Unigene Opens The Way To Amidated Peptides
Making long peptides in large quantities has never been this chemist's idea of a good time. But these days it's all a matter of engineering and scaleup. Not that these are trivial activities, but at least our synthesizers and genetically engineered microbes know what they're doing most of the time. Amidated peptides, however, are still a tough nut to crack. Microbes can't add a –CONH2 group to the C-terminus, so the pharmaceutical industry is forced to do a lot of "dirty" chemistry on otherwise clean intermediates. These added chemical steps cost money, which is why custom synthesis of exotic peptides can run several dollars per milligram, and human calcitonin, used to treat osteoporosis, costs as much as $400 for half a milligram.
Unigene Laboratories, Inc. (Fairfield, NJ) has discovered a way to produce calcitonin without using chemical steps at the end of the synthesis. Unigene's strategy, based on their patented amidating enzyme, can be adapted to the synthesis of other important amidated peptides such as neuropeptides and hormones.
Fermentation first produces a modified version of calcitonin in bacteria. This intermediate contains an extra glycine residue at the C-terminus. The intermediate is isolated by lysing the bacteria and HPLC purification, which after lyophilization gives a very stable white powder. At this point the terminal glycine serves as an "activator" for the amidating enzyme, which oxidatively replaces the glycine with –NH2. The byproduct is a highly oxidized C2 material.
Calcitonin is available as a nasal spray and in injectible form. Unigene is working on both dosage forms and expects the injectible to be approved shortly in Europe, and the spray to hit the market in about 18 months. Unigene is also collaborating with Warner Lambert on an oral form of calcitonin which should provide easier, more consistent dosing. Since the oral form is also far less active than either the injectible or spray calcitonin, much more of the hormone needs to be produced to meet the anticipated demand for an oral product. Unigene expects to receive a total payout from the Warner Lambert deal of $54 million before launch for reaching certain milestones, "and quite a large royalty per year, amounting perhaps to several hundred million dollars per year in peak years," said Ron Levy, Unigene VP.
"Using a combination of fermentation and our amidating enzyme significantly lowers cost of producing calcitonin, to unheard of levels," Levy stated. "For multi-kilogram production levels, we can achieve greater than 90% cost reduction."
And, according to Levy, the process is eminently scalable. "By basing the process on fermentation rather than chemistry we can scale to any desired production level very simply."
Saving 90% of manufacturing costs is an achievement, but Unigene is not stopping there. The company is working on a technique for inducing bacteria to excrete calcitonin into the fermentation broth. If it works, cell lysis and associated processing steps will be eliminated, perhaps allowing continuous production.
Unigene recently received notices of allowance for US Patent 5,789,234, covering the amidating enzyme process (the enzyme was patented in 1987), and for a second patent covering oral calcitonin delivery. The new enzyme patent effectively extends Unigene's proprietary position on this technology for another 17 years.
Markets, Pricing, and Competitive Strategy
The worldwide market for injectible calcitonin and the nasal spray is about $800 million, but Levy projects demand will be much larger for the oral dosage form. "Worldwide, just 15-20 kg of calcitonin are produced each year, for treating about 1 million patients. Since the oral form is so much less efficient than other delivery routes, we'll probably have to produce between 75 and 100 kg per year to treat the same 1 million patients." But Levy suggested that oral calcitonin might produce much higher demand for the drug from the tens of millions of Americans suffering from osteoporosis.
"As for price, the benchmark is set by Merck's calcitonin, which costs about $2 per dose, or $800 per patient per year," Levy told Pharmaceutical Online. "The Sandoz nasal spray is in this price range, and the new Lily drug is a bit more. We expect to come in around this level with the oral drug."
For more information: Ronald Levy, vice president, Unigene, Inc., 110 Little Falls Rd., Fairfield, NJ 07004. Telephone: 973-882-0860. Fax: 973-227-6088.