Mechanisms of Drug Actions

Projects

There are examples of student work below the instructions.

Case Study Project

Along the lines of the case studies developed in the second half of the course, each student will prepare a case study as a 5-page paper to be submitted at the end of the term. The case study should address the concepts, challenges and strategies discussed in class for understanding and dealing with problems in drug development, but you choose the problem to discuss. This is not a book report! There is an element of background research on the drug or toxicity, which you must discuss in the paper, but the bulk of the work should be a critical analysis, a commentary, or a new approach to solving or dealing with a problem in drug development or a problem with an existing drug.

Project Steps

1. Choose the Topic of Your Case Study
2. Develop your Proejct
3. Meet with Instructors to Discuss Your Project as the Term Progresses
4. Write a Paper that Summarizes you Analysis
5. Submit the Paper

Step 1: Choose the Topic for Your Case Study

Choose a topic based on your own interests and experiences, or from those described below. Submit a topic choice and a brief statement ofthe issue or problem that you will address. Due date for topic choices: Recitation 5.

Examples of project topics and broad themes / issues to address:

M-Enoxaparin – Topic: generic versions of biological products and an interesting story

• Low molecular weight heparin developed by Momenta® and approved by the FDA in 2010 as a “bioequivalent” (generic) to Lovenox® (enoxaprin sodium), the best-selling anticoagulant marketed by Sanofi
• Enoxaprin sodium consists of a complex mixture of sulfated polysaccharides (“heparin”) derived from pig intestinal mucosa; virtually all heparin is obtained from Chinese suppliers
• Momenta® developed a method to define the sequences of complex carbohydrates and is creating generic equivalents to currently marketed products
• Recent contamination of Chinese supplies of heparin caused hundreds of deaths worldwide

Zetia® (ezetimibe) – Topic: do we really know the mechanism of action of many drugs?

• Different mechanism of cholesterol reduction than statins
• Studies suggest a lack of protective effect in cardiovascular disease as observed with statins
• Recent studies also suggest an increased risk of some cancers. Is this related to the mechanism of action of the drug (on–target versus off–target toxicity)?

Vioxx® – Topic: rare toxicities and the need for so many NSAIDS

• NSAIDS and cardiotoxicity
• Consider the problem of rare events emerging after clinical trials (statistics of small numbers: thousands of patients in clinical trials versus millions taking the drug)
• Why do we need Vioxx in the face of all of other NSAIDS available?

Valproic acid, felbamate, pregabalin – Topic: risk vs benefit in the use of toxic drugs for chronic therapy

• Antiepileptic / psychotropic agents with liver toxicity, aplastic anemia
• Is it right to balance clinical utility with a clear risk for toxicity for intractable diseases?
• Valproic acid and pregabalin are also now being used to manage chronic pain (fibromyalgia, diabetic neuropathy). With pregabalin, is this an extension of the market to accommodate loss of patent in 2018?

TGN1412 antibody – Topic: risks of biologically-based therapeutics.

• This CD28 superagonist antibody produced by TeGenero was proposed to stimulate T cells for the treatment of autoimmune disease and cancer
• Pre-clinical studies were based on incorrect inter-species genomic data, which led to a “miscalculation” of the dose for humans; six healthy volunteers died in Phase I studies
• This disaster also pointed to the lack of regulatory oversight in the uncharted territory of biological therapeutics

Tamoxifen vs raloxifene – Topic: safety of breast cancer prevention with prophylactic therapy

• Breast cancer therapy and prophylaxis
• Consider the problem of chronic prophylactic treatment with toxic agents to prevent disease
• Which agent is best?

Vancomycin and other antibiotics – Topic: antibiotic resistant bacteria and the lack of new antibiotics

• Vancomycin was once considered to be the last line defense in many infectious diseases
• Consider the problem of microbial resistance to antibiotics, occurring on a global scale
• Why isn’t the drug industry more active in developing new antibiotics?
• How would you go about addressing the resistance problem?

Avastin® – Topic: very expensive drugs with limited utility and limited efficacy

• Genentech brand of Bevacizumab, a humanized monoclonal antibody that blocks VEGF mediated angiogenesis in tumors
• Approved for metastatic colon cancer and a few others
• Controversial FDA approval for metastatic breast cancer later revoked since tumors shrank but survival was not affected
• Extends life by ~4 months and costs $100,000 per year

Ropinirole vs. Pramipexole – Topic: Drug companies seek new disease targets for old drugs

• Drugs used to treat “restless leg syndrome”: a complex, rare and controversial syndrome
• GlaxoSmithKline brand of ropinirole first approved for Parkinson’s disease
• GSK later fined for off-brand marketing of ropinirole, though drug later approved
• The “Restless Leg Foundation” receives most of its money from drug companies

PCSK9 antibodies – Topic: safety and efficacy of biological drugs in the chronic treatment of lipid disorders

• Several companies (Amgen®, Pfizer®, Sanofi®) are scrambling to develop antibodies against this enzyme, based on extremely significant drops in cholesterol caused by PCSK9 inhibition
• How well will an antibody-based therapy work for chronic treatment?
• At what level does cholesterol reduction become toxic? Who sets the standard for the target level of cholesterol in the treatment of lipid disorders and cardiovascular disease?
• How useful will this drug be for anything other than the genetically determined heterozygous FH disease or for rare statin-intolerant high cholesterol?

EPZ-5676 histone methyltransferase inhibitor – Topic: drugs for small populations, personalized medicine

• EPZ-5676 is a small molecule inhibitor of the DOT1L histone methyltransferases enzyme and is being evaluated for use in a subset of patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL)
• Some patients with AML and ALL a rearranged (translocated) MLL gene, which causes redistribution of DOT1L
• How specific is EPZ-5676 for DOT1L–there are many histone methyltransferases? How large a fraction of the AML and ALL population have the rearrangement? Is this an “orphan disease ?”

Step 2: Develop Your Project

The case study topic should be thoroughly researched in terms of the fundamental drug issues raisedin class: ADME, toxicity, mechanism, whatever is relevant to your case study. You should use this “book report” information as a platform for addressing a larger question about drug development.

The overall approach to the project is as follows:

1. Thoroughly review the literature concerning the drug, drug class, mechanism(s) of action ortoxicity, metabolism, pharmacokinetics of the drug, other ADME issues. Comment on an important problem with the topic, such as the implications of the topic for the clinical utility of a specific drug or drug class or for drug development in general. This is a very important part of your project. You need to use the facts you learn to help you articulate a thoughtful discussion of a larger problem or implication. The goal here is a high-level, thoughtful analysis of a topic, not a book report.

Some seed ideas to help you get going:

• Clearly state the problem that you wish to address and state it early:
  • Balancing toxicity with clinical utility (e.g., when is a drug too toxic for use in humans under any circumstances?)
  • Approval of drugs that are not efficacious?
  • Very rare toxicities: how to avoid them or predict them?
  • Development of resistance to drugs?
  • Some other burning issue?
• Discuss the disease target somewhere in your paper and presentation
  • Which disease is being treated?
  • What is the pathophysiology of the disease?
• Discuss the mechanism of action of the drug
  • Is the proposed mechanism proven for the disease or presumed / supposed?
  • Similarities and differences between mechanisms of action and toxicity?
• Discuss the ADME issues–relationship of ADME to mechanism or toxicity
• Discuss the mechanism(s) of toxicity–similar to mechanism of action
• The major part of the project: think!
  • Draw some conclusion or state an opinion about the drug and the problem
  • Is the perception of the general public or the perceived risk justified?
  • Can you propose a solution to the problem?
  • Can you design experiments that are needed to establish the facts?
  • Are there better drugs or drug class choices for the disease?
  • Why do we continue to use a particular drug?
  • Was the withdrawal (if appropriate) justified?
  • Give us your opinions, conclusions, proposals

Step 3: Meet with Instructors to Discuss Your Project as the Term Progresses

We will use the recitation periods to meet with student teams to discuss progress and problems with your project.

Step 4: Write a Paper that Summarizes Your Analysis

The results of your research and analysis should be presented as a 5-page paper (maximum, single-spaced, 12 point font), exclusive of title page, references and graphics. This should include relevant structures of drugs and drug metabolites and any other graphical data deemed critical to the case.

The paper should contain the following sections:

1. Face page: title, author and 150 word abstract; does not count toward 5-page maximum.
2. Introduction: state the problem or topic and provide background information. 1 page.
3. Pharmacokinetics and pharmacodynamics review. 1–2 pages.
4. Discussion: develop your analysis, ideas, thoughts or solutions. 2–3 pages.
5. Bibliography: any length; does not count toward 5-page maximum.

Step 5: Submit the Paper

The paper is due on the last day of class.

Examples of Student Work

• George’s Marvelous Medicine: Perspectives on the Heparin Contamination Crisis (PDF) (Courtesy of Ebaa F. Al-Obeidi. Used with permission.)
• Rituximab: Prospects for Treatment of Multiple Sclerosis (PDF) (Courtesy of an MIT Student. Used with permission.)
• Gut Reactions: The Importance of Gut Microbial Effects on Drug Metabolism and Disposition (PDF) (Courtesy of Alice Tzeng. Used with permission.)