Why MDNA11 and MDNA113 Are the Next-Gen IO Backbone Big Pharma Can’t Afford to Miss

After a Decade of Strategic Drift and Innovation Malaise

Introduction: The Illusion of Innovation and the Complexity Value Mirage

In April 2024, Barron’s published a damning and deeply introspective look at the prevailing dysfunction across Big Pharma’s valuation frameworks, provocatively headlined: Big Pharma Stocks Need a Rethink. The Stocks Aren’t Working (link in References). While this article used Pfizer as its case study, its implications cut across the entire industry. The critique was far more than a reaction to a single company’s recent stumbles—it was an indictment of an industry-wide capital strategy that continues to hemorrhage billions in search of complexity disguised as innovation. Pfizer, Merck, and Bristol Myers Squibb, once seen as conservative stewards of durable innovation, have devolved into acquisition-heavy, platform-chasing giants, often generating less shareholder return per dollar of R&D than any comparable sector in the S&P 500.

The pattern is now familiar: acquire late-stage assets at platform-level prices, divest consumer-facing businesses, redeploy capital into narrowly scoped biologics or hyper-engineered fusions, and call it innovation. But the cracks are showing. Most of these moves reflect a desperation to offset looming patent cliffs with short-duration gain rather than long-horizon strategy. Worse, these platforms often fail to integrate into broader therapeutic ecosystems, offering little room for biomarker-based expansion, tumor-agnostic deployment, or immune reconditioning. Platform optics mask pipeline fragility.

Nowhere is this misallocation clearer than in Pfizer’s trajectory. Since 2019, the company embarked on a hyperactive spree, acquiring Seagen ($43B) to gain ADC exposure, CTI Biopharma ($1.6B) for a narrow myelofibrosis drug, and spending another $2B on TL1A—an immunology asset targeting Crohn’s and ulcerative colitis. It also shed its consumer health assets, poured $50B into R&D, and booked more than $80B in COVID-era vaccine revenue. And yet, the outcome is sobering: a stock price that dropped 33% in five years, even as the S&P 500 soared. Investors rewarded none of it. The needle on long-term innovation confidence did not move.

This is not merely a misstep; it is structural failure. Pfizer’s aggressive capital rotation strategy failed to deliver resilience, growth, or investor trust. Its high-profile deals have generated few new value anchors and no demonstrable transformation in the company’s ability to address immune-resistant cancers—arguably the most urgent unmet need in oncology today. It reflects a deeper flaw in innovation strategy: equating molecular complexity with immune sophistication, and mistaking capital deployment for clinical momentum. This kind of complexity is not optionality—it is inertia.

Yair Einhorn’s framing—comparing TL1A’s narrow inflammation play to the broader promise of immune reprogrammers—further underscores this divide: Pfizer pursued symptom modulation; MDNA11 offers structural immune reset. It isn’t just that MDNA11 is a better molecule—it’s that it represents a fundamentally different model for rebuilding the immune interface with tumors.

This divergence is why MDNA11 stands out not only as a superior molecular design—but as a rebuke to the prevailing model itself. In this vacuum of system-aligned development, Medicenna stands out—not by doing more, but by building smarter.

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Part I: A Patent Cliff Without a Parachute

By 2030, Pfizer’s primary commercial revenue engines—drugs generating over $17 billion annually—will lose exclusivity. The firm’s response has been to double down on expensive, late-stage assets that are frequently narrow in scope and weak in platform leverage. One such acquisition was PF-06480605, a TL1A-targeting antibody purchased at a $2B valuation. While TL1A may play a role in autoimmune disease, it offers no known therapeutic value in solid tumors, checkpoint-refractory cancers, or the immunologically “cold” tumor microenvironments that dominate oncology’s unsolved frontier.

This strategy encapsulates a deeper flaw: mistaking molecular intricacy for clinical versatility. Pfizer and its peers have long operated under the assumption that biologic complexity is equivalent to therapeutic durability. But biosimilar erosion, payer skepticism, and mechanistic redundancy across cancer pipelines have invalidated this thesis. Today, complexity is more often a sign of desperation than foresight.

The Barron’s chart tracking multi-decade returns is devastating: despite high-profile approvals and deal flow, companies like Pfizer, Merck, BMS, GSK, and J&J have all underperformed the S&P 500 over the last 5, 10, 15, and 20-year windows. Only Eli Lilly and Novo Nordisk have beaten the index, and almost exclusively due to obesity drug tailwinds. Outside of those, the narrative is unambiguous: Big Pharma’s model is broken.

TL1A and CTI: Complexity Without Leverage

TL1A and CTI are both symptoms of a failing playbook, though they represent very different mechanistic domains. CTI’s JAK2 inhibitor pacritinib is a hematology drug for myelofibrosis—a narrow, chronic indication with a high toxicity burden and very little room for immunotherapy-style synergy or expansion. TL1A, on the other hand, is being developed for inflammatory bowel diseases like Crohn’s and ulcerative colitis. It is a legitimate target in autoimmune conditions, but one with no oncology relevance. TL1A has no crossover into solid tumors, no checkpoint synergy, no biomarker expansion, and no relevance to antigen escape, myeloid suppression, or T cell dysfunction. As Yair Einhorn noted in his April 2024 thread, Pfizer’s $2B valuation of TL1A represented a remarkable bet on a molecule with limited autoimmune utility and no oncology relevance—highlighting just how far the industry has drifted from therapeutic leverage toward inflated specialty valuations.

In both cases, Pfizer paid platform-level valuations for what are fundamentally niche assets. This pattern matches Einhorn’s broader critique—that Big Pharma is now routinely paying like it’s acquiring platform companies, while anchoring to assets that are mechanistically narrow, biologically siloed, and lacking immune-modulatory range. Neither CTI nor TL1A unlocks systemic leverage across oncology, nor do they enable strategic repositioning in immune checkpoint–resistant indications. This becomes even more glaring when viewed against the backdrop of Merck’s Keytruda franchise, which—though not owned by Pfizer—serves as the benchmark for what a strategic, durable IO platform looks like. While Merck faces its own patent cliff with Keytruda post-2028, it at least built its risk around a dominant IO platform. Pfizer’s IO exposure, in contrast, remains scattered and low-leverage.

Part II: The Merck–Halozyme Collision Revisited

The Merck–Halozyme litigation wasn’t just a legal skirmish—it was the downstream manifestation of a strategic miscalculation. Merck had relied on a familiar pharmaceutical playbook: extend the life of a blockbuster asset via formulation tweaks and delivery upgrades rather than by introducing fundamentally new biology. But in a post-patent, post–Zero Iinterest Rate Policy(ZIRP) era where payers scrutinize marginal utility and regulators are less tolerant of evergreening, that strategy is increasingly brittle.

By April 2025, Halozyme’s 15-patent lawsuit alleging Merck’s subcutaneous Keytruda infringed on rHuPH20 technology had triggered not just investor anxiety, but broader doubt about the viability of Merck’s outpatient conversion thesis. Licensing talks had failed. Halozyme, protective of its subcutaneous delivery franchise, had every incentive to make an example of Merck. And Merck had little leverage. Why? Because SubQ Keytruda was never granted New Molecular Entity (NME) status. This is not just a legal scuffle though—it is a structural fault line in Merck’s post-LOE (Loss of Exclusivity) strategy. And it is precisely this type of structural fragility that MDNA11—and its subQ-engineered counterpart, MDNA113—were designed to avoid.

That detail—the regulatory distinction between a new molecule and a new format—was the linchpin. SubQ Keytruda, despite being designed for push injection and ease of delivery, remains chemically identical to the IV version. The FDA recognized this, issuing only a supplemental BLA. With that classification came consequences:

• No reset on biologic exclusivity (the clock still ends in the 2028 range)

• No insulation from biosimilars unless the core molecule is reformulated

• No new pricing or reimbursement codes beyond administration billing

This left Merck exposed. It had invested in manufacturing, rollout strategy, and formulary discussions for a product whose legal protection was now both fragile and indirect. Even if it were to win in court, the best-case scenario would still yield only partial protection. A licensing agreement with Halozyme—if forced—would cut into margins, dilute differentiation, and undermine the very justification for the formulation’s existence.

The contrast with Medicenna is immediate and instructive. MDNA11 is an NME—by sequence, structure, and function. It isn’t derived from Proleukin or Bempegaldesleukin. It doesn’t depend on conditional logic or masking domains. It is a rationally engineered IL-2 superkine fused to albumin to optimize half-life and lymphatic delivery. It engages IL-2Rβγ exclusively, avoiding Treg expansion, and it avoids every known toxicity pitfall that plagued IL-2’s early generations.

Merck tried to extend relevance through formulation. Medicenna created relevance by engineering a molecule for unmet needs from scratch. This wasn’t retrofit. It was reinvention. And in today’s regulatory and reimbursement climate, that’s the difference between being litigated… and being funded.

In June 2025, Merck’s legal standoff with Halozyme became the signature failure of its post-Keytruda strategy. The biotech filed suit claiming Merck’s subcutaneous Keytruda formulation infringed on 15 patents relating to Halozyme’s rHuPH20 delivery platform, which facilitates rapid subQ injection through enzymatic extracellular matrix disruption.

This wasn’t a surprise. Merck had failed to license rHuPH20. Their attempt to bypass or work around the platform’s IP boundaries became the downfall of their most important life-cycle extension strategy. Keytruda, which generates over $30B annually, was approaching its IV patent cliff. SubQ was meant to redirect up to 40% of U.S. volume to outpatient injection settings by 2028. The subQ pivot was intended not only to preserve market share, but to re-anchor Keytruda inside outpatient infrastructure, where time, cost, and staffing pressures increasingly favor push injection over infusion.

This infrastructural pivot—meant to transition Merck’s flagship therapy into outpatient settings—was dissected in detail in our June 2 analysis, “An IL-2 Cytokine to Underpin the Architecture of Real-World Oncology.” There, we outlined how the absence of NME designation created not just a regulatory shortfall, but a commercial dead end: no exclusivity window, no reimbursement reset, and no IP insulation from Halozyme’s patented delivery platform. Merck’s legal entanglement was not incidental. It was a byproduct of trying to retrofit infrastructure onto a molecule never designed for it.

But by the time Halozyme filed suit in June 2025, the regulatory limitations were already baked in. Keytruda's subcutaneous formulation, identical in sequence to its IV predecessor, had been classified by the FDA as a supplemental BLA—not a New Molecular Entity. That meant no 12-year exclusivity reset, no biosimilar insulation, and no reimbursement differentiation. Merck’s entire outpatient conversion plan now hinged on either prevailing in court or paying royalties to the very platform provider it had attempted to bypass.

Contrast this with MDNA11: an NME by both structural and regulatory standards, with no third-party IP exposure, and a direct path to full exclusivity. Medicenna didn’t attempt to stretch an old franchise. They engineered a new one.

Part III: MDNA11 and the Simplicity That Rewires Immunotherapy

In the age of over-engineered immune platforms, MDNA11 represents a stunning act of restraint—and that restraint is exactly what makes it powerful. Where Big Pharma has layered on conditional activation domains, PEGylation shields, bispecific toggles, and costly cold-chain dependencies, Medicenna’s MDNA11 chooses architectural purity. It doesn't attempt to mimic natural IL-2 activity. It improves upon it.

At its core, MDNA11 is a monomeric β/γ-selective IL-2 superkine. It binds the IL-2 receptor β and γ chains but excludes the α chain (CD25), thereby avoiding the expansion of regulatory T cells (Tregs) and associated immunosuppressive toxicity. That distinction is not academic—it’s the difference between a drug that promotes tumor shrinkage and one that fuels immune dysfunction. But Medicenna didn’t stop at receptor refinement. They fused MDNA11 to human albumin, extending its half-life while enhancing lymph node trafficking—positioning it for systemic delivery without the crash-and-burn pharmacokinetics of first-generation IL-2.

What makes MDNA11 even more notable is what it doesn’t include. No PEGylation, which derailed Nektar’s NKTR-214. No antibody conjugates, which burden ADCs with manufacturing complexity and safety liabilities. No hyaluronidase, which entangled Merck in Halozyme’s IP. No conditional logic, which continues to frustrate tunable cytokines in development. MDNA11 is a study in streamlined potency—one protein, one fusion, one purpose: to prime the immune system for durable antitumor response.

And it’s working.

In the ABILITY-1 Phase 1/2 trial, MDNA11 has shown signals of efficacy across multiple cold and checkpoint-refractory tumors. In melanoma patients with prior anti–PD-1 exposure, it achieved a 29.4% objective response rate (ORR), including one complete response (CR) and multiple durable partial responses. In MSI-H tumors, it posted a 50% ORR—despite patient histories that included multiple failed therapies. It has demonstrated monotherapy activity in MSS colorectal cancer, which is considered virtually untreatable by immunotherapy standards. And its safety profile has been exemplary: low-grade toxicities, no vascular leak syndrome, no steroid premedication requirements.

These aren’t just clinical milestones. They are proof of architectural competence. Medicenna built MDNA11 with modern deployment in mind. It’s outpatient-ready. It’s compatible with checkpoint inhibitors. It avoids the Treg rebound that haunted Proleukin and the toxicity profile that buried bempegaldesleukin. It demonstrates a foundational immune reset—one that expands the stem-like TCF1⁺ CD8⁺ pool and supports long-term immune surveillance.

In comparison, Pfizer spent $43 billion acquiring Seagen, whose ADC platforms—though promising—still face deployment bottlenecks, cold-chain dependency, and increasingly crowded tumor label competition. It spent another $2 billion on TL1A, a cytokine asset with no proven oncology value, no checkpoint synergy, and no pan-tumor logic. These deals were not platform strategies. They were platform reactions—big swings made in the absence of internal biologic leverage.

Future applications of MDNA11 extend far beyond checkpoint combos (see my previous articles: (8) Undeclared, Unmodeled, Uncapped & it’s follow up article Gold Stars…). This is reinforced by emerging results in tumor types traditionally unresponsive to immunotherapy. Notably, two endometrial cancer patients in the combination cohort achieved a confirmed PR and a near-complete response (CR), despite one having prior checkpoint exposure. These outcomes suggest that MDNA11's immune remodeling effects may reach beyond the checkpoint-naïve and cold tumor spectrum into checkpoint-experienced yet still refractory disease. Together, these findings highlight MDNA11's modular potential across biomarker-dense and biomarker-absent malignancies alike. VEGF blockade, WNT inhibition, and even STING agonism could benefit from MDNA11’s TME remodeling foundation. It is a true anchor molecule—reprogrammable, portable, and scalable.

The chart below, featured in Barron’s and shared by analyst Yair Einhorn, highlights the $100B in blockbuster drugs facing U.S. patent expiration by 2030. As shown, Merck’s Keytruda ($25B), BMS’s Opdivo, and Pfizer’s Ibrance are among the most exposed. These expiring monopolies contextualize the urgency for next-generation immune solutions like MDNA11.

MDNA11 was developed on a fraction of that budget. Yet it has delivered not only responses but a redefinition of what IL-2 cytokines can do—without the baggage that pharma’s recent acquisitions brought with them.

This is not about bigger molecules. It’s about smarter ones.

Part IV: Market Opportunity and Execution Strategy

With over 1 million annual cases of advanced solid tumors in the U.S., MDNA11’s application across checkpoint-refractory indications positions it competitively within the $50 billion global immunotherapy market. If approved in just three tumor types—MSS CRC, endometrial cancer, and PDAC—the molecule could conservatively capture $2–3 billion in annual revenue based on 10–20% penetration in high-need populations. While WTX-124 and STK-012 are a part of the next wave of IL-2 innovation as well, neither has yet demonstrated clinical responses akin to MDNA11’s CPI-experienced or biomarker-agnostic solid tumors results. MDNA11’s projections, therefore, may ultimately exceed those of near-peers—especially given its emerging activity in cold tumors and large, high-value indications like endometrial cancer.

From a commercial perspective, the opportunity is expanding beyond salvage-line niches. While PRISM-11 previously modeled a $1.7–2.3B opportunity in MSS CRC, PDAC, and anal SCC (see Article 6: Confidence in Layers), the emergence of endometrial cancer as a viable high-margin indication materially expands this valuation. Notably, MDNA11 has produced a 50% ORR (2/4) in endometrial tumors—none of which were MSI-H—with at least one patient previously exposed to checkpoint inhibitors. This is highly consequential for Merck: the $28.9B global endometrial market (2023) is largely gated behind biomarker restrictions, and Merck’s Keytruda–Lenvima combo failed to expand label approval following underwhelming trial results.

If MDNA11 enables Keytruda to break into non–MSI-H endometrial cancer, it unlocks a multi-billion-dollar expansion in Merck’s women's health oncology franchise with limited competition and high payer tolerance. Analyst Joe Gantoss summarized it bluntly: “If MDNA11 can expand Merck's market share in endometrial cancer, it would be worth several billions.”

Part V: Combo Architecture as IP Expansion Strategy

What makes the MDNA11 + Keytruda combination uniquely valuable isn’t just efficacy—it’s the ability to generate new intellectual property across multiple billion-dollar indications where Merck’s current checkpoint strategy is gated, incomplete, or aging. In the post-ZIRP world, growth isn’t powered by new targets—it’s powered by IP-extendable combinations that deliver exclusivity, differentiation, and reimbursement leverage.

Take MSS CRC, for example. The confirmed PR in a TMB-H MSS CRC patient, combined with spatial transcriptomic evidence of immune exclusion and CD8+ margin trapping, suggests a reprogrammable subtype previously out of reach for Keytruda. A novel combination regimen here would qualify for new combo-based exclusivity, providing Merck with a strategic anchor in one of the last major immunotherapy white spaces.

The same applies to non–MSI-H endometrial cancer, where MDNA11 achieved a 50% ORR in the combination arm—an outcome not seen with Keytruda–Lenvima, which failed to expand its label. As analyst Joe Gantoss noted, even a moderate expansion into this indication could be worth several billion dollars for Merck. But more importantly, the regulatory and commercial pathway would be distinct, enabling a new BLA with its own data, timeline, and IP tail.

Critically, this logic also applies to MSI-H tumors like PDAC and gastric cancer, where Keytruda has only tumor-agnostic labels and weak payer adoption. MDNA11 demonstrated responses—including a confirmed CR in MSI-H PDAC—creating the foundation for indication-specific combo filings in settings where Merck currently lacks durable, reimbursed presence.

Across these verticals, MDNA11 offers Merck:

· Label-driven combo expansion in both MSI-H and MSS tumors

· IP protection timelines that outlast Keytruda’s primary patents

· The ability to anchor new exclusivity claims without needing new molecules

· And a scalable, checkpoint-compatible backbone with clean safety and fixed dosing

In this light, MDNA11 isn’t just an immune modulator—it’s a franchise extension tool for the largest IO drug on earth.

Part VI: MDNA113 — A Precision Payload with Tumor-Locked Logic

Where MDNA11 rewires the immune system at the level of systemic priming and lymph node reconditioning, MDNA113 takes the baton and delivers targeted tumor-site amplification. But it doesn’t do so with brute force—it does so with molecular intelligence, spatial precision, and complete independence from the infrastructure entanglements that derailed Merck’s subcutaneous Keytruda.

MDNA113 is a BiSKIT—short for “bifunctional superkine immunotherapy.” It is not a reformulated IL-2. It is not a PEGylated variant. It is not a prodrug hidden behind synthetic masking logic or antibody fusions with legacy toxicities. It is a rationally constructed, tumor-activated immune payload.

Here’s how it works:

• The core is Medicenna’s βγ-selective IL-2 superkine—the same reprogramming engine as MDNA11.

• That IL-2 is fused cis to an anti–PD-1 antibody. This allows checkpoint inhibition and cytokine activation to occur on the same cell, maximizing local T cell engagement while minimizing systemic spillage.

• A tumor-targeting IL-13Rα2 domain acts as a protective mask, keeping the IL-2 inert until it reaches the tumor.

• A protease-sensitive linker, cleavable by MMPs enriched in the tumor microenvironment, acts as the tripwire. Once cleaved, the IL-2 is unmasked and fully reactivated—only in the tumor site.

This is not hypothetical design. It has been validated in preclinical models:

• In IL-13Rα2⁺ MC38 flank tumors, MDNA113 induced complete tumor regression in 6 out of 8 animals.

• When rechallenged with the same tumor, 100% of those mice rejected new tumor growth—demonstrating long-term immune memory.

• Biodistribution studies showed sustained tumor localization with minimal systemic exposure.

• Importantly, peripheral cytokine spikes were absent. There was no global lymphocyte activation, no surge in off-target Tregs or NKs—just focused, localized immune engagement.

This is the subQ cytokine delivery platform Merck wishes it had. But unlike subQ Keytruda, which still uses the original pembrolizumab molecule and depends on Halozyme’s patented rHuPH20 enzyme for tissue diffusion, MDNA113 was engineered from scratch for the subQ era. It does not rely on any third-party platforms. It does not require special storage or infusion infrastructure. And most importantly, it functions as an NME—entitled to full exclusivity and protected IP.

But here’s the catch—and here’s the power.

Why MDNA11 Likely Boosts MDNA113

While Medicenna has not formally stated any sequencing relationship requirements relative to MDNA113 with MDNA11 to function optimally, our synthesis of their platform architecture, paired with independent research leads us to a clear working thesis: MDNA11 is the foundational priming agent that can boost MDNA113 to deliver its full potential.

MDNA113, though engineered for subQ delivery and tumor-specific activation, does not include albumin fusion. It lacks the pharmacokinetic tail and lymph node trafficking necessary to drive early expansion of TCF1⁺ stem-like CD8⁺ T cells—the very subset that checkpoint reactivation depends on. Its function is targeted and potent—but confined to the site of protease-triggered activation. MDNA11, by contrast, is albumin-fused, systemically circulated, and demonstrably expands memory-precursor immune populations. In our view, MDNA113 is not just boosted by MDNA11—it is primed by it. This isn’t theoretical synergy. It is architectural sequencing.

This layered design reaffirms a core thesis introduced in our June 2 article, “An IL-2 Cytokine to Underpin the Architecture of Real-World Oncology.” There, we proposed that cytokines like MDNA11 and MDNA113 are not simply biologic agents—they are structural assets. Their pairing doesn’t represent a novel combination. It represents an immunologic scaffold for CPI expansion. That same logic applies here: MDNA11 conditions the immune system, while MDNA113 amplifies the signal—at the right site, with the right specificity, and without systemic cost.

For checkpoint-resistant tumors, and for subQ cytokine deployment strategies, MDNA11 + MDNA113 is not a combo. It is a cascade. It’s immune choreography:

• MDNA11 primes the periphery and reprograms checkpoint-resistant tumors by rebuilding the immune network that anti–PD-1 agents need to work.

• MDNA113 enters afterward, delivering subcutaneous, tumor-specific payloads that activate only in the presence of MMP-cleavable signals and IL-13Rα2 expression.

This sequence—systemic reset followed by local execution—is something Merck cannot replicate with Keytruda, no matter how elegant the formulation or how persistent the legal fight. MDNA11 and MDNA113 represent not just immune intervention—but immune strategy.

Part VII: Merck, Meet Your Next Anchor

Keytruda is Merck’s defining franchise—but its durability is in doubt. With 42% of Merck’s oncology revenue tied to it and biosimilars expected post-2028, Merck must now extend Keytruda’s reach or risk a multi-billion-dollar freefall.

As argued in An IL-2 Cytokine to Underpin the Architecture of Real World Oncology, MDNA11 doesn’t merely amplify existing IO mechanisms—it resensitizes checkpoint-failed tumors by restoring stem-like memory populations, enabling renewed cytotoxicity under anti–PD-1 pressure. MDNA11 offers three things no other IL-2 program has demonstrated:

1. Checkpoint synergy in cold, biomarker-agnostic tumors

2. Durable T cell remodeling without toxicity trade-offs

3. Low-cost, combinable manufacturing without systemic risk

Merck already has a clinical collaboration with Medicenna. But absent full acquisition or structured co-development, the company risks letting this solution slip into the hands of a competitor—or worse, watching it scale independently while Keytruda wanes.

The visual below from Stifel Healthcare, widely circulated by analyst Yair Einhorn, reinforces the extent of Merck’s dependency on Keytruda: with projected 2024 revenue of $32.7B and 2030 projections slipping to $25.1B. This concentration risk is unmatched among peers, and further strengthens the rationale for MDNA11 as a modular, next-generation immune remodulator capable of backfilling Keytruda’s therapeutic footprint.

Part VIII: Deployment, Tariff Resilience, and Execution Strategy

In the evolving landscape of oncology, the distinction between a promising molecule and a successful medicine increasingly hinges on deployability. Modern healthcare systems, shaped by post-COVID realities, inflationary pressures, tariff considerations, and the shift towards outpatient care, demand therapies that are not only effective but also logistically feasible. Medicenna’s MDNA11 and MDNA113 are engineered with these imperatives in mind, offering a stark contrast to the complex strategies employed by larger pharmaceutical companies.

Design Features Enabling Seamless Deployment:

• MDNA11:

  • Manufacturing Simplicity: Produced in CHO cells using standard purification processes, MDNA11 leverages albumin fusion for half-life extension, circumventing the complexities associated with PEGylation or antibody conjugation.

  • Stability and Scalability: Its stability allows for administration in community infusion clinics, broadening access beyond specialized academic centers. It eliminates the need for cryogenic handling or genetically modified cell expansion, simplifying logistics.

• MDNA113:

  • Subcutaneous Administration: Designed for subcutaneous injection, MDNA113 does not rely on third-party technologies like Halozyme’s rHuPH20, reducing dependencies and potential licensing issues.

  • Tumor-Specific Activation: Featuring a tumor-specific activation mechanism via MMP-cleavable IL-13Rα2 masking, it ensures safety and efficacy when delivered outside traditional infusion centers.

  • Regulatory Advantages: As a New Molecular Entity (NME), MDNA113 secures exclusivity without the need for orphan designations or complex patent strategies.

Strategic Advantages in a Constrained Environment:

Medicenna’s approach addresses several critical challenges faced by the pharmaceutical industry:

• Tariff Resilience and Supply Chain Sovereignty:

  • The ability to manufacture domestically aligns with policies promoting industrial resilience, potentially mitigating tariff impacts and ensuring supply chain stability.

  • Unlike Merck’s SubQ Keytruda, which faces royalty-bearing agreements and manufacturing capacity constraints due to its reliance on Halozyme’s technology, MDNA11 and MDNA113 can scale through partnerships with U.S.-based CDMOs.

• Logistical Efficiency:

  • Both molecules are room-temperature stable, eliminating the need for cold-chain logistics, which are costly and complex.

  • Their production in standard CHO systems avoids the use of exotic or proprietary technologies, facilitating easier scale-up and technology transfer.

  • They are patent clean, free from PEG, viral vectors, or isotope carriers, and aligned with policy-led reshoring efforts, ensuring no IP minefields or licensing risks.

Synergistic Integration with Existing Therapies:

Rather than competing with established checkpoint inhibitors like Keytruda, MDNA11 and MDNA113 are designed to complement and enhance their efficacy:

• Sequencing for Optimal Immune Response:

  • MDNA11: Primes the immune system by expanding TCF1⁺ stem-like CD8 cells and reconditioning the tumor microenvironment, setting the stage for effective immunotherapy.

  • MDNA113: Deploys this primed immunity with precision, utilizing subcutaneous administration and tumor-specific activation to target PD-1⁺ exhausted cells directly.

This strategic sequencing not only amplifies the therapeutic impact but also aligns with the outpatient care model, reducing the burden on infusion centers and enhancing patient accessibility. It fits seamlessly into outpatient-compatible, immunologically rational, globally scalable oncology combinations, extending the reach of existing CPI assets rather than imposing additional regulatory complexity.

Learning from Big Pharma’s Missteps

The challenges faced by Merck with SubQ Keytruda serve as a cautionary tale. By attempting to retrofit an existing molecule for new delivery methods without fundamentally rethinking its design, Merck encountered legal and logistical hurdles, such as the April 2025 Halozyme lawsuit over patent infringement. In contrast, Medicenna’s proactive approach in designing MDNA11 and MDNA113 to be inherently suitable for modern deployment needs positions these therapies advantageously, with no PEGylation, hyaluronidase dependency, cold chain requirements, or licensing risks.

Frictionless by Design

In an era marked by payer fatigue, provider burnout, and geopolitical uncertainties affecting trade and supply chains, the streamlined architecture of MDNA11 and MDNA113 is not merely advantageous—it is indispensable. These molecules embody a new paradigm in immunotherapy: one that is not only biologically innovative but also operationally efficient and strategically aligned with the future of oncology care. By being frictionless by design, MDNA11 and MDNA113 are poised to integrate seamlessly into existing treatment frameworks, enhancing the durability and expansiveness of current therapeutic strategies, acting as catalysts rather than competitors.

PART IX: Conclusion- From Compatibility to Integration — MDNA11 and MDNA113 as the Backbone of Future Oncology

Merck and Pfizer did not fail because they lack great drugs—they stumbled because the infrastructure of modern oncology is no longer passive. The health system now demands therapies that align with outpatient constraints, pricing expectations, regulatory transparency, and mechanistic clarity. In this new model, deployment readiness is not an optimization layer. It is the floor.

Viewed in that light, MDNA11 and MDNA113 are not challengers to checkpoint inhibitors—they are complements. Amplifiers. Gate openers. In a future where Keytruda and its successors must continue to deliver value beyond their first-line legacy indications, cytokine-based immune remodeling is not a threat. It is a necessity.

MDNA11, with its clean monotherapy responses and ability to reverse checkpoint failure, offers a way to expand Keytruda’s label into tumors where anti–PD-1 agents have failed alone. MDNA113, with its tumor-localized, MMP-cleavable delivery and PD-1 checkpoint activation, offers the most precise subcutaneous follow-on to systemic priming yet conceived.

These are not competitive endpoints. They are handoffs. Sequential biology, designed for a 21st-century treatment sequence.

Checkpoint Renewal as Strategic Imperative

This is why Medicenna doesn’t need to disrupt or replace existing CPI franchises—it should be understood as a critical extension of them. The MDNA11 and MDNA113 platform does not compete with Keytruda; it enables it. Where checkpoint inhibitors face resistance, diminishing returns, or stalled label expansion, Medicenna’s cytokine architecture offers a biologically validated way to recondition the tumor microenvironment, restore immune responsiveness, and unlock treatment potential in tumors previously deemed ineligible.

For Merck—or any immuno-oncology incumbent—the opportunity isn’t merely to defend market share. It’s to re-anchor the strategic relevance of checkpoint inhibition for the next decade by integrating a platform that is mechanistically complementary, infrastructure-compatible, and regulatorily clean. Their frictionless architecture—no Halozyme dependency, no PEG, no cold chain—makes them deployable globally. Their IP integrity and NME classification make them protectable. Their biology makes them indispensable.

In that sense, the SubQ Keytruda story is not a warning. It is an invitation. For Merck, BMS, J&J, or any pharma serious about owning outpatient immunotherapy for the next 20 years, the Medicenna platform isn’t adjacent—it’s essential. The shortcut Merck took revealed the limitations of a retrofit mindset. The roadmap Medicenna offers isn’t just an alternative. It’s the new backbone. Merck and Pfizer tried to buy relevance. Medicenna built it. MDNA11 reprograms immune failure into checkpoint responsiveness. MDNA113 delivers that reprogrammed state into tumors, cleanly, scalable, and with no IP drag. Together, they represent the only IL-2 platform advancing with monotherapy responses, mechanistic clarity, and forward compatibility with outpatient deployment.

The shortcut Merck took led to litigation. The roadmap Medicenna followed leads to reinvention.

📚 References and Citations

1. Barron’s (April 2024). “Big Pharma Stocks Need a Rethink. The Stocks Aren’t Working.”
Link (via Yair Einhorn thread): Big Pharma Stocks Need a Rethink. Investors Keep Making the Same Mistake.
Referenced in: Introduction, Part I, and Part III

2. PRISM-11 Article Series (2024–2025).
Substack essays establishing foundational confidence tiers, CPI synergy models, and TAM projections.

o Article 1: Billion Dollar Layup

o Article 2: Beyond the Salvage Floor

o Article 6: Confidence in Layers

o Article 8: The Biomarker Mosaic

o Undeclared, Unmodeled, Uncapped and Gold Stars…
Referenced throughout: TAM modeling (Part IV), Combo architecture (Part V), Mechanistic cascade (Conclusion)

o For a deeper exploration of the cytokine-as-infrastructure thesis—including visual schematics and the outpatient-oriented logic of MDNA11/113 integration—refer to our June 2 article, “An IL-2 Cytokine to Underpin the Architecture of Real-World Oncology.”

3. Stifel Healthcare Equity Research (2024).
Oncology exposure chart widely cited in industry analysis of Keytruda’s declining exclusivity value.
Sourced and visualized in Einhorn thread (see above).
Referenced in: Part VI, Merck market risk modeling

4. T Cell Priming and Lymph Node Immunobiology

o Im et al., Cell Reports (2021): “TCF1+ stem-like CD8 T cells as the cornerstone of checkpoint response.”

o Kallies et al., Nature Immunology (2020): “Lymph node activation as a requirement for immunologic memory expansion in chronic tumors.”
These papers support the underlying rationale for MDNA11 as a priming scaffold for durable response to agents like MDNA113.
Referenced in: Part V, MDNA113 dependency modeling

5. Medicenna Investor Disclosures (2022–2025).

o AACR 2023 & 2025 Posters on MDNA11 and MDNA113

o Public MD&A reports on BiSKIT platform and IL-2 beta/γ engineering
Retrieved from: https://ir.medicenna.com/news-releases
Referenced in: Part III, Part V

6. Spatial Immunogenomics & Cold Tumor Remodeling (2023–2025)

o Ji et al., Nature Cancer (2023) – "Spatial reprogramming of immune exclusion in MSS colorectal metastases."

o Honigsberg et al., JITC (2024) – "Peripheral priming and stromal infiltration in TMB-H CRC: A spatial analysis."
Referenced in: Part V – CRC combo opportunity and spatially informed TME logic

7. Spatial Transcriptomics Atlas (June 2025)

o Nature Medicine / Cell Press consortium (2025).
“Spatial immune dynamics across checkpoint-ineligible tumors: colorectal, endometrial, pancreatic.”
Highlights CXCL9/10 boundary remodeling, TCF1⁺ T cell re-infiltration, and immune-excluded TMB-H MSS subtypes.
Referenced in: Part V – CRC expansion, spatial validation for combo-IP strategy

8. Fu et al., “IL-2–inducible T cell kinase (ITK) deficiency sustains CAR-T efficacy” (JCI, 2025) (JCI178558)

9. Einhorn, Yair (2024).
Analyst commentary and visual framing of structural oncology challenges.

· TL1A skepticism and platform misallocation: link

· Keytruda revenue cliff and oncology concentration risk: link
Referenced in: Part I, III, VI, and visual anchors in Conclusion

10. PersimmonTi (2025).
Commentary on Keytruda subQ formulation strategy and regulatory risk:

“Keytruda subQ: not an NME = no exclusivity.”
Source: Twitter/X commentary thread (May 2025)
Referenced in: Part II, Part IV

11. Gantoss, Joe (2025).
Analyst commentary on endometrial cancer TAM and commercial impact of MDNA11 + Keytruda combo. Discussed during and after AACR 2025.
Referenced in: Part IV, Part V

12. Source: FactSet, company reports. Chart reproduced in Barron’s (April 2024): “Blockbusters on Borrowed Time: More Than $100 Billion in U.S. Pharma Sales Face Patent Expiry by 2030.”