By Randall Osborne
In a week of good news and bad news for Protein Design Labs (PDL), the company released favorable results from clinical trials of a leukemia treatment and announced that its partner in four other drugs, Boehringer Mannheim GmbH, is dropping two of them.
"The story's a little bit of a mixed bag," said Jon Saxe, president of Mountain View, Calif.-based PDL.
Wall Street registered the bad news. PDL's stock (NASDAQ:PDLI) closed Tuesday at $39.375, down $7.38, a drop of 15.7 percent.
Boehringer, of Mannheim, Germany, entered the development pact with PDL in late 1993. Corange Ltd., the parent company of Boehringer, made the deal, which included a $75 million stock purchase and was said to be worth up to $131 million more. (See BioWorld Today, Nov. 1, 1993, p. 1.)
Since then, Roche Holding Ltd., of Basel, Switzerland, has made known its agreement to buy Corange, pending regulatory approval.
PDL's terms with Boehringer were renegotiated a year later, lowering the milestone payments. To date, Boehringer has paid $117 million to PDL, which includes the equity purchase. The rest was in license fees and milestone payments, Saxe said, and no more milestone payments remain to collect. (See BioWorld Today, Dec. 6, 1994, p. 1.)
"Financially, [Boehringer's move] has no impact at all," Saxe said.
Boehringer said it is giving up the rights to PDL's human antihepatitis B antibody, known as OST 577, and PDL's human anticytomegalovirus antibody, called Protovir. Also, Boehringer is terminating a Phase II study of OST 577.
In that study, OST 577 was being evaluated against chronic hepatitis B. Sixteen of a planned 200 patients had been enrolled. "That was disappointing to us," Saxe said.
Disappointing to Boehringer, Saxe said, were the side effects arising in the patients studied: abnormal levels of protein in the urine and fever. The side effects are "self-resolving," and part of a normal immune response, Saxe said.
"You stop the drug and, just like having the flu, it goes away," he said. "In people whose viral load has been diminished, you're not going to see that side effect. Of course, that has to be robustly shown in the clinic."
Saxe said development of OST 577 will continue, probably with a nucleoside analogue such as lamivudine, although the clinical plan has yet to be clearly defined. Lamivudine is under development by BioChem Pharma Inc., of Laval, Quebec, and Glaxo Wellcome plc, of London.
"The world has changed" since Boehringer started developing OST 577, he said. "Inteferon alfa was the only approved treatment for hepatitis B. [Now,] it looks like the nucleoside analogues are going to be the drug of choice. You use those products to get the viral burden now, and you use our product to knock the disease out."
To satisfy FDA requirements, PDL will be searching for partners among a particular group, Saxe added. "One of the issues is that, from a regulatory point of view, we can't study our product with a nucleoside until one is approved, or unless we hook up with a company sponsoring a nucleoside," he said.
Among the companies with nucleosides in development are Glaxo Wellcome and SmithKline Beecham plc, of London; and Triangle Pharmaceuticals Inc., of Durham, N.C., Saxe said.
Protovir's fate is uncertain. "We're debating what to do with it," Saxe said. "It's not going to make much difference financially, one way or another."
Boehringer is keeping the rights to PDL's SMART Anti-L-Selectin antibody, which blocks white blood cells from starting the process of passing through cell walls and causing damaging overreactions in situations of trauma, such as those common in gunshot and accident victims.
Boehringer plans to begin clinical trials of the antibody next year, Saxe said.
Another antibody to which Boehringer has retained rights is related to certain cardiovascular conditions, he added. The company is "in the very final stages of animal testing," he said.
Leukemia Drug Shows Promise In Phase II
A third PDL antibody, known as the SMART M195, is in a Phase II clinical trial from which promising data were reported at the annual meeting of the American Society of Hematology in San Diego.
The antibody was added to standard therapy for acute promyelocytic leukemia (APL). Thirteen evaluable patients with newly diagnosed APL showed no residual disease after treatment including the antibody, and 15 patients enrolled in the trial remain in complete remission, with a median duration of more than 20 months.
Typically, APL patients go into remission near the end of the course of the disease. "It's somewhere between a year, and a year and a half," Saxe said. "Then they relapse and only live for a matter of months."
Data from another ongoing trial for M195 were reported at the meeting. The Phase I study uses the antibody with the alpha-emitting radioisotope Bismuth-213 in patients with relapsed or refractory myeloid leukemia. Nine patients have been treated in the dose-escalation study. They showed radiation doses to the sites of disease 10,000 to 40,000 times greater than estimated doses to the whole body.
PDL also is conducting a Phase II/III trial of M195 in acute myeloid leukemia at multiple centers.
Saxe took the Boehringer news in stride. "We got one product progressing along nicely, with encouraging clinical data," he said. "Drug development is not a smooth curve. It's a swath, and you just hope the general slope of the swath is upward." *