Sue Pearson Ph.D. Freelance Writer GEN

Predictions for 2017

“With over 750 regenerative medicine firms world-wide, 271 cell and gene therapies in Phase I/II, 66 products in Phase 3, and promising CAR-T cell therapy results and marketed therapies, there’s a lot more optimism now about this sector,” states Kurt Gunter, M.D., chief medical officer at Cell Medica. Speaking at the recent International Society for Cellular Therapy (ISCT), in London, U.K., Gunter continues: “In the past 12 months, we have seen several academic, big pharma, and biotech collaborations, including our own partnerships with Baylor College of Medicine and University College London, and significant acquisitions on the life science supplier side.”

However, speakers and delegates at the conference acknowledged that there are still significant challenges surrounding commercialization and adoption of these therapies. Simon Ellison, senior manager, advanced therapies, at Fisher BioServices says: “Developing cell and gene therapies is worthwhile, yet very tough. And key things to consider are: How do we set up a successful manufacturing supply chain? What does the patient need as a consumer? And how will we obtain reimbursement?”

GMP In a Box

Catherine Bollard, M.D., Ph.D., professor of pediatrics at Childrens National Medical Center, and The George Washington University, Washington D.C., and ISCT president states: “We still need to simplify manufacturing so that it is cost-effective. However, to broaden applicability, the options are centralized manufacturing versus single-center manufacturing. To make the latter truly broadly applicable, we need to seriously consider the “GMP in a box” concept to produce cell and gene therapies that are as close to off-the-shelf products as possible.” While many cited contract development and manufacturing organizations (CDMOs) such as Lonza, PCT, and WuXi as leading the pack in developing large-scale manufacturing solutions for allogeneic therapies, they still felt that because many autologous therapies require post-thaw processing and expansion in the laboratory there is a significant need for automation here, too.

Marc Turner, M.D., Ph.D., medical director at the Scottish National Blood Transfusion Service suggested that companies developing an advanced therapy needed to start with the end in mind. He warns: “Most of these therapies require decoupling in a healthcare environment such as a pharmacy, blood bank, or stem cell processing facility. But firms should try to avoid directly delivering into a clinical environment, as many clinical staff are not trained or interested in doing any manufacturing QC on these advanced products. Also, clinical environments are busy, sometimes chaotic, places where procedures can be delayed by unforeseen emergencies. Therefore, scientists need to ensure that their cell and gene therapies can be brought into the clinical environment and released in a simple, controlled way.”  

Paul Veys, M.D., director of the Bone Marrow Transplant Unit at Great Ormond Street Hospital (GOSH), which is currently running two CAR-T clinical trials and has successfully treated two infants with relapsed-refractory CD19-positive B cell acute lymphoblastic leukemia (ALL) states: “Autologous CAR-T-cells can sometimes be difficult to manufacture, especially in infants or heavily treated patients.” According to Veys, his colleague Waseem Qasim, MBBS, Ph.D., and his group manufactured universal CAR19 (UCART19) T cells in conjunction with Cellectis. To do this, they used lentiviral transduction of nonhuman leukocyte antigen-matched donor cells and simultaneous transcription activator-like effector nuclease (TALEN)-mediated gene editing of T cell receptor α chain and CD52 gene loci. Dr. Veys concludes: “We are currently evaluating the Miltenyi CliniMACS Prodigy to automate UCART19 production using cord blood T-cells. We are achieving 60% transduction and 13-fold expansion utilizing this system.” 

In addition to Miltenyi, GE Healthcare Life Sciences is making a serious bid to be a major player in lab-based cell and gene therapy automation. At ISCT, they showed end-to-end laboratory processing solutions with their Biosafe products, (which GE acquired in 2016) including the recently launched Sefia™ cell-processing system and automated cryopreservation capabilities with the acquisition in 2017 of U.K.-based Asymptote, a specialist in cryochain technology. 

Asymptote automated cryopreservation technology and software. [GE Healthcare]

New Delivery Models

Another issue discussed at the ISCT conference is that cell and gene therapies are not always easy to administer. Olav Hellebø, CEO at ReNeuron’s says: “We need to realize that delivery models for cell therapies may not be what we are currently used to with biologics and small molecules.” He continues: “For example, our CTX cell therapy to treat patients post-stroke contains a neural stem cell line that must be delivered directly to the brain via stereotactical surgery. Also, our human retinal progenitor cell therapy to treat retinitis pigmentosa needs to be injected behind the eye. However, brain surgeons do stereotactical surgery all the time and ophthalmology surgeons use infusion cannula in the eye all day, every day, so both can deliver these therapies safely without any problem.”

According to Hellebø, the difficulties faced by anti-TNF biologics to treat rheumatoid arthritis in the 1990s are like some of the challenges faced by cell and gene therapies today. He concludes: “At UCB, their original formation of an anti-TNF alpha biologic would not go through a standard syringe. So rather than saying this formulation is unusable, UCB redesigned the syringe—that’s the mind set we have to adopt with cell and gene therapies.”  

A Patient-Centric Approach

Sven Kili, MB ChB, vice president, head of cell and gene therapy development at GlaxoSmithKline, reminded cell and gene therapy developers that there is a patient at the center of all this interesting research and development. Dr. Kili comments: “To take part in the Strimvelis gene-therapy trial, patients had to come to Milan, [Italy], which often meant moving their entire family with a one-year-old to another country so we as a pharma company had to try to make that transition seamless before and after therapy, not just during the treatment phase. Our job was to not make their lives more challenging.”  According to Dr. Kili, a big pharma can help a biotech or academic group by bringing a deep infrastructure, global pharmacovigilance, and process-development know-how to reduce the cost of goods in manufacturing an advanced therapy.

Dr. Kili concludes: “With Strimvelis, the first patient was dosed in 2000, and our product was approved in 2016, that’s a very long-timeline. So, we need to collaborate more as an industry to get these advanced therapies to market more rapidly.”

Who’s Going to Pay?

To guarantee that cell and gene therapies are adopted, there must be a clear payment strategy put in place soon. Dr. Turner states: “Reimbursement is critical, and when looking at reimbursement costs for the product, pharma and biotechs need to consider the cost of companion diagnostics, additional therapies such as immune suppression, the administration required to follow up a patient, and lost opportunity costs. For example, a patient receiving CAR-T therapy may take up an ITU [intensive treatment unit] bed that could be used by another emergency patient.”

Dr. Bollard, comments: “Many cell and gene therapies have a long half-life and offer a lifelong fix, which is not something that makes them commercially attractive. So, for example, with therapies such as the CAR-T cells, the price point should be based on the cost of this therapy versus how much a bone-marrow transplant would cost for a pediatric ALL patient.”

Hellebø also made the point that cell and gene therapies are so specialized that the practitioners delivering them will not be based in general practitioner’s surgery and to commercialize them will therefore require a much smaller sales and medical marketing force. He estimated that in the U.S., this would be around 150 specialist reps, compared to the 400–450 reps required to sell small-molecule-based drugs. He comments: “Consumers will also be important in ensuring the success of cell and gene therapies. In the U.S., if a patient requests Humira, 95% will be prescribed it and this strategy could work for ensuring adoption of some advanced therapies. Since the price of prescription drugs in the U.S. is double the price throughout the rest of the world, if a cell or gene therapy is to be commercially successful, it must do well there as that’s where the lion’s share of the profits come from.”

Light at the End of the Tunnel?

According to Dr. Turner, there is a second valley of death for cell and gene therapies because getting marketing approval does not guarantee that these therapies will be used. Miguel Forte, M.D., Ph.D., from mC4Tx and chief medical officer at Bone Therapeutics, as well as chair of the commercialization committee at ISCT, states: “A decade ago, we were like mad scientists trying to untangle the science. Now, we are more aware that cell and gene therapies work [and] we need to look at manufacturing to make them industrially viable and that means focusing on cost of goods.”

He concludes: “2017 is a critical year because we are beginning to see CAR-T cells having good success in Phase I/II trials and approaching the market. It is not the ability to launch these products that is going to be a problem, but ensuring that there is a pathway for adoption. We are seeing the light at the end of the tunnel with commercializing cell and gene therapies, but we still don’t know how long the tunnel is.”

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