SUVN-502 | 5-HT6 receptor antagonist | Treatment for Alzheimer's Disease

SUVN- 502 is a novel, potent, and selective 5-HT₆ receptor antagonist with K_i of 1.71 nM and exhibited antagonist like inhibition with EC₅₀ of 0.103 mM. SUVN-502 is effective in animal models of cognition. In microdialysis studies, SUVN-502 enhanced brain acetylcholine and glutamate levels in rat ventral hippocampus and frontal cortex. SUVN-502 has completed all regulatory safety and toxicity studies.

5-HT₆ receptor a member of serotonin family predominates in brain regions associated with cognition and behavior. The blockade of 5-HT₆ receptors leads to an improvement of cognitive performance in a wide variety of learning and memory paradigms.

Drugs in Clinical Pipeline: CT1812 | Abeta Oligomers Receptor Antagonist | Treatment for Alzheimer's Disease

CT1812, works by a completely novel mechanism to stop the binding of toxic proteins that build up in the brains of Alzheimer's patients known as Abeta oligomers.

CT1812, a novel oligomer receptor antagonist is the only drug candidate that has demonstrated not only prevention but it also displaces binding of Abeta oligomers to receptors on brain cells. By stopping the initiating event in the Abeta oligomer cascade, this first-in-class drug candidate completely blocks downstream synaptotoxicity and restores memory to normal in aged transgenic mouse models of Alzheimer's disease.

Drugs in Clinical Pipeline: BI 409306 | PDE9A Inhibitor | Phosphodiesterase 9A Inhibitors | Treatment for Alzheimer's Disease

Phosphodiesterases (PDEs) in the brain have shown to play an important role in synaptic plasticity and cognitive function. Among those PDEs is PDE9A, which specifically regulates the second messenger cGMP in neurons related to NMDA receptor signaling and is expressed in cognition relevant regions of the brain. Thus, PDE9A inhibitors are hypothesized to improve cognitive function via increasing NMDA receptor related cGMP signalling pathway to strengthen synaptic plasticity.

BI 409306 is a potent PDE9A inhibitor, which strengthens synaptic plasticity as demonstrated by increased hippocampal long-term potentiation (LTP). Systemic application of BI 409306 to rats increased cGMP levels in the CSF and brain indicating functional target engagement. Moreover, BI 409306 shows low nanomolar potency against PDE9A.

Drugs in Clinical Pipeline: Saracatinib

Saracatinib [N-(5-Chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methyl-1-piperazinyl)ethoxy]-5-[(tetrahydro-2H-pyran-4-yl)oxy]-4-quinazolinamine] is an orally available, reversible, ATP-competitive c-Src kinase inhibitor (IC₅₀ = 2.7 nM) which is in clinical development for the treatment of a wide range of tumor types. It inhibited other Src tyrosine kinase family members investigated (c-Yes, Fyn, Lyn, Blk, Fgr, and Lck), with high selectivity observed against a panel of other protein kinases involved in signal transduction. It should no activity against Csk (IC₅₀ greater than 1000 nM), the intracellular negative regulator of Src activation. Saracatinib showed moderate activity aginst EGFR (IC₅₀ = 66 nM), and was virtually inactive against KDR (IC₅₀ ~ 21 uM).

The only other notable activities observed were versus Abl (in common with other ATP-competitive Src inhibitors, IC₅₀ ((v-Abl) = 30 nM) and versus activating mutant forms of the EGFR (L858R and L861Q, IC₅₀ = 5 and 4 nM, respectively) [1,2].

AstraZeneca believes that Saracatinib is likely to have a therapeutic benefit as an anti-invasive agent, with potential for activity in early and advanced solid tumors, leukemia, and metastatic bone disease. Moreover, investigators recently characterized a molecular pathway by which β-amyloid damages neurons, and showed that the protein termed Fyn kinase is crucial. Saracatinib has good activity against Fyn kinase. Chronic Saracatinib administration is well tolerated in humans, and the investigators propose to test its potential as a novel Alzheimer's disease modifying therapy. 

The activity of Saracatinib is as follows:

IC₅₀ (c-Src enzyme assay) = 2.7 nM

IC₅₀ (v-Abl enzyme assay) = 30 nM

IC₅₀ (c-Yes enzyme assay) = 4 nM

IC₅₀ (Fyn enzyme assay) = 10 nM

IC₅₀ (Lyn enzyme assay) = 5 nM

IC₅₀ (Blk enzyme assay) = 11 nM

IC₅₀ (Fgr enzyme assay) = 10 nM

IC₅₀ (Lck enzyme assay) = less than 4 nM

Common Name: Saracatinib

Synonyms: AZD 0530; AZD-0530; AZD0530

IUPAC Name: N-(5-Chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methyl-1-piperazinyl)ethoxy]-5-[(tetrahydro-2H-pyran-4-yl)oxy]-4-quinazolinamine

CAS Number: 379231-04-6

Mechanism of Action: Kinase Inhibitor; c-Src Inhibitor

Indication: Various Cancers; Anti-Tumor Therapy; Treatment of Alzheimer's Disease

Development Stage: Phase III

Company: AstraZeneca

c-Src kinase is a nonreceptor tyrosine kinase that acts as a signal transduction inhibitor that is a critical component of multiple signaling pathways that control cell growth, proliferation, invasion, and apoptosis. While c-Src kinase is highly regulated and active only at low levels in most normal cells, studies have shown that c-Src kinase is upregulated in many human tumor types. Recently emerging data support the hypothesis that the predominant consequence of increased c-Src activity in tumor cells is to reduce cell adhesion, facilitate motility, and thereby promote an invasive phenotype. Consequently, there is considerable interest in the inhibition of c-Src kinase as a treatment for cancer and in particular as an antiinvasion strategy. Studies have shown that c-Src kinases have a function in imatinib-resistant CML and ALL and that inhibitors of c-Src and Bcr-Abl kinases have activity against both imatinib-sensitive and imatinibresistant cell lines. c-Src kinase activity is also implicated in metastatic bone disease, a characteristic of late-stage progression of many solid tumor types, for example, breast and prostate, and of leukemias. In animal models, inhibition of c-Src kinase has been shown to limit invasion of bone metastases and destructive bone resorption [2].

Inhibition of c-Src activity in cells was evaluated in mouse NIH 3T3 cells transfected with constitutively active human c-Src. Saracatinib displayed IC₅₀ values of 76 nM in the proliferation assay (c-Src-transfected NIH3T3 cells) and 140 nM in the migration assays (A549 cells) [2]. Animals treated with Saracatinib orally once daily at doses of 6 (mg/kg)/d for 18 days show greater than 95% inhibition of tumor volume and tumor weight at the end of the experiment.

Saracatinib potently inhibited the in vitro proliferation of Src3T3 mouse fibroblasts and demonstrated variable antiproliferative activity in a range of human cancer cell lines containing endogenous Src. Sub micromolar growth inhibition of five of the human cancer cell lines tested with Saracatinib (tumor types: colon, prostate, lung, and leukemia) was observed with IC₅₀ values of 0.2-0.7 uM. In the microdroplet migration assay, Saracatinib reduced the migration of human lung cancer A549 cells in a concentration-dependent manner (IC₅₀ = 0.14 uM). Saracatinib at concentrations of 0.01-0.5 uM demonstrated a clear dose-dependent antimigratory effect compared with untreated controls in monolayer scratch assays of human breast cancer MDA-MB-231 cells. Moreover, in rat and mouse tumor model, complete tumor growth inhibition was observed (100% inhibition at 25 mg/kg/day in mice and 10 mg/kg/day in rats) [1]. 

References:

1. Green, T. P.; et. al. Preclinical anticancer activity of the potent, oral Src inhibitor AZD0530. Mol Oncol 2009, 3(3), 248-261.

2. Hennequin, L. F.; et. al. N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5- (tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor. J Med Chem 2006, 49(22), 6465-6488.

3. ClinicalTrials.gov Safety and Tolerability of AZD0530 (Saracatinib) in Alzheimer's Disease. NCT01864655 (retrieved 01-09-2015)

4. ClinicalTrials.gov Study to Evaluate the Safety and Effects AZD0530 on Prostate and Breast Cancer Subjects With Metastatic Bone Disease. NCT00558272 (retrieved 01-09-2015)

5. ClinicalTrials.gov AZD0530 to Treat Recurrent Stage IIIB/IV NSCLC Previously Treated With Combination Chemotherapy. NCT00638937 (retrieved 01-09-2015)

6. ClinicalTrials.gov Saracatinib in Treating Patients With Stage III or Stage IV Melanoma That Cannot Be Removed By Surgery. NCT00669019 (retrieved 01-09-2015)

Drugs in Clinical Pipeline: Verubecestat

Verubecestat [N-[3-[(5R)-3-amino-2,5-dimethyl-1,1-dioxo-6H-1,2,4-thiadiazin-5-yl]-4-fluorophenyl]-5-fluoropyridine-2-carboxamide] is an oral, potent and selective small molecule inhibitor of BACE that has progressed into Phase III studies demonstrating significant and dose-dependently reduction in the levels of amyloid beta (Aβ) in the cerebrospinal fluid (CSF) of Alzheimer’s patients and healthy volunteers.

The β secretase, widely known as β-site amyloid precursor protein cleaving enzyme 1 (BACE1), initiates the production of the toxic amyloid β (Aβ) that plays a crucial early part in Alzheimer's disease pathogenesis. BACE1 is a prime therapeutic target for lowering cerebral Aβ concentrations in Alzheimer's disease, and clinical development of BACE1 inhibitors is being intensely pursued. It is expected that developing a new treatment for Alzheimer's disease which reduces amyloid beta will not only improve symptoms, but also help slow down the progression of the disease. Verubecestat reduces the overall amount of amyloid beta by inhibiting Beta-site amyloid precursor protein cleaving enzyme (BACE). Single and multiple (daily for 14 days) oral doses of Verubecestat were analyzed for safety, tolerability, pharmacokinetics, and pharmacodynamics. In healthy volunteers, Verubecestat was well tolerated and no serious adverse events were reported.

This novel compound was discovered and also being developed at Merck.

The activity of Verubecestat is as follows [1]:

K_i (BACE1 binding assay) = 1.753 nM

K_i (BACE2 binding assay) = 0.37 nM

Common Name: Verubecestat

Synonyms:  MK-8931; MK8931; MK 8931; SCH-900931; SCH 900931; SCH900931

IUPAC Name: N-[3-[(5R)-3-amino-2,5-dimethyl-1,1-dioxo-6H-1,2,4-thiadiazin-5-yl]-4-fluorophenyl]-5-fluoropyridine-2-carboxamide

CAS Number: 1613380-81-6

Mechanism of Action: BACE1 Inhibitor; Beta-site amyloid precursor protein (APP) cleaving enzyme 1 Inhibitor

Indication: Alzheimer's disease; Treatment of Dementia

Development Stage: Phase III

Company: Merck

Phase I Study

MK-8931 was tested in 88 healthy volunteers (18–45 years old) as a two-part randomized, double-blind, placebo-controlled rising single dose (RSD) and rising multiple dose (RMD) studies were conducted in healthy adults, 18-45 years of age. In the RSD, the pharmacodynamic effects of MK-8931 (20, 100, 550-mg) were assessed in 3 sequential cohorts. In the RMD, 5 sequential cohorts were administered 10 to 250-mg MK-8931 daily for 14 days. CSF Aβ40, Aβ42 and sAPPβ concentrations were determined over 36 hrs postdose (Day 1 in RSD; Day 14 in RMD) using samples collected via lumbar catheterization. Determining whether MK-8931 was able to enter the brain and engage its target, the β-secretase enzyme, were primary goals of the study. To do so, biomarkers of BACE1 activity were measured in the CSF, including Aβ40, Aβ42, and sAPPβ, the latter being the BACE1-cleaved ectodomain of APP. MK-8931 markedly reduced levels of Aβ in the CSF in a sustained and dose-dependent manner. A single oral dose of 100 or 550 mg of MK-8931 decreased CSF Aβ40 levels by 75% or 92%, respectively, at 36 hours after dosing. Levels of Aβ42 and sAPPβ in the CSF were also reduced to similar extents. Multiple oral dosing of MK-8931 lowered Aβ levels in the CSF by over 90%. MK-8931 has a plasma half-life of ~20 hours, suggesting that a single daily oral dose may maintain stable drug levels in vivo. MK-8931 was well-tolerated and demonstrated a profound reduction in CSF Aβ. Thus, MK-8931 presents a unique opportunity to test the amyloid hypothesis of AD pathogenesis [2].

Phase Ib Study

MK-8931 was tested in a randomized, double-blind, placebo-controlled, multiple-dose study in mild-to-moderate AD patients. Subjects were administered 12, 40 or 60-mg MK-8931 or daily for 7 days. CSF Aβ40, Aβ42 and sAPPβ concentrations were determined over 36 hours postdose on Day7 using samples collected via lumbar catheterization. A semi-mechanistic mathematical model was developed to describe Aβ40, Aβ42 and sAPPβ modulation in CSF and used to generate dose-response profiles for AD patients. Following placebo administration, mean CSF concentrations of Aβ40, Aβ42 and sAPPβ increased relative to baseline. By contrast, administration of MK-8931 resulted in a dose-dependent and sustained reduction in CSF Aβ levels with mean percent reduction from baseline of up to: Aβ40=84%, Aβ42=81%, and sAPPβ=88%. CSF modulation of Aβ40, Aβ42 and sAPPβ was best described by a sigmoid Emax model and transit compartments accounted for the delay between brain and lumbar CSF Aβ. Based on dose-response profiles generated using this model, targeted CSF Aβ reductions between 50-75% and between 75-100% from baseline are predicted to be achieved in AD patients at dose levels of 12 and 40mg MK-8931, respectively. This study is the first demonstration of a pharmacodynamic effect of BACE1 inhibition in AD patients. Multiple doses of 12 to 60-mg MK-8931 resulted in a dose-dependent reduction in CSF Aβ, similar to that observed in healthy volunteers and have enabled robust dose-response modeling. Dose-response profiles predict that 12 and 40mg MK-8931 will inhibit Aβ production by greater than 50% and greater than 75%, respectively, in the majority of AD patients [3].

Phase I Study Involving Japanese Adults

Two-part randomized, double-blind, placebo-controlled rising single dose (SD; Part-1) and multiple dose (MD; Part-2) study conducted in healthy Japanese adults, ages 18-55. In Part-1, three single doses of MK-8931 (20, 100, 450-mg) were assessed in a single cohort. In Part-2, 2 cohorts were administered 80 or 150-mg MK-8931 daily for 14 days. The pharmacodynamic effect of MK-8931 was determined following the 450 mg dose in Part -1 and in the 80 mg Cohort in Part-2 by assessment of CSF concentrations of Aβ40, Aβ42 and sAPPβ 24 hours after the last dose compared to baseline values. Single and multiple MK-8931 doses were generally well-tolerated; adverse events (AEs) were mild-to-moderate in intensity and no subjects discontinued due to AEs. Following SD and MD administration, maximum MK-8931 concentrations were achieved at ~2 hr and there was a dose-related increase in plasma exposure. The terminal phase half-life was 16-21 hr. Over the dose range tested, exposure (AUC) in Japanese was similar to that observed previously in non-Japanese.  Following single and multiple dose administration, MK-8931 was well-tolerated and the pharmacokinetics in Japanese was similar to non-Japanese. MK-8931 also demonstrated a profound reduction in mean CSF Aβ in Japanese, similar to that observed in non-Japanese [4].

References:

1. Scott, J. D.; et. al. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions and their use. US8729071B2 (example 25)
2. Forman, M.; et. al. The novel BACE inhibitor MK-8931 dramatically lowers cerebrospinal fluid Aβ peptides in health subjects following single- and multiple-dose administration. Alzheimers Dement 2012, 8, P704.
3. Forman, M.; et. al. The novel BACE inhibitor MK-8931 dramatically lowers CSF beta-amyloid in patients with mild-to-moderate Alzheimer's disease. Alzheimers Dement 2013, 9(4), P139.
4. Forman, M.; et. al. A study to evaluate the pharmacokinetics and pharmacodynamics of single and multiple oral doses of the novel BACE inhibitor MK-8931 in Japanese subjects. Alzheimers Dement 2012, 8(4), P186.

Drugs in Clinical Pipeline: AZD3293

AZD3293 [4-Methoxy-5''-methyl-6'-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazole]-4''-amine] is an oral, potent and selective small molecule inhibitor of BACE that has been shown in Phase I studies to significantly and dose-dependently reduce levels of amyloid beta (Aβ) in the cerebrospinal fluid (CSF) of Alzheimer’s patients and healthy volunteers.

Amyloid beta (Aβ) deposition in the brain is thought to be one of the causes of Alzheimer's disease. It is expected that developing a new treatment for Alzheimer's disease which reduces amyloid beta will not only improve symptoms, but also help slow down the progression of the disease. AZD3293 may reduce the overall amount of amyloid beta by inhibiting Beta-site amyloid precursor protein cleaving enzyme (BACE). BACE1 is the first step in the processing of APP to Aβ peptides, and its inhibition is an attractive target for therapeutic intervention to stop the production of Aβ.

This novel compound was discovered at AstraZeneca which have taken it up to Phase II trials. In September 2014, AstraZeneca and Eli Lilly and Company (Lilly) announced an agreement to jointly develop and commercialise AZD3293 as a potential treatment for Alzheimer’s disease.

Common Name: AZD3293

Synonyms:  AZD3293; AZD 3293; AZD-3293; LY3314814; LY 3314814; LY-3314814

IUPAC Name: 4-Methoxy-5''-methyl-6'-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazole]-4''-amine

CAS Number: 1628076-74-3

Mechanism of Action: BACE1 Inhibitor; Beta-site amyloid precursor protein (APP) cleaving enzyme 1 Inhibitor

Indication: Alzheimer's disease; Treatment of Dementia

Development Stage: Phase II

Company: AstraZeneca/Eli Lilly

The potency of AZD3293 in cellular models on secretion of Aβ40 has been studied in SHSY5Y/APP cells (human neuronal cells over expressing human APPwt), N2A cells (mouse neuronal cells), primary mouse neurons and primary guinea pig neurons, using ELISA technology. Mice treated with AZD3293 as a single administration, or repeated administrations twice daily during 7 days, demonstrated a statistically significant dose- and time-dependent reduction of the levels of Aβ40, Aβ42 and sAPPβ in plasma and brain. Guinea pigs treated with AZD3293 as a single administration demonstrated a statistically significant dose- and time-dependent reduction of the levels of Aβ40, Aβ42 and sAPPβ in plasma, CSF and brain. In vitro potency in mouse and guinea pig primary cortical neuronal cells was strongly correlated to potency in mouse mouse and guinea pig in vivo potency [1].

To check the hypothesis that whether AZD3293 causes a dose dependent decrease of sAPPβ, and increase of sAPPα, clinical data for soluble fragments alpha (sAPPα) and beta (sAPPβ) were collected during a Multiple Ascending Dose study in elderly Healthy Volunteers, with the BACE inhibitor AZD3293. It was expected that a dose dependent decrease of sAPPβ, and increase of sAPPα would result from BACE1 inhibition in this study. CSF and plasma in healthy volunteers were sampled pre-treatment and during 24h continuous CSF sampling after 14 days of 15 and 50 mg dosing. Plasma and CSF sAPP α and β data were compared to corresponding AZD3293 concentration data to assess PK/PD correlations. The results were on the expected lines, where a dose-dependent sustained decrease in CSF of sAPPβ, and broadly dose-dependent increase of sAPPα, were observed. While sAPPα levels generally increased, data were variable with no apparent dose dependency. Within the linear range of the sAPPβ assay, a direct correlation between AZD3293 concentration (Cmax) and sAPPβ inhibition was observed on a similar timeline to effects seen for Aβ40/42. The observations are consistent with the hypothesized mechanism of action of AZD3293 and indicate that sustained inhibition of BACE1 leads to reduced sAPPβ levels and increased flux through the non-pathogenic α-secretase-mediated pathway [2].

References:

1. Haeberlein, S. B.; et. al. AZD3293, a potent and selective orally active, brain-permeable BACE1 inhibitor. Alzheimer's and Dementia 2013, 9(4), P813.
2. Hoglund, K.; et. al. Monitoring the soluble amyloid precursor protein alpha (sappa) and beta (sappb) fragments in plasma and csf from healthy individuals treated with bace inhibitor azd3293 in a multiple ascending dose study: pharmacokinetic and pharmacodynamic correlate. Alzheimer's and Dementia 2014, 10(4), P447.

Drugs in Clinical Pipeline: E2609

E2609 is a novel, small molecule, BACE1 inhibitor that has been shown in nonclinical studies to inhibit the production of Aβ40 and Aβ42 in brain, reducing Aβ in cerebrospinal fluid (CSF) and plasma after oral dosing. Beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is a key enzyme responsible for the production of Aβ peptides.

Amyloid beta (Aβ) deposition in the brain is thought to be one of the causes of Alzheimer's disease. It is expected that developing a new treatment for Alzheimer's disease which reduces amyloid beta will not only improve symptoms, but also help slow down the progression of the disease. E2609 may reduce the overall amount of amyloid beta by inhibiting BACE.

A single oral administration of E2609 in non-human primates significantly reduced plasma Aβ1-40 and Aβ1-42 levels equally, with an estimated plasma IC₅₀(unbound) of 1.3 nM, concordant with the potency of the cell-based assay. E2609 reached a rapid equilibrium between plasma and CSF with near identical t_max, and had a moderate to high CNS penetration. A single oral administration of E2609 led to an equal reduction of both CSF Aβ1-40 and Aβ1-42 levels. At effective doses, a peak reduction of up to ~90% was observed in CSF that was sustained for 24 hours or more. The pharmacodynamic parameters for CSF Aβ lowering (plasma IC₅₀, plasma IC₅₀(unbound) and k_out) were estimated as 35.0 nM, 9.7 nM, and 0.148 hr-1 for Aβ1-40, and 33.2 nM, 9.2 nM, and 0.148 hr -1 for Aβ1-42, respectively [1].

This novel compound was discovered at Eisai through a collaborative partnership between centres in Britain, Japan and the United States (US). In March 2014, Eisai and Biogen Idec signed a collaboration agreement to jointly develop E2609.

Common Name: E2609
Synonyms:  E2609; E 2609; E-2609
IUPAC Name: -
CAS Number: -
Mechanism of Action: BACE1 Inhibitor; Beta-site amyloid precursor protein (APP) cleaving enzyme 1 Inhibitor
Indication: Alzheimer's disease; Treatment of Dementia
Development Stage: Phase II
Company: Eisai/Biogen

The E2609 story got a lot of interest since the 2012 AAIC conference in Vancouver, Canada, where Eisai presented data to suggest that E2609 lowers Aβ concentration in the brain, CSF, and plasma of rats and guinea pigs, and that it lowers CSF and plasma Aβ in non-human primates. These Phase I study results confirmed E2609 'Proof of Mechanism' for preventing amyloid beta production by BACE inhibition in humans.

The two E2609 Phase I studies presented at the AAIC 2012 comprised a single oral ascending dose study (SAD, Study A001-001) and a 14-day multiple oral ascending dose study (MAD, Study A001-002). The SAD study showed a reduction in plasma amyloid beta levels, whilst the MAD study showed a statistically significant reduction of cerebrospinal fluid (CSF) amyloid beta levels.

SAD Study

This was a single-center, randomized, double-blind, placebo-controlled study in 8 cohorts of healthy adult subjects aged 30 to 55 and 1 cohort of healthy elderly subjects aged 65 to 85 [2]. Each cohort comprised 8 subjects, with 6 randomized to a single dose of E2609 and 2 to placebo. Healthy young subjects received single doses of 5, 10, 25, 50, 100, 200, 400 or 800 mg. Healthy elderly subjects received a single dose of 50 mg. Subjects were dosed after fasting overnight. Blood samples were collected predose and at multiple time points up to 144 h postdose to measure plasma concentrations of E2609 and Aβ peptides. Safety and tolerability were assessed by adverse events (AE), vital signs, electrocardiograms, and clinical laboratory blood tests. The maximum dose-dependent reduction of plasma amyloid beta (1-X) relative to baseline was 52% at 5 mg, and 92% at 800 mg. E2609 showed acceptable tolerability across all doses, and the most common adverse events included headache and dizziness.

MAD Study

MAD study was a randomised, double-blind, placebo-controlled, multiple ascending dose study conducted in 50 healthy adult volunteers [3]. Subjects were divided into five cohorts, with each cohort receiving E2609 doses of between 25 mg and 400 mg per day for 14 days. The study measured amyloid beta levels both in plasma and CSF. Preliminary interim analysis results showed that E2609 demonstrated a clear reduction in plasma amyloid beta (1-X) levels and a dose-dependent reduction in CSF amyloid Beta(1-X) in subjects who received daily doses of between 25 mg and 200 mg. The percentage decrease in CSF amyloid Beta(1-x) after 14 days dosing compared to baseline was statistically significant, with E2609 demonstrating a 46.2%, 61.9%, 73.8% and 79.9% difference in percentage decrease compared to placebo in the 25 mg, 50 mg, 100 mg and 200 mg cohorts, respectively. No clinically significant safety concerns were observed following repeated oral dosing of up to 200 mg. Several cases of orolabial herpes relapse were observed in the 200 mg cohort, however, while being evaluated, the significance of these cases is unknown as the blind remains unbroken on the safety data.

References:

1. Lucas, F.; et. al. Novel BACE1 inhibitor, E2609, lowers Aβ levels in the cerebrospinal fluid and plasma in nonhuman primates. Alzheimer's and Dementia 2012, 8(4), P224.

2. Lai, R.; et. al. First-in-human study of E2609, a novel BACE1 inhibitor, demonstrates prolonged reductions in plasma beta-amyloid levels after single dosing. Alzheimer's and Dementia 2012, 8(4), P96.

3. Albala, B.; et. al. CSF amyloid lowering in human volunteers after 14 days’ oral administration of the novel BACE1 inhibitor E2609. Alzheimer's and Dementia 2012, 8(4), S743.

4. ClinicalTrials.gov Dose-Finding Study To Evaluate Safety, Tolerability, and Efficacy of E2609 in Subjects With Mild Cognitive Impairment Due to Alzheimer's Disease (Prodromal Alzheimer's Disease) and Mild Dementia Due to Alzheimer's Disease. NCT02322021 (retrieved 24-04-2015)

5. ClinicalTrials.gov Evaluation of the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of E2609 in Healthy Subjects. NCT01511783 (retrieved 24-04-2015)

6. ClinicalTrials.gov An Study to Determine the Bioavailability of E2609 Tablets Compared to Capsules and the Effect of Food on Absorption. NCT01716897 (retrieved 24-04-2015)

'Mad Cow' might help in fighting Alzheimer’s and Parkinson’s Diseases

'Mad Cow' might help in fighting Alzheimer’s and Parkinson’s Diseases

Scientists from The Scripps Research Institute (TSRI), Florida have for the first time discovered a killing mechanism that could underpin a range of the most intractable neurodegenerative diseases such as Alzheimer’s, Parkinson’s and ALS. It is a commonly known idea that misfolded proteins are a representative occurrence in the family of diseases comprising, Alzheimer’s, Parkinson’s diseases, ALS and other conditions.

In an ongoing study the researchers have revealed the mechanism of toxicity of a misfolded form of the protein that underlies prion diseases, such as bovine spongiform encephalopathy (“mad cow disease”) and its human equivalent, Creutzfeldt-Jakob disease.

The scientists used a misfolded form of the prion disease protein, called TPrP. Salient features of their findings are:

1. Using biochemical techniques, the researchers demonstrated that TPrP induces neuronal death by profoundly depleting NAD+ (nicotinamide adenine dinucleotide).

2. Restoring NAD+ proved to be the critical factor for the rescue of neurons subjected to TPrP injury. Even when added three days after TPrP exposure, an infusion of NAD+ reversed within only a few hours the fate of neurons that had been doomed to destruction.

3. Loss of NAD+ is suggestive of some other neurodegenerative diseases, such as Parkinson’s where NAD+ depletion could play a role in mitochondrial failure.

References:

1. News article

2. The article is published in the journal Brain. No citation is provided.