Overview of #409 – Inside modern drug development: the science, economics, and regulatory hurdles behind bringing new medicines to patients
Peter Attia interviews physician-scientist and drug developer Dr. Lloyd Klickstein about how modern medicines are actually discovered, developed, tested, approved, and commercialized. Using bimagrumab as the central case study, they walk through the full drug-development pipeline—from unmet medical need and target selection, to preclinical work, IND filing, phase 1–3 trials, manufacturing, patents, and market strategy. The conversation also explores obesity, sarcopenia, muscle-preserving therapies, selective mTOR inhibition, and a newer frontier in cancer prevention.
Key Takeaways
- Drug development starts with patients and unmet need, not with molecules.
- The industry distinguishes between:
- Incremental drugs: better dosing, better delivery, or improved versions of existing therapies.
- Transformational drugs: new mechanisms, new indications, or entirely new therapeutic categories.
- Most drug programs fail, and the biggest goal is often to fail early rather than late.
- Biologics and antibodies are often favored when the target requires very high affinity and specificity.
- Patent protection, exclusivity, and manufacturing quality are as important as biology.
- In obesity and muscle-loss disease, weight loss alone is not enough; preserving lean mass is increasingly important.
- The future of obesity treatment may be combination therapy: potent weight loss plus muscle-preserving agents.
- A second major theme is the possibility of preventive medicine, including pharmacologic cancer prevention.
How New Drugs Are Actually Discovered
Starting Point: Unmet Clinical Need
Klickstein explains that good drug development begins by asking:
- What disease burden is not being adequately treated?
- What therapy is missing?
- Is the goal an incremental improvement or a true breakthrough?
He describes a Novartis effort to catalog roughly 7,000 unmet clinical indications and then organize them into broad strategic buckets. That process helped identify new areas like:
- healthy aging
- renal disease
- fibrotic disease
- ENT conditions
- muscle loss/frailty
Choosing the Drug Modality
They review the major drug classes:
- Small molecules: classic chemical drugs
- Biologics: antibodies, proteins, peptides, soluble receptors
- Gene therapies
- Devices: from syringes and auto-injectors to apps and implants
The choice depends on the disease biology, target accessibility, delivery needs, and commercial practicality.
Drug Development Economics, Patents, and IP
Why Drugs Cost So Much
Klickstein compares drug development to building a skyscraper:
- thousands of people involved
- many years of work
- very high capital cost
- high probability of failure
A successful program may take:
- 10–15 years of effective exclusivity after launch
- huge upfront spending before revenue arrives
Patent Strategy
They discuss how companies protect assets through:
- composition-of-matter patents
- formulation patents
- process/manufacturing patents
- dosing and route-of-administration patents
- method-of-use patents
- device patents
He notes that companies sometimes try to “stack” patents to extend exclusivity, though this can be controversial.
Trade Secrets
Although less common in modern pharma, trade secrets can still matter. Examples discussed include:
- Armour Thyroid
- Acthar Gel
The main lesson: intellectual property in pharma is often a mix of science, law, and strategy.
The Bimagrumab Story: From Target Biology to Human Trials
Why This Target?
Bimagrumab was developed for muscle loss and later repurposed in obesity-related settings. The biology centers on:
- myostatin
- activins
- activin receptors
These pathways act as brakes on muscle growth. Blocking them can promote muscle hypertrophy.
Why an Antibody?
The affinity between the ligands and receptors is extremely high, so a high-affinity antibody makes more sense than a small molecule. The team used a screening platform to identify antibodies that could:
- bind strongly enough
- block both myostatin and activin signaling
- work across relevant assay systems
Preclinical Validation
In animals, bimagrumab produced dramatic results:
- increased muscle mass
- improved strength
- better running performance in rodents
- visible muscle enlargement
They also studied:
- pharmacology
- toxicology
- distribution
- manufacturing feasibility
Human Safety Signals
In early human studies, on-target side effects included:
- muscle cramps/spasms
- acne in younger populations
- diarrhea
A notable preclinical concern was cardiac hypertrophy in rats, but this appeared proportional to the animals’ overall size increase and did not emerge as a clear prohibitive toxicity.
Obesity, Sarcopenia, and Why Muscle Matters
Why This Indication Matters
Attia and Klickstein spend time on sarcopenia and frailty because they are clinically meaningful and common in older adults.
Klickstein argues that frailty and muscle loss deserve much more attention because:
- they worsen function
- they increase falls and disability
- they may carry mortality risk comparable to or worse than some cancers
Falls Are Hard to Measure
A memorable section of the conversation covers attempts to objectively measure falls using:
- accelerometers
- wearable devices
- observational studies in frail older adults
Those efforts largely failed, illustrating one of the central problems in drug development: you can’t develop well if you can’t reliably measure the endpoint.
The Role of Nutrition and Combination Therapy
Nutrition Matters
A key insight from the bimagrumab program was that protein intake influenced the size of the effect:
- more protein led to better muscle gain
- low protein intake could still lead to muscle loss even with treatment, though bimagrumab could blunt it
This suggests that drug therapy may work best when paired with nutrition.
Obesity + Muscle Preservation
The program ultimately evolved from sarcopenia into sarcopenic obesity and then into broader obesity treatment, especially once GLP-1 therapies changed the field.
In combination with agents like:
- semaglutide
- tirzepatide
bimagrumab showed:
- strong weight loss
- substantial fat loss
- preservation of lean mass
- impressive total body weight reduction in the high-dose combination arm
A key finding from the BELIEVE study:
- roughly 22–23% body-weight loss at the high-dose combination
- about 45% fat loss
- evidence that muscle-preserving therapy could complement incretin-based weight loss
Regulatory and Clinical Trial Lessons
INDs and Phase 1
They explain the IND process:
- permission from regulators to give a new drug to humans
- requires preclinical pharmacology, toxicology, and manufacturing data
- requires GMP manufacturing standards
Why GMP Matters
Good Manufacturing Practice ensures:
- correct identity
- purity
- sterility/contamination control
- reproducibility
- batch-to-batch consistency
Attia and Klickstein use this to contrast legitimate drug development with poorly regulated gray-market peptide products.
Trial Design and Patient Selection
A major theme is the tension between:
- testing in healthy volunteers for clean data
- testing in patients when risks are higher or benefits are needed to justify exposure
They also discuss:
- sentinel dosing
- cohort escalation
- exposure margins in animals vs humans
- choosing trial sites based on recruitment, cost, investigators, and regulatory climate
What Happened with Bimagrumab Commercially
Novartis and Versanis
Novartis ran multiple studies but eventually moved the asset forward differently as the field changed. The drug was later licensed and developed further through Versanis Bio.
The Obesity Landscape Changed
The arrival of highly effective GLP-1 drugs transformed the commercial and clinical context. The strategy shifted from:
- standalone sarcopenia/obesity development to
- combination therapy with incretins
Lilly Acquisition
The asset was eventually acquired by Eli Lilly, which is continuing related development work. Klickstein notes that the larger field has now become interested in similar muscle-preserving pathways.
Another Major Theme: Preventive Medicine and Cancer Prevention
Drug Discovery for Prevention
Klickstein’s newer focus is cancer prevention, based on the idea that some drugs work by suppressing pathways that normally protect against cancer.
Example: Serafinib and Skin Cancer
He notes that some kinase inhibitors used in cancer treatment can paradoxically increase skin cancer risk, implying that the inhibited pathway may be cancer-protective.
His current hypothesis:
- carefully stimulate that protective pathway
- potentially reduce cancer risk, especially skin cancer
Why Skin Cancer First?
Skin cancer is common enough that it can be tested in a feasible prevention trial, especially in people at very high risk.
He also mentions a parallel strategy:
- test compounds in cancer cell line panels
- identify sensitive tumors
- melanoma appears especially sensitive in early screens
mTOR, Longevity, and Selective Inhibition
The discussion ends with selective mTORC1 inhibition and its possible role in longevity and healthspan.
Main Points
- Biology is highly conserved from yeast to mammals
- mTOR inhibition likely has benefits, but the effect in humans is still uncertain
- The major challenge is selectivity
- Sustained rapalog exposure can affect mTORC2, complicating the picture
- Better TORC1-selective agents may be needed before the biology can be tested cleanly in humans
Klickstein also notes concern that findings from fasting and mTOR biology in rodents may not translate directly to older humans.
Final Takeaways
- Drug development is a long, expensive, and highly iterative process
- The best programs combine:
- strong biology
- good endpoint selection
- manufacturability
- regulatory strategy
- commercialization realism
- Bimagrumab is a useful case study in how a drug can evolve across indications as the field changes
- The future may belong to:
- combination obesity therapy
- muscle-preserving interventions
- true preventive medicine
- and perhaps, eventually, pharmacologic cancer prevention