Alzheimer's: New drug trial

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CNBC
Biogen

Skeptical Alzheimer's experts expressed surprising optimism regarding Biogen's BAN-2401 drug. Dr. Ronald Peterson is one of the world's top experts on Alzheimer's and Director of the Mayo Clinic Alzheimer Disease Research Center. See him discuss results from Biogen's positive phase-2-trial Alzheimer's treatment. 

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1. The final analysis at 18 months of the 856 patient Phase II clinical study in early Alzheimer’s disease demonstrated statistically significant slowing in clinical decline and reduction of amyloid beta accumulated in the brain
2. First late-stage study data successfully demonstrating potential disease-modifying effects on both clinical function and amyloid beta accumulation in the brain
3. New data provide compelling evidence to further support amyloid hypothesis as a therapeutic target for Alzheimer’s disease

Statistical Significance

Biogen announced positive topline results from the Phase II study with BAN2401, an anti-amyloid beta protofibril antibody, in 856 patients with early Alzheimer's disease. The study achieved statistical significance on key predefined endpoints evaluating efficacy at 18 months on slowing progression in Alzheimer’s Disease Composite Score (ADCOMS) and on reduction of amyloid accumulated in the brain as measured using amyloid-PET (positron emission tomography). 

Study 201 (ClinicalTrials.gov identifier NCT01767311) is a placebo-controlled, double-blind, parallel-group, randomized study in 856 patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) or mild Alzheimer's dementia (collectively known as early Alzheimer’s disease) with confirmed amyloid pathology in the brain. Efficacy was evaluated at 18 months by predefined conventional statistics on ADCOMS, which combines items from the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog), the Clinical Dementia Rating Sum of Boxes (CDR-SB) scale and the Mini-Mental State Examination (MMSE) to enable sensitive detection of changes in early AD symptoms. Patients were randomized to five dose regimens, 2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly and 10 mg/kg biweekly, or placebo.

Slowing Down Alzheimer's

Topline results of the final analysis of the study demonstrated a statistically significant slowing of disease progression on the key clinical endpoint (ADCOMS) after 18 months of treatment in patients receiving the highest treatment dose (10 mg/kg biweekly) as compared to placebo. Results of amyloid PET analyses at 18 months, including reduction in amyloid PET standardized uptake value ratio (SUVR) and amyloid PET image visual read of subjects converting from positive to negative for amyloid in the brain, were also statistically significant at this dose. Dose-dependent changes from baseline were observed across the PET results and the clinical endpoints.

Clinical Benefit

Further, the highest treatment dose of BAN2401 began to show statistically significant clinical benefit as measured by ADCOMS as early as 6 months including at 12 months.

BAN2401 demonstrated an acceptable tolerability profile through 18 months of study drug administration. The most common treatment emergent adverse events were infusion-related reactions and Amyloid Related Imaging Abnormalities (ARIA). Infusion related reactions were mostly mild to moderate in severity. Incidence of ARIA-E (edema) was not more than 10% in any of the treatment arms, and less than 15% in patients with APOE4 at the highest dose per the study protocol safety and reporting procedures. 

Detailed results of the study will be presented at future academic conferences.

Impressive 18-Month Results

“The 18-month results of the BAN2401 trial are impressive and provide important support for the amyloid hypothesis,” said Jeff Cummings, M.D., founding director, Cleveland Clinic Lou Ruvo Center for Brain Health. “I look forward to seeing the full data set shared with the broader Alzheimer’s community as we advance against this devastating disease.” 

“This is the first late-stage anti-amyloid antibody study to successfully achieve statistically significant results at 18 months, further validating the amyloid hypothesis,” said Lynn Kramer, M.D., Chief Clinical Officer and Chief Medical Officer, Neurology Business Group, Eisai. “We will discuss these very encouraging results with regulatory authorities to determine the best path forward. We continue to work towards the goal of delivering BAN2401 to patients and healthcare professionals as early as possible.” 

“The prospect of being able to offer meaningful disease-modifying therapies to individuals suffering from this terrible disease is both exciting and humbling,” said Alfred Sandrock, M.D., Ph.D., executive vice president and chief medical officer at Biogen. “These BAN2401 18-month data offer important insights in the investigation of potential treatment options for patients with Alzheimer’s disease and underscores that neurodegenerative diseases may not be as intractable as they once seemed.” 

As reported in December 2017, the study did not achieve its primary outcome measure which was designed to enable a potentially more rapid entry into Phase III development based on Bayesian analysis at 12 months of treatment. Upon the final analysis at 18 months using predefined conventional statistical method, the study did demonstrate a statistically significant slowing of disease progression on the key clinical endpoint (ADCOMS) after 12 months of treatment in patients receiving the highest treatment dose (10 mg/kg biweekly) as compared to placebo. 

MORE INFORMATION:

1. About BAN2401
   BAN2401 is a humanized monoclonal antibody for Alzheimer’s disease that is the result of a strategic research alliance between Eisai and BioArctic. BAN2401 selectively binds to neutralize and eliminate soluble, toxic Aβ aggregates that are thought to contribute to the neurodegenerative process in Alzheimer’s disease. As such, BAN2401 may have the potential to have an effect on disease pathology and to slow down the progression of the disease. Eisai obtained the global rights to study, develop, manufacture and market BAN2401 for the treatment of Alzheimer’s disease pursuant to an agreement concluded with BioArctic in December 2007. In March 2014, Eisai and Biogen entered into a joint development and commercialization agreement for BAN2401 and the parties amended that agreement in October 2017.
2. About ADCOMS
   Developed by Eisai, ADCOMS (AD Composite Score) combines items from the ADAS-Cog (Alzheimer’s Disease Assessment Scale-cognitive subscale), CDR-SB (Clinical Dementia Rating Sum of Boxes) and the MMSE (Mini-Mental State Examination) scales to enable a sensitive detection of changes in clinical functions of early AD symptoms and changes in memory. This Study 201 utilizes ADCOMS as its key endpoint for assessing clinical symptoms.

SOURCES:

• CNBC Television
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Merck Makes A 'Speculative' Step Into Alzheimer's

Caregivers and healthcare professionals, here is some great information

Here is a great dementia resource for caregivers and healthcare professionals,

Your residents will love the Amazon Kindle Fire

Here is information on being the best caregiver you can be

Here is a way for nurses administrators, social workers and other health care  professionals to get an easyceu or two

Follow alzheimersideas on twitter

The Dementia Caregiver's Little Book of Hope [Kindle Edition

Forbes

Although several rivals have recently experienced setbacks with Alzheimer’s compounds, Merck hopes to defy the odds with plans to take a pill into a Phase II/III study with patients who suffer from mild-to-moderate stages of the disease. And while one analyst calls the move speculative, the decision underscores an ongoing willingness to place big bets on tackling Alzheimer’s, a market that may offer the pharmaceutical equivalent of a Powerball payoff.

To be specific, Merck (MRK) will test a beta-amyloid precursor protein site-cleaving enzyme, or BACE, inhibitor, which the drugmaker notes is the first drug with this type of mechanism to advance to this stage of clinical research. The Phase II portion of the new trial will enroll 200 patients and be completed by late 2013. The Phase III segment would then begin with 1,700 patients, and there is speculation that  second Phase III trial might also be attempted with only earlier-stage patients.

The decision comes after Bristol-Myers Squibb halted testing of an Alzheimer’s compound, and Pfizer and Johnson & Johnson gave up on their bapineuzumab compound, which failed to meet two Phase III primary endpoints in patients with mild-to-moderate stages of disease (read here). Eli Lilly, however, is proceeding with its solanezumab compound, which slowed cognitive decline in patients with mild disease, but showed no statistically significant reduction in functional decline (see this).

“Merck is committed to advancing the understanding and treatment of Alzheimer’s disease,” says Darryle Schoepp, a senior vp and head of neuroscience and ophthalmology at Merck Research Laboratories, in a statement. The trial, by the way, will study one of three oral doses of the compound, called MK-8931, which will be administered daily versus a placebo.

The effort underscores that a significant level of interest remains, at least among some researchers and executives, to study compounds in later-stage patients, despite the recent setbacks. For its part, Merck notes that its BACE inhibitor recently demonstrated a reduction in cerebral spinal fluid, or CSF, a biomarker, in a Phase I study. By contrast, Roche recently doubled the size of a trial testing a compound in patients with early-stage disease. And so one analyst, while noting that Merck may give Lilly a ‘run for its money,’ expresses caution.

In a research note, ISI Group analyst Mark Schoenebaum writes that Merck could end up on the same timeline to market as Lilly  if the FDA asks Lilly to do another confirmatory Phase III trial of its compound. If not, though, Merck would be about three years behind. He adds that the Merck drug “appears to prevent (almost entirely) the formation of new amyloid beta plaques in the brain.” The Lilly drug, however, leads to removal of existing plaques.

But while he called the 90 percent reduction in CSF “impressive,” Schoenebaum points out that “the meaning of bio-markers is no longer clear.” Why? The Pfizer and J&J compound had good biomarker data, but no clinical impact, while the Lilly data revealed some clinical impact despite very mixed biomarker data. And he continues, “we do not believe that Merck has any clinical efficacy data at this point upon which it is basing its Phase II/III decision. Thus, one must still view the Phase III as highly speculative.”

Indeed, there is increasing belief that, to be truly effective, a drug will have to combat the disease in its earliest stages, before signs of dementia appear. Although the biomarker data is encouraging, as Schoenebaum points out, this is far from a reliable predictor. Merck obviously needs the data to get to Phase III, but a payout is far from clear. The odds, in fact, may yet wind up resembling a ballooning Powerball kitty.