Crenezumab

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Crenezumab
Monoclonal antibody
Type Whole antibody
Source Humanized (from mouse)
Target 1-40-β-amyloid
Clinical data
ATC code
  • none
Identifiers
CAS Number
ChemSpider
  • none
UNII
Chemical and physical data
Formula C6442H9966N1706O2018S40
Molar mass 144.88 kg/mol
 NYesY (what is this?)  (verify)

Crenezumab is a fully humanized monoclonal antibody against human 1-40 and 1-42 Beta amyloid, which is being investigated as a treatment of Alzheimer's disease.[1] Crenezumab is highly homologous to solanezumab, another monoclonal antibody targeting amyloid-β peptides.[2]

Development[edit]

Crenezumab was developed by Ruth Greferath, Ph.D. and Claude Nicolau, Ph.D. at the Swiss-based biopharmaceutical company AC Immune, which focuses on developing targeted therapeutics for misfolded proteins that cause neurodegenerative diseases, such as Alzheimer's and Parkinson's disease.[3] AC Immune was founded in 2003 by current CEO Andrea Pfeifer, Ph.D.[4] and funded primarily by German billionaire Dietmar Hopp.[5] In 2016, AC Immune filed for an IPO valuing the company at $700 million[6] and subsequently sold 6.9 million shares for net proceeds of $68.73 million.[7]

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.[8] It is believed that crenezumab works by causing beta amyloid proteins to transition from an insoluble to a soluble form,[9] inhibiting aggregation and promoting disaggregation of existing plaques.[10]

Crenezumab was licensed to Genentech, Inc. in 2006.[11] Genentech is fully responsible for the clinical development, manufacturing, and commercialization of crenezumab.[10]

Patent[edit]

Crenezumab is protected under US Patent US7892544, which was filed June 12, 2007.[12] As of November 2016, there are two other drugs in development which also target beta amyloid, namely solanezumab and aducanumab.

Clinical trials[edit]

ABBY study[edit]

ABBY was a phase II study 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.[13] Patients treated with high-dose intravenous crenuzumab 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 score of 22-26) who received high-dose intravenous crenezumab did show a significant reduction in cognitive decline, but not in global function decline.[13]

BLAZE study[edit]

BLAZE was a phase II study 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.[13]

ADAD trial[edit]

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.[14] The $100 million trial will be funded by Genentech, the Banner Alzheimer's Institute, and the National Institutes of Health. Participants in the study will be recruited from an extended family in and around Medellín, Colombia.[15] Approximately one-third of the 5,000 family members carry an autosomal dominant allele of presenilin-1 (PSEN1) 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.[14]

CREAD study[edit]

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.[16] 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 is expected to conclude in 2021.[17]

References[edit]

  1. ^ "Statement On A Nonproprietary Name Adopted By The USAN Council: Crenezumab" (PDF). American Medical Association. 
  2. ^ http://www.nature.com/srep/2015/150409/srep09649/full/srep09649.html
  3. ^ "AC Immune | R&D strategy". www.acimmune.com. Retrieved 2016-11-21. 
  4. ^ "AC Immune | Senior management team". www.acimmune.com. Retrieved 2016-11-21. 
  5. ^ "Genentech, J&J partner AC Immune files IPO for Alzheimer's pipeline | FierceBiotech". www.fiercebiotech.com. Retrieved 2016-11-21. 
  6. ^ "Swiss Alzheimer's biotech AC Immune eyes $700 million IPO valuation". Reuters. 2016-09-14. Retrieved 2016-11-21. 
  7. ^ SA, AC Immune. "AC Immune Reports Third Quarter 2016 Results". GlobeNewswire News Room. Retrieved 2016-11-21. 
  8. ^ "Zapping Pathological Proteins in Alzheimer's | GEN Genetic Engineering & Biotechnology News - Biotech from Bench to Business | GEN". GEN. Retrieved 2016-11-14. 
  9. ^ "Genentech and AC Immune: Exclusive License Agreement" (PDF). Retrieved 14 Nov 2016. 
  10. ^ a b "AC Immune receives significant milestone payment from Genentech" (PDF). Retrieved 15 Nov 2016. 
  11. ^ "Roche Signs First Alzheimer's Deal Of 2011 As Crucial Progress Awaited"
  12. ^ Pfeifer, Andrea; CH; Pihlgren, Maria; CH; Muhs, Andreas; CH; Watts, Ryan (February 22, 2011), United States Patent: 7892544 - Humanized anti-beta-amyloid antibody, retrieved 2016-11-21 
  13. ^ a b c "Roche announces phase II clinical results of crenezumab in Alzheimer's disease". www.roche.com. Retrieved 2016-11-15. 
  14. ^ a b "Testing a Drug That May Stop Alzheimer’s Before It Starts"
  15. ^ "Alzheimer’s Stalks a Colombian Family"
  16. ^ "AC Immune receives milestone payment for crenezumab moving into phase III clinical development in Alzheimer's disease" (PDF). Retrieved 15 Nov 2016. 
  17. ^ "CREAD Study: A Study of Crenezumab Versus Placebo to Evaluate the Efficacy and Safety in Participants With Prodromal to Mild Alzheimer's Disease (AD) - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2016-11-15.