#409 ‒ Inside modern drug development: the science, economics, and regulatory hurdles behind bringing new medicines to patients | Lloyd Klickstein, M.D., Ph.D.
The episode features Dr. Lloyd B. Klickstein, a physician-scientist and drug developer, who demystifies the complex process of modern drug development. Using bimagrumab as a case study, he explains how new medicines are discovered, engineered, tested, and brought to patients, highlighting the scientific, regulatory, and economic challenges involved.
Deep Dive Analysis
14 Topic Outline
Lloyd Klickstein's Path to Drug Development
The Drug Discovery Process: Identifying Unmet Needs
Classes of Molecules: Small Molecules vs. Biologics
Patent Law and Drug Exclusivity
Challenges in Measuring Clinical Endpoints: Falls
Myostatin and Activin Signaling in Muscle Growth
Engineering and Screening Therapeutic Antibodies
Pre-Clinical Development: Toxicology and Pharmacokinetics
Clinical Trials Phase 1: First-in-Human Studies
Clinical Trials Phase 2: Bimagrumab for Sarcopenia and Obesity
Bimagrumab's Effects on Fat Mass and Type 2 Diabetes
The BELIEVE Study: Bimagrumab with Semaglutide
Selective mTOR Inhibition and Geroprotection
A Novel Pharmacologic Approach to Cancer Prevention
18 Key Concepts
Small Molecules
Chemicals used as drugs, historically derived from dye companies, which can sometimes have off-target effects due to their less specific binding properties.
Biologics
Drugs that are not chemicals, encompassing antibodies, peptides, soluble receptors, and gene therapies, generally characterized by high specificity in their action.
Gene Therapies
A specialized category of biologicals involving the delivery of genetic material, which can be complex depending on the chosen delivery vectors and targeting strategies.
Trade Secret
A form of intellectual property where a formula or process is kept confidential indefinitely, without patent protection, making it challenging for competitors to replicate.
Composition of Matter Patent
A patent granted for the unique chemical structure of a new drug, providing a monopoly for a limited duration, typically 20 years from the filing date.
Sarcopenia
A medical condition characterized by a reduction in muscle mass accompanied by impaired muscle function, frequently observed in frail elderly individuals.
Myostatin
An endogenous protein that inhibits muscle growth; blocking its action can lead to increased muscle size, particularly evident in rodent models.
Activin A
A protein that, alongside myostatin, contributes to the inhibition of muscle growth in humans; blocking its receptor can result in an increase in muscle mass.
TGF-beta Superfamily
A large family of receptors that primarily signal through SMADS, regulating a wide array of gene programs, including those involved in muscle size control.
FC Fusion Protein
A biotechnology technique that attaches a protein to the FC region of an antibody, thereby extending its half-life in the bloodstream and facilitating its purification.
Phage Display Technology
A recombinant DNA method employed to generate and screen thousands of candidate antibodies in vitro, offering a more efficient alternative to traditional immunization techniques.
Pharmacodynamics (PD)
Refers to the effects that a drug exerts on the body, which are meticulously measured in clinical studies to evaluate its efficacy and mechanism of action.
Pharmacokinetics (PK)
The study of how a drug moves through the body, encompassing its absorption, distribution, metabolism, and elimination over time.
Good Manufacturing Process (GMP)
A stringent set of high-quality standards and comprehensive documentation required for drug manufacturing, ensuring the purity, activity, and sterility of the product.
Idiosyncratic Liver Toxicity
Unpredictable liver damage caused by a drug, a frequent reason for drug withdrawal from the market, often difficult to foresee during preclinical testing.
Cytokine Release Syndrome
A severe, acute inflammatory reaction resulting from an overactive immune response, which can sometimes be triggered by certain therapeutic antibodies.
Ethnic Sensitivity Studies
Phase 1 studies conducted in specific ethnic populations (e.g., Japanese) to assess drug dosing, exposure, safety, and tolerability, accounting for potential genetic or physiological differences.
mTORC1
A master regulatory complex that integrates nutritional inputs and dictates whether cells should grow or activate recycling pathways like autophagy, crucial for cellular metabolism.
12 Questions Answered
New drugs are discovered by identifying unmet medical needs in patients, looking for conditions without existing therapies, and then exploring incremental improvements or quantum leaps in treatment.
Drugs are broadly categorized into small molecules (chemicals), biologics (proteins, antibodies, gene therapies), and devices, each with different manufacturing and regulatory considerations.
A patent grants a 20-year monopoly from filing in exchange for public disclosure of how to make the drug, with practical exclusivity often lasting 10-15 years from launch.
Drug development is costly and often fails due to the long timelines, extensive testing, high number of risks at each stage, and the need to minimize all but identified and accepted risks.
Failing early in drug development is crucial to avoid the immense financial and time costs associated with late-stage failures, especially in Phase 3 or after commercialization.
Myostatin is an inhibitor of muscle growth; blocking it, or its receptors (like with activin A), allows muscles to grow larger by suppressing proteins involved in muscle degradation.
GMP (Good Manufacturing Process) ensures high-quality standards and extensive documentation in drug manufacturing, guaranteeing that the product is pure, active, sterile, and matches its label.
The risk of a serious adverse event for healthy volunteers in a drug study should ideally be no greater than the risk of being struck by lightning in a year (approximately one in 100,000).
Some countries, like Japan and China, require ethnic sensitivity studies to ensure drug dosing and exposure are safe and tolerable in their specific populations, due to potential genetic or physiological differences.
Yes, studies with bimagrumab showed that higher protein intake within tested boundaries led to more muscle built, suggesting nutrition can augment drug effects on muscle hypertrophy.
mTOR inhibition is believed to be geroprotective in humans due to highly conserved biology across species, though the effect size is expected to be modest and selective mTORC1 inhibition is a key challenge.
A novel approach involves identifying drugs that cause cancer (by inhibiting cancer-protective pathways) and then developing agents that gently activate those protective pathways to prevent cancer.
11 Actionable Insights
1. Prioritize Unmet Medical Needs
Focus drug discovery on conditions without existing therapies or where significant improvements are needed, rather than incremental changes to existing drugs. This approach yields the greatest value for society and patients.
2. Minimize Drug Development Risks
Identify and minimize risks at every step of drug development, as risks multiply across the program. Accept only identified and accepted risks, and aim to “fail fast” if a project is not viable.
3. Optimize Protein Intake for Muscle Growth
Ensure adequate protein intake when using muscle anabolic agents, as studies show that higher protein consumption (e.g., more than recommended daily amount) augments muscle building effects, potentially overcoming substrate limitations.
4. Consider Combination Therapy for Obesity
Explore combination therapies for obesity management, as this approach can offer superior fat loss while preserving lean mass, potentially achieving bariatric surgery-like results.
5. Utilize Preventive Medicine for Health
Shift focus from “sick care” to “healthcare” by prioritizing preventive medicine. This involves developing drugs and strategies to prevent common causes of morbidity and mortality, leading to healthier longevity.
6. Assess Drug Safety with Lightning Standard
When testing new medicines in healthy volunteers, ensure the risk of a serious adverse event is extremely low, using a probabilistic formula (e.g., risk no greater than 1 in 100,000 annual lightning strike) to justify exposing healthy individuals.
7. Avoid Unregulated Gray Market Peptides
Do not purchase peptides from unregulated manufacturers, as these products lack quality control (GMP), may not contain what’s on the label, and often lack reproducible scientific data, posing significant risks.
8. Target Cancer Prevention by Activating Pathways
Develop drugs that gently activate cancer-protective pathways. This novel approach aims to prevent cancers by counteracting mechanisms that, when inhibited, can lead to tumor growth.
9. Standardize Clinical Trial Measurements
Ensure clinical endpoints are objectively measurable and standardized. Reliable assessment tools are critical for robust drug development, as measurement challenges can halt promising programs.
10. Factor in Regulatory and Market Endpoints
Design clinical trials by balancing scientific ideals with regulatory requirements and investor expectations. This ensures eventual approval and commercial viability, aligning biological goals with practical outcomes.
11. Leverage Global Clinical Trial Locations
Strategically choose clinical trial locations worldwide to optimize recruitment, access to experienced investigators, supportive regulatory environments, and cost-effectiveness.
9 Key Quotes
I personally, and this may be different for different people, but I personally start with the patients and the clinical indications. And essentially, you're looking for what's not there.
Lloyd Klickstein
A patent is essentially a monopoly on being able to make use and sell the drug in exchange for telling everybody how to do it.
Lloyd Klickstein
The worst outcome in drug development is failing in phase three. Actually, that's probably not true. The worst outcome is succeeding in phase three and failing commercially, but failing early, super important.
Lloyd Klickstein
The fundamental tenet of science is if it's real, it's reproducible. This has not been reproduced.
Lloyd Klickstein
Every really successful program has been almost killed or killed several times before it eventually makes it out into humans and then eventually commercialization.
Lloyd Klickstein
The three biggest challenges of any clinical study are recruitment, recruitment and recruitment.
Lloyd Klickstein
Good biology abuts regulatory simplicity for Lutton.
Peter Attia
I believe that the paradigm for managing obesity is going to be induction and maintenance of remission, probably combination and injectable therapies to get people to their, you know, to move them categorically from obese to non-obese. And then they need something for maintenance, which might be something like orforglopron or some oral GLP-1 agonist to maintain appetite and satiety.
Lloyd Klickstein
We need to get away from being a sick care system to a healthcare system. And the way you do that is with preventive medicine.
Lloyd Klickstein
1 Protocols
Drug Development Checkpoints (Large Companies)
Lloyd Klickstein- Assemble all accumulated data.
- Create comprehensive slide decks for presentation.
- Present findings to major decision-making committees.
- Obtain feedback from stakeholders and experts.
- Adjust program courses and strategies based on feedback.
- Continuously reevaluate and reassess the program's progress and risks.