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2017: The year cell and gene therapies came of age

2017 was a turning point for cell and gene therapies. The year saw three regulatory approvals, 850 companies focused on this space, and 946 clinical trials underway globally. Financings jumped from USD 4.2 billion in 2016 to USD 7.5 billion in 2017. Mergers and acquisitions also grew from USD 1.053 million in 2016 to  USD 13,539 million in 2017.

To continue that trend, the rate of acceleration must increase, patient access must increase, and reimbursement mechanisms must be developed, according to panelists speaking at the 10th Annual Biotech Showcase, January 810 in San Francisco.

As the science advances, researchers are looking at the cells themselves to identify not just which cells to administer but to identify the right mixture of cells. “There’s a lot to learn,” says Bob Azelby, executive VP and chief commercial officer at Juno Therapeutics.

Panelists also are interested in combination therapies to enhance efficacy. “There are two types,” James Nobel, CEO, Adaptimmune, points out. In one, another drug and multiple constructs are returned to the body. In the other, new molecules are introduced to reinvigorate the T cells. Engineering the CAR molecule as well as the CAR-T cell also was mentioned, as researchers address the microenvironment.

Cell manufacturing was a recurring topic where deep expertise is needed. “Manufacturing needs to be faster, more scalable and cheaper,” said Pascal Touchon, senior VP and global head, cell and gene, Novartis Oncology, although panelists held specifics close to the vest.

Whether manufacturing capabilities can keep up with the expected growth appears to be a moot point. The manufacturing model currently is being evaluated to determine whether manufacturing will occur in centralized processing facilities that serve the globe or in a distributed environment. Manuel Litchman, president, CEO and director, Mustang Bio, predicts the distributed model will disappear. “Companies are working on that, but none has adopted it at this point.”

Whichever ultimately dominates, “within 5 to 10 years, manufacturing will be more scalable, cheaper and faster,” Touchon predicts, enabling the changes that will help the industry meet growing demands.

The more immediate issue is the supply chain, Azelby says. “Currently, the limited supply chain drives up the cost of goods,” so automation and a more mature supply chain eventually will reduce that pressure.

Cell and gene therapy development is growing from a group of individual markets to become a truly international industry. China, for example, recently wrestled with the issue of whether CAR-T products represented a process or a product and in December determined that they are products. This distinction means the CFDA will oversee previously unregulated studies that often were launched by small companies and hospitals, Touchon says.

In the US, cell therapy has gained regulatory backing, and regulators have amazingly positive attitudes about these therapies, panelists agree.

Although companies and payers are collaborating to find new models for reimbursement, much remains to be done, panelists agree. “We can’t have a traditional way to look at access,” Touchon says. Rather than what he terms a “year-end-budget” approach, he recommends value-based strategy that look at ways to show value for patients, society, the medical system, the payer, and any other stakeholders.

“It’s an issue of complexity,” Litchman says, broaching relative value of multiple infusions for cell therapy versus single administrations and the possibility of a cure.

Looking beyond orphans

Cell and gene therapies often have focused on rare or orphan diseases, but they increasingly are addressing more mainstream conditions. “We’re on the way toward making a huge impact in patients’ lives,” predicts Amber Salzman, president and CEO, Adverum Biotechnologies, speaking in the following panel discussion. “In the past, the challenge was to fix enough of the cells to make a difference in the disease. Now we actually have a shot at correcting enough cells and of enough different types to make that difference.”

Panelists say they are developing therapeutics for hemophilia, wet age-related macular degeneration, hereditary angioedema, and other conditions. One (the Gladstone Institute) is growing new muscle cells for the heart, and CRISPR Therapeutics plans to bring CRISPR-based gene editing to the clinic later this year for sickle cell anemia.

In the early days, the industry was divided into transgenic expression and androgynous gene modification approaches, but those methodologies are maturing so that the choice of methodology is becoming more of a medical decision than a technical one. For instance, “a gene editor may be best for diseases in childhood, because the cure potentially lasts for life,” says Sandy Macrae, president and CEO, Sangamo Therapeutics. “We have a suite of capabilities to apply to a medical program.”

The decision often is based on the efficiency of vector delivery and gene expression, and also includes a consideration of the gene editing platform and various approaches to introducing molecular scissors. There also are opportunities for epigenetic programming, using gene editing tools to turn on or off genes at specific loci. For example, CRISPR can be used in Duchenne’s muscular dystrophy to regenerate skeletal disease.

Several hurdles remain before these therapeutics can be approved, however. One of the first is identifying an effective delivery mechanism. Although adeno associated viral vectors may seem the best option, researchers also are exploring using a combination of vectors for a single therapy, to ensure high expression levels as well as delivery.

Scale-up and manufacturing also need attention. BioMarin Pharmaceutical, for example, uses an insect cell system. “We’re comfortable the process can go to Phase III, but it’s still early days for delivery system,” says Geoff Nichol, Senior VP, global clinical development and chief medical officer.

Beyond that, companies must plan for manufacturing two to three years in advance, and it may take up to 18 months to receive supplies. “Having your own manufacturing facilities helps. Having multiple facilities gives you options for contingencies as well as better quality control,” Macrae says.

“There are ways to go about this without a lot of early investment,” Salzman points out. She favors relationships with manufacturers “who can follow our batch records. We don’t rely on manufacturers to do the scaling. We ensure we can scale the process and work with a good GMP facility,” which expands their pool of CMOs.

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