Issue #192·

Novartis spent $12B on a drug that just flopped its Phase III trial

A $12 billion acquisition thesis crumbled overnight when Novartis' flagship RNA drug missed its primary endpoint in myotonic dystrophy, dragging competitors down with it. Meanwhile, small cell lung cancer got its first real win in decades, and a CRISPR therapy is one FDA decision away from making history.

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Novartis' $12 Billion Bet Just Hit a Wall

Novartis' del-desiran, the centerpiece of its $12 billion Avidity Biosciences acquisition, failed its Phase III HARBOR trial in myotonic dystrophy type 1, missing the primary endpoint of improved hand opening time. Novartis shares dropped more than 10%, and competitors Dyne Therapeutics and Sarepta fell in sympathy. The drug was supposed to validate Novartis' entire RNA therapeutics strategy; UBS had estimated up to $2 billion in peak sales before the miss. Novartis still has two other programs from the Avidity platform, but this was the flagship proof of concept, and it flopped.

Why it matters: This isn't just one trial failing. It's the foundation of a multi-billion-dollar acquisition strategy showing cracks, and it raises uncomfortable questions about whether antibody-guided RNA drugs can deliver in muscle diseases at all.

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Oncology Wins

Small Cell Lung Cancer Just Lost a Round It's Been Winning for Decades

Amgen's Imdelltra plus AstraZeneca's Imfinzi hit the gold standard in oncology: a statistically significant overall survival benefit in first-line maintenance for extensive-stage small cell lung cancer. The DeLLphi-305 trial (563 patients) is the first Phase 3 win for a bispecific T-cell engager in this setting, validating the strategy of combining T-cell engagers with checkpoint inhibitors across the industry.

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The Immunotherapy Target Everyone Abandoned Just Delivered a Double-Take

Inhibrx's six-armed OX40 agonist INBRX-106, combined with pembrolizumab, posted a 44.0% response rate in head and neck cancer versus 21.4% for pembro alone. In HPV-positive patients, responses hit 80%. After Roche, AstraZeneca, and BMS all failed with OX40 drugs, these results suggest the problem was engineering, not biology.

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A Lung Cancer Drug That Works After KRAS Inhibitors Stop

BridgeBio's BBO-8520 posted a 75% response rate at 500mg (combined with pembrolizumab) in KRAS G12C-mutant lung cancer patients who had already failed prior KRAS inhibitors. The dual ON/OFF mechanism hits the protein in both active and inactive states, offering a potential salvage therapy where none currently exists.

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Regulatory and Pipeline Milestones

AstraZeneca's COPD Biologic Goes From Zero Consensus to $5B Forecast

Tozorakimab hit its primary endpoint in two Phase 3 trials, cutting COPD exacerbations by 29-30% on top of standard inhaler therapy. The FDA granted Priority Review with a Q1 2027 decision date. AstraZeneca raised its peak sales target to over $5 billion, up from a consensus forecast of essentially zero before the data dropped.

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One Shot to Rewrite Your DNA: CRISPR Therapy Gets FDA Fast Track

Intellia's lonvo-z, which would be the first-ever in vivo CRISPR gene editing therapy, scored FDA Priority Review with a March 2027 decision date. Phase 3 data showed an 87% reduction in hereditary angioedema attacks from a single infusion, with 62% of patients becoming completely attack-free. No advisory committee meeting is currently planned.

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A Blood Test That Catches Breast Cancer Outsmarting Treatment

The FDA approved Guardant's liquid biopsy as a companion diagnostic for AstraZeneca's camizestrant, enabling doctors to catch ESR1 resistance mutations through routine blood draws rather than waiting for scans. The SERENA-6 trial showed switching therapy early cut progression risk by 56%.

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Pipeline Movers

Roivant's Lung Drug Posts Data That Has Analysts Taking Notice

Roivant's inhaled drug mosliciguat crushed its Phase 2 primary endpoint in pulmonary hypertension, delivering a 56.3% reduction in pulmonary vascular resistance and a 52.7-meter gain in walking distance at Week 24. The stock surged 20%. Phase 3 is already underway.

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The Pill That Wants to Replace Your Injection for Rare Swelling Attacks

Pharvaris' once-daily oral pill deucrictibant posted an 83% reduction in hereditary angioedema attacks in Phase 3, rivaling injectable therapies that currently dominate the market. The stock jumped on the news, with analysts raising targets as high as $79. An FDA decision on the on-demand formulation is set for April 2027.

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