A muscle antibody Novartis abandoned matched weight-loss surgery's fat loss when combined with GLP-1
This muscle-building antibody, abandoned by Novartis, achieved 45.7% fat loss and 22%-23% weight reduction when combined with semaglutide for 72 weeks—the first drug therapy to match weight-loss surgery's fat-loss results.
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The easiest medicines to develop matter least; the hardest create the most value
Drug development follows two paths. One makes incremental improvements—atorvastatin and rosuvastatin as successors to mevastatin and lovastatin, or converting injectables to oral drugs—carrying low risk and enjoying strong industry favor. The other targets entirely new indications where disease definitions don't yet exist, requiring simultaneous persuasion of doctors, patients, payers, and regulators. This path is harder but creates more value. Yet the entire system is structurally biased toward low-risk work.
— Lloyd KlicksteinNursing home admission is deadlier than a cancer diagnosis
As a rheumatologist, Klickstein observed that frail older people entering nursing homes face ~90% three-year mortality—worse than many cancer prognoses—yet medicine treats it with far less urgency. This observation directly led to the creation of Bimagrumab.
— Lloyd KlicksteinWithout a way to measure falls, the program had to be abandoned
To find a measurable endpoint for fall prevention, the team tested triaxial accelerometers on Boston ice skaters (with video validation), then on 60 nursing-home residents with prior falls over a six-month follow-up that recorded 117 actual fall events. The device caught only 17% of real falls; of its alerts, only 17% corresponded to actual falls. Even MIT's Dina Katabi's WiFi-based motion detection couldn't solve the problem. Without a measurable endpoint, the fall-prevention program was abandoned.
— Lloyd KlicksteinWhat works spectacularly in mice fails dramatically in humans
Knockout mice lacking myostatin grow muscle like Schwarzenegger; Bimagrumab in mice produced even greater muscle growth (~30%), with stronger muscles and faster running. The same antibody in humans only increased muscle 4–8%, almost entirely in elderly subjects. This species gap was core to why Novartis abandoned Bimagrumab as a standalone sarcopenia treatment.
— Lloyd KlicksteinOne accident changed how first-in-human trials are dosed forever
Two decades before Bimagrumab, the CD28 agonist antibody TGN1412 caused catastrophic injury in first-in-human trials. Researchers suspect cross-linking of CD28 receptors triggered extreme T-cell activation and acute cytokine release syndrome, killing some volunteers. That accident prompted industry-wide adoption of sentinel dosing—giving one or two volunteers a dose first, observing effects before enrolling the next cohort—replacing TGN1412's approach of dosing six volunteers simultaneously.
— Lloyd KlicksteinRejected by 53 investors, then the market suddenly shifted their way
When Versanti Bio licensed Bimagrumab from Novartis in February 2021, obesity was perceived as a wasteland for drug development—nearly all prior obesity drugs had failed commercially. The team approached 53 investors; almost none showed interest. They raised $70 million, 30% short of their $100 million target. Months later, semaglutide data changed the landscape entirely. The team quickly reoriented toward Bimagrumab + GLP-1 in mice, discovering the combination's effects on fat loss and muscle preservation were synergistic and, in Klickstein's words, unprecedented.
— Lloyd KlicksteinFirst drug therapy to match weight-loss surgery's fat-loss results
BELIEVE tested semaglutide and Bimagrumab across nine arms (a factorial design of high/low doses). At 72 weeks, the high-dose combination group achieved 22–23% body-weight loss and 45.7% fat-mass reduction—Klickstein's first drug therapy to match weight-loss surgery's fat-loss results. A downside emerged: LDL cholesterol rose ~20%, which Klickstein attributes to the antibody's direct action on hepatic activin receptors. He argues this is manageable with additional medication and doesn't negate the therapy's value.
— Lloyd KlicksteinCancer-causing drugs reveal protective pathways against cancer itself
Klickstein's new company reverses this logic: mining "cancer-causing drugs" to find cancer-protective pathways. Sorafenib, a multikinase inhibitor, triggers skin cancer in ~10% of elderly patients—evidence that it suppresses a "ribotoxic stress" pathway normally protecting cells. His hypothesis: gently reactivating this pathway prevents cancer. Phase-2 trials are running in people with ≥5 prior skin cancers and 50% annual recurrence rates. Broad Institute screening of thousands of tumor cell lines showed melanoma is exceptionally sensitive to this mechanism, suggesting it might also become a melanoma treatment.
— Lloyd KlicksteinIn their own words · checked verbatim
the three-year mortality rate approached 90%. So being a frail elderly person who has to go to a nursing home was worse than cancer.
Lloyd Klickstein10:28
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. That's basically what a patent is.
Lloyd Klickstein16:53
it's the poster child for what I would argue is the absolute greatest grift of the entire health and wellness industry.
Lloyd Klickstein1:20:42
I don't want to expose people to a risk greater than that of a lightning strike in a year.
Lloyd Klickstein1:25:58
they had extremely strong T cell activation and an acute cytokine release syndrome in healthy volunteers. Some of them died.
Lloyd Klickstein1:28:01
Everybody thought it was a wasteland for drug development. Every drug that had been developed in obesity had failed commercially.
Lloyd Klickstein1:53:57
you skate to where the puck is going to be. It's Jay Bradner's favorite saying, but the puck was going someplace else now, right? Semaglutide was going to become the standard of Clare or some incretin agonist.
Lloyd Klickstein1:55:57
the fat loss was 45.7% of starting body fat. Now that's what you get with bariatric surgery. So this, to me, this is the first medical therapy that gives fat loss equivalent to or superior than bariatric surgery.
Lloyd Klickstein2:05:25
Figures
| Unmet clinical indications Novartis identified | ~7,000 | 8:27 |
| Three-year mortality rate for nursing-home residents | ~90% | 10:28 |
| Therapeutic antibodies reaching IND human testing | ~30% | 1:13:25 |
| Falls recorded in 60 elderly residents over 6 months and device detection rate | 117 actual falls; device detected 17% | 33:34 |
| Muscle gain from Bimagrumab in mice versus humans | Mice ~30%; humans 4–8% | 1:01:02 |
| HbA1c reduction in 48-week type 2 diabetes trial | ~0.7–0.8 percentage points (absolute) | 1:50:51 |
| BELIEVE trial: high-dose combination group 72-week results | Body weight: 22–23% reduction; fat mass: 45.7% reduction | 2:05:25 |
| LDL cholesterol increase in BELIEVE trial | ~20% | 2:07:26 |
Glossary
- myostatin
- A natural protein that suppresses muscle growth; blocking it causes animals' muscles to grow dramatically.
- activin A
- A member of the TGF-β superfamily alongside myostatin that similarly inhibits muscle growth.
- Fc fusion protein
- A therapeutic protein fused to an antibody's Fc region to extend its half-life in the bloodstream.
- INN
- The WHO-standardized system for assigning universal generic drug names.
- sentinel dosing
- In first-in-human trials, dosing one or two subjects first, observing results before proceeding to the next cohort.
- ribotoxic stress
- A cell-death signaling pathway triggered by ribosomal damage.
How to listen
For professionals and investors interested in drug-development pipelines, biotech venture funding, and the GLP-1 market.
The mid-section discussion of mTOR inhibitors and longevity (2:11–2:16) is mostly speculative and can be skipped.