10 October 2012. Today, scientists of the Dominantly Inherited Alzheimer Network (DIAN) announced that they have chosen two investigational monoclonal antibodies for clinical trials that will try to prevent dementia in people who are on the path to Alzheimer’s disease due to an inherited autosomal-dominant mutation. The trial will also test an investigational BACE 1 inhibitor, but this third drug selection is not finalized yet.

Expected to start in early 2013, the trial is going to be a worldwide clinical study evaluating whether one or more of these experimental treatments can halt or reverse pathological changes in the preclinical biomarkers known to be present in the trial participants. The second phase of the trial will assess whether such biomarker effects effectively halt the Alzheimer’s process so that the participants develop no clinical symptoms.

“This trial is the result of a groundbreaking collaboration between academic institutions, pharmaceutical companies and patient advocacy groups, with key support from regulatory groups,” Randall Bateman, Washington University School of Medicine in St. Louis, said in a press release issued by Washington University. Bateman heads DIAN’s Pharma Consortium (see ARF related news story), in which 10 companies nominated 15 drugs for selection in this trial and gave scientific advice on its design. Bateman also heads the network’s Trial Unit (DIAN TU), which consists of academic experts who chose from among the nominations and will conduct the trial.

“This is a very exciting moment in Alzheimer’s disease research, and it gives me renewed hope for a future without Alzheimer’s,” says DIAN participant Brent Whitney. “I hope my grandchildren someday learn of this condition in history books, like I learned about polio.” Whitney is a relative of the families with the so-called Volga German presenilin 2 mutation that causes Alzheimer’s disease. For more on his family and their research participation in DIAN and reaching back 25 years (see Part 4 of this series).

Each of the three chosen drugs targets amyloid-β in a slightly different way. Each has passed earlier clinical trials that evaluated target engagement, safety and effectiveness. Gantenerumab is a humanized antibody made by Roche that binds to all forms of aggregated Aβ and helps remove them from the brain. Gantenerumab is currently in an international Phase 2/3 trial known as SCarlet RoAD in prodromal Alzheimer’s disease.

“Roche is honored that gantenerumab was selected by DIAN to be a part of this groundbreaking Alzheimer’s disease study,” says Luca Santarelli, head of Roche Neurosciences. “This clinical test supports Roche’s commitment to provide earlier treatment options to those at risk for this devastating disease.” (For more on Roche’s Alzheimer’s drug pipeline, see Alzforum interview with Santarelli.)

Solanezumab is a different humanized monoclonal antibody, by Eli Lilly and Company. Just yesterday at the American Neurological Association annual meeting in Boston, Massachusetts, it was reported to have slowed the decline in cognition and perhaps even function in Phase 3 clinical trials of mild AD (ARF related news story). This is the first time an anti-amyloid medication has achieved any benefit on Alzheimer’s symptoms. The effect was very small, and scientists agreed that future tests of solanezumab should be done at earlier stages of the disease process. This antibody binds to soluble forms of amyloid-β after they are produced, on the assumption that it can be cleared before it clumps together into plaques.

Also selected for potential inclusion in the trial is a β-secretase (BACE) inhibitor also by Lilly. This small molecule drug is in a Phase 2 clinical trial of MCI due to AD or mild AD. Whereas the two antibodies are thought to promote clearance of Aβ in its amyloid or per-amyloid forms, the BACE inhibitor is intended to cut down on production of Aβ. (For more on Lilly's and other BACE inhibitors in trials, see ARF related news story.)

“We are pleased that Lilly was chosen to contribute solanezumab, and potentially our β-secretase inhibitor, for use in this pioneering Alzheimer’s disease study,” said Jan Lundberg, who head Lilly Research Laboratories. “We look forward to collaborating with the DIAN TU investigators, along with the other public and private partners, to better understand if early treatment with these investigational medicines can influence this terrible disease."

This trial will bring to three the number of therapeutic antibodies being tested in preclinical Alzheimer’s. Earlier this year, the Alzheimer’s Prevention Initiative announced that would begin testing Genentech’s crenezumab in the Colombian kindred of autosomal-dominant AD, also beginning in early 2013 (ARF related news story).

For the DIAN trials, Roche and Lilly have agreed to make the treatments available at no cost. The two companies will provide supporting grants for each drug to help make the trial possible. The trial also is supported by a grant from the Alzheimer’s Association, and the DIAN researchers have applied for support through the National Institute on Aging, which is currently reviewing the grant application. Leading researchers from across the AD field, as well as colleagues in pharma companies, have consistently said that they are hoping for a significant public contribution toward the cost of these trials. Public funding would facilitate faster and more comprehensive sharing of DIAN trial data with the field at large so other groups can learn from it for future clinical and basic studies. The AD field overall is moving toward data sharing with public-private initiatives such as ADNI and the API crenezumab trials.

The DIAN trial will include 160 mutation carriers in their thirties, forties, or fifties, who range from 15 years before to 10 years after the expected onset of symptoms. The trial also will monitor the health of 80 DIAN participants who did not inherit their family's mutation. Mutation carriers will be randomly assigned to receive one of three investigational drugs or placebo; non-carriers will receive placebo. This raises the chance for each carrier to be on drug to 75 percent. Even though DIAN participants respect the scientific need for placebo, they have asked for creative solutions to boost their chances of being on drug. “Normally in clinical trials there is a 50/50 chance of receiving the active drug or a placebo, but the efficient design of testing three drugs will allow us to significantly boost the number of participants who receive active treatments,” Bateman said.

The design allows trial participants to stay blinded to their mutation status, because it enrolls non-carriers into a mixed non-carrier/carrier placebo group. This is another feature DIAN families had requested. Throughout the planning process leading up to today’s announcement, DIAN scientists have updated participants in webinars and have asked their feedback on what is particularly important to them.

The observational DIAN study has shown that starting as early as 15, even 20 years prior to symptoms, mutation carriers have biomarker changes that show the disease is beginning to take hold in the brain. The trial will monitor these markers to see whether the new treatments slow or stop the presymptomatic disease process. This first part of the trial will last for two years. It will be extended into a cognitive outcomes trial if one or more of the drugs appear successful in the biomarker part.

Trial sites include the Alzheimer’s Disease Research Center at Washington University and other centers in North America, Europe, Australia and elsewhere. For patients, family members, doctors and researchers interested in the DIAN trial, the DIAN Trials Unit has launched an expanded registry. For more information or to register for potential participation in the trial, go to www.DIANXR.org or call 1-800-747-2979.

For more on DIAN’s latest research data, its continuing efforts to address its participants’ need for confidentiality, and for testimonies from participants themselves, see Part 2, Part 3, and Part 4 of this series.—Gabrielle Strobel.

This is Part 1 of a four-part series. See also Part 2, Part 3, and Part 4.
Read a PDF of the entire series.