Cell & Gene Therapy

Big Pharma’s Quest for Blockbuster CAR-T

It has been a full three years since, first Novartis, then Gilead, took the medical world by storm by gaining FDA approvals for chimeric antigen receptor (CAR) T-cell therapies, billed as the cornerstone of future cancer care. While such treatments are undoubtedly game-changing from a scientific standpoint and have demonstratively delivered considerable clinical benefits to a small number of patients with severe and uncommon forms of cancer, they have yet to come anywhere close to fulfilling investor expectations.

It has been a full three years since, first Novartis, then Gilead, took the medical world by storm by gaining FDA approvals for chimeric antigen receptor (CAR) T-cell therapies, billed as the cornerstone of future cancer care. While such treatments are undoubtedly game-changing from a scientific standpoint and have demonstratively delivered considerable clinical benefits to a small number of patients with severe and uncommon forms of cancer, they have yet to come anywhere close to fulfilling investor expectations.

Written by Louis Haynes on 27.04.2020
Written by Louis Haynes on 27.04.2020

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Gilead’s well-documented experience of flattening revenues and the difficulties in building a blockbuster cell and gene franchise is perhaps illustrative of the enormity of the task ahead. Last year the Californian-based biopharma heavyweight generated some USD 450 million from sales of Yescarta, its flagship CAR-T product for non-Hodgkin lymphoma constituting an upswing of 73 percent from the year before, but still way off the pace for a drug that the company had to fork out nearly USD 12 billion to acquire in the first place.

Many will also be watching to see if Roche’s USD 4.3 billion gamble on Philadelphia-based gene therapy pioneer, Spark Therapeutics, bears fruit. While Spark co-founder Katherine High has heralded the deal as “a resounding affirmation of the burgeoning vibrancy of the genetic engineering field,” some analysts have been quick to point out that the Swiss giant had to considerably raise its initial offer (from USD 75 per share to as high as USD 114.50) to get the deal over the line, and will now have its work cut out recouping and generating return on that investment. “Ultimately the company had to go big or go home, however completion will likely saddle Roche with many of the pricing and profitability challenges of its rivals,” reflects Reuters’ John Miller.

Integrating Cell & Gene

The quest to craft high-return CART T franchises is certainly throwing up new dilemmas. Indeed, one gets the distinct impression that Big Pharma is still grappling with how to structurally integrate cell and gene therapies within their mainstream portfolios.

Many industry insiders, for instance, attribute the early success of the roll-out of Novartis’ headline CAR-T therapy treatment for B-cell acute lymphoblastic leukaemia to the company’s pioneering willingness to adopt a ‘firm within a firm’ organisational setup with the establishment of an autonomous global business unit dedicated solely to developing and launching state-of-the-art, next-generation oncology medicines.

“The overarching idea was to create a nimble outfit, with speedy decision-making powers that could accelerate the development and commercialization of radically disruptive and non-conformist therapies of this nature. Having such an arrangement in place was absolutely fundamental to the ability to be a trailblazer in CAR-T, providing an unparalleled sense of purpose, direction and focus,” recalls one former senior executive deeply involved in the decision making at the time.

And yet, the non-oncology related components of Novartis’ cell and gene offering remain somewhat fragmented and spread out across the business. The company’s landmark, one-time gene therapy for rare inherited retinal disease, Luxturna, for example, is handled directly by the pharma unit, while its gene solutions for spinal muscular atrophy sit within Avexis, a fully owned subsidiary.

Trade-offs

Novartis’ Cell and Gene Therapy Head for Europe Emanuele Ostuni lifts the lid on some of the main trade-offs encountered when managing such assets. “The polarity between being separate and integrated requires some fine balancing. On the one hand, we need to operate at high speed and with great agility, neither of which is truly in the DNA of large lumbering organizations. On the other side, the tremendous resources, history and knowledge that Novartis affords, especially in the area of haematology, offer unique advantages that we wish to capitalize upon,” he explains.

“Were we to work in complete isolation, we would surely miss a fantastic opportunity to leverage these capabilities and learning. At the same time, if we were to operate just like any other franchise, we would risk constraining our overall flexibility and ability to react swiftly… The optimum solution thus manifestly lies somewhere in between,” he reasons.

Interestingly, Gilead seems to have been mulling over exactly the same sort of conundrum. Last summer’s surprise announcement that Kite Pharma, the beating heart of the Gilead’s cell and gene program, is to be flung out into an autonomous business unit again, having initially been absorbed into the broader group, is perhaps testament to the special requirements of managing such therapies. “So as to safeguard what we consider to be a leadership position and in the interest of proper focus, we have concluded that the best course of action is to reconfigure Kite as an independent business unit that will wake up and go to sleep every day thinking about how to be leaders in oncology cell therapy,” confidently argues Gilead’s new CEO Daniel O’Day.

Also of interest will be how BMS sets about organising its own arsenal of cell and gene treatments. Having finalised the takeover of Celgene last year for a mighty USD 74 billion, the drug developer, which is currently in the midst of a wholesale restructuring and rebranding, is widely anticipated to become the third player to successfully introduce a CAR-T to the global marketplace. Exactly how the company intends to structure the management of its newly acquired cell and gene therapy for diffuse large B-cell lymphoma alongside an existing CAR-T development program for multiple myeloma, co-developed by the independent biotech, Bluebird Bio, remains to be seen.

We need to appreciate that it takes significant time and patience for radically ground-breaking therapies like regenerative medicine and cell and gene technologies to settle, take root and begin to hit their stride.

Janet Woodcock, Center for Drug Evaluation and Research (CDER) US FDA

Trial and improvement

Much of this, of course, boils down to the fact that cell and gene therapies are deployed in a fundamentally different manner to traditional pharmaceuticals and exhibit alternative characteristics. The classic pharma model, therefore, is no longer fit-for-purpose and bespoke structures are instead required, that big pharma is still in the midst of engineering.

It’s worth remembering that, in CAR-T, there are no medicine boxes or vials on the shelf that are delivered to pharmacies or hospitals. Each batch is only produced once the pharma company receives a patient’s cells. They need to operate in a completely integrated way with the company’s supply service and manufacturing teams to ensure that there is the timely pick-up of a patient’s cells once he or she is considered treatment eligible and, once a patient is identified, the timely delivery of the final product to the physician and patient becomes critical. “Logically we are finding ourselves having to rethink our entire modus operandi and business management model… this is very much a journey of learning and experimentation,” concedes Ostuni

Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER) at the US FDA very much concurs that this journey has just begun. “We need to appreciate that it takes significant time and patience for radically ground-breaking therapies like regenerative medicine and cell and gene technologies to settle, take root and begin to hit their stride. There is ever so much for companies still to do and figure out. It’s certainly no slam dunk!” she affirms.

Seeking New Cancer Frotiers

The future prospects of CAR-T portfolios will also, of course, hinge largely upon the ability to expand out these novel treatments beyond the existing limitations of a highly restricted eligible patient pool, and to extend the indication to new areas such as solid tumours.“From the very outset, there’s been a groundswell of interest in this paradigm-shifting class of medicines and that has meant that drug makers at the forefront of this new science have had to be especially attentive to managing expectations. After all, right now only very few blood cancer patients are actually CAR-T eligible,” explains Novartis’ Ostuni.

Pointing out that his own company’s CAR-T offering is currently only approved for third-line use in two very distinct forms of cancer, he signals that patients, investors and the practitioners should be prepared for a marathon, not a sprint. “It is really important to step back and recognise the wonder of it all. We have come so very, very far and should not forget how amazing it is that we are now able to genetically engineer patient cells, put them back into the patient, remove cancers for a long time, and give these patients a new lease of life. At the same time as celebrating, however, we mustn’t take it for granted and think that this approach will work for every single tumour in every single patient,” he counsels.

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