After Solanezumab, What’s Next? Alzheimer’s Options Take The Stage At CTAD

Lilly will make its first presentation of solanezumab data from the recently failed Phase III EXPEDITION3 study during the Clinical Trials in Alzheimer’s Disease meeting where researchers will discuss amyloid beta and other hypotheses in Alzheimer’s disease Dec. 8-10 in San Diego.

Industry executives and biopharmaceutical analysts are reluctant to say that the failure of Eli Lilly & Co.’s solanezumab in a third Phase III clinical trial is the end of the road for the amyloid-beta hypothesis in Alzheimer’s disease, so does that mean another company could effectively treat the memory-stealing affliction with a drug that targets the menacing protein, or will other approaches be required?

The answer seems to be that multiple and combined approaches will be needed to slow the progression of Alzheimer’s and manage its symptoms, and targeting the amyloid-beta protein that causes plaques to build up in the brains of Alzheimer’s patients still could be of use in the disease. Researchers from industry and academia will discuss several options in development during the Clinical Trials in Alzheimer’s Disease (CTAD) conference from Dec. 8 to 10 in San Diego.

Data from Lilly’s Phase III EXPEDITION3 trial for solanezumab will be presented during a late-breaker presentation on Dec. 8.

Lilly made a big bet that its amyloid-targeting monoclonal antibody could slow the cognitive effects of Alzheimer’s and improve the ability for patients with mild to moderate forms of the disease to perform normal, daily tasks. It was not a major surprise in late November, however, when the company said solanezumab did not succeed in EXPEDITION3, since the antibody failed in two prior Phase III studies – just like several other fallen amyloid-targeting candidates. (Also see "Lilly’s Solanezumab Fails, But The Surprise Would Have Been Success" - Scrip, 23 Nov, 2016.)

Datamonitor Healthcare analyst Maha Elsayed said that “the failure of solanezumab does not necessarily have to mean that the amyloid hypothesis no longer holds true,” because it’s unclear how much of an impact the Lilly biologic has on modulating amyloid levels in the brain. Pharmacokinetic modeling has suggested that solanezumab has limited central nervous system (CNS) penetration, Elsayed noted, meaning that the antibody’s impact on amyloid may not be great enough to translate into a clinical effect.

The Datamonitor analyst said it will be important to understand how early in the disease that amyloid should be targeted – perhaps even before a mild or moderate Alzheimer’s diagnosis – or whether targeting the protein tau may be more closely correlated with slowing disease progression, providing a greater benefit in later stages of Alzheimer’s.

Despite those questions, Elsayed said Phase I data for Biogen’s amyloid-targeting biologic aducanumab have been encouraging, so far. There are “some mechanistic differences between aducanumab and solanezumab that could suggest that the failure of one does not have to apply to the other,” she said. “For example, aducanumab is targeting beta-amyloid fibrils and oligomers, directly impacting beta-amyloid plaques … whereas solanezumab is targeting soluble monomers of beta-amyloid and this approach may be less effective in reducing the toxicity of amyloid pathology.”

An analysis of long-term data from Biogen’s Phase I clinical trial will be presented at the CTAD meeting, but data from two ongoing Phase III studies for the monoclonal antibody are not expected until 2022.

Amyloid-Targeting Isn’t The Only Option

The next Alzheimer’s drug in line for potential US FDA approval does not target the amyloid-beta protein that causes plaques to build up in the brains of Alzheimer’s patients. Phase III data for Axovant Sciences Ltd.’s 5-HT6 antagonist intepirdine are expected in 2017, followed soon after by a new drug application (NDA) submission to the FDA, assuming the study’s results are positive.

Targeting 5-HT6 has disappointed other drug developers in the past, including H. Lundbeck AS and Otsuka Pharmaceutical Co. Ltd., whose idalopirdine failed in the first of two Phase III studies in October. Pfizer’s 5-HT6 antagonist PF-05212377 failed in a Phase II study, but analyses of data that the big pharma presented in July noted differences between the Pfizer and Axovant drugs and development programs that could result in a positive outcome for intepirdine. (Also see "Full Monty On Pfizer’s Failed 5-HT6 Alzheimer’s Drug Leaves Hope For Class" - Scrip, 25 Jul, 2016.)

Axovant Chief Development Officer Lawrence Friedhoff said in an interview with Scrip that the company has done its best to design and execute an efficient Phase III trial that mirrors the successful Phase IIb study for intepirdine as an add-on to Pfizer Inc.’s now-generic Aricept (donepezil) – a drug for which Friedhoff led the development as an R&D executive at Pfizer. Intepirdine probably will be dosed on top of existing symptom-treating therapies, if the drug is approved, he noted.

Friedhoff said intepirdine also could be prescribed in combination with disease-modifying drugs – perhaps even amyloid-targeting treatments – if a therapy that slows or halts the progression of Alzheimer’s ever makes it to the market.

“We never looked upon the [amyloid-targeting] antibodies as competitors,” he said. “It’s certainly unlikely that we’re going to discover the cure for Alzheimer’s and that you’re going to be able to take this pill or combination of pills to make it go away. It will be like a lot of diseases of old age where you take multiple medications that change as you progress, like with high blood pressure, diabetes and heart disease.”

Friedhoff said the Alzheimer’s research and drug development field has reached the conclusion that targeting amyloid alone is not the best path forward in treating the disease.

Axovant recently acquired intellectual property to make higher doses of cholinesterase inhibitors more tolerable. The company also has a 5HT-2A inverse receptor antagonist called nelotanserin that, like intepirdine, is being tested in a Phase II study for Lewy body dementia.

“These are modest steps, but when you add these modest steps together you can turn a disease that can be rapidly fatal into one that can be managed effectively for many years,” Friedhoff said. “If you can slow progression by a third and another drug can slow progression by a third and another one can too, you essentially have a cure.”

Patient enrollment in the Phase III MINDSET clinical trial for intepirdine should be completed by the end of 2016 and Axovant should be able to report the trial’s results in late 2017. An NDA filing is expected by the end of next year.

Axovant will have two oral and two poster presentations on Dec. 9 during the CTAD meeting showing data on drug interactions between intepirdine and Allergan PLC’s Namenda (memantine) in healthy subjects; placebo-controlled data on changes in how much patients depend on others for daily activities; results as an adjunct to donepezil (Aricept and generics) in terms of functional efficacy; and Phase IIb efficacy results for the intepirdine/donepezil combo in patients who completed the study.

One Drug To Eiminate Multiple Targets

Anavex Life Sciences Corp. is developing a drug candidate for Alzheimer’s and other diseases that targets the sigma-1 and muscarinic receptors to restore balance, or homeostasis, in cells. President and CEO Christopher Missling told Scrip that its sigma 1 receptor agonist turns the protein on, so that it attacks anything in cells that causes an imbalance, whether that’s amyloid-beta, tau, inflammation or other causes.

“It’s a backup plan for restoring homeostasis if the day-to-day pathways of homeostasis are not working as before,” Missling said. “It’s like a fire truck near a house. If something happens, fire truck has to be there quickly. The protein is always in the endoplasmic reticulum and doesn’t act unless there’s distress.”

Anavex has reported several updates from the ongoing Phase IIa clinical trial for Anavex 2-73 in Alzheimer’s disease – with varying responses from the company’s investors – and will present nine- and 12-month safety results during the CTAD meeting. (Also see "Anavex Stock Price Crash: A Fault By Trial Design?" - Scrip, 29 Jul, 2016.)

“We are very mindful of our resources, so we will do the best thing for the asset,” Missling said in regard to next steps for Anavex’s lead drug candidate. It’s possible that Anavex will launch a mid- or late-stage trial in Rett syndrome, Parkinson’s disease or another indication in 2017 to move the asset through development faster than it can in Alzheimer’s and at a lower cost.

“Other Alzheimer’s compounds do not have that optionality,” Missling said.

He noted that Alzheimer’s is a complex disease that may require multiple treatments, including combinations of novel agents. Avanex 2-73 could be combined with a lot of its competition, given the oral drug’s tolerability to date and its efficacy in the ongoing Phase IIa study. The company already is testing Anavex 2-73 Plus, which combines its drug with Aricept.

“We are agnostic to the a-beta hypothesis,” Missling said. “We do believe it is toxic, but it has to be looked at where it and what it’s doing. Some researchers say it is neuroprotective. We believe we are independent of any hypothesis, because if it’s overexpressed, it gets targeted; if not, it stays where it is.”

A Targeted Treatment Seeks New Life

Alzheon CEO Martin Tolar told Scrip that solanezumab’s failure strengthened “our belief that we must define Alzheimer’s populations based on a distinct biological phenotype. This will enable us to develop medicines for Alzheimer’s using the successful cancer playbook of finding genetically-defined patients who overexpress the underlying disease pathology and are uniquely sensitive to a treatment.”

The fact that multiple drugs have failed in Alzheimer’s disease is a key reason why Alzheon is using a precision medicine approach for the development of ALZ-801. A planned Phase III program for the company’s prodrug of its own failed Alzheimer’s therapy tramiprosate is focused on patients with the APOE4 genotype – a group of people with the highest risk of developing Alzheimer’s and who experience the earliest onset and fastest disease progression.

“Our new insights are defining a more targeted, higher probability [of success] development path to advance promising drug candidates,” Tolar said, by directing the right drugs to the right patients at the right stage of their disease.

Alzheon will present data during the CTAD meeting from a Journal of the Prevention of Alzheimer’s Disease publication about the effect of tramiprosate on people with the APOE4/4 genotype, which showed the highest efficacy signal in the company’s Phase III studies in North America and the EU, which failed in 2007.

“This description of preferential efficacy of tramiprosate in APOE4/4 homozygotes is the first for an amyloid-targeted agent,” Tolar said. Tramiprosate and the follow-on drug ALZ-801, which is formulated with increased bioavailability and reduced gastrointestinal side effects, interact with soluble beta amyloid peptide monomers to prevent the formation of amyloid plaques.

An oral CTAD presentation on Dec. 9 will show that APOE4/4 genotype patients with mild Alzheimer’s disease had the best response to tramiprosate in terms of cognitive and functional outcomes. A Dec. 8 poster presentation describes Phase Ib clinical pharmacology data for ALZ-801.

“We have completed a bridging Phase I program with prodrug ALZ-801 including 163 subjects where ALZ-801 demonstrated bioequivalence as well as an improved safety and tolerability profile versus tramiprosate. The next step for the program is a Phase III [study] with ALZ-801,” Tolar said.

Alzheon has designed a 400-patient Phase III pivotal study for ALZ-801 based on an end-of-Phase II meeting with the FDA to test the prodrug in patients with mild Alzheimer’s disease who have the APOE4/4 genotype.

“Our target remains to start the study in the second half of 2017 and we are completing funding and partnership discussions to advance the program,” Tolar said.

Other CTAD Presentations Of Interest

Other drugs and clinical trials to be highlighted during the CTAD meeting include:

• The Phase III trial for TauRx Pharmaceuticals Ltd.’s tau aggregation inhibitor LMTX, which failed earlier this year (Also see "TauRx’s Data Massage Can't Work Out The Kinks Of Failed LMTX Study" - Scrip, 28 Jul, 2016.);
• Phase I results for Pfizer’s gamma secretase modulator PF-06648671;
• Phase III study designs for Lilly’s beta secretase cleaving enzyme (BACE) inhibitor LY3314814/AZD3293, which is being developed in partnership with AstraZeneca PLC (Also see "AZ, Lilly's BACE Inhibitor Clears Safety Hurdle And Raises Class Hopes" - Scrip, 8 Apr, 2016.);
• Phase I results for the amyloid-targeting vaccine ABvac40 developed by Araclon Biotech SL and Grifols SA (Also see "Grifols-Backed Biotech Sees Early Promise With Alzheimer's Vaccine" - Scrip, 2 Aug, 2016.);
• Long-term follow-up safety and efficacy results for AADvac1, a tau-targeting vaccine that Axon Neuroscience GmbH is testing in Phase II;
• Clinical pharmacology data for the Phase II p38 MAP kinase inhibitor neflamapomid (VX-745), which Vertex Pharmaceuticals Inc. licensed to EIP Pharma LLC in 2012;
• Phase I data in progressive supranuclear palsy for AbbVie Inc.’s anti-tau monoclonal antibody ABBV-8E12, which began enrolling patients for a Phase II Alzheimer’s study in October;
• Novartis AG’s and Amgen Inc.’s BACE inhibitor CNP520 as a candidate for the Alzheimer’s Prevention Initiative Generation Study (Also see "Amgen, Novartis Trade Rights For Migraine, Alzheimer's Drugs" - Scrip, 2 Sep, 2015.);
• The Phase III study for Archer Pharmaceuticals Inc.’s nilvadipine in mild-to-moderate Alzheimer’s;
• Phase IIa results related to cognitive improvements for patients treated with the PPAR gamma and delta agonist T3D-959 from T3D Therapeutics Inc.;
• Phase II extension study data for Pharnext SAS’s PXT-864, a proprietary combination of baclofen and acamprosate;
• Three years of Phase II data for ladostigil from Avraham Pharmaceuticals Ltd. (Also see "Investors back Avraham Pharmaceuticals' Alzheimer's disease study" - Scrip, 14 Apr, 2010.); and
• Baseline characteristics of patients enrolled in the Phase II/III EPOCH trial for Merck & Co. Inc.’s BACE inhibitor verubecestat (MK-8931). (Also see "Merck's Promising Early Alzheimer's Data Can't Quell Efficacy Concerns" - Scrip, 4 Nov, 2016.)