Episode 153 - September 5, 2025

Summary

• Biotech’s tape has genuinely turned, and the hosts credit rates more than M&A. XBI is up 11.9% over the past month versus 2% for the S&P, nonfarm payrolls of 22,000 (vs. ~75,000 consensus) have “cemented a rate cut for September,” and Greg notes the move since May is “the largest upward trend in over a decade” excluding COVID euphoria. John Maraggonor: if the Fed cuts meaningfully, investors will shrug off FDA/tariff/MFN uncertainty — “it feels better than it’s been for a while.”
• Sanofi fell ~10% on a technically positive readout because amlitelimab met its primary endpoint but likely trails Dupixent, reopening the patent-cliff bear case. Sam Fazeli cited Dupixent’s expected 2030 sales of $2.5B and 38% of revenue; it loses protection in 2031, and “a $25 billion” gap would be tough to fill. Cross-trial, the OX40 asset looks “pretty similar” to Amgen’s rocatinlimab, potentially leaving it a second- or third-line cycling option. Paul’s meta-point: large caps now trade like small caps, where one competitor readout creates “this big new bear case” overnight.
• Ionis’ olezarsen Phase 3 delivered 50–70% triglyceride lowering plus a pancreatitis benefit, setting up another ASO-vs-siRNA cage match with Arrowhead’s zodasiran. John Maraggonor called the data “fantastic” — the pancreatitis signal may let the class avoid an outcomes trial — while Arrowhead’s open-label PALISADE cut two-year pancreatitis events from ~20% to 4% on quarterly dosing. The commercial caveat was that this “is not a KOL market,” and five-digit pricing “is going to be associated with a narrowing of the patient population.”
• Obesity orals reset expectations downward on efficacy — and the panel split on whether cheap orals actually expand the market. Lilly’s oral showed 10.5% weight loss vs. 2.2% placebo in obese diabetics; Viking’s oral hit 12% at 13 weeks but with 28% discontinuations versus 18% on placebo. Sam thinks injectable-level 22–25% targets are “just crazy high and you probably don’t need that” for maintenance. Brian Skorney argued cheaper small-molecule orals plus PCP prescribing could broaden uptake; John pushed back that Lilly and Novo have no incentive to “think dramatically differently on pricing.” Sam’s shop still models $100B in 2030 obesity sales across multiple drugs, Lilly outpacing Novo, unrevised.
• Insmed has become a $30B+ commercial story with three legs: Arikayce (>$400M this year), the just-launched Brinsupri, and TPIP. Brensocatib’s Phase 3 readout preceded more than a 500% stock move; it is the first approved drug for bronchiectasis with a $5B+ peak-sales target. United Therapeutics’ surprise IPF win for Tyvaso sent UTHR up 30%+ and INSM up 7% on the read-through that “wherever Tyvaso works, TPIP may work there as well.”
• John Maraggonor unveiled his third act with Clive: Corsera, an annual shot against PCSK9 and angiotensinogen for primordial cardiovascular prevention priced at “hundreds of dollars per annual dose.” The thesis is that ASCVD is cumulative exposure, so treating healthy 40- and 50-year-olds flagged by an AI risk tool built with UK Biobank data can take “cardiovascular disease off of your tombstone” — “frankly the most important thing I’ve ever gotten involved with from a public health perspective.” The first program starts in the clinic in a month after two years in stealth.
• Vaccine politics are “coming to a head”: Trump’s Truth Social post, RFK’s Senate testimony, and FDA requests involving placebo-controlled booster trials from Novavax, Moderna and BioNTech. Sam sees revenue falling while trial costs rise, questions the circulating-spike-protein requirement, and on the imminent autism report says, “I’d be shocked if vaccines are not mentioned.” ACIP reconvenes on the 18th.
• The catalyst calendar is dense: World Lung’s ivonescimab HARMONi OS, AZ’s FLAURA-2 OS, and a heavy neuro fall. HARMONi needs an OS confidence interval excluding 1, with a hoped-for HR around 0.75–0.8 and China/ex-China consistency the key tell. Paul thinks Lilly’s Alzheimer’s prevention interim “could come any time” and is likely to work, though ~90% screen-failure rates cloud commercial viability; he is optimistic on Bristol Myers Squibb’s KarXT in Alzheimer’s psychosis, cautious on Novo’s GLP-1 readout, and flags uniQure’s Huntington’s data as a test of whether CBER’s “Peter Marks doctrine” talk is real. Eric Schmidt also highlights Axsome’s Auvelity and Neumora’s symptomatic Alzheimer’s programs.

Deep dive

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