Part 2 of a three-part story.

At AAIC 2017 in London last month, researchers introduced data from ongoing Phase 1 trials of a plethora of small-molecule drugs, including BACE inhibitors, a γ-secretase modulator, and a phosphodiesterase inhibitor. Though early days, the candidates looked safe for further testing.

Researchers from Merck, Pfizer, and Novartis outlined safety data from their ongoing BACE inhibitor trials. This enzyme cleaves the extracellular domain from the amyloid precursor protein, leaving a C-terminal fragment that γ-secretase processes further to release the Aβ peptide. Researchers had raised concerns with targeting BACE because it comes in two isoforms and each cleaves multiple proteins. Fears that blocking cleavage of any one of these substrates might cause serious side effects had led to calls for caution (Dec 2013 conference news). At the doses used and with new inhibitors that are more specific for BACE1 than for BACE2, so far the strategy appears to have avoided any safety pitfalls.

Ruolun Qiu from Pfizer in Cambridge, Massachusetts, reported on safety, tolerability, and pharmacokinetics from two small trials of PF-06751979. Qiu said this compound is a selective inhibitor of BACE1, blocking this CNS isoform with 30-fold more potency than the more peripherally expressed BACE2. In keeping with this, Qiu reported that in mice, a dose of PF-06751979 that reduces Aβ by 55 percent caused no hypopigmentation of their fur, unlike a similar dose of a non-selective BACE inhibitor. BACE2 plays a critical role in the generation of melanin in the skin and hair follicles.

Reviewing the human data thus far, Qiu said the drug seems well tolerated. Placebo or single ascending doses from 3 to 540 mg were given to 16 healthy young men in their 30s; multiple ascending doses of 5 to 275 mg or placebo were administered over 14 days to 50 more men and women around the same age. Ten Japanese volunteers received 125 or 275 mg, or placebo, over the same time frame. Lastly, 24 volunteers in their 60s and 70s were given 50 or 125 mg, or placebo, also for 14 days.

In these trials, this BACE2 inhibitor seemed safe, Qiu said. Two volunteers discontinued due to adverse events; one of them was on placebo, the other developed a skin rash. Treatment-related adverse events were mild, said Qiu, and included fatigue, headache, insomnia, and acne. Levels of the enzyme plasma transaminase temporarily increased in one person on placebo, one on 125 and one on 275 mg of PF-drug, but this was asymptomatic. There were no serious adverse events, Qiu said.

Pharmacokinetic data suggested that the drug is suitable for once per day dosing, said Qiu. Both the maximum concentration and total amount in the blood increased with dose, and on average the maximum concentration was reached in three to four hours. Half-life in the blood was about 30 to 40 hours. Qiu claimed the drug entered the brain well but showed no CSF data for inhibitor levels. She did show that 50, 125, and 275 mg of drug reduced CSF Aβ42 by 70, 85, and 95 percent, respectively. Qiu did not show data for sAPPβ or sAPPα, but said they tracked in the expected direction.

Cristina Lopez-Lopez from Novartis, Basel, Switzerland, reviewed a three-month dose ranging and tolerability study for the BACE inhibitor CNP520, which is being tested in the ongoing Generation secondary prevention trials conducted by the Alzheimer’s Prevention Initiative (Jul 2014 conference news). Lopez-Lopez said that Novartis now has data on five studies that include 422 subjects, 355 on drug. She said that up to now, testing has revealed no eye, skin, cardiovascular, or cognitive problems. She said across these trials, adverse events were similar among placebo and drug groups, except for one case of pruritus.

A three-month dose ranging trial administered placebo or up to 85 mg CNP520 daily to healthy volunteers over 60. Novartis researchers use pharmacometric modeling to predict doses that would lead to 80 and 50 percent reduction in CSF Aβ in 90 percent of people on the given dose. This turned out to be 15 and 50 mg/day for the high and low reduction, respectively. On this base, Generation 1, which will test CNP520 and Novartis’ Aβ immunotherapy CAD106 in homozygous ApoE4 carriers, will use 50 mg of the BACE inhibitor, and Generation 2, 15 and 50 mg doses. The latter is recruiting both heterozygous and homozygous ApoE4 carriers. Lopez-Lopez noted that in clinical and preclinical studies, ApoE genotype does not alter reduction in CSF Aβ by the drug.

Describing a new line of attack on BACE, Juliya Kalinina from Merck & Co., West Point, Pennsylvania, described how a new inhibitor, MBi-10, reduced CSF levels of Aβ oligomers (AβOs). Merck researchers led by Mary Savage have developed an immunoassay to detect these ephemeral Aβ species (Savage et al., 2014). Kalinina gave no details on this compound save to say it potently inhibited APP processing in vitro and in vivo, and that it is highly selective for BACE1 over BACE2. In monkeys, a related BACE inhibitor, MBi-5, reduced Aβ monomers, AβOs, and sAPPβ in the CSF but not sAPPα, said Kalinina.

What about in people? Kalinina and colleagues administered a single dose of placebo, 10, 60, or 800 mg MBi-10 to each of 24 healthy men. The researchers then collected serial CSF samples over 36 hours and assayed for Aβ monomers and oligomers species. Levels of Aβ40 and AβOs gradually fell from the time the drug was taken. The reduction was dose-dependent, reaching 10 percent relative to baseline. Kalinina noted that the kinetics and extent of the changes were similar for the two forms of Aβ, suggesting that monomers and oligomers rapidly reach equilibrium.

Other researchers at the meeting were intrigued by the findings but wondered what they mean. Jeff Cummings, Cleveland Clinic at the Lou Ruvo Center, Las Vegas, noted that there are many different species of oligomers and asked Kalinina if she knew exactly what was being detected in the assay. She acknowledged that they don’t know for sure, but that this is something they are studying at Merck.

Green Light for γ-Secretase Modulator and Phosphodiesterase Inhibitor
Researchers from Pfizer showed data from three Phase 1 trials of their γ-secretase modulator PF-06648671. As is the case for BACE, γ-secretase cleaves many substrates besides the amyloid precursor protein (APP), most notably Notch, and in clinical trials inhibitors led to serious adverse reaction in patients (Oct 2015 news). Researchers are now focused on modulators. These have no effect on γ-secretase endopeptidase activity, thus allowing it to cleave Notch and other substrates as usual. Instead, these drugs modulate subsequent carboxypeptidase activity of the enzyme that sequentially cleaves three-amino acid peptides from the Aβ peptide before releasing it. The idea is to coax the enzyme to make shorter, less amyloidogenic peptides. Jae Eun Ahn reported how he used pharmacokinetic modeling to determine how plasma concentration of the PF-06648671 affected CSF concentrations of various Aβ species, including Aβ42, Aβ40, Aβ38, and Aβ37.

Ahn said that the GSM blocked production of Aβ42 more than 40, and boosted production of Aβ37 more than 38, showing that the modulator shifted the cleavage of APP toward generating shorter Aβ peptides. He concluded that 100 mg/day and 350 mg/day doses would reduce Aβ42 by 50 and 66 percent, respectively, while increasing Aβ37 two- and fourfold. He said these results will be used to guide dosing in future Phase 2 or 3 trials.

Reporting on a totally different approach, Robert Lai, Eisai, Hatfield, U.K., described results of a Phase 1 trial of a phosphodiesterase-9 inhibitor, E2027. Blocking PDE9, a strategy that other companies have tried before to no avail, boosts levels of cyclic GMP in the brain. This purportedly strengthens synaptic activity and may attenuate the toxic effect of Aβ on neurons (Jan 2010 conference news). 

Eisai tested E2027 in a four-part Phase 1 proof-of-target-engagement study. Part A gave single doses of 10 to 1,200 mg to non-elderly healthy controls, while part B looked at taking this drug with food. Parts C and D tested single ascending doses in healthy elderly and in non-elderly Japanese volunteers. To measure cGMP levels, the researchers collected serial CSF samples from volunteers in parts B through D.

Lai reported that the drug was readily absorbed, reaching maximum concentration in the blood within two to four hours. The maximum concentration and the total amount seen in the blood, a.k.a. area under the curve in pharma parlance, increased with the dose but plateaued at 800 mg. The AUC ticked up 20 percent when the drug was taken with food, and the maximum blood concentration jumped about 50 percent. The pharmacokinetic data was similar in Japanese and other ethnicities.

E2027 increased cGMP in the CSF, with single doses of 100 and 400 mg showing a three- and fourfold increase before a slow decline. Levels remained above baseline three hours after dosing. Lai said the drug seemed well tolerated.—Tom Fagan


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News Citations

  1. Cloistered Retreat Takes the Pulse of BACE Research
  2. Novartis to Partner with Banner Health on ApoE4 Prevention Trial
  3. Avagacestat Demise Has Silver Lining for CSF Biomarkers
  4. Copper Mountain: Can CREB Save Memory?

Therapeutics Citations

  1. PF-06751979
  2. PF-06648671

Paper Citations

  1. . A sensitive aβ oligomer assay discriminates Alzheimer's and aged control cerebrospinal fluid. J Neurosci. 2014 Feb 19;34(8):2884-97. PubMed.

Other Citations

  1. CNP520

External Citations

  1. trial
  2. Generation 1
  3. Generation 2

Further Reading

No Available Further Reading