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Crenezumab is a fully
humanized monoclonal antibody Humanized antibodies are antibodies from non-human species whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans. The process of "humanization" is usually applied to monoclonal ant ...
against human 1-40 and 1-42
beta amyloid Amyloid beta (Aβ, Abeta or beta-amyloid) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor pro ...
, which is being investigated as a treatment of
Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
. Crenezumab is highly homologous to
solanezumab Solanezumab (proposed INN, LY2062430) is a monoclonal antibody being investigated by Eli Lilly as a neuroprotector for patients with Alzheimer's disease. The drug originally attracted extensive media coverage proclaiming it a breakthrough, but ...
, another monoclonal antibody targeting amyloid-β peptides. In June 2022, the US
National Institutes of Health The National Institutes of Health (NIH) is the primary agency of the United States government responsible for biomedical and public health research. It was founded in 1887 and is part of the United States Department of Health and Human Service ...
announced that the drug failed as a medication for
early-onset Alzheimer's disease Early-onset Alzheimer's disease (EOAD), also called younger-onset Alzheimer's disease (YOAD), is Alzheimer's disease diagnosed before the age of 65. It is an uncommon form of Alzheimer's, accounting for only 5–10% of all Alzheimer's cases. Ab ...
following the results of a decade-long clinical trial.


Development

Crenezumab was developed by Ruth Greferath, Ph.D., and Claude Nicolau, Ph.D., before the Swiss-based biopharmaceutical company AC Immune was founded, which focuses on developing targeted therapeutics for misfolded proteins that cause neurodegenerative diseases, such as Alzheimer's and
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
. AC Immune was founded in 2003 by current CEO Andrea Pfeifer, Ph.D. and funded primarily by German billionaire Dietmar Hopp. In 2016, AC Immune filed for an
IPO An initial public offering (IPO) or stock launch is a public offering in which shares of a company are sold to institutional investors and usually also to retail (individual) investors. An IPO is typically underwritten by one or more investment ...
valuing the company at $700 million and subsequently sold 6.9 million shares for net proceeds of $68.73 million. To develop crenezumab, AC Immune utilized its SupraAntigen technology, which involves injecting mice with liposomes that contain several hundred peptide mimics of antigens in order to generate a multitude of antibodies, from which the ones with best specificity are selected. It is believed that crenezumab works by causing beta amyloid proteins to transition from an insoluble to a soluble form, inhibiting aggregation and promoting disaggregation of existing plaques. Crenezumab was licensed to
Genentech Genentech, Inc. is an American biotechnology corporation headquartered in South San Francisco, California. It operates as an independent subsidiary of holding company Roche. Genentech Research and Early Development operates as an independent cent ...
, Inc. in 2006. Genentech is fully responsible for the clinical development, manufacturing, and commercialization of crenezumab.


Patent

Crenezumab is protected under US Patent US7892544, which was filed 12 June 2007. As of November 2016, there are two other drugs in development which also target beta amyloid, namely
solanezumab Solanezumab (proposed INN, LY2062430) is a monoclonal antibody being investigated by Eli Lilly as a neuroprotector for patients with Alzheimer's disease. The drug originally attracted extensive media coverage proclaiming it a breakthrough, but ...
and aducanumab.


Clinical trials


ABBY study

ABBY was a
phase II study The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...
that evaluated the effects of crenezumab in patients with mild-to-moderate Alzheimer's Disease, which concluded in 2014. The primary endpoints were reduction in cognitive decline and global function decline. Patients treated with high-dose intravenous crenezumab showed non-significant reductions in both cognitive decline and global function decline, while patients who received subcutaneous crenezumab did not improve on either measure. Exploratory analysis of patients with the mildest symptoms (as defined by a
Mini Mental State Examination The Mini is a very small two-door, four-seat car, produced for four decades over a single generation, with many names and variants, by the British Motor Corporation (BMC) and its successors British Leyland and the Rover Group, and finally (b ...
score of 22-26) who received high-dose intravenous crenezumab did show a significant reduction in cognitive decline, but not in global function decline.


BLAZE study

BLAZE was a
phase II study The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...
that also concluded in 2014 and evaluated the effects of crenezumab in patients with mild-to-moderate Alzheimer's Disease, however its primary endpoint was changes in brain amyloid load, with secondary endpoints of changes in other biomarkers, cognition, global function, and activities of daily living. The resultant data showed no significant difference between either high-dose intravenous or subcutaneous crenezumab and placebo.


API ADAD Columbia trial

In May 2012, it was announced that the efficacy of crenezumab will be tested in a five-year trial against
early-onset Alzheimer's disease Early-onset Alzheimer's disease (EOAD), also called younger-onset Alzheimer's disease (YOAD), is Alzheimer's disease diagnosed before the age of 65. It is an uncommon form of Alzheimer's, accounting for only 5–10% of all Alzheimer's cases. Ab ...
. The $100 million trial will be funded by
Genentech Genentech, Inc. is an American biotechnology corporation headquartered in South San Francisco, California. It operates as an independent subsidiary of holding company Roche. Genentech Research and Early Development operates as an independent cent ...
, the Banner Alzheimer's Institute, and the
National Institutes of Health The National Institutes of Health (NIH) is the primary agency of the United States government responsible for biomedical and public health research. It was founded in 1887 and is part of the United States Department of Health and Human Service ...
. Participants in the study will be recruited from an extended family in and around
Medellín Medellín ( ; or ), officially the Special District of Science, Technology and Innovation of Medellín (), is the List of cities in Colombia, second-largest city in Colombia after Bogotá, and the capital of the department of Antioquia Departme ...
,
Colombia Colombia, officially the Republic of Colombia, is a country primarily located in South America with Insular region of Colombia, insular regions in North America. The Colombian mainland is bordered by the Caribbean Sea to the north, Venezuel ...
. Approximately one-third of the 5,000 family members carry an
autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
allele of presenilin-1 (
PSEN1 Presenilin-1 (PS-1) is a presenilin protein that in humans is encoded by the ''PSEN1'' gene. Presenilin-1 is one of the four core proteins in the gamma secretase complex, which is considered to play an important role in generation of amyloid bet ...
) that causes the early-onset form of Alzheimer's disease. The trial will test the effect of the drug on 300 individuals who have the PSEN1 mutation, but do not yet show symptoms of the disease. In June, the NIH announced the preliminary results stating that crenezumab failed to give "clinical benefit in cognitively healthy people who have a rare genetic mutation that causes early-onset Autosomal Dominant Alzheimer's Disease (ADAD)." The Banner Alzheimer’s Institute also concurred, as the executive director Eric Reiman said, "We’re disappointed that crenezumab did not show a significant clinical benefit."


CREAD study

In July 2015, Genentech announced it was moving crenezumab into a phase III study, known as CREAD, to evaluate the effects of crenezumab in patients with prodromal-to-mild Alzheimer's Disease. This study aims to enroll 750 individuals between the ages of 50 and 85 at 233 international sites. The primary outcome measure for this trial is change in clinical dementia rating, with secondary outcomes of changes in cognition, quality of life, and time to clinically evident decline, among others. The study was expected to conclude in 2021 but Roche has withdrawn its support in the middle of Phase III due to the initial assessment. As the studies gave no positive results, Genentech ended the last two clinical trials (CREAD 1 and CREAD 2) in January 2019.


References

{{monoclonals for bone, musculoskeletal, circulatory, and neurologic systems Anti-amyloid monoclonal antibodies