Sitting at our desks, between the ceaseless stream of Zoom calls and action items, we must from time to time take stock of the trajectory upon which cancer therapy seems destined to follow. Why? If for no other reason than the fact that seemingly anything and everything is being tried, and the long-term result – barring a massive rotation of fundings and partnering dollars away from oncology – could very well be the end of cancer as the formidable foe we now cower from. If its days are to be numbered, then let’s start counting.
As noted in the prior piece, we have set out to release a serialized sequence of contributions “in which we discuss next-wave biologics (proteins, cell therapies) and associated platform technologies including diagnostics that collectively appear poised to upend our entire approach to the management of cancer. Each subsequent contribution will be informed both by our understanding of emerging technologies and firsthand discussions with many of the leading innovator companies developing them. Companies of the likes of Tidal/Sanofi, Aleta, Obsidian, Abintus, Spotlight, Strand, and Xyphos/Astellas. We’ve spoken with them all, and while each offers a unique vision of the future, common themes are beginning to emerge.”
Before diving more deeply into the scientific rationale, value proposition, and competitive contextualization behind each of these companies and their associated technologies, we figured it helpful to first delineate some therapeutic paradigms, be they established or emerging, into which said platforms might be positioned. After all, not every company is telling the same narrative, and there may well be more than one narrative called upon to give each cancer patient – be they old or young, early stage or late, solid tumor or liquid – the fighting chance they need. So let’s start with the table of contents in this collection of narratives before jumping ahead in the story.
Write What You Know
There’s an old adage in writing which states that you should “write what you know.” It is a piece of writing advice that many aspiring authors are probably sick of hearing, but one that nonetheless serves as an excellent starting point for both nonfiction and fiction writers.
In biotech, when it comes to discovery and development of therapeutic technology, innovators may have the opposite problem: they act solely from what they know, perhaps too enamored of the science, giving too much credence to the innovation, often overweighting the uniqueness, sometimes losing sight of the so what, the clinical benefits that must accrue from a novel approach, whose value is not defined by the novelty alone. Said early-stage biotechs should be mindful of what their science means in the translational sense and how that science should be positioned in the strategic sense. Despite having done the hard work of inventing the technology, raising the funds, and showing it might work in animals or even human patients, an understanding of the strategic implications underscored by the technology is often lacking for companies developing new therapeutic approaches. Namely, let’s try to move past what a company and its technology is to what the platform needs to be positioned to achieve. That is, the so what of the approach.
So let’s pause for a brief moment to consider that in fact this is where we do spend a lot of time with our clients, who are mostly nascent, early stage, pre-POC biotechs. And while the mantra of “write what you know” is a sound adage, the insights we often provide for our clients is telling them the story they don’t necessarily know (or sometimes they’d rather not hear), so they can then be better prepared to relay a clearer, more believable, more meaningful story to investors, prospective partners, etc. For while money does still flow into companies with shiny new toys, and new MOAs and therapeutic modalities can garner significant startup funding, the next stage requires the realization, and the facts behind it, to demonstrate why new and novel divorced from the “so what?” can be a dangerous path forward.
Once upon a time in biotech’s (not too) distant past, novelty was valued in and of itself, but these days, and increasingly, in times of intense in-kind and broader competition, and even in the US in Oncology with an upping in payer scrutiny, the question of what clinical benefit, and for which patients, has become truly paramount. Differentiation, value proposition, positioning—these are our watch words. So the topics below are not academic, but real-world, critical decisions that each company, with its focus on a specific target and specific indications, must consider. Where clinical development strategy meets business strategy and triangulates with the unmet needs of patients.
Oncology-focused companies are each writing their own unique narratives, but certain themes are beginning to coalesce in this, the beginning of the end of cancer. Here are some initial thoughts, but please send us your comments on those stories we might’ve missed.
- Fit to Purpose: “The blockbuster model is dead.” “It’s a buyer’s market.” “Diagnostics are under-valued.” These, and similar adages, find themselves appended onto this narrative. Companies under this rubric are committed to breaking down barriers between the right therapy and the right patient. It’s an intuitive story, one that should appeal to a broad array of investors: develop sophisticated therapeutic technologies that are appropriately flexible in their amenability to tailoring towards myriad nuances that distinguish one patient, one tumor, from each and every other. Even those approaches within this category that stop short of personalization at such a granular level embrace the tenet arguing for a plastic solution against such an agile foe. Approaches of this ilk include the so-called universal cells coupled with soluble adaptor molecules, personalized antigen and TCR discovery-based platforms, and yes, even the somewhat dog-eared approach of expanded tumor-infiltrating lymphocytes (TILs), each of which both require and augur a futuristic standard of care characterized by facile genome sequencing, longitudinal monitoring, and real-time identification of actionable therapeutic targets. Provocative? Sure! But the savvy investor hesitates to throw open her checkbook with abandon, her imagination piqued but countermanded by concerns by the unprofitability of diagnostics, the dearth of actionable targets, the regulatory red tape obscuring line of sight between here and there. But, for those willing to anchor their dreams to sound strategic decision-making, disciplined Gantt charts, and a clear vision of both a perfect future and the future perfect, this is a story with gold at the end of its rainbow.
- Hit Hard, Hit Early: It’s no coincidence that we have this story following the previous one. For this is an idea that anchors itself to an empirical dogma that has gotten us so far in the war against cancer. It is an idea, in fact, that dates back to that War on Cancer, waged by Nixon, fought by Frei, Freireich, Farber, Zubrod, DeVita and others. The idea of hitting hard, hitting early. Knock cancer back on its heels from day one, ne’er to return. Snuff it out at the first sight of relapse, be it clinical, cytological, or biochemical. But while the philosophy remains unchanged from that advanced by those pioneers some 6 decades prior, those gaining traction on this type of story today are wielding a new set of weaponry, one that promises to build upon gains that have arguably left little headroom for improvements of comparable magnitude. In short, the low-hanging fruit has long been picked, and any hard-hitting approach worth its salt is one purporting to exploit unseen vulnerabilities in an opponent that has had to weather slings and arrows beyond compare. However, one mantra remains fairly consistent over the decades of evolving cancer therapy that any new approach must contend with: you cannot knock-out only 90% or 95% of the tumor, as you will inevitably face relapse. This recurrence, furthermore, is likely to be a further-evolved and Darwinian pressure-selected subset of tumor cells even better able to spread havoc. Enter cancer immunotherapy, the old-new approach of propping up host immunity to do what our direct shots arguably have never been properly equipped to achieve: total and lasting annihilation of cancer enhanced through a plasticity and adaptability to match that of the tumor. And so, a proxy war it will be, but one that may actually work. Hard-hitting bispecific antibodies, chimeric antigen receptor (CAR)-modified T-cells, antibody cocktails, regimens comprised of which may single-handedly be capable of not only destroying malignant tissue but effecting collateral damage, catalyzing a chain-reaction, stimulating a longer-lasting demilitarized zone into which future bad actors dare not tread. While this category admittedly extends beyond immunotherapy to non-immune based modalities (e.g., bystander effect of ADCs), we will restrict our discussion herein only to the former. It’s also worth noting that such a story is not mutually-exclusive with the application of sophisticated diagnostics, though their use in these cases would be positioned at the outset of treatment rather than, in the case of the prior category, with surgical precision throughout the course of a patient’s treatment history. Companies telling this story with their product candidates can and should hitch their wagon to the irrefutable truth that such an overarching strategy has worked time and again, and the pursuit of novel approaches towards such ends provide a compelling mix of clinical de-risking with pursuit of competitive and commercial white spaces.
- Democratized Care: There’s another story that has perhaps been whispered over the years, one that has embraced, if only tacitly, the limitations, consequences, and opportunities afforded by costly new therapies only available to the well-educated and well-resourced patient. “What about everyone else?!” this story shouts. Or perhaps more cynically, “what about those razor-thin profit margins?”, a question that inevitably has come to force boardrooms to reckon with the concept of competing on price and access. Without going into Op-Ed territory, let’s simply say that Pharma is an industry that has seemingly managed to circumvent the rules of supply and demand which dictate pricing in every other market. But pharmaceuticals have continued to become costlier, and at a rate many consider incommensurate with the value they create. Those left holding the bill, be it the insurance provider, the government, the hospital, or increasingly the patient, have become smarter and more organized over time. So yes, perhaps there is a market for those companies and technologies positioning themselves in alignment with this trend. Examples include in situ immunomodulators (“endogenous reprogramming”) or iPSC-derived NK cell therapies as alternatives to more costly, complicated, and toxic ex vivo CAR-Ts, administration of which must currently be restricted to tertiary referral centers that many patients cannot access. And this is without even venturing into the game-changing territory for cancer care that EQRx is blazing, along with emerging messaging from the likes of Checkpoint Therapeutics and Innovent/Lilly. The big bet here is that pockets of untapped profit lie fallow between the cracks currently playing host to costly novel therapeutics. As with those in the aforementioned first two categories, purveyors of this story must be visionaries committed to breaking trail, in this case upon a hillside thick with a history of premium pricing and customers dazedly slumped over the proverbial barrel. Good guys win in the end, and the message here is all about doing well by doing good.
- Tightened Innovation Loops: This is perhaps less a story than an idea starting to dawn on innovators as an ancillary to the translation of increasingly facile technologies. As we continue to reap deferred rewards first sewn with sequencing of the human genome, therapeutic technology is evolving to become both increasingly sophisticated and easy to manipulate. What we’re seeing, amazingly, are portfolio strategies in which the lead program serves merely as a stepping-stone to future products rather than the commercial Plan A’s they’ve always been dubbed. This story is largely unique to engineered cell therapies and their adaptor molecules, development of which can follow along tight circular, rather than linear, trajectories. The industry has long bemoaned the translational relevance of animal models, and the issue is only intensified with immunotherapies relying upon the complex interplay of human pathways. Whereas academics have always looked upon clinical trials as tools to learn about and optimize therapeutic options, industry-sponsored efforts have never been able to adopt such a stance. Until now, that is. Even if the blockbuster model is dead, commercial strategy must still rely upon the ability to advance really good products. So why not see how something works in humans and then course-correct or fine-tune accordingly? The x that must be solved for here is the ease with which therapies can be sequentially optimized. Returning to the first sentence in this paragraph, this is not only an idea starting to dawn on us, but quickly becoming a prospective strategy needed to compete among similarly-facile platform technologies. It is in many ways simply the technology-enabled and development timeline-facilitated next-gen version of the classic industry paradigm of Life Cycle Management strategy. While purveyors of this story will have the power of human data at their disposal, they and their investors must be committed to protracted developed costs and timelines, the omission of which leave their competition vulnerable to binary clinical failures due to efficacy shortcomings or life-threatening toxicity from their sub-optimal clinical candidates.
- Moving Beyond the “Location, Location, Location” View of Targets: Since the birth of monoclonal antibodies as a therapeutic modality, the function of antigen targets has been subsumed by their expression patterns. That is, targets are prized for having more homogenous expression on tumor tissue and less (or ideally no) expression on healthy host tissue. Targets have been embraced as an address that gets you to the house rather than an essential pillar keeping the house from collapsing upon itself. This again is less a story being told at the outset of platform creation, but in this case its one that can be appended post hoc onto any antigen-targeting technology. We spend a lot of time with clients asking us to help prioritize among different candidate targets, and one of the most overlooked criteria by many is that of target function. Afterall, cancers can evolve around most ablative events that take out massive chunks of its tissue, seeding future resistant tumors capable of surviving in the face of selective pressures to which it was previously exposed. But all things being equal, tumors are less likely to survive an attack on a target that not only lights it up but actually helps keep its lights on. Does patient prognosis correlate with target expression? Is the target known to serve a biological function beyond that as an appendage on the cancer cell’s surface? Such targets are difficult to identify, and once they are validated in the clinic they become lightning rods for competitive intensity. But antigen-targeting companies that ignore the function of their targets do so at their own peril. Assuming efficient workflows can be established, bespoke target- and targeting-identification approaches such as those being advanced by TScan/Novartis, Adaptive/Roche, and Achilles, may provide an optimal set of trade-offs between attractiveness and competitiveness of antigen targets. Multi-targeting and environmental-sensing technologies offer an alternative storyline whereby individual target function can be subsumed by an optimized mix of specificity and efficacy such that this play becomes a variant of the hit-hard, hit-early theme. Companies in this broad and growing category of approaches can boast their emphasis on the role of and actionability against the targets being pursued, a strategy that can help create formidable barriers to entry among such a crowded competitive landscape.
What’s in a story? After all, ours is an industry built on science and the people entrusted to shepherd it towards patients in need. Who cares what they say when its what they do that matters? Well, yes and no. The story being told by innovative biotechs is a surrogate for their appreciation of how value propositions align with emerging needs and the competitive context. We humans have been telling stories far longer than our ability developed to write them down. Our proclivity towards clever and compelling narration is woven into the fabric of our DNA. The good story-teller speaks power to truth. The good listener sees through smoke and mirrors, that which rings false. And the biotech executive who fails to comprehend, let alone convey, the strategic and positioning implications of her therapeutic technology may never have the opportunity to show the world what it can truly achieve.