"Controlled release" might sound like a judicial arrangement for the handling of small-time criminals who've paid their dues, but in drug development, of course, it means something else - referring loosely to the manufacture of longer-lasting versions of marketed compounds.
It can also refer to a big-money opportunity, and one that's catching on. Since 1995, the number of controlled-release formulations launched or under development has risen steadily, from 223 to 397, with an especially marked spike in the past three years, according to Pharmaprojects, a firm in the UK that tracks research and development. Of those, more than 250 are on the market as of the current year.
For biotechnology and pharmaceutical firms, improving on approved therapeutics this way can represent a safe, cost-efficient means of scaling regulatory walls, which prove to be much less steep for compounds already granted marketing approval in a particular form.
The Minneapolis-based Controlled Release Society defines controlled release as "the field of scientific activity concerned with the control in time and space of the biological effects of therapeutic agents," in order to "prolong the duration of action of an active agent, to minimize adverse reactions, or to maximize efficacy."
Big pharma, always better fixed for financial resources, has chalked up some of the more impressive hits in the field, Pharmaprojects noted. Among them are Procardia XL, a controlled-release version of nifedipine for hypertension from ALZA Corp., a unit of Johnson & Johnson; and Cardizem CD, the once-daily formulation of the calcium-blocker diltiazem (another anti-hypertensive) from Elan Corp. plc.
For pain, Elan also developed Avinza, approved in March 2002 and intended to treat, in a once-daily dose, moderate to severe pain that requires around-the-clock opioid therapy for a long period. Avinza consists of morphine sulfate in extended-release form, sold as capsules.
Biotechnology is active in finding ways to make drugs work longer, too. An example that springs to the minds of most industry watchers is Amgen Inc.'s Neulasta (pegfilgrastim), the longer-acting version of the white-blood-cell stimulator Neupogen (filgrastim).
Neulasta uses Enzon Corp.'s pegylation technology, which helps drugs stay in the body longer and is the subject of a cross-licensing of patents between Enzon and Nektar Therapeutics Inc., formerly Inhale Therapeutics Systems Inc. In January 2002, Enzon and Nektar entered the deal, under which Nektar would be the primary marketer of the pegylation technology to potential partners, but Enzon has rights to use it for its own products.
Engineering,' Not Delivery, Can Do The Job
Pegylation also enabled the approval of two other recently approved products: Pegasys for the treatment of hepatitis C, partnered for marketing with F. Hoffmann-La Roche Ltd.; and Somavert to treat acromegaly, from Pharmacia Corp. (merged with Pfizer Inc.).
Other drugs developed with pegylation are Schering-Plough Corp.'s PEG-Intron, a modified form of Intron A (interferon alpha 2-b); and Bristol-Myers Squibb Co.'s Definity, an ultrasound contrast agent.
Enzon describes PEG (which stands for polyethylene glycol) as a "relatively nonreactive and nontoxic" polymer frequently used in food and pharmaceutical products, which the company's technology attaches to proteins and small molecules.
Kenneth Zuerblis, chief financial officer of Enzon, is careful to distinguish pegylation from what many consider true controlled-release technology, considered more device oriented.
"What we do is effectively the same thing," Zuerblis told BioWorld Financial Watch. "But pegylation actually changes the molecule - disguises it and gets it to circulate more in the body."
A liposomal formulation would be more in the class of authentic controlled-release drugs, Zuerblis said, and Enzon has one of those, too: the antifungal Abelcet.
"It's basically the only product that got approved out of The Liposome Company," he said, a firm that was acquired in 2000 by Elan, which later divested Abelcet to Enzon and received a $360 million cash payment.
Enzon had news last week on its topoisomerase-I inhibitor PEG-Camptothecin for gastric and gastroesophageal junction cancers, which met its interim safety and efficacy criteria in the first part of a Phase II trial. More patients will be enrolled, the company said.
Camptothecin was originally developed by the National Institutes of Health but "was too toxic and had too short a circulation life," Zuerblis said. "With our technology, we were able to make it into a drug that could be properly dosed. We found a way to take the full-strength, original camptothecin and deliver it," using what Enzon calls "engineering" that can be applied to proteins and small molecules.
Along with Neulasta in the field of longer-lasting biotech drugs, Amgen has Aranesp, a recombinant erythropoietic protein - the extended release, second generation of the blockbuster Epogen (epoetin alfa) - first approved as a red blood cell booster for dialysis and nondialysis patients with chronic renal failure.
Risks: Patent Deadlines, Generics, Pharma
Recent newsmakers of less-monolithic status than Amgen include the likes of Pain Therapeutics Inc., which in early July started a pivotal trial with Oxytrex, a combination of immediate-release oxycodone and low-dose naltrexone for chronic, severe lower-back pain. The company offered no details about dosing, but entered a deal in January with Durect Corp. to develop a longer-acting version of oxycodone, which is approved for dosing up to four times a day.
At the end of June, Inex Pharmaceuticals Corp. entered a deal under which it would add about C$25.07 million (then valued at US$18.58 million) to its balance sheet through a stock sale, with proceeds going toward advancement of Onco TCS, which has proven strong in a pivotal Phase II/III trial against relapsed aggressive non-Hodgkin's lymphoma.
TCS stands for Transmembrane Carrier System, Inex's liposomal drug delivery technology to provide longer blood circulation, tumor accumulation and extended release of the drug - in this case, vincristine - at the cancer site.
Pain, though, is understandably an indication particularly alluring to controlled-release approaches. GlaxoSmithKline plc apparently thought so, when it entered a potential $160 million-plus deal with Pozen Inc. for a migraine treatment that deploys the latter's combination drug technology known as MT 400.
The method, proven in Phase II studies, couples a marketed triptan with a long-acting, nonsteroidal, anti-inflammatory compound. Pozen and GSK plan to further develop combinations of triptans (5-HT1B/1D agonists, which GSK has been researching since the 1970s) with the NSAID.
In May, Acorda Therapeutics Inc. pulled down $55.3 million in a financing to help its ongoing Phase III trial of Fampridine-SR for spasticity in spinal cord injury patients and a Phase II study against multiple sclerosis. Secondary endpoints in the Phase III study include bladder, bowel and sexual function. The drug is an oral, sustained-release formulation of 4-aminopyridine, a potassium channel blocker aimed at channels in demyelinated nerves.
Prostate cancer is an indication in which controlled release has proven valuable for Praecis Pharmaceuticals Inc., which has Plenaxis, or abarelix for injection suspension, under review by the FDA (with action due by Aug. 27) in a defined subpopulation of advanced patients for whom existing hormonal therapies may not be appropriate.
The drug, a gonadotropin-releasing hormone antagonist given in a one-month sustained-release formulation, was the center of a development and commercialization agreement between Praecis and Amgen, but the original new drug application in a broad patient population failed to win FDA approval in June 2001.
Phase III trials showed Plenaxis quickly knocked down testosterone levels while completely avoiding the initial testosterone "surge" characteristic of currently used leutinizing hormone-releasing hormone agonists.
By whatever name, Zuerblis said, finding ways to extend the efficacy-life of drugs is profitable business, but can be risky.
"With PEG-Intron, we created a whole new drug, but there's not a ton of PEG-Introns out there," he said.
By the time an extended version is developed of an existing compound, "you might be competing with generic [versions because the drug has gone off patent] or, more importantly, the pharma company may have developed something new," Zuerblis said.
"If there's that much value, the pharma company will be looking for ways to do it itself," he said.