White paper / Opinion
Edited by: Charles O. Johnson
Executive Summary
To maximize the impact of developing monoclonal antibody therapeutics against infectious diseases in and for LIC/LMIC environments, we must separate the effort to develop products which have an almost certain fate of commercial failure for the foreseeable future, from the effort to invest and develop a viable production infrastructure that can ultimately be utilized by the product pipeline to drastically de-risk product development and thereby significantly increase the chances of commercial success. This effort, along with precision-targeted funding to develop platform technologies enabling the leapfrog of mAb products to overcome typical LMIC infrastructure limitations must be the first steps taken before scarce resources are spent on developing actual products.
Download the PDF version:
Background
This piece was inspired by the Unitaid “Call for proposals: Establish viable business models for access to monoclonal antibodies in low- and middle-income countries” which is “…soliciting proposals to demonstrate feasibility and viability of business models that enable access to an affordable and sustainable supply of mAbs in LMICs, with a priority focus on mAbs for infectious diseases.“ This led me to ponder about the premise and practicality of what is trying to be achieved.
Access to monoclonal antibodies (mAbs) is important simply because it is a fantastic tool to fight all sorts of diseases. The numerous challenges and suggestions to make this access a reality in LMICs is explained in some detail in the online collaborative publication “Novel business models for accessible monoclonal antibodies for infectious diseases in low- and middle-income countries: Recommendations from a multistakeholder meeting convened by IAVI, Unitaid, the Medicines Patent Pool, and Wellcome” (herein referred to as the “Accessible MAb Publication”).
Cutting through (while not disregarding) all the flowery talk about humanity and compassion, the between-the-lines argument here is that mAb therapeutics seem mature enough considering how long it has been around and the increasing introduction of biosimilars into UMIC/HIC markets including players from China and India also making a foray. So now sort of seems as good as any time to make a push for everyone to have access to it, I presume the thinking goes. Well, I do not agree with this assessment.
You see, the global South, LIC/LMICs or however you try to group them, each region is unique in its situation and diverse as the genetic makeups and climates of these regions. The only common thread is underdeveloped infrastructure but the degrees and types of deficiencies are quite varied by State and region. Examples of weak infrastructure include the lack of a stable electrical grid to power a robust cold-chain distribution network or alternatively, advances in formulation technology to achieve locally ambient temperature stability, an insufficient pool of professionally trained labor to administer injections, the need for expansion of properly equipped medical facilities in which to do so, and sufficient healthcare budgets to pay for a more costly form of therapeutic on a per-patient basis compared to oral solid dosage forms or vaccines, etc. The list is long.
MAbs as a product category also depend on an extensive and robust upstream value chain to support production, distribution and administration. This supporting part of an industry is often overlooked by those without direct operational experience, despite the immense importance of a strong supply chain and experienced labor pool in maintaining quality, stability and controlling costs. And this is before even considering the magnitude of capital required to fund development programs and set up manufacturing.
The biggest reason I am skeptical about many of the recommendations within the Accessible MAb Publication is the heavily assumed reliance on aid funding underpinning the entire document. If the world and particularly LMICs have learned anything from the COVID-19 vaccine debacle, it must be that aid and philanthropy cannot be taken for granted or assumed. Therefore, all efforts must be made (and are to some extent) to plan and establish a viable, self-sufficient healthcare infrastructure.
Having said that, I am actually working to improve the healthcare situation in LMICs like most of you reading this, so let’s examine the situation in more detail and see if we can’t tease out a pragmatic plan that is viable and can simultaneously overcome the myriad challenges presented by a LMIC environment.
What LMICs have and lack in the mAb value chain
In terms of the typical drug development pathway, LMICs, owing to years of aid and establishment of numerous cooperative research institutions with the West have a surprising number of reputable research institutes that are capable of and actually perform identification and generation of drug candidates. Although limited in number, these institutions typically have a majority-Western-trained scientist staff conducting research in laboratories that are sometimes better equipped than many university laboratories in the US and Europe. And the quality of their research as well as passion for discovery is not any less than their international peers.
This surprise also extends to clinical trial infrastructure which, thanks to years of aid-driven product development efforts, the overall presence of functional ethics review boards in research hospitals make it possible to conduct sound clinical trials and research, although overall better quality control may be desirable. Unfortunately, everything else is almost non-existent.
Below is an overview of the major steps of a modern mAb drug development pathway and my admittedly grossly generalized evaluation of LMICs capacity of each, in the context of relative funding and size compared to UMIC/HIC counterparts:
Note that the steps have been grouped by color to represent research (light blue), development (powder blue) and commercial stages (dark blue).
I need to point out a few things here. First, as mentioned already, LMICs are capable of performing research and have been productive but are actually helpless when it comes to development and commercialization. It must also be noted that commercial stages are heavily policy-dependent. The nature of healthcare is such that without government involvement, a modern healthcare market cannot exist. Thirdly, pharmaceutical and biotech companies in UMIC/HICs have for the past two decades slowly moved away from pure in-house development and production to outsourcing a significant portion of development phase work to CROs (Contract Research Organizations) and CDMOs (Contract Development and Manufacturing Organizations).
Not shown here but just as critical is the near-complete absence of a local supporting supply chain. Fermentation chambers, centrifuges, nutrient powders, water filters, affinity columns, plasticware… You name it, it must be purchased from overseas and wait for months for delivery even for the most trivial of purchases. And you’ll be lucky if you didn’t have to pay off anyone during the import process, if you were lucky enough to make it even that far in the process which means you were fortunate enough to not be subjected to a government-imposed US dollar exchange restriction and could actually pay your vendor.
Also important is the availability of capital to fund the development work, which is generally difficult to come by in LMICs for the same reason mAb therapeutics are a difficult proposition. There simply is not a large enough market to entice investors with appealing returns. The same applies to setting up manufacturing which can conservatively run anywhere from $50 million into triple-digit million USD for competitive commercial-scale production. This can be equivalent to entire healthcare budgets of many LMICs.
Obviously, all of these components must be elevated above a certain level in order for local mAb development and production to become a reality. The only certainty is that it will take a long time to get there. I believe there is a certain order of activities in which to get there more efficiently, which we shall explore throughout this paper.
The state of mAb therapies: The nuance
The route of administration for marketed mAbs is more intravenous (IV) than subcutaneous (SC) in a roughly 70/30 split (Pitot A et al, 2022) signifying the challenges of biology and drug formulation, although it seems this situation is improving as newer products hitting the market – including the RSV mAb product Beyfortus® - are trending toward SC administration. But unless indications are developed for self-administration (which poses its own set of challenges), the gross deficit of professional healthcare labor in LMICs will continue to pose a bottleneck to widespread mAb therapy administration that cannot quickly be overcome.
A quick look at the entire list of 2023 FDA mAb approvals reveal refrigerated (2-8 ⁰C) storage conditions without exception. Without rectifying the lack of robust cold-chain distribution infrastructure – which was a major underlying reason for the disastrous COVID-19 vaccine rollout in Africa – no drug, mAb or otherwise is going to do much good.
A not so nuanced feature? The cost. And I’m not only talking about the drug substance itself but the total cost of delivering the product to the patient, including the injection device, transportation, storage and administration. Assuming SC or IM (intramuscular) administration, a pen-type injection device is not cheap by LMIC standards, especially as a single-use device. Avoiding an injection device may not make much sense as that would entail the additional labor cost of trained professionals to properly administer the shot. Manufacture the mAbs for pennies but if the injection pen costs $10 a pop, well…
So taking a look under the hood, these facts, combined with the underdeveloped situation of LMICs clearly suggest that mAb technology itself is in fact not as mature as needed to attain the widespread use to a similar magnitude enjoyed in HIC environments. Either logistics and administration infrastructure be developed at great cost over decades to emulate HIC environments or formulation and drug delivery technology advance significantly for new mAb products to leapfrog over most infrastructure requirements. Not to mention that we have to wait for healthcare budgets to catch up.
There is a silver lining, however. It just so happens that a vast majority of mAb therapeutics are produced from a common mammalian cell expression platform of Chinese Hamster Ovary (CHO) cells and the method of culturing those cells has largely settled into a fed-batch method of production. Without getting into too much technical detail, the modern mAb production framework has much more commonality than a typical chemical drug API (Active Pharmaceutical Ingredient) synthesis framework, making it conducive to setting up a common production infrastructure for shared use across many products. And this production commonality is precisely where we can start building a viable plan.
The truth about “viability” in the real world
The key operative and imperative here is “viable,” and therein lies the brutal truth: If it looked like the mAb opportunity could make money in LMICs, these calls for proposals would not need to be made. Viability in this context is a singular thing: Turning a profit – the more the better. Every idea and every penny must go into creating profit opportunities for an industry segment to lay its foundations on and grow organically. Everything else – the technologies, the products, the expertise, the regulatory framework – is pretty much useless if not prefaced by a clear and straightforward profit opportunity for all parties involved. And if a viable business model does not emerge, there will never be a sustainable industry.
The reason mAb therapies were commercially successful in HICs and propagated a healthy pipeline of drug candidates is because payers were willing to pay and patients were demanding better treatment options after burning through available therapy lines which were, in many cases, inadequate and stagnant for decades, i.e. rheumatoid arthritis and other autoimmune diseases. In LMICs where healthcare budgets are significantly subsidized and many patients often don’t have access to even first-line treatment options, mAbs may as well be as useful as a paperweight in the digital world.
MAb product development therefore becomes a tough proposition for LMICs and especially difficult when targeting infectious diseases. Viewed longitudinally, it is likely that all mAb applications for infectious diseases will remain as transient placeholder treatment options before handing over the heavy lifting of lasting prophylaxis to vaccines, ultimately relegating mAbs to emergency or immunocompromised patient use as witnessed in the case of COVID-19. It’s just how the immune system works, and why an infectious disease mAb therapy market is such a turn-off for investment.
As mentioned earlier, the fundamental argument for attempting to build up mAb capacity in LMICs is about having a tool “in case of emergency” not unlike a fire extinguisher. Almost everyone acknowledges there is no budget to accommodate mAb therapeutics in LMICs for the foreseeable future.
So unless there magically appears a few mAb therapies for infectious diseases difficult to replace with vaccines or chemical drugs it simply is impossible for infectious disease mAbs to become a viable business model. Considering how cheap and quick mRNA vaccines are to produce, I have a difficult time imagining how infectious disease mAbs can work as a standalone segment.
Another approach would be to attempt to build a substantial portfolio of infectious disease mAbs very quickly, thereby eking over the break-even point with a collection of a few dozen products. Except that this scenario is practically unattainable. The development costs of each individual development program will far outweigh the expected return on investment thereby risking stagnation and abandonment so often observed in new antibiotic development quests.
Adding insult to injury is the injection device issue where, while it is true that certain single-use insulin pen injectors cost as low as <$1 USD, annual volumes are in the billions. We have a bigger problem on our hands if humanity needs to pump out billions of injection devices for infectious diseases.
But as I analyzed above, the mAb product value chain is comprised of many different steps and parts, most of which are tightly intertwined with other areas of pharmaceuticals and healthcare. In other words, the effects of working on a particular part of the mAb value chain has implications reaching beyond that single mAb product and will almost certainly influence adjacent pharmaceutical and healthcare segments. Therefore, the return-on-investment proposition must not be anchored on mAb products themselves – especially not for infectious disease which is doomed – but revenue potential from adjacent business segments in the short- to medium-term and then maybe other indications for mAb therapeutics in the long-term.
An important point here is the truth that only local manufacturing is truly viable since foreign-based operators can always pick up and leave if conditions become unfavorable. I mean, pharmaceutical manufacturers simply cease to make critical drugs in their own countries of origin simply because they are unprofitable. And it is amusing to observe how fast the ESG headlines disappeared from corporate filings upon the economic downturn and executive job security became uncertain. Corporate management is beholden to shareholders, and shareholders care about the bottom line before anything else. This is the historically proven truth.
Realistically speaking, technologies and economic development necessary to make mAb products viable in LMIC environments and situations are decades away. I’m talking about securing ambient temperature stability, SC/IM self-administration and accompanying affordable injection devices, sustained-release formulations for single-visit or take-home therapy courses, a robust cold-chain logistics infrastructure etc. I’m also talking about governments making good on their promise to fund universal healthcare by increasing budgets to match pledged percentages of GDP and independent, tax-funded public health budgets sufficiently large enough to purchase mAb therapies for its population. Some of these challenges can be overcome with investment and sound policy, while some technological problems may simply be insurmountable because of biology and nature. What is clear, however, is that now is not the time to try and establish a commercially viable mAb product segment in LMICs, not the least for infectious diseases. It is simply not feasible nor viable.
What do we do then? Do we throw up our hands and give up? Absolutely not. I fully agree with the statement made in the Accessible MAb Publication: “Dismissing the need for expanded access to mAbs as an insurmountable challenge is not acceptable…” And didn’t I say a few paragraphs ago that we can start building a viable plan based on the commonality of mAb production technology while I just completely trashed any hope for a mAb product segment? Yes I did, and I meant both.
Having your cake… but not eating it (yet)
To summarize what we have established so far:
In the mAb therapeutic value chain, LMICs are most deficient in drug development infrastructure, despite possessing a fair capacity for discovery research,
Current mAb therapeutic technology is not amenable for widespread, mainstream administration in LMIC environments,
Modern mAb production technology has converged into a common methodology,
MAbs for infectious diseases will not be a substantial nor stable market for the foreseeable future, if ever.
Reverse-engineering from our findings, for mAbs as a category to be a viable proposition in LMICs we must:
Address the development gap between the discovery and clinical trial stages
Develop technology to leapfrog infrastructure limitations of LMICs (because it is cheaper and faster than building out infrastructure)
Engender a wholistic healthcare market to make the mAb class of pharmaceuticals – including mAbs for infectious diseases – a digestible product class within payer budgets
There is a perfect model that can accomplish a significant portion of the abovementioned roadmap, namely, the CDMO model. CDMOs neatly address the gap (sans the candidate screening) between drug candidate and clinical trial and are third-party services accessible to any and every party. Disregarding regulatory policy and healthcare budget for the moment as they are outside the scope of this paper, focusing on setting up strategic CDMOs and a robust supply chain to support efficient operations is the shortest viable path to setting the stage for future mAb drug class success. This is not a new idea either. TSMC of semiconductor fame, is a benchmark case study and presents a fantastic game plan for setting up a strategic CDMO. Another benchmark from the semiconductor industry would be Micron, which is focused on critical-but-not-cutting-edge chips that, without hyperbole, make our modern world run. Although the latter is not a CDMO per se, the importance of having an entity within the local value chain fulfilling the role of critical part supplier cannot be understated and teaches a lesson on how a bespoke hybrid CDMO model could be wise for LMICs.
A strong local CDMO backbone can serve as a metaphorical highway to efficiently bring the many mAb drug candidates collecting frost in the freezers of LMIC research institutions up to clinical trial snuff, complete with globally competitive GMP and quality management systems for approval anywhere in the world, not just for domestic markets. And the fact that the CDMO is locally based can provide the opportunity for developers to better control costs while also significantly reducing the risk of geopolitical and other external factors influencing development.
But there is a catch. That darn viability. We cannot sit idly by, twiddling our thumbs after setting up shop and wait patiently for the drug candidates to first find a commercial champion, then get funded before coming through to our CDMO doors. If licensing and funding were that easy to come by, this whole CDMO gambit wouldn’t really be necessary. So what to do?
Ideally, revenue could be generated immediately if a few marketed products could be manufactured under contract – starting as a CMO. One such product could be the RSV antibody product nirsevimab-alip (Beyfortus™) by AstraZeneca (which is also CHO cell-based) or the Phase 3 programs for S. aureus and P. aeruginosa from Aridis Pharmaceuticals. To further sweeten the pot and expand the revenue stream, a CMO deal that includes regional licensing could allow local pharma companies to gain valuable experience in marketing and handling mAb products. People in LMICs get all the same diseases as their counterparts in HICs including cancer and rheumatoid arthritis. So if the well-heeded albeit small but growing out-of-pocket (OOP) market is targeted, niches of demand could be found here and there, particularly in metropolitan regions. Perhaps lot-splitting or other operational tricks could be used to ensure a stable, high-quality, supply for the local market at low volumes while still fulfilling the contractual supply obligation to the originator as a CMO.
Building on this revenue, the CMO business can naturally morph into a full-fledged CDMO or even CRDMO for turn-key scale-up and manufacturing of mAbs as originally planned, further enhancing viability while simultaneously preserving and nurturing local capacity to rapidly scale-up and produce on-demand. A Samsung Biologics (~$2.3 B USD revenue in FY 2022) or WuXi Biologics (~$2.2 B USD revenue in FY 2022) of sorts for the region doesn’t sound too shabby.
This CDMO backbone can keep the segment warm and ready until the rest of the pieces, i.e. healthcare budgets, regulatory framework and an investor pool etc. can catch up to accommodate the mAb product class as another staple treatment option. And if an epidemic or another pandemic strikes in the meantime, LMICs will be ready to independently and rapidly develop and produce mAb therapies through the CDMOs in conjunction with local research institutions and government health offices.
This CDMO idea is to prepare, as much as practicable, a sustainable and viable business model that can fill in most of the gaps of LMIC infrastructure while maintaining the sobriety to acknowledge that many, many things must fall into place for mAbs as a product class can become truly viable.
Closing thoughts
The difficult truth about reality is that it must be confronted. LMICs need decades of steadfast investment to get to a point where mAb therapeutics in their current product manifestation can work as another treatment option. Even if some arm twisting, coercion and appeals to humanity can somehow get existing pharmaceutical companies to participate in some sort of local mAb manufacturing endeavor, we have seen much too often that the profit motive ultimately prevailing. Over decades we have witnessed a trail littered with “corpses” in terms of well-intentioned initiatives that made the donors feel good but ultimately ended up in new factories and equipment collecting dust because funds eventually dried up. And the stubborn focus on “getting things” to LMICs instead of fundamentally building up capability for LMICs to be independent, equal and (ironically) ultimately more lucrative trading partners has meant that very little, if any added value remained in those countries receiving aid to be reinvested for growth. A toxic and vicious cycle if there ever was one.
Heavy aid-subsidization of health budgets and time-limited grant-funded programs, coupled with the nearly universal single-payer, monopsonic structure of healthcare procurement in LMICs almost ensures instability and volatility of the revenue source for a given pharmaceutical company. This mercurial situation significantly elevates the risk profile of return on investment (ROI) calculations and is the major turn-off for business investment.
Therefore, in our present time and the foreseeable future, a truly viable mAb attempt (or any healthcare industry establishment attempt for that matter) must start on the premise of earning sustainable revenue. And considering the non-existent value chain and dearth of products applicable to LMIC budgets and situations, the most pragmatic solution for mAbs would be to setup a consolidated contract manufacturing facility to produce existing products and establish a revenue stream that can be extended by pooling nascent regional/continental production demand. This would at least hopefully establish a viable foundation that could make the LMIC mAb manufacturing sustainable. And when revenue and sustainability is visible, risk is reduced and investors all of a sudden become interested. Only then can mAb product development can commence in a sustainable, virtuous cycle.
References
IAVI, Unitaid, Wellcome, Medicines Patent Pool. (2023). Novel business models for accessible monoclonal antibodies for infectious diseases in low- and middle-income countries: Recommendations from a multistakeholder meeting convened by IAVI, Unitaid, the Medicines Patent Pool, and Wellcome . Unitaid.
Pitot, A., Heuzé-Vourc'h, N., & Sécher, T. (2022, August 26). Alternative Routes of Administration for Therapeutic Antibodies-State of the Art. Antibodies (Basel), 11(3), 56.
Unitaid. (2023, December). Call for Proposals: Establish viable business models for access to monoclonal antibodies in low- and middle-income countries. Retrieved from Unitaid: https://unitaid.org/call-for-proposal/establish-viable-business-models-for-access-to-monoclonal-antibodies-in-low-and-middle-income-countries/#en
Kommentare