409 ‒ Inside modern drug development: the science, economics, and regulatory hurdles

KEYPOINTS

• 01

  Real innovation starts from unmet medical need, not from a 'seventh statin'.

  Klickstein, who spent about 20 years at the Novartis Institutes for BioMedical Research, describes starting with patients and indications: his team listed roughly 7,000 clinical indications that were unmet. Incremental drugs are commercially attractive and low risk, so the industry is biased toward them; first-in-class drugs for conditions that may not even have diagnostic codes require educating doctors, patients, payers and regulators from scratch.

• 02

  Drug-development risk compounds multiplicatively, so killing failures early is the core skill.

  A new target in a new indication carries perhaps 20 separate risks (target, format, bioavailability, toxicity and so on). Even if each has a 90% chance of going right, multiplying them out leaves very little. Klickstein says he has personally killed programs and has never seen one that couldn't be stopped for some reason; big companies run two to four formal checkpoints, small companies run more frequent, faster ones tied to fundraising.

• 03

  Patent economics shape which drugs get made.

  A patent runs 20 years from filing, but practically a drug gets 10–15 years of exclusivity after launch to recover costs Peter compares to building the Burj Khalifa—thousands of people, many years, more than a billion dollars. Companies extend life by layering patents on process steps, doses and routes. The old '10 years and $1 billion' estimate is now considered low; Klickstein cites the Tufts center's much higher figures.

• 04

  Falls were the target Klickstein most wanted, but they proved unmeasurable.

  He frames falls as having roughly 11 causes; healthy people stumble constantly but catch themselves with reactive foot speed. In a study with geriatrician Lou Lipsitz in frail residents aged 80 to over 100, a wearable detected only about 17% of real falls (of 117 events found), and older people under-report falls for fear of losing independence. Without a measurable endpoint, the falls program was stopped.

• 05

  Bimagrumab blocks activin type II receptors to unlock muscle growth.

  The rationale came from myostatin-deficient 'double-muscled' animals (mice, cattle, dogs). Rather than chase myostatin alone, the Novartis team led by Chris Lu and David Glass built an antibody (code BYM338) against the activin type II receptor, preferring IIB but also hitting IIA, blocking signaling from several ligands. Follistatin, the gray-market favorite, would cost on the order of a million dollars a month at effective doses and has a short half-life.

• 06

  Modern antibodies are made human from the start, which complicates animal work.

  Klickstein says for 15–20 years antibodies have not been made in mice; they come from human libraries. Bimagrumab turned out to be immunogenic in mice (not rats), so the team 'murinized' it (CDD866) for mouse studies. Mice showed roughly 30% muscle-mass increases and were stronger and faster; humans get about 4–8%.

• 07

  First-in-human design is governed by a 'lightning strike' safety threshold.

  Klickstein's framework: if the risk of a serious adverse event exceeds roughly 1 in 100,000—about the annual U.S. lightning-strike risk—you should not use healthy volunteers but patients who might benefit. Serious harm to healthy volunteers happens about once a decade industry-wide; the TGN1412-type CD28 antibody disaster, which caused a cytokine storm at a tiny dose, is why trials now dose sentinel participants first.

• 08

  Phase 1 doses go as high as safely possible, but never above animal exposures.

  Bimagrumab went up to roughly 50–100 mg/kg in early testing to learn what overdose would look like, then multiple monthly doses to see pharmacodynamic effects (muscle by MRI/DEXA, blood muscle proteins like CK). Japan and China require ethnic-sensitivity phase 1 data; China's notification-based process is making it increasingly popular for early trials.

• 09

  More muscle did not reliably mean better function.

  Novartis ran around 16 phase 2 studies. The drug reliably increased muscle size, but older adults' 4–8% gain yielded only about a 9-meter improvement in six-minute walk—neither Peter nor Klickstein thinks that prevents falls. In rodents, function improved because mass rose 20–30%.

• 10

  The surprise was fat loss and improved glucose control.

  A 48-week study in type 2 diabetics at 10 mg/kg monthly for 12 doses produced substantial fat loss and HbA1c reductions of about 7–8% (relative), with only standardized dietary advice. That pivoted the program toward obesity.

• 11

  A new cancer-prevention idea: find what drugs that cause cancer are inhibiting.

  If a drug causes cancer, it probably inhibits a protective pathway. Sorafenib, a multikinase inhibitor for kidney and liver cancer, causes skin cancers in about 10% of older patients. Klickstein's company is developing a compound to activate that pathway, testable in people 50+ with prior skin cancer, who have about a 50% chance of another within a year—so 100–120 people could show prevention in phase 2.