«PrevBlockbuster Outlook 2017 NextEU Parliament votes into law twin regulations for IVDs, medical devices»

Long, winding road to commercialization is not unusual

By Brian Orelli
BioWorld Staff Writer
Twitter

Download Case Study: Global Surgical Manufacturer Ensures a Positive Prognosis

It's been a long road for Generx (Ad5FGF-4), a gene therapy designed to express fibroblast growth factor-4 (FGF-4) to increase vascularization in the heart.

The therapy was developed from work at the University of California, San Diego, and built into Collateral Therapeutics Inc. in 1995. A year later, Schering AG partnered with San Diego-based Collateral to develop Generx. And, in 2002, the Berlin-based pharma bought Collateral to gain full rights to Generx and Collateral's other less-mature gene therapy programs. (See BioWorld Today, March 21, 2002.)

A few years later, Schering decided to move away from cardiovascular therapies and licensed Generx to newly formed Cardium Therapeutics Inc., which was started by Christopher Reinhard, who had moved to Schering from Collateral Therapeutics where he was president and chief operating officer. Schering was subsequently purchased by Bayer Pharma AG, of Leverkusen, Germany, adding an additional stakeholder, which had nothing to do with development, to the mix. (See BioWorld Today, Oct. 21, 2005.)

Fast forward to 2014, when Shanxi Taxus Pharmaceuticals Co. Ltd., a subsidiary of Shenzhen Forntsea Taxus Industry Capital Management, acquired a stake in Cardium Therapeutics, which was renamed Taxus Cardium Pharmaceuticals Group Inc. (See BioWorld Insight, March 5, 2014.)

To monetize Generx, in 2015, Taxus Cardium spun Generx out into Angionetics Inc. and, last July, sold a 15 percent stake in the company to Huapont Life Sciences Co. Ltd., of Chongqing, China, for $3 million. As part of that deal, Huapont gained access to sell Generx in mainland China, with Angionetics due an undisclosed royalty on net sales.

Taxus Cardium plans to spin Angionetics out fully and "divest itself after a planned public financing sometime – possibly, depending on market conditions, later in the year," according to Reinhard, who is CEO of Angionetics.

Long development time

The long, winding road is just par for the course, Reinhard told BioWorld Insight. "Every gene therapy company and regenerative medicine has a long history of development," he said, pointing to Cambridge, Mass.-based Bluebird Bio Inc., which was founded in 1992 as Genetix Pharmaceuticals Inc. and is still trying to get its first gene therapy approved after recently improving manufacturing protocol to increase the vector copy number.

Unlike Bluebird's therapy, which uses lentiviral vectors, Generx is based on an adenovirus to get the DNA into the heart cells because long-term expression isn't needed. "In our case, you grow a blood vessel and you're done," Reinhard said. "You don't need angiogenic proteins expressed in the heart ad infinitum."

Reinhard said he thinks Generx is expressing the right gene, FGF4, which is a regulatory gene that activates multiple vascular endothelial growth factors (VEGF), which ultimately stimulate blood vessel formation. "We think that a regulatory gene that helps modulate angiogenic growth factors in a specific way is more utilitarian than trying to pick one VEGF, which is lower in the cascade," Reinhard said. "We allowed nature to figure that out."

Where Reinhard's team has made development progress is in the transfection process to get the gene into the heart cells so FGF4 can be expressed. They noticed that patients that were more ischemic, restricting the blood supply, had higher transfection and more expression. The working hypothesis is that ischemia increases the expression of coxsackievirus and adenovirus receptor, which adenoviruses, like the one used in Generx, use to get their DNA into cells.

To increase the efficacy in the next phase III trial, Angionetics will select patients with myocardial ischemia and further transiently increase the ischemia using a balloon catheter before delivering Generx with nitroglycerin, which increases permeability.

Angionetics plans to start a 326-patient phase III trial, called AFFIRM, in the middle of this year, testing Generx compared to placebo in patients with advanced coronary artery disease who have myocardial ischemia and refractory angina, defined as no longer responsive to anti-anginal medications and not a candidate for mechanical intervention. To select for patients with ischemia, Angionetics will enroll patients with three- to seven-minute times on an exercise treadmill test (ETT), which tests how long patients can last on the treadmill before having to stop because of chest pain (angina).

The primary endpoint of the study will be improvement in ETT. Ranexa (ranolazine, Gilead Sciences Inc.), the last drug approved by the FDA to treat angina, showed patients taking Ranexa were able to exercise for just 24 seconds to 34 seconds longer than those taking placebo depending on the dose and how long after taking the pill the measurement was taken, so the efficacy bar isn't particularly high.

AFFIRM will also measure change in CCS angina class, change in weekly angina frequency and nitroglycerin usage, and change in quality of life, assessed using the Seattle Angina Questionnaire, as secondary endpoints.

If approved, Reinhard said he believes Angionetics could market Generx on its own, but he's open to finding a U.S. partner or selling the company, "We'd let the market decide that process."

Because Generx is an off-the-shelf gene therapy, the manufacturing costs are relatively low compared to patient-specific therapies, so Angionetics plans to price Generx on par with stents, which cost $2,000 to $5,000. "We'd like to price it to really move it into the marketplace," Reinhard concluded.