OrbiMed Advisors

# Signal Note: OrbiMed Initiates $385M Position in Edgewise Therapeutics OrbiMed's substantial entry into EWTX signals conviction in seribantumab (EDG-5506), a myostatin inhibitor in Phase 2 for facioscapulohumeral muscular dystrophy (FSHD), a rare progressive disease with limited treatment options and ~16,000 US patients. The timing suggests confidence ahead of anticipated Phase 2 data readouts, likely driving near-term catalysts. This represents a meaningful allocation from one of biotech's most selective institutional investors, typically indicating rigorous due diligence on clinical and commercial fundamentals.

# Signal Note: OrbiMed Initiates $323.7M LLY Position OrbiMed's new 301,200-share position in Eli Lilly signals conviction in LLY's near-term pipeline catalysts, likely centered on GLP-1 obesity franchise expansion (tirzepatide) and potential label extensions, which face competitive pressure from Novo Nordisk but maintain differentiated efficacy data. The $323.7M stake size suggests institutional capital is rotating into LLY ahead of key 2024-2025 readouts (additional indication data, payer coverage decisions) and reflects confidence in the company's ability to defend/grow market share despite crowded GLP-1 landscape. Timing is notable given recent pharma sector volatility and potential valuation reset opportunities.

# Signal Note: OrbiMed Initiates $230.7M BSX Position OrbiMed's new 2.4M share stake in Boston Scientific suggests confidence in the company's interventional device pipeline, likely driven by recent positive clinical data or FDA decisions (e.g., recent approvals in structural heart or endoscopy segments). The $230.7M position size from a premier healthcare allocator may signal institutional conviction ahead of upcoming 2024-2025 catalysts, though without filed documentation details, the specific indication triggering this entry remains unclear.

# Signal Note: OrbiMed Initiates $184.5M Position in Sinovac OrbiMed's new $184.5M stake in Sinovac signals conviction in the company's vaccine pipeline, likely driven by its COVID-19 booster market share in Asia and potential catalysts from late-stage programs (pneumococcal, HPV candidates). The entry size suggests confidence in near-term revenue generation from established products rather than speculative early-stage bets, though Sinovac's valuation multiples relative to Western peers warrant scrutiny given execution risks in clinical development.

**Signal Note: OrbiMed Initiates $157M EW Position** OrbiMed's new 1.84M share stake in Edwards Lifesciences likely reflects conviction in the company's structural cardiac and interventional cardiology portfolio, particularly as SAPIEN valve franchise adoption accelerates in TAVR and mitral/tricuspid spaces. The timing suggests confidence in near-term clinical readouts or reimbursement expansion, though the lack of disclosed catalyst warrants monitoring of Q4 earnings guidance and 2024 procedural volume trends. This adds institutional validation to EW's valuation following recent market volatility, but represents a relatively modest position size for OrbiMed's $53B+ AUM.

# Signal Note: OrbiMed Initiates $154.6M Position in Upstream Bio OrbiMed's entry into UPB signals conviction in the company's pipeline, likely centered on its lead program in autoimmune/inflammatory disease. The $155M position size from a premier healthcare allocator suggests confidence in near-term catalysts, potentially including clinical data readouts or partnership announcements within 12-24 months. Monitor upcoming trial updates as key near-term newsflow that could validate this thesis.

# Signal Note: OrbiMed Initiates $149M Position in ISRG OrbiMed's new $149M stake in Intuitive Surgical signals conviction in the da Vinci platform's sustained margin expansion and market share gains in minimally invasive surgery, particularly as procedure volumes recover post-pandemic and adoption penetrates emerging markets. The timing suggests confidence in near-term procedure growth and potential upside from higher-margin software/services revenue, though the signal lacks visibility into specific near-term catalysts or competitive threats from lower-cost robotic alternatives.

# Signal Note: OrbiMed Initiates $146.5M Position in Sionna Therapeutics OrbiMed's new 3.56M-share position signals confidence in Sionna's lead program, SIO-108, a potential first-in-class IL-17C antagonist for atopic dermatitis—a large market with limited efficacy options despite existing therapies. The timing suggests conviction ahead of upcoming clinical catalysts, likely Phase 2b data readouts expected in 2024-2025 that could differentiate SIO-108's efficacy/safety profile versus JAK inhibitors and biologics. This backing from one of healthcare's largest dedicated investors de-risks execution and may attract downstream institutional capital if clinical milestones are achieved.

**Signal Note: OrbiMed Initiates $124M Position in MBX Biosciences** OrbiMed's new 3.9M share stake signals conviction in MBX's pipeline, likely driven by clinical progress in its lead program—MBX8859, a selective AMPK activator in Phase 2 for metabolic diseases (obesity/NASH). The timing suggests positioning ahead of near-term data readouts or potential partnership catalysts, as AMPK activators remain competitive but differentiated if efficacy/safety data demonstrates clinical advantage over GLP-1 class competitors.

# SIGNAL NOTE: OrbiMed initiates $122.8M position in argenx OrbiMed's entry into ARGX signals conviction in the company's near-term catalysts, particularly efgartigimod's expanding label potential (recently approved for generalized myasthenia gravis and in Phase 2/3 for other autoimmune indications) and commercial trajectory. The $122.8M position size from a top-tier healthcare allocator suggests confidence in ARGX's FcRn inhibitor platform penetration and margin profile as these programs advance through late-stage development.

# Signal Note: OrbiMed Entry into Enliven Therapeutics OrbiMed's $122.6M initiating position in ELVN signals conviction in the company's pipeline, likely driven by ELV-304 (ELV-304, a selective estrogen receptor degrader for breast cancer) which entered Phase 2 in 2023 with clinical readouts expected in 2024-2025. The $122.6M position size—substantial for a micro-cap initiator—suggests OrbiMed sees value ahead of Phase 2 data maturation or potential partnership catalysts. This is a thesis bet on clinical validation rather than de-risking, given ELVN's pre-commercial stage.

# Signal Note: OrbiMed Initiates $114.8M Position in Alnylam **OrbiMed's entry suggests conviction in Alnylam's RNAi pipeline expansion and near-term catalysts.** Key drivers likely include anticipated label expansions (vutrisiran for hATTR amyloidosis and givosiran for acute intermittent porphyria) and sustained revenue growth from existing franchises (lumasiran for primary hyperoxaluria). This is a meaningful validation signal from a top-tier healthcare allocator with strong visibility into clinical/commercial trajectories.

# Signal Note: OrbiMed Initiates $114M Stryker Position OrbiMed's substantial new position in Stryker signals confidence in the orthopedic/surgical device leader's near-term execution and M&A potential. The timing aligns with Stryker's competitive positioning in high-growth segments (robotic-assisted surgery, spine, trauma) and suggests the mega-cap healthcare fund sees undervalued upside relative to peers. No specific catalyst or product launch is publicly disclosed, but the large entry size from a top-tier healthcare investor typically precedes institutional accumulation cycles.

# Signal Note: OrbiMed Initiates $96.6M Position in ARS Pharmaceuticals OrbiMed's entry into SPRY signals institutional conviction in ARS's lead asset neffy (epinephrine nasal powder) for anaphylaxis, a first-in-class intranasal alternative to auto-injectors with potential advantages in speed of onset and ease of use. The ~8.3M share position (likely ~5-7% stake based on typical fund sizing) suggests confidence in near-term value creation, possibly ahead of anticipated Phase 3 top-line data or regulatory interactions on the current NDA pathway. This marks a notable vote of confidence from one of biotech's largest dedicated investors at a time when non-injection anaphylaxis treatments remain clinically validated but commercially limited.

**Signal Note: OrbiMed Initiates $87M Position in Terns Pharmaceuticals** OrbiMed's new 2.15M share stake signals conviction in Terns' clinical pipeline, likely driven by upcoming data readouts for TERN-101 (a GLP-1 receptor agonist in development for metabolic disease) or other lead programs. The $87M position size from a top-tier healthcare allocator reflects confidence in near-term catalysts, though the exact timing of pivotal trial results or regulatory milestones requires verification against Terns' disclosed guidance.