From Patient Needs to Market: The Drug Development Journey

Drug development starts by identifying unmet patient and clinical indications rather than focusing on pre-existing research targets.

There is a clear distinction between incremental improvements to existing therapies and quantum, paradigm-shifting leaps that address entirely new medical needs.

While incremental progress is commercially stable and lower risk, it often lacks the broader societal value of pioneering new fields, especially when creating therapies for indications that currently lack diagnostic codes.

These needs were categorized into various groups, including healthy aging, ENT, renal diseases, and fibrotic diseases.

The program, which began with initial research, expanded significantly to include dozens of projects under the new unit.

This systematic approach aimed to identify areas of high medical need that were not receiving adequate research and development attention within the pharmaceutical industry.

Developing a new drug, especially one intended for widespread use, requires thousands of individuals, many years of effort, and costs exceeding a billion dollars, akin to constructing the world's largest skyscraper.

Unlike a building that can generate returns over decades, drug patents provide a very limited 20-year term from the filing date for companies to recover their investment and potential profits before generic competition is permitted.

In practice, the period of market exclusivity for a new drug typically ranges from 10 to 15 years after its launch, leaving a compressed window for return on investment.

This limited exclusivity necessitates careful financial planning and a high success rate to justify the substantial upfront investment in research and development.

A core principle is to minimize risks at every stage, identifying and accepting only critical uncertainties, and being prepared to 'fail fast' if a project is not viable to conserve resources.

The most detrimental outcome is not an early failure, but rather a late-stage success in Phase 3 trials that ultimately results in commercial failure due to market or adoption issues.

Strategic decisions, such as developing an oral drug for an elderly sarcopenia patient population, are vital for ensuring the eventual widespread adoption and commercial success of a therapy.

Effective risk management involves a constant balance between the potential benefits of a new medicine and the inherent unknowns and uncertainties at each developmental checkpoint.

In the 1990s, the images of myostatin knockout mice, nicknamed 'Arnold Schwarzenegger' mice, generated significant excitement among medical students.

Muscle growth is a complex process governed by nutrition, physical activity, and intricate biochemical pathways, with myostatin acting as a key inhibitor of muscle hypertrophy.

In humans, the regulation of muscle growth is more complex than in rodents, requiring the inhibition of both myostatin and activins for substantial muscle enlargement.

These regulatory proteins signal through the TGF beta superfamily of receptors, which in turn activate SMAD transcription factors to control gene programs related to muscle size.

Myostatin signaling specifically suppresses proteins such as MuRF1 and MAFbx, which are known to initiate muscle degradation, thereby preventing excessive muscle growth.

The target ligand-receptor affinity is exceptionally high, in the nanomolar to low-picomolar range, necessitating an inhibitor capable of binding within the low-picomolar range to effectively block ligand binding.

Therapeutic antibodies are chosen over small molecules for this purpose because they can achieve the necessary high binding affinity and specificity required to effectively block these pathways.

This approach contrasts with small molecules, which typically struggle to achieve such high affinities for complex receptor interactions, making biologics a more suitable choice for this type of inhibition.

Other foreign antibodies, like rabbit anti-thymocyte globulin, also remain clinically relevant for similar immunosuppressive purposes.

Antivenoms, often derived from horse serum, are another class of foreign antibodies; however, repeat exposure carries a risk of severe serum sickness responses.

Toxicology assessments employ a weight-of-evidence approach, integrating all accumulated data to balance potential risks against anticipated benefits.

Irreversible organ toxicity, especially affecting the heart or brain, is typically a definitive reason to halt a drug development program.

While non-human primate studies show muscle hypertrophy with bimagrumab, it is not as pronounced as in rodents, but still sufficient to build confidence for further development.

Paradoxically, sometimes there is more project capital available in a small company than in a big company because the small company typically has fewer projects, meaning more of the money goes toward those specific initiatives.

In contrast, large pharmaceutical companies manage hundreds of projects simultaneously, leading to intense internal competition for a fixed pool of research and development dollars.

Despite internal competition, large firms possess vast capital reserves and do not rely on public markets to fund each individual project, unlike smaller companies.

I have seen both scenarios, where some big company projects receive high-profile status and robust funding, while others operate within constrained resources.

This process ensures that what is on the label is what is in the bottle.

While commercial drugs often involve multiple manufacturers for substance, formulation, and packaging, the infrastructure is well-controlled and documented. In contrast, online peptides lack these guarantees, and purchasing them from non-verified manufacturers is considered a mistake by the speaker.

However, the researchers noted that the animals also experienced an enormous change in body size due to muscle hypertrophy. When the heart size was normalized to body size, it was found to be normal.

Recovery studies showed that when administration ceased, muscle and heart size reduced. The research team made an argument to regulators that the observed findings were physiological responses to the drug's effects on muscle growth rather than direct cardiac toxicity.

Clinical studies define healthy volunteers not strictly by age, but primarily as individuals without diagnosable disease or concomitant medications that could confuse any assessments.

The BEMA studies specifically focused on older adults who were healthy to properly assess muscle mass and strength changes using methods like DEXA and MRI, without the interference of underlying health conditions.

Researchers monitor adverse effects such as muscle spasms or cramps, and ensure they stay within established safety limits without exceeding exposures tested in animals.

The three biggest challenges of any clinical study are recruitment, recruitment, and recruitment. Companies choose locations based on site reliability, the regulatory environment, and cost.

China has become a popular location for investigator-initiated studies, which can be conducted with less supporting data than typically required for an IND application.

Australia and New Zealand offer a 'clinical trial notification' process, while Taiwan is recognized for its centralized clinical environment and high-quality investigators.

Japan requires ethnic sensitivity studies with phase one trials in Japanese people before larger studies, as they must ensure dosing and exposure are safe and tolerable given differences in genetic background and average body size.

The FDA requires an IND application for studies conducted under its oversight, regardless of where the trial was previously conducted.

Novartis conducted approximately 16 phase two studies to evaluate Bimagrumab across various indications. The drug reliably and predictably increases muscle size, but the researchers noted that in humans it increases size by 4-8%, with eight being the absolute max, which is less than the 20 to 30% or more observed in rodents.

The gains in muscle size in human trials were not accompanied by substantial improvements in performance assessments. The research team noted that they had previously intended to co-develop a nutritional component to this therapy to potentially boost results, as it was suggested that subjects might have been substrate-limited or protein synthesis-limited rather than drug-limited, but were unable to fully pursue that after Novartis sold their nutrition unit.

Regarding the variability in results, researchers observed a trend toward more muscle mass in males versus females and in younger versus older individuals, though they emphasized there is a lot of variability. Further studies were conducted on protein intake, where it was observed that within boundaries, the more protein subjects ate, the more muscle they built, though the effect of higher protein intake beyond the tested levels has not been formally tested.

The project eventually faced challenges as it moved through the research stages within the company. Reflecting on the development process, it was noted that big companies often struggle with communication across teams, and in retrospect, the researchers wish they had maintained the nutritional element of the project to potentially improve outcomes.

A study involving type 2 diabetics ran for 48 weeks with a dose of 10 migs per kig monthly. During this study, researchers observed that the patients experienced the expected muscle mass increase, and interestingly, they saw a substantial fat mass decrease and hemoglobin A1C decreased by about 7 or 8% absolute.

When asked if these results were on account of insulin sensitivity or a larger reservoir for glucose disposal, the response was that it was both of those things. The patients had standardized dietary advice to follow during the study period.

Novartis eventually made a strategic decision to spin out the drug, judging the effect size not significant enough for their portfolio. The spin-out occurred in 2021, and discussions regarding the transition had been ongoing since 2020.

Following the spin-out, the asset was acquired by Versanis Bio in 2021. The team at Versanis Bio planned to develop it in older adults with low muscle mass and impaired muscle function who were also obese, as they believed this was the patient population most likely to benefit, despite the general lack of interest in obesity drug development at the time.

In a study with 507 enrolled patients, researchers successfully achieved intended pharmacological effects, demonstrating partial responses with low doses and full responses with high doses for both individual drugs and their combinations across the four combination arms.

The primary endpoint for the study was body weight. The researcher personally wanted waist circumference as the primary endpoint because it is considered more closely linked to important clinical outcomes, but body weight was used due to regulatory requirements and to satisfy investors and potential acquirers; DEXA scans were included in every single patient despite being considered expensive.

In the high-dose combination group, the body weight lost at 72 weeks was 22-23% of starting body weight, and the fat loss was 45.7% of starting body fat, which the speaker stated is comparable to bariatric surgery.

Functional testing, primarily grip strength, showed only small and variable improvements, and an unexpected increase in LDL cholesterol was also observed in the study.

This is considered an on-target effect due to activin receptor activity in the liver.

The mechanism, whether involving interference with LDL clearance or increased synthesis, is still being studied. The speaker believes that if developed independently, the drug could have progressed to phase three trials despite this LDL effect, as such outcomes can be monitored and treated.

Testing the effects of intermittent fasting on mTOR activity in humans presents significant challenges, primarily due to the invasive nature and difficulty of obtaining necessary liver biopsies to measure these cellular changes directly.

Individuals in this high-risk group face a 50% chance of developing another skin cancer within a year, making them a suitable population to assess preventative interventions.

The study design would involve testing low-dose, high-dose, and placebo arms to measure cancer prevention, with the speaker expressing a hope that the intervention could prevent 50% of cancers.

The primary focus is on skin cancer prevention, which represents a significant medical need. While the speaker suspects the drug could work on multiple cancer types, they note it would be nearly impossible to test this broadly before approval due to the rarity of cancer incidence.