Key Moments
409 ‒ Inside modern drug development: the science, economics, and regulatory hurdles
Peter Attia MDKey Moments
Drug development is a complex, high-stakes gamble, with a single successful drug costing billions and taking over a decade to develop, facing immense regulatory and economic hurdles.
Key Insights
The drug development process typically takes 10-15 years and can cost $2-4 billion per approved drug, a significant investment with a high failure rate.
The "rule of thumb" for risk in healthy volunteer studies is that the risk of an adverse event should not exceed one in 100,000, approximately the risk of being struck by lightning.
Bagramab, initially developed to treat sarcopenia, showed a modest 4-8% increase in muscle mass in humans but also a significant 45.7% reduction in body fat in combination with semaglutide, akin to bariatric surgery.
While bagramab increased muscle size, it did not significantly improve muscle strength or function in humans, a key differentiator from its effects in rodents.
The development of Bagramab highlighted the critical role of nutrition and lifestyle factors in potentiating drug efficacy, an area often overlooked by big pharma.
A novel cancer prevention drug concept targets a ribotoxic stress pathway, aiming to gently turn it on to prevent cancer, starting with skin cancers where incidence is high.
Identifying unmet medical needs and the incremental vs. novel drug approach
Drug development begins with identifying unmet medical needs, focusing on either incremental improvements to existing therapies (e.g., oral vs. injectable, less frequent dosing) or pursuing novel, "quantum step" therapies for conditions that are poorly understood or lack any effective treatment. While incremental improvements are lower risk and commercially attractive, novel therapies, though more challenging and failure-prone, offer the greatest societal value. Lloyd B. Klickstein, a physician-scientist with extensive experience, emphasizes starting with patients and clinical indications to find what's "not there," distinguishing between making existing drugs better and creating entirely new therapeutic avenues. This process can involve establishing new regulatory pathways and creating awareness for previously unrecognized conditions.
The science and economics of drug intellectual property and protection
The drug development process is underpinned by intellectual property (IP) law, primarily patents, which grant a temporary monopoly in exchange for disclosing the invention. A patent term is typically 20 years from filing, but practical market exclusivity often ranges from 10 to 15 years due to the time taken for development and regulatory approval. This limited period must recoup the substantial investment, estimated at $2-4 billion per approved drug, and generate profit. Companies employ various strategies, such as patenting the composition of matter, manufacturing processes, formulations, and even methods of use, to extend protection. In some cases, trade secrets are used, as with early thyroid hormone preparations, but this is less common for complex modern drugs. The patent landscape significantly influences drug pricing and accessibility.
From target identification to molecular classes: Small molecules vs. biologics
The initial stages of drug discovery involve identifying a therapeutic target and selecting a molecule class. Small molecules are essentially chemicals, historically derived from dye chemistry, and include a vast array of compounds. Biologicals, a broader category, encompass antibodies, proteins, peptides, and gene therapies. Devices, regulated separately, include anything from apps to implants. The choice between small molecules and biologics depends on the target, the disease, and sometimes company infrastructure. For instance, complex targets requiring high affinity binding, like that of myostatin and activins to their receptors, often necessitate biologics like therapeutic antibodies, as achieving such specificity with small molecules can be exceptionally challenging. This decision impacts development timelines, manufacturing processes, and regulatory pathways.
The journey of Bagramab: From mouse models to human trials
The development of Bagramab, an antibody targeting myostatin and activins, illustrates the drug development pipeline. Initial research in rodents showed significant muscle hypertrophy by inhibiting myostatin, leading to the hypothesis that blocking myostatin and activin receptors could be a strategy for muscle wasting conditions like sarcopenia. Early in vitro work involved complex assays to screen thousands of potential antibody candidates for high affinity binding to the target receptors. Preclinical studies in rodents and primates demonstrated muscle hypertrophy, though the effects were less pronounced in primates than in rodents. Importantly, Bagramab showed promise in sarcopenic patients, leading to broader development.
Navigating clinical trials: Phases, patient selection, and regulatory hurdles
Drug development progresses through distinct clinical trial phases. Phase 1 studies, typically in healthy volunteers, assess safety, tolerability, and pharmacokinetics. A key principle is minimizing risk, aiming for adverse event rates below one in 100,000. For Bagramab, phase 1 involved older healthy volunteers to assess safety and potential effects on muscle mass and strength. Phase 2 studies then evaluate efficacy in the target patient population, often involving dose-ranging to find optimal therapeutic levels. For Bagramab, phase 2 studies explored its effects in sarcopenic obesity and type 2 diabetes, revealing muscle mass increases, fat mass reduction, and improvements in HbA1c. Filing an Investigational New Drug (IND) application with the FDA is crucial for initiating human trials, requiring extensive preclinical data and demonstration of Good Manufacturing Practices (GMP).
Bagramab's complex trajectory: Efficacy, commercialization, and future potential
While Bagramab reliably increased muscle size by 4-8% in human trials, its effect on muscle strength was modest, and it showed a significant 45.7% reduction in body fat when combined with semaglutide, a result comparable to bariatric surgery. This potent fat loss, coupled with improvements in HbA1c in diabetics, spurred interest in obesity and metabolic disease. Despite these findings, Novartis outlicensed the asset, and subsequent development by Versanis (later acquired by Eli Lilly) focused on the combination therapy. The "Believe" study demonstrated impressive weight and fat loss, but also an unexpected increase in LDL cholesterol. The drug's future development, particularly in combination therapies with GLP-1 agonists, remains active, exploring its potential beyond sarcopenia.
Exploring new frontiers: mTOR inhibition and cancer prevention
Beyond muscle and metabolic health, the conversation touches on mTOR inhibition for longevity and a novel approach to cancer prevention. While mTOR inhibition has shown promise in extending lifespan in model organisms, its effect in humans is still under investigation, with potential modest effects and challenges related to selectivity and side effects. A more concrete area of development is a drug designed for cancer prevention. This concept stems from observing that certain drugs used to treat cancer, like sorafenib, paradoxically increase cancer risk in some patients by inhibiting protective pathways. The proposed preventive drug aims to "gently" activate a ribotoxic stress pathway, which is constitutively active and offers cancer protection when its signaling is too weak. Initial focus is on skin cancers, where incidence is high and prevention is testable, with potential broader applications across various cancer types.
Mentioned in This Episode
●Software & Apps
●Companies
●Organizations
●Books
●Drugs & Medications
●Studies Cited
●Concepts
●People Referenced
Common Questions
Drug development often begins by identifying unmet clinical needs and patient populations. Companies look for drugs that don't exist but are needed, prioritizing areas where they can make a significant impact on health outcomes. This can include incremental improvements to existing treatments or quantum steps for entirely new indications.
Topics
Mentioned in this video
Where the speaker worked in a laboratory between college and medical school, sparking his interest in science.
Notified by drug companies about potential abuse of new drugs like Bimagrumab to develop screening assays.
Collaborated with the speaker's new company to screen tool compounds against cancer cell lines.
Where Brian Seed developed the FC fusion protein technology.
Mentioned as the likely origin of the term 'translational medicine'.
International Classification of Diseases, 10th edition, codes for medical indications, which new, undescribed indications might lack.
Mammalian Target of Rapamycin, a pathway believed to be geroprotective in many species and a target for selective inhibition in humans.
International Classification of Diseases, 11th edition, codes for medical indications, which new, undescribed indications might lack.
A protein involved in targeting muscle proteins for degradation, suppressed by activin receptors.
A protein involved in targeting muscle proteins for degradation, suppressed by activin receptors.
The clinical operations person for the study on measuring falls in elderly patients.
A clinician involved in the healthy volunteer studies for Bimagrumab.
Partner at Atlas Venture who was involved in funding Versuspio.
Founder of Novartis Institutes, who recruited the speaker and later tasked him with finding unmet medical needs.
Mentioned as an individual from Medici involved in funding Versuspio.
The then CEO of Novartis who recruited Mark Fishman to found Novartis Institutes.
Considered the 'father of myostatin' for discovering its biology.
Author of 'The Transformed Cell', which articulated the process of drug discovery and inspired Peter Attia.
A geriatrician who collaborated with the speaker on a study to measure falls in elderly nursing home residents.
Worked with the speaker at Adid Bio, an adviser who wanted Bimagrumab.
CMO brought into Versuspio, allowing the speaker to transition to President and CSO.
Mentioned for his saying 'skate to where the puck is going to be' in drug development.
Developed the technology for FC fusion proteins at Mass General.
Mentioned as an individual from Medici involved in funding Versuspio.
MIT professor using Wifi-type devices to measure people's movements in their homes, considered for assessing falls.
Led a team in the discovery project for Bimagrumab at Novartis Institutes and was a discoverer of the muscle protein degradation pathway.
Experienced drug developer who taught the speaker his framework for patient selection in Phase 1 trials, prioritizing healthy volunteers with minimal risk.
Worked with the speaker at Adid Bio, an adviser who wanted Bimagrumab.
Super experienced CEO brought in to lead Versuspio after the semaglutide data emerged.
Worked with the speaker at Versuspio to raise money for Bimagrumab development.
A multikinase inhibitor used to treat renal cell carcinoma and hepatocellular carcinoma, which causes skin cancers as a side effect, illustrating a cancer protective pathway.
An example of a drug that was protected by trade secret, a desiccated thyroid hormone.
An mTOR inhibitor, discussed for its potential intermittent dosing for selective mTOR inhibition.
Mentioned as an example of anabolic agents that increase muscle size but not strength without resistance training.
An older statin drug, mentioned in the context of incremental improvements in drug development.
A very potent toxin mentioned as an example of an agent that irreversibly turns on the ribotoxic stress pathway.
An endogenous inhibitor of the myostatin/activin pathway, once a popular recreational agent in gray markets.
An antibody developed to treat muscle diseases, initially for frail elderly people, later studied for sarcopenic obesity.
A very potent toxin mentioned as an example of an agent that irreversibly turns on the ribotoxic stress pathway.
An older statin drug, mentioned in the context of incremental improvements in drug development.
An mTOR inhibitor, discussed for its potential intermittent dosing for selective mTOR inhibition.
Another example of a drug protected by trade secret, purified from pig pituitaries, used as a 'rheumatology smart missile'.
A GLP-1/GIP agonist, mentioned alongside semaglutide for its efficacy in obesity.
A therapeutic antibody (CD28 agonist) that caused a severe cytokine release syndrome in healthy volunteers, resulting in deaths and influencing study design.
GLP-1 agonist, whose data on obesity (from Novo Nordisk) dramatically changed the landscape of obesity drug development.
A very potent toxin mentioned as an example of an agent that irreversibly turns on the ribotoxic stress pathway.
A GLP-1 agonist, mentioned alongside semaglutide for its efficacy in obesity.
An mTOR inhibitor, used in preclinical studies to extend life in mice and potentially dogs.
Classic example of a product whose formula is protected by trade secret instead of patent.
Company that attempted to manage mTOR inhibition side effects through a combination of catalytic and allosteric inhibitors.
An investment firm that liked the Versuspio story and funded the company.
A company that licensed the FC fusion protein technology from Mass General to make Etanercept (Enbrel).
Collaborated with Novartis on the therapeutic antibody project for Bimagrumab.
The company that acquired Bimagrumab after Novartis spun it out and Versuspio developed it.
More from Peter Attia MD
View all 345 summaries
140 min407 ‒ Preventing cardiovascular and Alzheimer’s disease: lowering LDL early, APOE4, and more
77 minBlood pressure: how to measure, manage, and treat high blood pressure (AMA #48 rebroadcast)
130 min406 ‒ Migraine, cluster headache, and tension headache: symptoms, causes, prevention, and treatment
39 minMetabolic liver health: how to assess risk, catch dysfunction early, and more (AMA 88 sneak peek)
Ask anything from this episode.
Save it, chat with it, and connect it to Claude or ChatGPT. Get cited answers from the actual content — and build your own knowledge base of every podcast and video you care about.
Get Started Free