In a First for a Rare Cancer, Merck Secures FDA Nod for WELIREG — But Market Access and Safety Risks Loom Large
A New Chapter for a Neglected Cancer
The U.S. Food and Drug Administration has approved Merck’s WELIREG® for patients aged 12 and older with advanced pheochromocytoma and paraganglioma . These ultra-rare neuroendocrine tumors—affecting an estimated 2,000 Americans annually—have long lacked systemic treatment options, leaving patients and physicians tethered to surgery or off-label regimens with modest effect.
The FDA’s green light, based on the Phase 2 LITESPARK-015 study, grants WELIREG the distinction of being the first oral, systemic therapy specifically approved for advanced PPGL. But while the label fills a long-standing treatment void, its real-world adoption faces a gauntlet of diagnostic, financial, and safety challenges that go well beyond the typical oncology launch playbook.
Clinical Results Offer Durable, If Modest, Gains
In the pivotal trial, WELIREG demonstrated a 26% objective response rate in 72 patients, with a median duration of response reaching 20.4 months—both meaningful in a disease where no systemic oral options had previously existed. Notably, roughly one-third of patients also saw a sustained 50% or greater reduction in blood pressure medication usage over six months, a vital clinical win given the hypertensive burden tied to catecholamine-secreting tumors.
Despite the headline figures appearing conservative compared to WELIREG’s performance in other cancers—such as the 49% ORR seen in von Hippel-Lindau–associated renal cell carcinoma—the PPGL results are clinically significant. “This is not a disease where you’re chasing high shrinkage rates,” noted one oncology specialist at an academic center. “It’s about symptom control and safety—making sure these patients don’t go into crisis.”
A High-Cost Entrant in a Low-Incidence Market
While Merck’s move to capture this orphan oncology niche has scientific merit, the commercial story is more nuanced. With an estimated U.S. incidence of only 2,000 new PPGL cases annually, the total addressable market is small, yet lucrative. At a list price of roughly $26,400 per month, potential annual revenue could top $600 million if all eligible patients were treated—though analysts widely anticipate lower real-world uptake due to infrastructure and reimbursement constraints.
Last year, belzutifan generated $509 million in global sales across all indications. Analysts see the PPGL approval contributing an incremental $150–250 million annually, a figure that, while modest in Merck’s broader portfolio, bolsters the narrative of HIF-2α inhibition as a scalable commercial platform.
The Competitive Void—and Why It Matters
Until now, patients with unresectable or metastatic PPGL had little beyond palliative options. Radiotherapeutic Azedra, approved in 2018, showed clinical benefit but was withdrawn in 2023 due to poor uptake and manufacturing hurdles. Off-label treatments—such as tyrosine kinase inhibitors sunitinib or cabozantinib—remain viable but lack regulatory backing and carry complex side effect profiles.
WELIREG’s oral route and favorable pharmacokinetics set it apart. “You’re looking at a once-daily pill versus nuclear isolation or infusion therapy,” said one health economist. “That kind of convenience matters, especially in diseases where specialist centers are few and far between.”
The Safety Trade-Off: Anemia, Hypoxia, and Monitoring Demands
The clinical narrative isn’t without caveats. Nearly all trial participants experienced anemia, with 22% facing Grade 3 events. Hypoxia was also a concern, affecting 13% of patients, with 10% experiencing severe (Grade 3) episodes. Both side effects carry black-box warnings and necessitate vigilant monitoring of hemoglobin levels and oxygen saturation.
These requirements could stretch already-thin oncology clinic resources and create logistical hurdles, particularly in community settings. “It’s not a plug-and-play drug,” one specialist warned. “If you don’t have the infrastructure to track labs and pulse oximetry weekly, this could become problematic.”
Adoption Barriers: From Underdiagnosis to Payer Scrutiny
Beyond safety, real-world uptake faces structural headwinds. PPGL’s rarity means underdiagnosis is common, with many oncologists encountering only one or two cases in a career. Genetic testing infrastructure remains patchy, and multidisciplinary centers with PPGL expertise are clustered in urban academic institutions.
Reimbursement will also be a friction point. Value assessments in analogous settings have shown cost-effectiveness ratios north of $300,000 per quality-adjusted life year , well above accepted thresholds. While WELIREG is shielded from Medicare price negotiation under current rules for single-orphan-use drugs, commercial payers are likely to demand rebates or outcomes-based arrangements.
What Comes Next: Data, Europe, and Downstream Options
Looking ahead, Merck’s to-do list includes launching confirmatory trials that move beyond response rates and into progression-free and overall survival endpoints. Real-world data through registries will be critical in validating benefit across broader populations. Regulatory filings in Europe and other markets are in motion, with conditional EU approval already granted in February 2025.
Meanwhile, biomarker refinement and combination strategies—particularly pairing WELIREG with checkpoint inhibitors or TKIs—may expand the therapy’s reach. Merck also faces the longer-term challenge of preparing for generic competition post-2031, though formulation IP and patent extensions may provide a buffer.
Strategic Implications for Merck: More Than Just Numbers
For Merck, WELIREG’s third FDA approval may not significantly move the P&L in the near term, but it sends an important message to investors: the company can execute post-Keytruda, not just with mega-blockbusters but in disciplined rare-disease launches.
The 2019 acquisition of Peloton Therapeutics, which brought belzutifan into Merck’s fold for $1.05 billion, now appears increasingly prescient. Each new indication not only extends the drug’s revenue arc but also validates the commercial potential of targeting HIF-2α—a once-niche mechanism now gaining traction.
A Calculated Advance in a Narrow Field
WELIREG’s approval marks progress in a space long defined by medical inertia. Yet that progress is conditional—not just on molecular response, but on the healthcare system’s ability to identify, monitor, and afford treatment for a tiny but vulnerable population. For patients with PPGL, it’s a long-overdue step forward. For Merck, it’s a carefully calculated bet on a small population, high-price model that could inform the next era of oncology strategy.
Bottom Line: WELIREG’s entry into the PPGL space may not yield blockbuster revenues, but it sharpens Merck’s post-Keytruda playbook—balancing science-driven rare-disease expansion with pragmatic commercial execution. For now, it’s the only systemic oral therapy in its class—and for a neglected patient population, that alone changes the stakes.