One of the sneakier and more challenging diseases is the liver condition brought about by the dreaded hepatitis C virus, which chronically afflicts about 2.7 million people in the U.S. - each at risk of fibrosis, cirrhosis, liver cancer, liver failure, or all of the above, and ultimately death.
The Centers for Disease Control and Prevention counsels testing for anyone who has injected illegal drugs or received a blood transfusion before July 1992. Also at risk are those who were given clotting factors made before 1987, as well as patients on long-term kidney dialysis.
HCV has been anything but simple to attack.
"This has turned out to be a very difficult field for drug development," said Michael Partridge, director of corporate communications for Vertex Pharmaceuticals Inc. Standard therapy is injected pegylated interferon-alpha and ribavirin, a regimen Vertex and others have sought to improve upon.
Vertex and Idun Pharmaceuticals Inc. had HCV-related news last week, by a coincidence that must have been a happy one for the companies and patients living with the insidious virus.
With Mitsubishi Pharma Corp., Vertex entered a deal worth up to $33 million for the development and commercialization of the latter's Phase I HCV drug, known as VX-950, in Japan and the Far East. Most of the money will come before the end of 2006, and the sum includes $17 million to help Vertex get the drug through Phase II trials. Tokyo-based Mitsubishi likely would have an easier time designing trials and, ultimately, winning approval overseas with U.S. studies to back up the effort.
VX-950 is Vertex's lead oral protease inhibitor for HCV, bolstered by preclinical data suggesting it gains excellent exposure in the liver and trims levels of HCV RNA in the replicon system, as well as infectious virus assays, within days. The Phase I study in 35 healthy volunteers began earlier this month.
"HCV protease inhibitors in general have certainly taken a long time, but Vertex is the leader in the field," Partridge told BioWorld Financial Watch. "We're one of the few companies that have been able to get [one] in development" for the indication, he added.
HIV is another story. For that virus, Vertex's structure-based drug design has resulted in a pair of protease inhibitors developed with GlaxoSmithKline plc: Agenerase and Lexiva. A third-generation protease inhibitor under way with GSK, VX-385, looks good preclinically.
A sad, if potentially lucrative, fact is that the HCV germ also affects about one-fourth of HIV-infected people in the U.S., and the U.S. Public Health Service/Infectious Diseases Society of America guidelines recommend all HIV patients be screened.
Also for HCV, Vertex owns all rights to the oral drug merimepodib (also known as VX-497), an inhibitor of inosine monophosphate dehydrogenase (IMPDH). Blocking IMPDH reduces intracellular guanosine triphosphate, needed for DNA and RNA synthesis, and Vertex is developing merimepodib in combination with standard therapy, soon to enter Phase IIb trials in treatment-experienced patients, Partridge said.
Idun, for its part, closed the first tranche of a planned $65.6 million financing, hauling down $27 million through a preferred-stock private placement - aiming to use the "vast majority" of the cash to develop its caspase inhibitor IDN-6556 for liver conditions, including HCV, said Steven Mento, president and CEO.
In the fall, Idun started a Phase IIb trial of IDN-6556 in patients undergoing liver transplants to evaluate whether the apoptosis blocker could decrease the cellular liver damage that can occur during the transport and transplant periods. The donor liver gets the drug during transport to the transplant center, and so does the liver recipient. That application of the drug is intravenous; all others would be oral.
The rest of the money likely will come "around the end of next year," Mento said. Among the projects are a large HCV study, to begin later this month, and a pilot study in Asia testing the drug against hepatitis B. Results from a pilot study with IDN-6556 in fatty liver recently were reported.
Another novel approach being tried against HCV involves Toll-like receptors, glycoprotein molecules found on surfaces of antigen-presenting cells that recognize microbial structures and, when bound to them, trigger innate immune responses in the body. (See BioWorld Financial Watch, March 22, 2004.)
TLRs are named for the Toll gene in the Drosophila fruit fly, helping the insect fight fungal infections, a gene that scientists began investigating with regard to humans when researchers found it shares cytoplasmic sequences with the interleukin-2 receptor. Coley Pharmaceutical Group Inc. has Actilon, a TLR9 agonist, in Phase II trials against HCV.
Maxim Pharmaceuticals Inc. has yet another strategy against the disease. The company's Ceplene (histamine dihydrochloride) is designed to lessen oxidative stress, reversing immune suppression and protecting immune cells and improving the efficiency of T- and NK-cell-activating agents, such as IL-2. Ceplene is in Phase II trials against HCV, as Maxim awaits word from the FDA regarding a new drug application to use Ceplene in metastatic malignant melanoma patients. The compound recently hit its primary endpoint in a Phase III study against acute myeloid leukemia.
Liver-drug firm Metabasis Therapeutics Inc. (which made headlines last week when it priced an initial public offering at $35 million) entered a deal at the start of this year with Merck & Co. Inc. to use the former's HepDirect prodrug technology in developing small molecules for HCV.
Idun's financing gave the company the oomph it needed to compete in the HCV race. MPM Capital led the deal. Other new investors included Sutter Hill Ventures, Prospect Venture Partners, Pacific Rim Ventures and Aberdare Ventures. As part of the arrangement, Luke Evnin from MPM Capital and Jeffrey Bird from Sutter Hill Ventures will join Idun's board, bringing the total number of board members to six.
"We're obviously very happy with the investor group, and the size of the investment really puts us in a strong position," Mento said. He called the placement a "transforming event," and said the first tranche will take the privately held company through at least two more years.