GSK has re-entered the pulmonary arterial hypertension arena with a $950 million acquisition of 35Pharma, positioning itself to directly challenge Merck’s blockbuster Winrevair with a Phase 2-ready activin ligand designed for superior bleeding and safety profiles. Meanwhile, the FDA’s landmark “Ultra-Rare Framework” codifies regulatory flexibility for individualized genetic medicines, while a sudden enrollment freeze for MacroGenics’ bispecific following a patient death signals lingering clinical safety hurdles for complex immunotherapies.

📅 Week Ahead

Thu 2/26 – Sat 2/28: ASCO GU 2026 (San Francisco) — Genitourinary cancers symposium continues

Sat 2/28: PDUFA Super-Saturday — BioMarin (Palynziq expansion), Ascendis Pharma (navepegritide for achondroplasia)

March 5: Medtronic MiniMed IPO pricing expected

Top Story: GSK Acquires 35Pharma for $950M to Challenge Winrevair

What Happened: GSK announced an agreement to acquire 35Pharma, a Canada-based clinical-stage biopharmaceutical company, for $950 million in cash. The acquisition centers on HS235, an investigational medicine that has completed Phase 1 trials with Phase 2 studies starting imminently in pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with heart failure with preserved ejection fraction (PH-HFpEF).

The Asset: HS235

HS235 targets the activin receptor signaling pathway, a clinically validated mechanism in pulmonary arterial hypertension. The molecule is designed with enhanced selectivity, specifically reducing binding to BMP9 (bone morphogenetic protein 9) and BMP10—ligands associated with bleeding and telangiectasia adverse events seen with current therapies.

The Competitive Context: Merck’s Winrevair

Merck’s Winrevair (sotatercept), another activin receptor therapy, reached $1.4 billion in 2024 sales, validating the mechanism and demonstrating substantial market opportunity. However, Winrevair is associated with bleeding events and telangiectasia (visible blood vessels on skin) due to BMP9/BMP10 pathway interference.

HS235’s Differentiation Strategy:

By engineering enhanced selectivity away from BMP9/BMP10, HS235 aims to:

• Maintain efficacy in reducing pulmonary vascular resistance
• Reduce bleeding complications
• Minimize telangiectasia incidence
• Potentially enable use in broader patient populations

Pulmonary Arterial Hypertension Market:

PAH affects approximately 40,000-50,000 U.S. patients with progressive disease characterized by:

• Elevated pulmonary artery pressure
• Right heart failure
• Significant morbidity and mortality
• Five-year survival rates of approximately 50-60%

The pulmonary hypertension market (including PAH and PH-HFpEF) is forecast to reach $18 billion by 2032, driven by:

• Improved diagnosis and earlier detection
• Expanding treatment options
• Novel mechanisms like activin pathway targeting
• Combination therapy strategies

GSK’s Strategic Rationale:

The acquisition provides GSK with:

• Late-stage asset with validated mechanism
• Potential best-in-class profile addressing current therapy limitations
• Entry into high-growth pulmonary hypertension market
• Competitive positioning against Merck’s established franchise

Development Timeline:

Phase 2 trials in PAH and PH-HFpEF are starting imminently in first half 2026. If successful, Phase 3 programs could initiate in 2027, targeting potential approval in 2029-2030.

What to Watch: Phase 2 dosing schedules, safety data comparing bleeding rates to Winrevair, efficacy signals in both PAH and PH-HFpEF populations, and partnership or commercialization strategies.

FDA Launches Accelerated Framework for Ultra-Rare & N-of-1 Therapies

What Happened: The FDA issued landmark draft guidance establishing a dedicated regulatory pathway for individualized therapies, specifically antisense oligonucleotides and gene editing approaches targeting ultra-rare genetic diseases.

The “Plausible Mechanism Framework”:

The guidance allows for full approval based on “substantial evidence” from non-traditional, small-scale trials when randomized controlled trials are biologically or ethically unfeasible. This represents formal codification of regulatory flexibility for N-of-1 (single patient) and ultra-rare disease therapies.

Key Policy Elements:

Evidentiary Standards:

Approval can be based on:

• Clear understanding of disease pathogenesis
• Rational therapeutic mechanism addressing root genetic cause
• Preclinical evidence supporting mechanism
• Small-scale clinical evidence (potentially single patients or small cohorts)
• Post-marketing surveillance and monitoring protocols

Qualifying Technologies:

The framework specifically addresses:

• Antisense oligonucleotides (ASOs): Targeting specific RNA sequences
• Gene editing: CRISPR, base editing, prime editing approaches
• Individualized gene therapies: Custom-designed vectors for unique mutations

When This Applies:

The pathway is intended for situations where:

• Patient population is extremely small (potentially single patients)
• Unique genetic variants require personalized therapeutic design
• Randomized controlled trials are ethically or practically impossible
• Strong mechanistic rationale supports probable efficacy
• Disease is serious or life-threatening with no alternatives

The “Makary-Kennedy” Regulatory Philosophy:

This guidance represents the FDA leadership’s stated commitment to:

• Regulatory flexibility aligned with modern biology
• Reducing barriers to innovative therapeutic approaches
• Enabling access for patients with ultra-rare conditions
• Accepting higher uncertainty in exchange for addressing unmet need

Capital Barrier Reduction:

By allowing approval without traditional Phase 3 requirements, the framework dramatically lowers:

• Development costs (potentially tens to hundreds of millions of dollars saved)
• Development timelines (2-4 years faster to approval)
• Patient requirements (from hundreds to potentially single patients)

Academic Medical Center Impact:

Major medical centers with gene therapy programs (Penn, Stanford, Harvard/Boston Children’s, UCSF) are positioned to:

• Develop individualized therapies for patients with novel genetic variants
• Obtain regulatory approval without pharmaceutical company involvement
• Treat ultra-rare patients previously considered “untreatable”

Commercial Model Questions:

The framework raises important questions:

• Pricing: How to price therapies developed for single patients?
• Reimbursement: Will payers cover N-of-1 therapies?
• Manufacturing: What quality standards apply to individualized products?
• Post-marketing: How to monitor long-term safety in tiny populations?

What to Watch: Final guidance publication following public comment period, first approvals under the pathway, payer coverage policy development, and whether the framework successfully enables ultra-rare disease access.

MacroGenics Clinical Hold: Bispecific Safety Concerns

What Happened: The FDA mandated an enrollment freeze (announced February 23) for MacroGenics’ lorigerlimab (PD-1 x CTLA-4 bispecific antibody) following a patient death. The safety review focuses on four patients who experienced severe side effects.

The Safety Events:

Four patients experienced Grade 4 (life-threatening) adverse events:

• Two cases of severe thrombocytopenia (dangerously low platelet counts)
• One case of myocarditis (heart muscle inflammation)
• One case of neutropenia progressing to septic shock, resulting in death

Lorigerlimab Profile:

The drug is a bispecific antibody simultaneously blocking:

• PD-1: Checkpoint inhibitor mechanism (like pembrolizumab, nivolumab)
• CTLA-4: Additional checkpoint inhibitor mechanism (like ipilimumab)

The combination aims to provide dual checkpoint blockade in a single molecule, potentially offering advantages over separate drug combinations.

Immune-Related Adverse Events:

The observed toxicities represent classic immune-related adverse events (irAEs) seen with checkpoint inhibitors:

• Thrombocytopenia: Immune-mediated platelet destruction
• Myocarditis: Immune attack on heart muscle (rare but potentially fatal)
• Neutropenia/sepsis: Immune-mediated white blood cell depletion leading to infection

The Bispecific Safety Challenge:

Dual checkpoint blockade combinations (PD-1 + CTLA-4) are known to cause higher toxicity rates than single agents. The question is whether bispecific format:

• Concentrates both mechanisms at tumor sites (improving efficacy, reducing systemic toxicity)
• Or creates unpredictable pharmacology leading to severe irAEs

FDA’s Evolving Tolerance:

The enrollment freeze signals that the FDA’s tolerance for severe immune-related adverse events in crowded oncology indications is decreasing, particularly when:

• Effective alternatives exist
• Patient death occurs
• Toxicity patterns suggest mechanistic safety issues

MacroGenics Platform Risk:

The company’s entire development strategy focuses on bispecific antibodies. A full clinical hold (beyond enrollment freeze) would:

• Cast doubt on the platform’s safety profile
• Reduce confidence in other pipeline assets
• Potentially trigger partnership renegotiations
• Impact company valuation significantly

What to Watch: FDA safety data review conclusions, whether enrollment freeze escalates to full clinical hold, detailed safety analysis presentation, and implications for other PD-1/CTLA-4 bispecifics in development.

Oncology & Rare Disease Updates

Pfizer: Braftovi Traditional Approval in Colorectal Cancer

What Happened: The FDA converted the accelerated approval for Braftovi (encorafenib) in combination with cetuximab and chemotherapy into full traditional approval for first-line treatment of BRAF V600E-mutant metastatic colorectal cancer.

BREAKWATER Trial Results:

• Overall survival: 30.3 months vs. 15.1 months (hazard ratio 0.49, representing 51% reduction in death risk)
• Objective response rate: 61% vs. 40%
• Statistical significance: p<0.0001

The doubling of median survival establishes a new standard of care for BRAF V600E-mutant colorectal cancer, affecting approximately 10% of metastatic colorectal cancer patients (roughly 15,000 U.S. patients annually).

Cardiff Oncology: CRDF-004 Strong Phase 2 Results

What Happened: Cardiff Oncology reported robust Phase 2 data for onvansertib plus FOLFIRI/bevacizumab in first-line RAS-mutated metastatic colorectal cancer.

Results:

• Objective response rate: 72.2% vs. 43.2% for standard of care
• Progression-free survival: Hazard ratio 0.37 (p<0.05), representing 63% reduction in progression risk

RAS-Mutated Colorectal Cancer:

RAS mutations (KRAS, NRAS) occur in approximately 50% of colorectal cancers and confer resistance to EGFR-targeted therapies. Effective treatment options beyond standard chemotherapy combinations are limited.

Onvansertib Mechanism:

Onvansertib inhibits Polo-like kinase 1 (PLK1), a critical regulator of cell division. PLK1 inhibition may synergize with chemotherapy in RAS-mutant tumors by disrupting mitotic checkpoints.

Development Path:

The strong Phase 2 results support advancement to Phase 3 registration trials in first-line RAS-mutant metastatic colorectal cancer.

Vanda Pharmaceuticals: Imsidolimab BLA Accepted

What Happened: The FDA accepted the Biologics License Application for imsidolimab in generalized pustular psoriasis (GPP), setting a PDUFA date of December 12, 2026.

Strategic Significance:

This sets up Vanda for its third approval in a 12-month cycle, following:

• Nereus approval (December 2025)
• Bysanti approval (February 2026)
• Potential imsidolimab approval (December 2026)

Generalized Pustular Psoriasis:

GPP is a rare, severe form of psoriasis characterized by widespread pustule formation, systemic inflammation, and potential life-threatening complications. Limited approved therapies exist.

Imsidolimab Mechanism:

The drug is an anti-IL-36 receptor antibody blocking interleukin-36 signaling, a key pathway in pustular psoriasis pathophysiology.

Clinical & Research Updates

Longeveron: Stem Cell Therapy for Aging Frailty

What Happened: Longeveron published Phase 2b results in Cell Stem Cell showing that laromestrocel (mesenchymal stem cell therapy) improved 6-minute walk distance by 63.4 meters at nine months (p=0.0077) in patients with clinical frailty.

Clinical Significance:

A 63.4-meter improvement in 6-minute walk distance represents clinically meaningful functional improvement in frail elderly patients. For context:

• Minimal clinically important difference in heart failure: 30-40 meters
• The observed improvement substantially exceeds this threshold

TIE-2 Biomarker:

The study identified TIE-2 (receptor tyrosine kinase involved in vascular stability) as a potential biomarker for responsiveness to mesenchymal stem cell therapy.

Why This Matters:

Mesenchymal stem cell therapies have historically struggled with:

• Unpredictable response rates
• Lack of biomarkers identifying responders
• Difficulty achieving regulatory approval

TIE-2 biomarker validation could provide:

• Patient selection criteria for Phase 3 trials
• Diagnostic-linked commercial pathway
• Predictable response rates supporting approval

Aging Frailty Market:

Frailty affects approximately 10-15% of adults over 65, representing millions of patients. No approved pharmaceutical therapies specifically target frailty, making this a high-unmet-need indication.

Novo Nordisk: $2.1B Oral Biologics Partnership

What Happened: Novo Nordisk inked a massive $2.1 billion deal with Vivtex to develop next-generation oral formulations for peptides and proteins using Vivtex’s GI-ORIS screening platform.

Technology Platform:

GI-ORIS uses “gut on a chip” technology to:

• Model human intestinal absorption
• Screen formulation strategies for oral delivery
• Predict bioavailability of large molecules
• Optimize oral formulations before clinical testing

Strategic Rationale:

Novo’s portfolio consists primarily of injectable therapies:

• GLP-1 agonists (semaglutide, liraglutide)
• Insulin products
• Factor VIII/IX for hemophilia

Oral formulations could:

• Improve patient convenience and adherence
• Extend product lifecycles through new formulations
• Compete against emerging oral alternatives
• Reduce cost of goods (oral manufacturing simpler than biologics)

Technical Challenge:

Proteins and peptides are poorly absorbed orally due to:

• Degradation by stomach acid and digestive enzymes
• Large molecular size limiting intestinal permeability
• Poor stability in gastrointestinal environment

Successful oral delivery platforms overcome these barriers through absorption enhancers, protective formulations, or chemical modifications.

Abcuro: Inclusion Body Myositis Program Termination

What Happened: Abcuro confirmed its KLRG1 antibody failed all primary goals in Phase 2/3 muscle disease trial, effectively ending the program’s development for inclusion body myositis.

Implication:

Inclusion body myositis remains an extremely challenging disease for drug development, with no approved therapies and consistent trial failures across multiple mechanisms.

Corporate Developments

GSK: $1B Frontier Biotechnologies Kidney Deal

What Happened: GSK licensed two siRNA (small interfering RNA) kidney disease assets from Frontier Biotechnologies for $40 million upfront and up to $963 million in milestones.

Strategic Positioning:

This continues GSK’s aggressive expansion into oligonucleotide therapeutics targeting inflammation-driven renal conditions, complementing the 35Pharma acquisition in creating a comprehensive renal/cardiovascular franchise.

Charles River Laboratories: Strategic Divestiture

What Happened: Charles River Laboratories announced the sale of its CDMO (contract development and manufacturing organization) and Cell Solutions businesses to GI Partners, and European discovery assets to IQVIA, for approximately $145 million total.

Financial Impact:

The divestitures will:

• Reduce 2026 revenue by approximately $200 million
• Add approximately 100 basis points to operating margin
• Add approximately $0.10 to non-GAAP earnings per share

Strategic Rationale:

Charles River is focusing on higher-margin core businesses:

• Preclinical research models
• Safety assessment services
• Discovery services

Divesting lower-margin CDMO and cell solutions businesses improves profitability even while reducing top-line revenue.

Quantum Surgical: J&J Microwave Ablation Acquisition

What Happened: Quantum Surgical acquired Johnson & Johnson’s NeuWave Medical microwave ablation system, integrating it into Quantum’s Epione robotic platform under new parent company Precision IO Group.

Technology:

Microwave ablation destroys tumors using electromagnetic energy to heat and kill cancer cells. The technology is used for:

• Liver tumors
• Kidney tumors
• Lung tumors
• Other solid tumors

Integration with robotic surgical platforms aims to improve precision and outcomes.

Policy & Public Health

HHS Vaccine Lawsuit: States Challenge ACIP Replacement

What Happened: A coalition of 15 states filed suit challenging HHS Secretary Kennedy’s replacement of the ACIP (Advisory Committee on Immunization Practices) committee, seeking to invalidate January’s childhood immunization schedule changes.

Legal Arguments:

The lawsuit alleges Kennedy:

• Unlawfully fired existing ACIP members
• Appointed replacements lacking scientific qualifications
• Violated procedural requirements for committee composition
• Changed immunization schedules without proper review process

ACIP Role:

The Advisory Committee on Immunization Practices provides evidence-based vaccine recommendations that:

• Guide clinical practice
• Determine insurance coverage requirements
• Inform public health policy
• Influence vaccine uptake nationally

Market Implications:

Uncertainty around vaccine recommendations affects:

• Vaccine manufacturer revenue projections
• Healthcare provider immunization programs
• Insurance coverage policies
• Public health planning

New Zealand: 30-Day Approval Pathway

What Happened: New Zealand is implementing a new 30-day verification pathway for drugs approved by two trusted regulators (FDA, EMA, TGA, Health Canada, UK MHRA, etc.) to drastically shorten domestic launch timelines.

Strategic Impact:

The pathway:

• Reduces approval timeline from months/years to 30 days
• Recognizes regulatory decisions from trusted agencies
• Accelerates patient access to innovative therapies
• Positions New Zealand as attractive market for rapid launch

International Precedent:

Similar reliance pathways exist in:

• Singapore (recognizes FDA, EMA approvals)
• Australia (has expedited pathways for certain approvals)
• Canada (Project Orbis for oncology)

New Zealand’s 30-day timeline is among the most aggressive internationally.

FDA: Impella Heart Pump Safety Warning

What Happened: The FDA issued a safety warning regarding Impella heart pump Generation 1 Purge Cassettes after four injuries related to cassette leaks, urging transition to Generation 2 components.

Device Context:

Impella is a mechanical circulatory support device used in:

• Cardiogenic shock
• High-risk percutaneous coronary intervention
• Heart failure support

The purge cassette is a critical component preventing blood clots in the device.

Clinical Significance:

Cassette leaks can lead to:

• Air embolism
• Device malfunction
• Patient injury

The FDA’s alert prompts healthcare facilities to transition to safer Generation 2 components.

Strategic Themes

The Activin Pathway Value Explosion

GSK’s $950 million acquisition of 35Pharma for a Phase 1/2 asset validates extraordinary market appetite for activin pathway therapies following Winrevair’s commercial success. This signals:

• Structural valuation surge for preclinical/early-stage cardiovascular assets
• High-conviction institutional positioning in PAH/PH-HFpEF mechanisms
• Acquisition appetite from major pharmaceutical companies lacking presence

Investment Implications:

Any companies with activin pathway programs, even preclinical, should experience valuation rerating.

Bispecific Safety Wall Persists

MacroGenics’ enrollment freeze following patient death reinforces that:

• Off-target toxicity remains primary hurdle for bispecific antibodies
• FDA tolerance for severe immune-related adverse events is declining
• Crowded oncology indications face higher safety bars
• Platform risk affects entire company valuations

Companies developing bispecific antibodies, particularly dual checkpoint inhibitors, face elevated regulatory scrutiny.

Regulatory Divergence: Flexibility vs. Rigor

The FDA simultaneously demonstrates:

• Flexibility: Ultra-rare framework enabling N-of-1 approvals with minimal data
• Rigor: Clinical holds for safety signals in competitive oncology indications

This creates bifurcated development environment where:

• Ultra-rare genetic diseases face reduced barriers
• Common diseases with existing alternatives face heightened standards

Frequently Asked Questions

Q: Why is GSK paying $950M for a Phase 1/2 asset?

Merck’s Winrevair validated the activin pathway commercially ($1.4B sales), proving market size and mechanism. HS235’s enhanced selectivity potentially addresses bleeding limitations that constrain current therapy. For a $18B market opportunity by 2032, $950M represents reasonable risk-adjusted investment if HS235 can capture significant share with superior safety profile.

Q: What does the Ultra-Rare Framework actually enable?

It allows approval of individualized genetic medicines (antisense oligonucleotides, gene editing) for ultra-rare diseases based on plausible mechanism and small-scale evidence rather than traditional Phase 3 trials. This could enable treatment of patients with unique genetic variants affecting only dozens or single patients globally—previously economically impossible.

Q: How serious is the MacroGenics clinical hold?

Very serious. A patient death from septic shock following bispecific therapy, combined with three other Grade 4 events, raises fundamental safety questions. If the safety review determines the toxicity pattern is mechanistic (inherent to dual checkpoint blockade) rather than manageable, the entire lorigerlimab program and potentially other pipeline assets could be jeopardized.

Q: Will HS235 actually have better safety than Winrevair?

Preclinical data suggests enhanced selectivity away from BMP9/BMP10 should reduce bleeding and telangiectasia, but this requires clinical validation. Phase 2 safety data comparing rates of these adverse events to Winrevair’s established profile will be critical. Theoretical advantages don’t always translate to clinical reality.

Q: What is TIE-2 and why does it matter for Longeveron?

TIE-2 is a receptor involved in blood vessel stability. Longeveron’s finding that TIE-2 levels correlate with mesenchymal stem cell therapy response provides potential biomarker for patient selection. This addresses MSC therapy’s historical problem: unpredictable response rates. If validated in Phase 3, TIE-2 testing could identify responders, improving success rates and regulatory approval chances.

Q: Why is Novo paying $2.1B for oral delivery technology?

Novo’s portfolio is heavily weighted toward injectables (GLP-1s, insulin, hemophilia factors). Oral formulations could: extend product lifecycles as patents expire, improve patient adherence and market share, reduce manufacturing costs, and compete against emerging oral alternatives. The investment reflects strategic imperative to develop oral capabilities.

Q: What happens if the states win the vaccine lawsuit?

If courts invalidate ACIP committee composition and recent recommendations, it could require: reconstitution of ACIP with properly qualified members, review and potential revision of recent immunization schedule changes, temporary uncertainty affecting vaccine coverage and clinical practice, and delays in future vaccine recommendations pending legal resolution.

Q: Is the New Zealand 30-day pathway good or risky?

It accelerates patient access to therapies already vetted by trusted regulators (FDA, EMA, etc.), which is beneficial for patients with serious diseases. Risk is minimal since drugs must have two regulatory approvals from recognized agencies. The main concern is ensuring adequate post-marketing surveillance in New Zealand’s smaller population.

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This analysis is for informational purposes and does not constitute investment advice. All information verified as of February 26, 2026.