By Alissa Poh

Oct. 1, 2008 | In Britain, people often use the phrase “pegging away” to describe working hard at something.

Across the pond, in New Jersey, the folks at Prolong Pharmaceuticals are also pegging away, attaching polyethylene glycol (PEG) to a variety of protein-based drugs. Or, to use the proper term, “pegylating” these drugs to improve pharmacokinetics, extend circulation time and decrease toxicity, all of which make for enhanced therapeutic effects.

Prolong’s focus on pegylation technology is hardly surprising. Its founder, Abe Abuchowski, came up with this idea in the first place as a graduate student, before establishing it as a bona fide drug delivery system when he started Enzon in 1983. But Abuchowski left 13 years later when Enzon elected to steer away from this technology, since “pegylation was my whole life, and I no longer saw a role for me there.” He kept his finger on pharma’s pulse, however, even as a stay-at-home dad and part-time consultant. And right around 2000, he decided that it was time to take advantage of several important, recent developments in the biotech industry. For starters, many of the original blockbuster drugs had expired or expiring patents, so companies were scrambling to create generic versions; also, biotech had begun moving offshore, taking hold throughout the world.

“I saw the opportunity to reintroduce our technology in other parts of the world and develop global partnerships,” Abuchowski says. “I also felt that pegylation had not gone as far or as fast as it should have, which indicated to me that there was something missing – an art to it that people didn’t quite grasp.”

Global partnerships will be a key ingredient in Prolong’s recipe for success, now that blockbusters like erythropoetin (EPO), interferon, and granulocyte cell stimulating factor (GCSF) are readily available in countries like India and China, with more companies there meeting FDA standards. Back in 2002, when Abuchowski first felt the impetus to create Prolong, he outlined a basic business strategy: keep internal staff to a minimum (there are only seven employees), and look globally in terms of gaining access to and utilizing partner infrastructure. This would “save a lot of money and make things go quicker – everything you’d want in a low-risk kind of system,” he says.  

But it still took three years for any venture capitalists to bite. Then Zachary Berk, managing director of KBL Healthcare Ventures, came along and, as Abuchowski puts it, was “spirited enough” to add Prolong to KBL’s investment portfolio, becoming the company’s CEO and chairman in the process. “He’s one of the very few venture capitalists who actually saw the vision and understood the opportunities associated with this kind of global enterprise,” Abuchowski says.

“In terms of new drug development, the pharma industry has always been 99 percent US- and European-centric, so the idea of developing innovative products in partnerships with Asian companies is fairly new,” Berk says, adding that venture capitalists, to date, have had very little experience operating outside the U.S. He and Abuchowski are relying on their investment and banking team in Asia to “help cull through the hundreds of companies that could be potential partners.” This, along with the enticement of pegylation technology, should place Prolong “at the cutting edge of international partnerships,” he says.

 Supergenerics” and more

The current emphasis at Prolong is on getting three of their products – pegylated versions of EPO, hemoglobin, and GCSF – into the clinic. Two of these (PEG-EPO and PEG-GCSF) have been labeled “supergenerics,” as they bypass one major issue with biosimilars: the need to produce an exact copy of the biological molecule of interest. This is next to impossible with bigger molecules like antibodies and proteins, which are much more difficult to characterize than their smaller chemical counterparts. But that’s where the real beauty of pegylation lies, Abuchowski says. “We don’t have this problem, because a pegylated biologic drug is considered a new molecular entity and doesn’t have to be based on any previous molecule.”

EPO has made some waves recently, being associated with cardiotoxicity, as well as decreased survival in several cancer trials. Abuchowski acknowledges these as real issues, but where the first is concerned, Prolong’s pegylated version does allow for 1/20 of a regular EPO dose, just once a month, which should “lower the impact on cardiotoxicity dramatically, while still raising the patient’s hemoglobin levels.”

As for the cancer trials, it’s a function of the fact that EPOs cause red blood cell production, providing more oxygen to tissues – “and tumors being that type of tissue, when they get more oxygen, they grow faster,” Abuchowski says. “So I think the cancer market will be mitigated by this issue.” But on the other hand, he sees an opportunity to move into that market, radiosensitizing tumors through oxygen therapeutics, namely the third product in Prolong’s pipeline: PEG-hemoglobin. 

“Tumors typically become hypoxic, which makes them resistant to chemotherapy and radiation,” Abuchowski explains. “We’ve shown in several animal models that our PEG-hemoglobin hyperoxygenates tumors, so you can use 1.5 times less radiation and it’s still equally effective.”

This particular product has further potential when it comes to treating an array of anemias, ischemias, stroke and myocardial infarcts. PEG-hemoglobin lubricates blood flow, and being “only a molecule,” as Abuchowski says, it will easily traverse artery blockage, going where red blood cells can’t to provide initial tissue-saving oxygen, even before the big guns – clot-busting drugs – are brought out. 

Abuchowski and Berk have licensed the technology for PEG-EPO to Indian company Zydus Cadila, and they’re in the midst of a second license for PEG-GCSF, which they hope to finalize by year’s end. They’ve also received two NIH grants for studies on PEG-hemoglobin, with a third on the way to complete the work necessary for an investigational new drug application (IND).

“We expect all three to have INDs by the end of 2009,” Abuchowski says. “That would be our fourth year of operation, and a pretty good record.”

With Prolong’s global strategy, its pegylated drugs will complete foreign clinical trials before being licensed in the U.S. Raw materials are cheaper overseas, and the availability of naïve patient populations there makes for rapid and inexpensive trials. “We’ll be bringing more efficacious drugs back to compete with U.S. blockbusters at much lower costs,” Berk says.

According to Abuchowski, the science of pegylation may have expanded, but not so its applications. His colleagues at Prolong appreciate not only his intimate knowledge of this technology, but also his skill at translating laboratory work into large-scale productions that get moved rapidly into the clinic. With this “incredible experience base” to operate from, as Berk puts it, Prolong’s future in next-gen pegylation looks pretty bright.