Biotech Pioneer

By Cliff Mintz

Dr. Abraham Abuchowski, COO and president of Prolong Pharmaceuticals, grew up on a chicken farm in rural Vineland, NJ. Realizing that chicken farming wasn’t in his future, Abe attended Rutgers University, receiving a B.S. degree in 1970 and Ph.D. in biochemistry in 1975. During his thesis work, Abe developed a novel protein delivery system called PEGylation, which involved chemically linking the polymer polyethylene glycol (PEG) to proteins. He continued his work on protein PEGylation at Rutgers, first as a postdoctoral fellow, then as research assistant professor and Leukemia Society scholar until 1983, when he left to form Enzon, one of New Jersey’s first publicly traded and profitable biotechnology companies.

During his 13-year tenure as president and CEO of Enzon, Abe and his team optimized protein PEGylation, which led to the development of the first three FDA-approved PEGylated products. Recognizing the need for biotechnology advocacy, Abe formed and served as the first chairman of the Biotechnology Council of New Jersey in 1994, which still exists today and has helped grow the New Jersey biotechnology industry. Abe left Enzon in 1996 and spent the next nine years in semiretirement — playing with his hobbies (woodworking, aviation, auto mechanics, and feeding chickens) on his farm in northwestern New Jersey and helping would-be entrepreneurs start up new biotechnology companies. In 2002, realizing that protein PEGylation still had enormous potential for the biopharmaceutical industry, he formed Prolong Pharmaceuticals, a company that focuses on developing novel PEGylated protein-based products.

Abe, who attributes his entrepreneurial success to martial arts training and participation in the McDonald Corporation management trainee program, is a biotechnology industry pioneer and is often referred to as the “Father of PEGnology.” Over the past 25 years, he has received numerous scientific and business achievement awards — most recently, the Dong Sung Pharmaceutical Award in Seoul, Korea for the development of PEGylation technology and the USC Marshall School of Business Outstanding Achievement Award.

I had an opportunity to catch up with Abe, who has two new PEGylated protein products in clinical development, to chat about the events that led to the development of protein PEGylation, his views on entrepreneurship, and the current state of the biotechnology industry.

How did you come up with the idea for protein PEGylation?

Abuchowski: My thesis advisor, Dr. Frank Davis, long believed that chemical conjugation of polymers to proteins may help alleviate some of the deleterious and potentially life-threatening side effects commonly associated with nonhuman proteins like insulin (isolated from animal sources) that were routinely used in the 1970s. Frank reasoned that the addition of an inert polymer to a protein might dampen host immune responses and reduce the side effects following the parenteral administration of nonhuman proteins. Because this was Frank’s pet project, he required all graduate students who wanted to work with him to “take a crack at protein conjugation.” Despite knowing that many graduated students had failed before me, I enthusiastically agreed to work on the protein conjugation project — I was young, brash, and naively overconfident at the time!

While there were many potential conjugation candidates to choose from, Frank decided on PEG mostly because it was a ubiquitous substance found in a wide variety of cosmetics, ointments, suppositories, and even food products. Further, and perhaps more importantly, PEG was generally regarded as safe by the FDA, which meant if we were successful, regulatory approval of PEG-protein conjugates would be less challenging. After developing some rudimentary protein conjugation chemistries, I began PEGylating any proteins that I could get my hands on. I PEGylated more proteins than I can remember. After creating the PEG-protein conjugates, I tested them (and their un-PEGylated counterparts) for immunogenicity, turnover rates, and circulating half–life times in a wide variety of standardized animal models that were being used at the time. And, as predicted, the PEGylated proteins were virtually non-immunogenic, had lower turnover rates, and exhibited vastly improved circulation times as compared with un-PEGylated controls.

Because at the time that we developed protein PEGylation, the use of proteins as drugs was very limited — the biotechnology industry was just coming to fruition — there wasn’t much excitement or commercial interest in our technology. Most scientists generally regarded PEGylation as an anachronistic technology. Nobody realized at the time that protein PEGylation would help to improve the characteristic and delivery of virtually any protein-based biotechnology product.

Why did it take over 25 years for PEGylation to be accepted as a bona fide protein delivery technology?

Abuchowski: Before I began working on protein PEGylation, many high-powered academic laboratories had diligently tried (and failed) to chemically modify proteins to reduce their immunogenicity — a vexing problem that severely limited the use of nonhuman therapeutic proteins in the 1970s. Also, at the time, many prominent scientists thought that the newly emerging field of genetic engineering could be used to overcome the immunogenicity problems that plagued nonhuman, protein-based therapies. Consequently, many of my peers mistakenly viewed protein PEGylation as a competing (rather than an adjunctive) technology and refused to acknowledge our work.

Despite several publications and reams of scientifically sound data, most scientists in the late 1970s refused to believe that protein PEGylation really worked! In retrospect, I suspect many of them refused to believe that a young chicken farmer from New Jersey could accomplish something that many of them failed to do! Nevertheless, I was convinced that protein PEGylation had the potential to revolutionize the emerging biotechnology industry. Further, I realized, unlike my colleagues, that I didn’t have to discover new proteins to make drugs — I could simply PEGylate existing, well-characterized ones that seemed like good drug candidates — a strategy that took others over 20 years to recognize.

After leaving Rutgers in 1983, I was determined to commercialize protein PEGylation. However, because pharma wasn’t interested in the technology, I had to form my own company (Enzon) to confirm PEGylation as a reliable protein delivery system. It was a huge gamble because there were many naysayers and nonbelievers in the scientific community who, I think, were hoping that I would fail. To overcome persistent doubts about the technology, we decided to PEGylate a protein that could be used to treat an otherwise fatal disease — thinking, that if we were successful, FDA would have no choice but to approve the drug. This resulted in development of Adagen, the first and only approved treatment for severe combined immunodeficiency disease (SCID). Interestingly, Adagen was approved in 1990 on the strength of data we collected from eight patients with SCID.

Because Adagen was approved as an orphan drug, the pharmaceutical industry continued to doubt the commercial and financial potential of protein PEGylation. To overcome these lingering doubts, we developed Oncospar (pegaspargase), an anticancer treatment for acute lymphocytic leukemia (ALL). ALL was an obvious choice to showcase the utility of protein PEGylation because patients with ALL frequently developed immune hypersensitivity to asparaginase, the only recognized ALL treatment at the time. PEGylating asparaginase rendered the enzyme nonimmunogenic, eliminated the hypersensitivity reaction, and brought asparaginase-refractory patients with ALL into remission. Oncospar received FDA approval in 1994.

While Enzon was able to gain approval for two PEGylated products in 11 years — a remarkable feat for a biotechnology startup — the commercial potential of protein PEGylation wasn’t fully realized until 2001, when Schering-Plough and Enzon introduced PEG-Intron as a treatment for hepatitis C infections. Within a year, PEG-Intron had captured 65% of the hepatitis C market and reached about a billion dollars in sales. Protein PEGylation had finally hit the big time!

What advantages does protein PEGylation offer over other potential protein delivery technologies?

Abuchowski: PEGylated proteins are generally nonimmunogenic, exhibit increased circulating half-lives (i.e. are longer acting), require fewer injections for therapeutic efficacy, have vastly improve tolerability and safety profiles, are resistant to proteolytic digestion, and are readily excreted in urine and feces. Sometimes, when the wrong chemistry is used to conjugate PEG to a protein, PEGylation may interfere with the biological or therapeutic activity of the molecule. Aside from that, I can’t easily think of any negative attributes associated with the technology. Believe me — I have tried for over 30 years to find problems with the technology, but I haven’t been able to!

As far as I know, there aren’t any competing FDA-approved protein delivery technologies on the market right now. There are several new delivery systems being developed, including several that use human serum albumin and other human endogenous proteins as delivery vehicles. To date, the FDA has approved eight PEGylated therapeutic proteins — most of which are multibillion-dollar blockbuster products. Further, there may be as many as 30 PEGylated proteins in clinical development. I think it is safe to say that protein PEGylation has become the gold standard of the protein delivery industry right now.

There are currently only a handful of companies like Amgen, Roche, Nektar, Schering-Plough, and Enzon that have taken advantage of PEGylation to deliver protein-based drugs. Why haven’t more biotech companies leveraged the power of protein PEGylation?

Abuchowski: As most scientists will tell you, there is a substantial amount of art — not just technical prowess — when it comes to optimizing scientific methods. While many of the numerous PEGylation chemistries out there are straightforward and easy to use, the key to creating a successful PEGylated product is choosing the best chemistry and the right-sized PEG that will impart the desired biological characteristics on a product. At present, there are numerous PEGylation chemistries and multiple different molecular species of PEGs that can be used to PEGylate proteins. The learning curve is steep for protein PEGylation, and unless somebody on your development team has prior experience with it, PEGylation can be a real hit-or-miss exercise.

In my opinion, many companies that try to PEGylate proteins spend too much time studying PEGylation chemistry and not enough time thinking about ways to optimize the PEGylation process for scale-up and manufacturing purposes. The days of charging 10 times the development costs of a product are gone — it is all about manufacturing efficiencies and pharmacoeconomics (the scientific discipline that compares the value of one pharmaceutical drug or drug therapy to another) now. It is no longer economically feasible for companies operating on slim margins to use a reaction that consumes 90% of your starting materials and yields only 10% product. Further, the manufacturing process has to be facile and lean. This is because the pharmaceutical operators who are charged with manufacturing a product are typically not Ph.D.s but people with high school and associate degrees. Processes need to be uncomplicated, robust, and scalable to be effective.

My almost 30 years in the biotechnology industry has taught me that the most critical step in creating a product is not science but the manufacturing and formulation processes. This is because patents that originally protect the scientific aspects of a product typically expire early in a product’s life cycle. Patents that are developed around manufacturing, formulation, and delivery are the ones that typically extend the life of a product and help to protect lucrative blockbuster drug franchises. A great example of this is Amgen’s EPO franchise. The composition of matter patents for EPO expired in 2004, but additional formulation and manufacturing patents will protect the franchise through 2017. I believe that the companies that understand manufacturing and commercialization will always trump companies that may have scientifically superior products.

What other products may benefit from protein PEGylation?

Abuchowski: Any protein-based product could possibly benefit from PEGylation. However, before PEGylating a protein, it is important to understand its biology and intended use. For example, early on, I PEGylated insulin and learned that increasing its circulation time was not such a good idea because it can easily lead to hypoglycemic shock. I think that you may see an increased use of PEGylation in single-chain antibodies, RNAi and oligonucleotide products, and even in nonviral-based gene delivery technologies.

While I believe some proteins can be delivered via the nasal or oral routes, these routes of administration are typically less efficient and not as cost-effective as parenteral delivery. That said, I think parenteral administration of protein-based drugs is here to stay.

What is the future of PEGylation in the biopharmaceutical industry? Are there any competing protein delivery technologies that may supplant it?

Abuchowski: I think that protein PEGylation has finally hit its stride, and that we will see more applications of the technology to biotechnology products in the future. There are many prospective therapeutic proteins out there that can’t be transformed into drugs because they may be too toxic, have poor circulating half-lives, or are turned over too rapidly following injection. PEGylation affords biopharmaceutical manufacturers an opportunity to increase a protein’s circulating half-life, improve its safety and tolerability profiles, and lower the cost per patient without sacrificing therapeutic efficacy. I think in today’s fast-paced and highly competitive market, the question is no longer whether or not to PEGylate, but when!

There are several companies working on new parenteral delivery technologies for biotechnology drugs. Most of these involve creation of fusion proteins, which genetically link a human carrier protein like serum albumin to a protein of interest. While these technologies are promising, they are more costly than PEGylation, and to my knowledge, none has been successfully scaled to commercial manufacturing levels. It is noteworthy that PEGylation became the de facto drug delivery system for protein-based drugs only after the introduction of PEG-Intron in 2001. This means it took the pharmaceutical industry about 19 years from the time I discovered the technology to recognize protein PEGylation’s utility and commercial potential. I suspect it may take as long or longer for a competing technology to supplant PEGylation as the gold standard for parenteral protein-based drug delivery.

You formed Enzon in the mid-1980s before there was a biotechnology industry to speak of and then formed Prolong Pharmaceuticals 20 years later when biotech had finally hit its stride. Many new entrants into the biotechnology industry contend that the drug commercialization paradigm has changed, and that it is much harder to get drugs approved today than in the past. What are your thoughts on these assertions?

Abuchowski: When I started Enzon there were no CROs, CMOs, or any other type of third-party vendors to help support operations. Consequently, we had to become a vertically integrated biopharmaceutical company so we could develop our products, manufacture them, and then sell them. While it was a lot of grueling, hard work, I was fortunate to have personally experienced each stage of the biopharmaceutical drug development paradigm, ranging from drug discovery through clinical development and marketing and sales. These experiences provided me with skill sets that have served me well over my 30 years in the biotechnology industry and enabled me to form Prolong in 2003 with much less money than it took to start Enzon. That said, the biotechnology industry landscape is much different than it was 25 years ago.

Almost every aspect of drug development can now be outsourced to competent and reputable third-party vendors. Consequently, there is absolutely no need for biotechnology companies to become vertically integrated today. CEOs who are intent on vertical integration are, in my opinion, wasting shareholders’ money and stroking their own egos. This is why so many biotechnology companies have failed and will continue to fail. In today’s world, companies are now expected to do a lot more with much less.

I don’t think gaining regulatory approval and commercializing biotechnology drugs is more difficult than it was in the 1980s. There is certainly more competition, but I think that is good for the industry as whole. While I was at Enzon, I worked very closely with FDA regulators and managed to get two drugs approved in 11 years. However, there is no question that, over the past decade or so, the relationship between the biotechnology industry and the agency has become very strained. Many biotechnology industry CEOs are angry and frustrated because the FDA isn’t approving new drugs as quickly as it has in the past. This has resulted in an intensive lobbying effort to relax the drug approval process. While this may lead to quicker drug approvals (and more money for drug company CEOs and their shareholders), I don’t think it would be in the best interest of the American public.

There is no question that the FDA could be improved and operated more efficiently and effectively. The agency has suffered from poor leadership, inadequate funding, and personnel shortages for the past eight years or so. However, I do believe the people who work at the FDA have the best interests of the public in mind.

Will the biotechnology industry be able to weather the current economic downturn?

Abuchowski: Yes, but it will be painful for inefficient companies and those who have no products in clinical development or on the market. Like others, I believe that about 60% of existing biotechnology companies will fail or be bought by big pharma over the next few years. This is because most of these companies are operating on venture capital money (which is getting harder to find) and haven’t been able to develop any products despite “being in business” for five or more years. Ironically, the venture capitalists may turn out to be their own worst enemies because they funded too many ill-conceived startups hoping to get quick returns on their investments without fully understanding the industry. The most important thing I learned about biotechnology companies is that while science and patents may be important, the success or failure of a biotechnology company invariably hinges on solid regulatory, commercialization, and manufacturing strategies. Companies that lack these are doomed to fail. I don’t expect this paradigm to change anytime soon as the biotechnology industry continues to evolve in the 21st century.