The Longfellow Letter

An American inventor and the “Wizard of Menlo Park,” Edison’s work was underpinned by a philosophy of relentless, high-volume, and often brute-force iteration.

The C&C Take: Failure as a Luxury

This quote, long a favorite of ambitious founders, has become a liability. The Edison-era “brute-force” model—testing 10,000 compounds—is precisely what drove R&D productivity into the ground. The data is stark: Phase 1 success rates have plummeted to 6.7% , and biopharma’s R&D internal rate of return (IRR) has fallen to a non-viable 4.1% , well below the cost of capital. The market can no longer afford to fund 10,000 failures.
The issue is not failure itself, but its cost. The current “biotech squeeze” is a market-driven corrective. The new mandate is not “fail fast,” but “fail decisively and cheaply.” The successful modern leader is not a persistent inventor, but a capital-efficient strategist who knows precisely when to terminate a program.

MassBio 2025 Patient Advocacy Summit

Date: November 6, 2025    

Overview: The C&C Take: Patient advocacy is no longer a “nice to have” communications function but a core strategic imperative. As regulatory and payer hurdles rise, incorporating the patient voice early is a critical de-risking strategy. This event is for leaders who must integrate patient-centricity into trial design and commercial strategy.   

Pharma Partnering Summit

Date: November 13–14, 2025    

Overview: The C&C Take: This summit is where the “Search & Develop” model is actioned. With internal R&D budgets under pressure, the hunt for external, de-risked assets is paramount. A high-stakes event for C-suite and BD&L leaders whose pipeline strategy is built on acquisition and partnership.   

MassBio: 2025 R&D Reimagined

Date: November 20, 2025    

Overview: The C&C Take: This event is for R&D leadership. The focus is not on incremental science but on the “new technologies and services”  that promise to fix the productivity crisis. A crucial session for CSOs mandated to accelerate their science and find the platforms to do it.  

The events of the last 45 days illustrate a market forcing a “Great Rationalization.” A clear bifurcation is now evident. Capital is abundant for proven, late-stage, de-risked value. It has evaporated for high-risk, high-cost discovery.

Hemab’s $157M Series C: The Market’s “Blank Check” for De-Risked Assets

Summary: Hemab Therapeutics, with dual headquarters in Cambridge and Copenhagen, announced an oversubscribed $157 million Series C led by Sofinnova Partners, with participation from Boston VCs like RA Capital and Novo Holdings.   

The C&C Take: This is not a “hot” funding environment; it is a hyper-rational one. This capital is not for discovery; it is for execution. Hemab delivered positive Phase 2 data , and this $157 million is the reward, earmarked to fund the pivotal trial. The market is sending an unambiguous message: the price of admission for a large growth round is no longer a preclinical story, but de-risked, pivotal-ready assets.   

TScan’s Pivot: “Strategic Ruthlessness” Becomes the Mandate

Summary: Waltham-based TScan Therapeutics is halting its Phase 1 solid tumor trial and laying off 30% of its workforce (66 employees). The pivot dedicates all resources to its hematologic malignancies program following positive FDA feedback on a pivotal trial design.   

The C&C Take: A textbook example of the “strategic ruthlessness” required to survive. TScan traded a high-cost, high-competition “moonshot” in solid tumors for a clear, FDA-aligned registrational path in hematologic malignancies. This pivot, while brutal, extended its cash runway into 2027. The key driver was positive regulatory feedback. In this market, “FDA alignment” is a bankable asset that de-risks the path to-market, and TScan wisely consolidated all resources behind it.   

Biogen’s R&D Reorg: The “Search & Develop” Model Becomes Law

Summary: Following a “year-long assessment” by new research head Jane Grogan, Cambridge-based Biogen is again restructuring R&D, with layoffs and an explicit goal to “shift resources to external opportunities.”   

The C&C Take: This is the final transformation of a Boston anchor from an “R&D” engine to a “Search & Develop” (S&D) model. Biogen is effectively outsourcing high-risk, early-stage discovery to the VC-backed ecosystem, a pragmatic admission that its internal engine is too slow. For founders and VCs in Kendall Square, this is a bat-signal: Biogen’s checkbook is open for partnerships and acquisitions.   

Final Synthesis: The Great Rationalization

These three events are three acts of the same play. The market is forcing a “Great Rationalization.” Capital is abundant for proven, de-risked value (Hemab). It has evaporated for high-risk discovery, forcing small companies into ruthless focus (TScan) and large companies into an externally-focused innovation model (Biogen). The “middle ground”—the slow, well-funded R&D project—is dead.

The strategic challenge defining our industry is the structural collapse of R&D productivity. The average cost to bring a drug to market now exceeds $2 billion , and R&D’s internal rate of return has fallen to a non-viable 4.1%. For years, AI was an incremental tool for prediction, defined by the 50-year quest to solve “Anfinsen’s Dogma”: could a computer predict a protein’s 3D shape from its 1D sequence?  AlphaFold largely solved this , but it was a descriptive tool, not a creative one.   

The revolution we are witnessing, driven by generative AI models like RFdiffusion  and platforms from companies like Boston’s own Generate Biomedicines , is the inversion of this paradigm. We are moving from prediction to generation. The new model does not find what nature made; it designs a novel protein de novo to perform a specific function. This shifts drug discovery from “archaeology” to “architecture.”   

The strategic impact is the antidote to the productivity crisis. First, it compresses discovery-to-candidate timelines from years to months. Second, it allows for de-risking from “Codon Zero,” “baking in” properties like high-yield manufacturability and low immunogenicity from the start. Finally, it unlocks new modalities, like designing for previously intractable targets (e.g., GPCRs) or creating “switchable” proteins. This is not an IT upgrade; it is a fundamental change in the R&D engine.   

In the 1960s, Christian Anfinsen conducted a Nobel-winning experiment. He took an enzyme, ribonuclease, and chemically “unfolded” it into a useless chain. When the chemicals were removed, the enzyme spontaneously refolded perfectly back into its functional 3D shape. This simple, profound test proved “Anfinsen’s Dogma”: a protein’s 1D amino acid sequence dictates its 3D structure. This dogma established the “sequence -> structure -> function” paradigm that defined biology for 50 years and, as we discussed in our Developing Insights, set the stage for the GenAI revolution that is now inverting it.