What is Bapineuzumab and what was its intended therapeutic purpose?

Bapineuzumab, also known by the nickname 'bapi,' is a humanized monoclonal antibody developed for potential therapeutic use in the nervous system. Its primary investigation was for treating Alzheimer's disease, with a secondary consideration for glaucoma.

What specific component of Alzheimer's disease pathology does Bapineuzumab target?

Bapineuzumab is designed to target beta-amyloid (Aβ) plaques, which are considered a key neuropathological hallmark believed to underlie Alzheimer's disease.

How does Bapineuzumab recognize the beta-amyloid peptide?

Bapineuzumab specifically recognizes the first five amino acid residues at the N-terminus of the beta-amyloid peptide when it adopts a helical conformation. This binding interaction is further stabilized by internal hydrogen bonds within the first three amino acids of the peptide.

What were the primary outcomes of the major clinical trials for Bapineuzumab conducted in 2012?

In 2012, two significant clinical trials concluded that Bapineuzumab did not produce substantial cognitive improvements in patients diagnosed with Alzheimer's disease.

Despite failing to improve cognition, what biological effects did Bapineuzumab demonstrate in clinical trials?

Although cognitive benefits were not observed, Bapineuzumab was shown to effectively lower key biomarkers associated with Alzheimer's disease. These included reductions in amyloid brain plaque burden and levels of hyperphosphorylated tau protein in the cerebrospinal fluid (CSF).

What significant safety concern, termed ARIA, was identified with Bapineuzumab treatment?

Bapineuzumab was the first antibody found to induce amyloid-related imaging abnormalities (ARIA). Specifically, it was associated with ARIA-E, characterized by the accumulation of fluid within brain tissue, particularly noted at the highest dosage levels.

Were there any observed safety differences based on the dosage of Bapineuzumab administered?

Yes, while the highest dose of Bapineuzumab was linked to ARIA, patients receiving lower doses of 0.5 mg or 1 mg did not exhibit these specific health risks. Consequently, patients on the highest dose were either withdrawn from trials or switched to lower doses.

Which pharmaceutical companies were involved in the development and progression of Bapineuzumab?

Bapineuzumab was initially co-developed by Élan and Wyeth. Later, Johnson & Johnson acquired significant assets related to the program from Élan, and Pfizer continued development after acquiring Wyeth in 2009.

When did Bapineuzumab advance into Phase III clinical trials?

Bapineuzumab entered Phase III clinical trials in December 2007, marking a significant step in its development pathway.

What led to the discontinuation of the intravenous formulation of Bapineuzumab?

Pfizer Inc. and Johnson & Johnson jointly announced in August 2012 the cessation of development for the intravenous formulation of Bapineuzumab. This decision was based on findings from two late-stage trials indicating the drug was no more effective than a placebo in patients with mild to moderate Alzheimer's disease.

What was the fate of the subcutaneous formulation of Bapineuzumab?

Johnson & Johnson discontinued the Phase 2 testing of the subcutaneous formulation of Bapineuzumab on July 16, 2013.

What is the chemical formula provided for Bapineuzumab?

The chemical formula listed for Bapineuzumab is C6466H10018N1734O2026S44.

What is the reported molar mass of Bapineuzumab?

The molar mass of Bapineuzumab is stated as 145,874.02 g/mol.

What is the CAS Registry Number associated with Bapineuzumab?

The CAS Registry Number for Bapineuzumab is 648895-38-9.

What is the UNII identifier for Bapineuzumab?

The Unique Ingredient Identifier (UNII) for Bapineuzumab is NC11WKO35D.

What is the ECHA InfoCard number for Bapineuzumab?

Bapineuzumab is associated with the ECHA InfoCard number 100.133.214.

What were the results of the earlier AN-1792 clinical trial concerning Alzheimer's immunotherapy?

The AN-1792 trial, which involved active immunization against human beta-amyloid, showed positive outcomes in removing plaques. However, it was halted because 6% of the participants developed aseptic meningitis.

How is Bapineuzumab classified in terms of its antibody type and source?

Bapineuzumab is classified as a whole antibody that is humanized, meaning it was originally derived from a mouse but has been modified to resemble human antibodies more closely, reducing potential immune reactions.

What does the term 'humanized antibody' imply about Bapineuzumab's origin and function?

A 'humanized' antibody, like Bapineuzumab, indicates that while its initial development may have involved non-human sources (such as mice), critical parts of the antibody structure have been altered to be more human-like. This modification is intended to decrease the risk of the patient's immune system rejecting the therapeutic antibody.

What is the significance of Bapineuzumab being the first antibody linked to ARIA-E?

Bapineuzumab's association as the first antibody to cause ARIA-E (amyloid-related imaging abnormalities involving fluid accumulation in brain tissue) highlights a specific safety profile related to targeting amyloid plaques, which required careful monitoring or led to trial adjustments.

What is Cerebrospinal Fluid (CSF) and why is it relevant to Bapineuzumab trials?

Cerebrospinal fluid (CSF) is the fluid that circulates around the brain and spinal cord. Measuring biomarkers like amyloid plaque and hyperphosphorylated tau protein levels in CSF, as was done in Bapineuzumab trials, can provide important information about the drug's biological effects on Alzheimer's pathology.

What does the term 'hyperphosphorylated tau protein' refer to in the context of Alzheimer's disease?

Hyperphosphorylated tau protein refers to tau proteins within brain cells that have undergone excessive phosphorylation (the addition of phosphate groups). This abnormal modification is a key component of neurofibrillary tangles, another significant pathological feature of Alzheimer's disease.

What is the potential implication of Bapineuzumab reducing amyloid brain plaque and hyperphosphorylated tau protein?

The observed reduction in these key Alzheimer's disease biomarkers suggests that Bapineuzumab was capable of interacting with and potentially clearing these pathological proteins from the brain, even though this did not translate into clinical cognitive benefits in the trials.

What is the role of Mathew Martoma in the history of Bapineuzumab?

Mathew Martoma, a former trader at S.A.C. Capital Advisors, was convicted of insider trading in February 2014. The conviction stemmed from trading based on confidential information about the cancellation of Bapineuzumab's clinical testing, which he received from neurologist Sid Gilman.

What specific charge was Mathew Martoma convicted of related to Bapineuzumab news?

Mathew Martoma was convicted of insider trading for using non-public information regarding the termination of Bapineuzumab's testing to make illegal trades.

What is the significance of the 4HIX.pdb reference in the context of Bapineuzumab?

The 4HIX.pdb reference likely points to a specific structural data file in the Protein Data Bank (PDB). This file would detail the three-dimensional structure of the beta-amyloid peptide fragment bound by Bapineuzumab, illustrating its helical conformation.

What does the Navbox at the end of the article illustrate regarding Bapineuzumab?

The Navbox categorizes Bapineuzumab as a 'Humanized' antibody within the 'Neurologic' therapeutic area, alongside other monoclonal antibodies targeting conditions like Alzheimer's disease, indicating its place within a broader landscape of neurological treatments.

What does the symbol '†' signify for drugs listed in the Navbox?

The symbol '†' next to a drug name in the Navbox indicates that the drug is currently undergoing Phase III clinical trials, representing a late stage of human testing before potential regulatory approval.

What does the symbol '‡' signify for drugs listed in the Navbox?

The symbol '‡' next to a drug name in the Navbox indicates that the drug has been withdrawn from the market, meaning it is no longer available for therapeutic use.

What does the symbol '§' signify for drugs listed in the Navbox?

The symbol '§' next to a drug name in the Navbox indicates that the drug never progressed beyond early development stages and did not reach Phase III clinical trials.

What is the general purpose of monoclonal antibody therapy?

Monoclonal antibody therapy involves using laboratory-produced antibodies that are designed to target specific molecules in the body, such as proteins on the surface of cancer cells or proteins involved in inflammatory or neurological diseases, to treat various conditions.

What is the potential connection between Bapineuzumab and glaucoma treatment?

Bapineuzumab was noted for possibly having therapeutic value in treating glaucoma, in addition to its primary investigation for Alzheimer's disease. This suggests its mechanism might be relevant to conditions involving optic nerve health or related pathologies.

Why has the effectiveness of drugs targeting brain plaques in Alzheimer's been questioned?

The efficacy of drugs aimed at clearing brain plaques has faced scrutiny, potentially due to the complex nature of Alzheimer's disease progression and the challenges in timing interventions effectively. However, it's suggested that such therapies might still be beneficial for prevention if given to individuals before symptoms appear.

What is the definition of 'aseptic meningitis' as seen in the AN-1792 trial?

Aseptic meningitis refers to meningitis, an inflammation of the membranes surrounding the brain and spinal cord, that is not caused by a bacterial infection. In the AN-1792 trial, it was a serious adverse event that contributed to the trial's termination.

What is the difference between active immunization (like AN-1792) and passive immunization (like Bapineuzumab)?

Active immunization, exemplified by the AN-1792 trial, involves stimulating the body's own immune system to produce antibodies. Passive immunization, as with Bapineuzumab, involves directly administering pre-made antibodies to provide immediate, but temporary, immune protection or therapeutic effect.

What does it mean for Bapineuzumab to be a 'whole antibody'?

Classifying Bapineuzumab as a 'whole antibody' signifies that it is a complete immunoglobulin molecule, comprising both heavy and light protein chains, rather than just a fragment of an antibody.

What is the significance of Bapineuzumab's chemical formula C6466H10018N1734O2026S44?

This formula details the exact number of atoms of each element (Carbon, Hydrogen, Nitrogen, Oxygen, Sulfur) present in one molecule of Bapineuzumab, highlighting its large size and complex composition as a protein.

What does the molar mass of 145,874.02 g/mol indicate about Bapineuzumab?

This molar mass value indicates that Bapineuzumab is a very large molecule, which is characteristic of proteins, specifically antibodies. It represents the mass of one mole of the substance.

What is the primary reason cited for the discontinuation of Bapineuzumab's development?

The primary reason for discontinuing Bapineuzumab's development was its failure to demonstrate significant cognitive improvements in patients during late-stage clinical trials, despite showing effects on biomarkers and presenting safety concerns like ARIA.

What is the relationship between Bapineuzumab and other anti-amyloid drugs like Aducanumab or Lecanemab?

Bapineuzumab is grouped with drugs like Aducanumab and Lecanemab under 'Anti-amyloid drugs' in the Navbox, indicating they share the common goal of targeting beta-amyloid pathology in neurological conditions, likely Alzheimer's disease.

What is the role of Sid Gilman in the context of Bapineuzumab and insider trading?

Neurologist Sid Gilman reportedly conveyed information about the cancellation of Bapineuzumab's testing to Mathew Martoma. This information was then used by Martoma for insider trading, leading to his conviction.

What is the potential therapeutic relevance of targeting the N-terminal region of the Aβ peptide?

Targeting the N-terminal region of the Aβ peptide, as Bapineuzumab does, is a strategy aimed at interfering with the formation, aggregation, or clearance of beta-amyloid, which is crucial in the context of Alzheimer's disease pathology.

What does the ATC code status indicate for Bapineuzumab?

The provided information states that Bapineuzumab has no assigned ATC (Anatomical Therapeutic Chemical) code, suggesting it has not been formally classified within this international drug classification system.

What is the significance of Bapineuzumab being listed under 'Circulatory' and 'Neurologic' systems in the Navbox?

While primarily known for its neurological target (beta-amyloid in Alzheimer's), Bapineuzumab's inclusion in sections related to circulatory and neurological systems in the Navbox might reflect broader research interests or potential off-target effects explored during its development, or simply its classification within a larger antibody grouping.

What does the term 'monoclonal antibody therapy' entail?

Monoclonal antibody therapy utilizes specific antibodies created in a lab that target particular cells or proteins. These antibodies can help the immune system fight diseases like cancer or autoimmune disorders, or in cases like Bapineuzumab, target pathological proteins in neurodegenerative diseases.

What is the potential implication of Bapineuzumab's failure to show cognitive improvement despite biomarker reduction?

The disconnect between biomarker reduction and lack of cognitive improvement suggests that either the biomarkers targeted are not the sole drivers of cognitive decline in Alzheimer's, or that the timing or mechanism of intervention with Bapineuzumab was insufficient to reverse established cognitive deficits.

What is the relationship between Bapineuzumab and the drug Ranibizumab mentioned in the Navbox?

Both Bapineuzumab and Ranibizumab are listed as humanized antibodies. Ranibizumab is specifically categorized under 'Angiogenesis inhibitor' and also under 'Circulatory' systems, while Bapineuzumab is under 'Neurologic' systems, indicating different therapeutic applications despite sharing the humanized antibody classification.

What does the term 'prophylaxis' mean in relation to Alzheimer's drug efficacy?

Prophylaxis refers to measures taken to prevent disease. In the context of Alzheimer's drugs targeting brain plaques, it suggests that these therapies might be more effective in preventing the onset or progression of the disease in individuals who are not yet symptomatic, rather than treating established cognitive impairment.

Bapineuzumab Wiki: Bapineuzumab: Charting the Course of Alzheimer's Therapeutic Research

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Overview

What is Bapineuzumab?

Bapineuzumab, nicknamed "bapi", is a humanized monoclonal antibody. It is designed to interact with the nervous system and was investigated for its potential therapeutic value in treating conditions such as Alzheimer's disease and possibly glaucoma.

Primary Target

The antibody specifically targets beta-amyloid (Aβ), a peptide that forms the characteristic plaques found in the brains of individuals with Alzheimer's disease. Bapineuzumab recognizes the extreme N-terminal residues of the Aβ peptide.

Clinical Outcomes

Despite its targeted approach, Bapineuzumab faced significant setbacks. In 2012, major trials indicated it failed to produce substantial cognitive improvements in patients. While it did lower key biomarkers like amyloid brain plaques and hyperphosphorylated tau protein in cerebrospinal fluid (CSF), this did not translate into clinical benefit.

Targeting Beta-Amyloid

The Beta-Amyloid Hypothesis

Bapineuzumab's development was based on the widely studied hypothesis that the accumulation of beta-amyloid (Aβ) plaques in the brain is a primary driver of Alzheimer's disease pathology. The antibody was designed to bind to these Aβ aggregates.

Molecular Recognition

Specifically, Bapineuzumab has demonstrated the ability to recognize the extreme N-terminal 5 residues of the Aβ peptide. It binds to this region when the peptide adopts a helical conformation, stabilized by internal hydrogen bonds involving the first three amino acids.

Prophylactic Potential?

While Bapineuzumab did not prove effective for treating established Alzheimer's disease, the concept of targeting Aβ has led to discussions about its potential efficacy for prophylaxis. This suggests that such therapies might be more effective if administered to individuals before significant clinical symptoms develop.

Mechanism of Action

Immunotherapy Approach

As a monoclonal antibody, Bapineuzumab functions as a form of immunotherapy. It is engineered to specifically bind to its target (Aβ) in the body, aiming to clear these pathological proteins or prevent their harmful effects.

Clearing Amyloid Plaques

The intended mechanism was for Bapineuzumab to bind to Aβ plaques, potentially marking them for clearance by the immune system or preventing further aggregation. Clinical data showed that the drug did indeed lower the levels of amyloid plaques and hyperphosphorylated tau protein in the cerebrospinal fluid (CSF) of treated patients.

Amyloid-Related Imaging Abnormalities (ARIA)

A significant concern that emerged during clinical trials was the occurrence of Amyloid-Related Imaging Abnormalities (ARIA). This condition, particularly ARIA-E (edema or swelling in the brain), was observed in patients receiving higher doses of Bapineuzumab. While lower doses showed no health risks, ARIA represented a serious potential side effect associated with Aβ-targeting therapies.

Clinical Trials & Development

Development Timeline

Bapineuzumab's development journey involved several major pharmaceutical players. It was initially co-developed by Élan and Wyeth. Later, a Johnson & Johnson affiliate acquired a significant portion of Élan's related assets. Following Pfizer's acquisition of Wyeth in 2009, Pfizer became a key partner in the program.

Phase II Trials: Initial trials showed encouraging results, leading to the progression into larger studies.
Phase III Trials: Initiated in December 2007, these large-scale trials aimed to confirm efficacy and safety.
2012: Two major Phase III trials concluded, reporting failure to demonstrate significant cognitive improvement over placebo.
2012: Pfizer and Johnson & Johnson announced the discontinuation of development for the intravenous formulation due to trial results.
2013: Johnson & Johnson discontinued Phase 2 testing of the subcutaneous formulation.

Regulatory & Safety Concerns

The emergence of ARIA-E, particularly at higher doses, posed a significant safety challenge. Patients receiving the highest doses were either removed from trials or switched to lower doses. This highlighted the complex risk-benefit profile of Aβ-targeting antibodies.

Questioning Efficacy

The failure of Bapineuzumab in late-stage trials contributed to a broader questioning of the efficacy of therapies solely focused on clearing existing amyloid plaques in patients with established Alzheimer's disease. It underscored the complexity of the disease and the need for alternative or complementary therapeutic strategies.

Risks and Challenges

Amyloid-Related Imaging Abnormalities (ARIA)

As mentioned, ARIA was a primary safety concern. ARIA-E (edema or swelling) and ARIA-H (microhemorrhages or hemosiderin deposits) are radiological findings associated with anti-amyloid therapies. These require careful monitoring during treatment.

Efficacy Debate

The central challenge was the lack of significant clinical efficacy despite biological activity. While Bapineuzumab reduced amyloid and tau biomarkers, it did not translate into meaningful improvements in cognition or daily function for patients with mild to moderate Alzheimer's disease. This raised questions about the timing and target of intervention.

Formulation Discontinuation

Both the intravenous and subcutaneous formulations faced discontinuation. The failure in late-stage trials led to the cessation of development for these versions, marking a significant setback for this specific therapeutic approach.

Historical Context

Origins and Partnerships

Bapineuzumab emerged from research into immunotherapy for Alzheimer's disease. Its development path involved collaborations and acquisitions, reflecting the high stakes and complex landscape of pharmaceutical research. Key entities included Élan, Wyeth, Johnson & Johnson, and Pfizer.

Legal Ramifications

The development and eventual discontinuation of Bapineuzumab were linked to a notable insider trading case. In February 2014, Mathew Martoma, formerly of S.A.C. Capital Advisors, was convicted based on non-public information about the cancellation of Bapineuzumab's testing, which he received from a neurologist involved in the trials.

Legal & Ethical Considerations

Insider Trading Case

The conviction of Mathew Martoma highlighted the critical importance of information control in pharmaceutical development. Martoma traded on advance knowledge of Bapineuzumab's trial failure, leading to significant financial gains before the news became public. This case underscored the ethical and legal responsibilities surrounding sensitive clinical trial data.

Information Sensitivity

The Bapineuzumab case serves as a stark reminder of how crucial and sensitive clinical trial outcomes are. The premature disclosure or misuse of such information can have severe legal consequences and impact market integrity.

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References

Phase 2 testing of the subcutaneous formulation of bapineuzumab is to be discontinued. Elan Corporation. Retrieved 2013-08-13.

A full list of references for this article are available at the Bapineuzumab Wikipedia page

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Bapineuzumab

💡 Dive in with Flashcard Learning! 💡

Overview ℹ️

🧪 What is Bapineuzumab?

🎯 Primary Target

📉 Clinical Outcomes

Targeting Beta-Amyloid 🎯

🔗 The Beta-Amyloid Hypothesis

🔬 Molecular Recognition

💡 Prophylactic Potential?

Mechanism of Action ⚙️

🛡️ Immunotherapy Approach

🧹 Clearing Amyloid Plaques

⚠️ Amyloid-Related Imaging Abnormalities (ARIA)

Clinical Trials & Development 🔬

📅 Development Timeline

⚖️ Regulatory & Safety Concerns

❓ Questioning Efficacy

Risks and Challenges ⚠️

🧠 Amyloid-Related Imaging Abnormalities (ARIA)

🤔 Efficacy Debate

🔄 Formulation Discontinuation

Historical Context ⏳

📜 Origins and Partnerships

⚖️ Legal Ramifications

Legal & Ethical Considerations ⚖️

📰 Insider Trading Case

🔒 Information Sensitivity

Teacher's Corner 🧑‍🏫

Edit and Print this course in the Wiki2Web Teacher Studio

True or False? 🤔

❓ Test Your Knowledge! ❓

Gamer's Corner 🎮

Are you ready for the Wiki2Web Clarity Challenge?

Explore More Topics

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References

📜 References

Feedback & Support 👍

To report an issue with this page, or to find out ways to support the mission, please click here.

Disclaimer ⚠️

📜 Important Notice

Dive in with Flashcard Learning!

Overview

What is Bapineuzumab?

Primary Target

Clinical Outcomes

Targeting Beta-Amyloid

The Beta-Amyloid Hypothesis

Molecular Recognition

Prophylactic Potential?

Mechanism of Action

Immunotherapy Approach

Clearing Amyloid Plaques

Amyloid-Related Imaging Abnormalities (ARIA)

Clinical Trials & Development

Development Timeline

Regulatory & Safety Concerns

Questioning Efficacy

Risks and Challenges

Amyloid-Related Imaging Abnormalities (ARIA)

Efficacy Debate

Formulation Discontinuation

Historical Context

Origins and Partnerships

Legal Ramifications

Legal & Ethical Considerations

Insider Trading Case

Information Sensitivity

Teacher's Corner

True or False?

Test Your Knowledge!

Gamer's Corner

Discover other topics to study!

References

Feedback & Support

Disclaimer

Important Notice