Randi Hernandez was science editor at BioPharm International from September 2014 to May 2017.

Randi Hernandez

	In separate press releases on April 11, 2017, GE Healthcare announced the company is beefing up its bioprocessing capabilities. The company purchased Asymptote, which specializes in cold chain technology for cell-based therapies, and will continue its partnership with Zenith Technologies, which offers automation solutions and process integration.

	According to the release, the software systems from Zenith will play “a central role in manufacturing coordination, control, and documentation,” and will help GE in its endeavors to incorporate continuous monitoring and maintain batch-to-batch consistency in its FlexFactory and KUBio manufacturing offerings. "Automation enables fewer manual operations in the biomanufacturing process and provides real-time data to customers to evaluate their operations more quickly, including batch data and investigations," Jan Makela, general manager, bioprocess, GE Healthcare Life Sciences told 

 "This greater efficiency can help reduce the non-productive time between production."

	When this publication asked Makela if the automation would be applied to all GE products, he said, "Zenith will be involved in providing ongoing support and customer-specific upgrades where required, as part of GE’s existing commitments to the large and growing base of FlexFactories. Zenith will be working, going forward, on developing the breadth of our automation offering for future customer needs, and also the connectivity to other IT systems used in production environments." According to Ger Brophy, general manager of GE Healthcare’s cell therapy business, GE healthcare supports more than 100 clinical stage companies between its various product lines. 

	The Asymptote acquisition will allow GE to enhance its cryochain technology, which will better protect sensitive cell therapies using liquid-nitrogen-free controlled-rate freezers. The press release says Asymptote provides “pioneering technologies that challenge standard cell cryopreservation and thawing practices.” GE hopes the acquisition will help the company further industrialize the cell therapy industry, according to statements from Brophy. GE's customers currently rely on liquid nitrogen-based cryofreezing technologies, Brophy tells this publication, which can "inadvertently introduce contaminants and infectious agents compromising the quality of the final therapeutic product."

	Asymptote’s web-based platform allows users to remotely standardize and monitor the freeze-thaw process of cell therapies across multiple sites. The improved visibility surrounding the status of the cellular products will help GE scale their phase shift activities with ease, the company says.

	Brophy adds. "Cold-chain management is a requirement for the vast majority of therapeutic manufacturing processes, regardless of where [the facilities] are located. Even in proximal manufacturing approaches, retaining samples or being able to pause the production through a freezing step is often introduced. GE supports both manufacturing models, and find them both to be prevalent in the industry today."

	The Asymptote acquisition and the Zenith investment are just the most recent investments from GE in regenerative therapy. Earlier in 2017, the company also invested in Biosafe SA, Vitruvian Networks, and BridGE@CCRM Cell Therapy Centre of Excellence, which are all support the manufacture of cell and gene therapies.

	GE will use Asymptote (along with its other technologies) in Cellular Biomedicine Group’s facilities to help them develop stem cell and chimeric antigen receptor T-cell (CAR-T) manufacturing capabilities.


	GE’s recent partnerships include the co-development of facilities with FujiFilm, Pfizer, BeiGene, and JHL. Through these partnerships, the other company has agreed to use GE technology (in part or in whole) to manufacture its products.

	In 2016, GE also sold its rights to an inactivated yellow fever vaccine to PnuVax under the condition that PnuVax purchase a FlexFactory from GE to manufacture the product. In February 2017, the Austrian Centre of Industrial Biotechnology forged a three-year pact with GE to optimize the performance of GE’s Chinese hamster ovary (CHO) cell line.

	It appears GE’s technology-both its legacy solutions and its recent investments in new bioprocessing products-is becoming more indispensable to various clients.

Articles

GE Healthcare continues to ramp up its offerings in the bioprocessing space with the purchase of Asymptote and a continued partnership with Zenith Technologies.

GE Healthcare: The Next Cell and Gene Therapy Manufacturing Giant?

	Genentech announced on March 28, 2017 the landmark approval of its monoclonal antibody (mAb)-based therapy Ocrevus (ocrelizumab), the first treatment approved by the agency that targets progressive forms of multiple sclerosis. The medication was also approved to treat relapsing-remitting forms of the disease, which affect a larger population of patients than the primary progressive form.  In clinical trials, results of which were published in the 

 in December 2017, ocrelizumab demonstrated 

 to Rebif (interferon beta-1a), a widely used treatment for relapsing forms of the disease. In two trials, OPERA I and OPERA II, the humanized mAb cut annualized relapse rates almost in half when compared with Rebif, and significantly helped improve measurements of walking speed, upper-limb movements, and cognition. Despite its benefits, infusion-related reactions occurred in approximately 34% of patients, and FDA 

 that the drug can lead to malignancies in some patients.

	Most of the existing treatments for relapsing multiple sclerosis (MS) and primary progressive MS (PPMS) work to manage the symptoms of the immune-mediated condition, which is characterized by damage to myelin surrounding nerve fibers of the central nervous system. Symptoms are associated with gradual CNS breakdown, and include fatigue, weakness, spasticity, weakness, numbness, problems with gait, vision problems, and gradual cognitive decline. Approximately 60,000 people are estimated to suffer from the progressive form of the disease, which is about 15% of the total population of people with MS, according to the 

	Ocrevus is to be administered by intravenous infusion every six months, and Roche, the arm of Genentech commercializing the medication, says it will be available within two weeks. The drug is genetically engineered to selectively bind to CD20-positive B cells and block their action. Because ocrelizumab does not bind to stem cells or plasma cells, Roche says the immune system will remain somewhat intact following the elimination of mature B cells. The approval comes a bit later than previously expected, as FDA extended review of the application for Ocrevus so that Roche could provide extra data surrounding the commercial manufacture of the drug.

	According to numerous news outlets, Roche reportedly said it would charge $65,000/year for the drug, which is approximately 24% less than the current price of Rebif ($86,000/year).

The mAb is the first approved treatment that targets the progressive form of the disease.

FDA Approves First Treatment for Primary-Progressive Forms of Multiple Sclerosis

 released on Jan. 12, 2016 describes 180-day exclusivity for generic-drug manufacturers and explains the number of conditions under which an abbreviated new drug applicant (ANDA) submitting a paragraph IV certification would forfeit eligibility to be the authorized generic manufacturer of a drug. The 180-day provision, which was originally a part of the Hatch-Waxman Amendments, was meant to provide an incentive for generic-drug manufacturers to challenge the patents that are covered in an originator’s ANDA as invalid, unenforceable, or not being infringed.

	Although the goal of the 180 days of exclusivity was originally to encourage potential generic-drug manufacturers to release competitors into the market, some say that the actual effect of the provision is that it keeps all generic versions of drugs off the market for longer periods of time. This could be because the authorized generic-drug manufacturer strikes a reverse payment deal with the originator manufacturer (through deals often called pay-to-delay or pay-for-delay agreements) to agree to not bring the generic to market for a certain period of time.

Isn’t pay-for-delay considered an “agreement”?


	The conditions in which a generic manufacturer would “forfeit” the right to the 180-day marketing period would be, as 

s in the Q&A document, “(1) failure to market; (2) withdrawal of application; (3) amendment of certification; (4) failure to obtain tentative approval; (5) entry into agreement with another applicant, the listed drug application holder, or a patent owner; and (6) expiration of all patents.”

	It would seem that entering into a pay-for-delay agreement with the patent holder would merit immediate forfeiture of the 180-day marketing exclusivity. But, as Suchira Ghosh, counsel at Axinn, Veltrop & Harkrider LLP, tells 

, for a forfeiture to happen, the Attorney General (AG) or the Federal Trade Commission (FTC) would have to make a formal complaint about the reverse payment agreement and that agreement would have to be found in violation of antitrust laws. Only then could FDA revoke the right to the 180-day period of marketing exclusivity. Ghosh says that FDA has never once revoked this privilege.

	"Although FDA states in the draft guidance that it has not yet applied this forfeiture provision to any ANDA applicants, presumably FDA could use this provision to strip a first applicant of its 180-day exclusivity if they enter into a pay-for-delay agreement that is held to be a violation of antitrust laws in a final decision by FTC or a court in a case brought by an AG or FTC," notes Ghosh. She says that even if an authorized generic-drug manufacturer settles a patent case, it will still seek to "hang onto their 180-day exclusivity."

	The problem? The FTC has not been able to successfully prove in court that reverse payments are illegal. As a result, these payments continue, and authorized generic-drug manufacturers are able to collect money from originator companies via reverse payments as well as secure revenue as a result of providing the first authorized generic to a drug.


	So, why hasn’t FDA gotten more involved and stripped the marketing privileges away from an authorized generic-drug manufacturer for entering into a reverse payment? For a few important reasons, says Ghosh: “The 180-day exclusivity period has often been triggered by the first applicant and run by the time the antitrust merits get decided by a court. That’s probably the main reason why this forfeiture provision has not been used by FDA-the 180-day exclusivity period no longer exists by the time the suit is getting decided by court or by the time the drugmakers and FTC are in settlement talks.”

	Additionally, FDA has made fewer forfeiture decisions as time has passed. “FDA is basically saying they will not make a forfeiture determination unless a subsequent applicant is ready for final approval within the first applicant’s 180-day window. It may be difficult for the stars to align so that a later filer is ready for final approval within that 180-day period,” she adds. Lastly, if a forfeiture would occur, it would likely be because of another provision: “The most common is the applicant’s failure to receive tentative or final approval within 30 months after ANDA submission,” says Ghosh. “It is very likely that this forfeiture provision could kick in to strip an applicant of its exclusivity before a final decision has been rendered in any antitrust action brought by the government.”

A new FDA Q&A document released on Jan. 12, 2016 describes 180-day exclusivity for generic-drug manufacturers and explains the number of conditions under which an abbreviated new drug applicant (ANDA) submitting a paragraph IV certification would forfeit eligibility to be the authorized generic manufacturer of a drug.