By Wayne Koberstein, Executive Editor, Life Science Leader magazine
Follow Me On Twitter @WayneKoberstein
Targeted drugs and personalized medicines are supposed to be the alternative to the billion-dollar-plus blockbusters that long drove Big Pharma R&D, marketing, corporate strategies, and consolidation. Now almost all large companies only mention blockbusters when they appear to stumble upon them. Many declare their commitment to research driven solely by medical need, and to “finding the right drug for the right patient,” regardless of market size. But does that strategy really serve patients — or unbridled pricing? With the decline of mass-market drugs has come the rise of “orphan blockbusters” — drugs with small populations and such high price tags that they generate revenues comparable to the preceding mass-market products — and create a new surge in medical costs.
The trend may be an excellent boon to companies large and small, but it is unlikely to be sustainable. Any practice that puts patients and payers in the position of choosing between treatment and financial crisis may come with an expiration date. Perhaps it is time to re-examine the proposition.
“The blockbuster model is alive and well, if compounds can be found that deliver high pharmacoeconomic benefits to large populations of patients,” says Eric de La Fortelle, CEO of therapeutic-antibody developer Delenex Therapeutics AG and a former global head of technology partnering at F. Hoffmann-La Roche. (See “Blockbuster Values.”)
Like de La Fortelle, most other experts contributing to this article seem to agree on this general point: Big-market blockbusters and “me-too” drugs may return as a worthy industry goal — but only if the ante is raised. Compared to the mega-drugs of the past, future blockbusters will need to reach a much higher bar of safety, efficacy, and affordability, likely trading premium prices for higher volume at lower margins.
Whether the future belongs to blockbusters or niche products is a high-stakes question for all innovator companies, large and small. Companies must gamble now on which direction they will take in research, though it will be many years before they know if the data and the market conditions justify their choice.
Are there any ways to hedge the bet: actions companies could take to avoid over-reliance on the niche model? One logical way is to place greater priority on exploring platforms that could expand, even if from an initial narrow target, to achieve breakthroughs in broad therapeutic areas — in a word, blockbusters.
Busting The Old Model
Of course, the matter is more than theoretical. Some companies, in some situations, have succeeded in developing products with mechanisms of action (MOAs) that apply to wide or multiple therapeutic areas. Other companies have such products still in development, and still others are seeking wider markets for existing drugs through new strategies such as novel delivery technologies. But with the preponderance of conventional wisdom now favoring niche and targeted drugs, those products are perhaps the exception that proves the rule. Shifting the balance significantly would require a more conscious commitment by companies to the search for broader MOA platforms and products. At least one company claims to have made the shift:
“We believe in the paradigm by which you can ultimately build to a blockbuster even if each separate disease, though an important unmet medical need, may not be a very large commercial opportunity,” says Rob Bazemore, CEO of Janssen Biotech. “That paradigm of success will carry us into the future.”
Does such a shift mean a return to market-driven R&D, where sales potential outranked science in a company’s research agenda? The answer is a qualified no — on the condition that patient and payer needs, not revenue goals, guide the critical decision-making in product development.
The last point calls for a short pause while the cynics sneer. Yet there are sound, practical reasons why companies should take such an approach, not the least among them is that patients and payers will demand it. Moreover, there is a growing awareness among company executives that the industry cannot continue with a “selfish” model of product development and pricing for either niche or blockbuster drugs, again because of external pressures and demands. Even if it is ultimately self-serving, companies must not only do good, but be seen as doing good, in the healthcare environment.
Challenging The Targeted Trend
Oncology offers the clearest contemporary examples of how the performance of many targeted drugs has fallen far short of their promise. Tumors routinely develop resistance to drugs targeting molecular pathways. What seems like a wealth of molecular and genetic targets in tumor cells may actually reflect their unfathomable heterogeneity.
Cutting off one pathway, or silencing a given gene, typically causes the tumor to find and use another one to stay alive and grow. Preselecting patients based on genetics or biomarkers may thus produce only modest or short-term benefits at best, followed by a fall-off in efficacy and, in many cases, a sharp rise in harmful side effects.
Although the imbalance of promise versus payoff is less obvious with targeted medicines for other diseases, the hazards are similar: drug resistance, molecular and genetic complexity, ambiguous biology, and murky pharmacokinetics, to name just a few. When targeted drugs fail to produce the breakthroughs once promised, pricing becomes an even more sensitive issue. Pressures on pricing are pulling companies in two opposite directions: stakeholders push upward; payers pull downward. Neither side is satisfied.
In the niche-product environment, companies also feel pressure on another front — to hype all potential advances, the earlier and more tenuous, the better. Sadly, journalists too often oblige with headlines and glowing copy touting the latest potential cure for cancer or other diseases, which is almost always based on bench science or preclinical studies and almost never bears fruit in the long run. People pushing the hype are rarely around when the trail grows cold.
Targeting is nothing new in pharmacotherapy. What is new nowadays is the “microtargeting” of ever tinier patient populations based on testing for distinguishing biomarkers. Single diseases are “recognized” as consisting of multiple conditions, each one requiring a unique treatment with its own MOA.
In the ultimate logical extension of the concept, doctors would diagnose every patient down to the molecular and genetic level and synthesize a compound specifically for that patient — all in the course of a single office visit. The entire biopharmaceuticals business would thus be reduced to one piece of physician-operated equipment.
Before we reached that Star Trek future, however, nearly all drugs would be linked to separate diagnostic tools, and the entire healthcare system would groan under the weight of their ballooning costs. Clearly, the system will look for more cost-effective alternatives, rewarding approaches based on disease mechanisms that affect many different patients. The niche products defined mainly by their limited efficacy would then wither on the vine; only those targeted at true orphan conditions — rare diseases with no other treatment options — would gain acceptance.
Of course, merely wishing for broad-based treatments does not make them appear. But current scientific and business trends may make them likely. Already active areas include antimicrobials, anti-inflammatories, metabolics, and immunotherapies for cancer and other conditions.
“The most obvious opportunities for new blockbusters may appear to be drugs against previous ‘undruggable’ targets, but there are also significant opportunities built around known targets and well-established pharmacology,” says Abbie Celniker, CEO of the therapeutic protein optimization company, Eleven Biotherapeutics.
Recently, I reported on Novadigm’s development of a vaccine engineered to generate a single antigen against members of two different kingdoms, bacteria and fungi (staph aureus and Candida) primarily to prevent sepsis but also related infections. Other companies, such as India’s Amrita Therapeutics, are designing compounds with multiple MOAs to treat more than one disease simultaneously. Immunology is now seen as the main alternative to targeted therapy in cancer, as evident in most major-company and many small-company pipelines.
Personalized medicine, whatever its ultimate success, shifts the traditional emphasis on patient symptoms to disease and drug mechanisms. Similarly, molecular targeting sometimes works in reverse — elucidating a pathway in a disease subtype leads to recognition of the same pathway in other conditions. One example is Roche/Plexxikon’s Zelboraf (vemurafenib), a BRAF inhibitor approved for mutant metastatic melanoma.
“Vemurafenib’s unique mode of action gives us the option of extending it potentially into other diseases where we see the same mode of action,” says Thorsten Gutjahr, Global Head of Biomarkers at Roche Diagnostics. “Of course, this has to be shown first clinically and validated, but it offers a potentially huge understanding of how to go forward clinically into other indications to develop the medicine.”
Other researchers and companies are focusing on ways to turn existing but under-used drugs into future blockbusters. For example, NuPathe and MAP Pharmaceuticals, also reported on recently, are applying new delivery technology to overcome the limitations of older migraine drugs, possibly opening up much larger markets among the vast number of patients now unable to tolerate or benefit from them.
The High Bar
Drug targeting, rather than endlessly segmenting diseases and research areas, may actually unify researchers to solve common problems and elevate drug therapy to a higher plane. Late last year, FDA’s Janet Woodcock told us that the International Serious Adverse Event Consortium (ISAEC), which she helped found to explore the genetic basis of SAEs, had discovered HLA (human leukocyte antigen) alleles linked to susceptibility to drug-induced liver injury (DILI), Steven-Johnson Syndrome, and toxic epidermal necrolysis. The discovery now guides screening for some widely used antibiotics and a CNS drug; similar techniques could be applied to more widespread SAEs (serious adverse events) and drug classes.
Such research would have to be central to any future development of blockbusters. Future blockbusters would face a much higher bar of safety and efficacy; they could earn wide use by large groups of patients only by offering a superior benefit-to-risk ratio. In many cases, they would do so by the same means now associated with niche medicines — companion diagnostics — whose added cost would be negligible next to the savings achieved in large patient groups.
Science, business, and customer demand all make the case that more companies developing new drugs should plan for the resurgence of blockbusters in a new form. It would thus be unwise for the industry as a whole to put all or most of its eggs in the single basket of niche products. Drugs targeted to small populations will need ever greater justification, even as the opportunities for broad-based breakthroughs in safety, efficacy, and affordability continue to expand. Where the medical need is broad and great, the industry should be equal to the challenge.
A number of “experts” — people with relevant drug-development experience in large and small companies —contributed ideas and quotations to this article. Below are selected quotes, some expanded from brief citations in the article.
Eric de La Fortelle, CEO of therapeutic-antibody developer Delenex Therapeutics AG and a former global head of technology partnering at F. Hoffmann-La Roche
“The blockbuster model is alive and well, if compounds can be found that deliver high pharmacoeconomic benefits to large populations of patients. More adventurous groups will eventually fight the frightening unknowns of areas like RNA therapeutics, cell therapy, gene-to-protein translation and splicing pathways, sophisticated delivery methods, and so on, to come up with a generation of completely novel compounds that will easily fit within the regulatory and payers’ constraints, and take huge markets by storm.”
Abbie Celniker, CEO, Eleven Biotherapeutics, a therapeutic protein optimization company
“The most obvious opportunities for new drugs may appear to be drugs against previous ‘undruggable’ targets, but there are also significant opportunities built around known targets and well-established pharmacology. This evolutionary — not revolutionary — approach to developing novel drugs based on known pharmacology can open up new opportunities for next-generation therapeutics with the dramatic improvements in specificity, stability, duration and potency, that are necessary in today’s environment to become market-leading drug products.”
G. Steven Burrill, CEO, Burrill & Company
“We’re not done with blockbusters. But we are done with one-size-fits-all drugs. Society can afford to pay a whole lot for things that work, so we need better correlation of the things that work with the problems we’re trying to solve. Enormous value can be created by the system as it moves into personalized medicine. Fifty-five percent of the drugs used in this country don’t work for the patients, we have a lot of room to improve that. I don’t know that we’re going to see many more $14-billion drugs like Lipitor, but we will see lots of billion-dollar-plus market opportunities.”
Paul Coggin, Principal, the consulting firm Wipro
“The blockbuster model still has plenty of runway, and large Pharma hasn’t abandoned it. In the metabolic area, there’s STILL great unmet need for therapies that truly improve (or maintain) beta cell function to halt the progression of diabetes. Should we also mention the significant needs associated with Alzheimer’s and other neurological conditions? What about oncology-related pain management therapies needed to deliver better tolerability and fewer undesired effects? New, better therapies in these areas and others can potentially be used to help millions and millions of people — and are blockbuster profit opportunities.”
Mary Lynne Hedley, President, CSO, co-founder, Tesaro
“Addressing the largest remaining underserved markets will require significant scientific advances. Initial advances will likely result in the development of moderately effective, widely used drugs that could be more reminiscent of the mega-blockbusters. Over time, as the science and understanding of these indications progresses, genetic and other biomarkers will become available and will be used to develop drugs with improved efficacy in better defined smaller patient populations within an indication, and the mega-blockbuster may be replaced by multiple modest blockbusters.”