Between the late 1950s and early 1960s, several thousand infants inWest Germany were born with weird deformities. Their perfectlyproportioned hands sprouted from their shoulders. Or neat feet fromtheir hips. The long bones of arms or legs (or both) were simplymissing. Many had cleft palates or other abnormalities.

Some 500 such births occurred during that time in Great Britain, butvirtually none in the U.S.

These birth defects were caused not by a bad, inherited gene, but byhuman error.

The mothers of those blighted children took the tranquilizerthalidomide during pregnancy to allay the nausea of morningsickness. Too late, their doctors learned that thalidomide isteratogenic _ harmful to the development of a fetus during the firstseven weeks of gestation.

In 1962, thalidomide was strictly and permanently banned in Europe.

Meanwhile, recalled biochemist David Stirling, a number ofpharmaceutical companies in the U.S. were actively pursuing FDAapproval of thalidomide, which has powerful sedative properties.

Stirling continued, "This happened about the time Europeanregulatory authorities had really started to put two and two together.At the FDA, the reviewer for thalidomide, Frances Kelsey, blew thewhistle. Fortunately, she took the time to review the data, so she gotthe credit for halting the approval process in the U.S. in time."

Now thalidomide has resurfaced as a potent, potential treatment forinflammatory and autoimmune diseases.

It slows down the production of the cytokine, tumor necrosis factor-alpha (TNF-alpha), Stirling told BioWorld Today, "which is almostcertainly the first cytokine in the inflammatory cascade to become up-regulated and over-produced."

That cascade starts, Stirling continued, "when you're challenged bysome cause of inflammation, be it an infection, a burn, an immunechallenge, whatever. And once that over-production of TNF-alphastops, it stops the over-production of other inflammatory cytokines,such as interleukin-1b and IL-6. This combination ultimately leads tothe clinical symptoms of inflammation, be it localized or systemic."

Stirling is executive vice president of pharmaceutical research &development at Celgene Corp. in Warren, N.J.

Celgene Re-recruits Thalidomide Clinically

His company has a formulation of thalidomide, trademarked Synovir,that now is in pivotal clinical trials for the treatment of cachexia(wasting) in AIDS patients. (See BioWorld Today, March 14, 1996,p. 1.)

Celgene also has synthesized and tested a series of three thalidomidestructural analogues _ one amide and two esters _ with increasedanti-TNF potency, and decreased teratogenicity. They are designed tomodulate the inflammatory response without shutting down theimmune response.

The company's first report on these small-molecule compoundsappears in the current issue of the journal Molecular Medicine,published July 25, 1996. Its title: Selection of novel analogues ofthalidomide with enhanced TNF-a inhibitory activity."

That enhancement reaches "100 percent _ up to 400-fold" the 50-to-80-percent decrease in monocyte output of TNF-alpha achieved bythe native thalidomide, the paper reports.

Those monocytes have their own built-in governor of excess TNF-alpha, namely, interleukin-10, which has limited, delayed-actioneffect. Celgene's compounds spare IL-10 while curbing TNF-alpha.

Mice injected with lipopolysaccharide (LPS) quickly develop aninflammatory attack similar to an acute infection. LPS constitutes thecell surface of bacterial microorganisms, including Salmonellaabortus, used in Celgene preclinical in vivo trials of its thalidomide-mimicking compounds. "The amide analogue," their paper reported,"protected 80 percent of LPS-treated mice against death fromendotoxin-induced shock, compared with 60 percent for nativethalidomide."

Celgene collaborates closely with The Rockefeller University'sLaboratory of Cellular Physiology & Immunology. Stirling andRockefeller scientist Gilla Kaplan are co-senior authors of theMolecular Medicine article.

Firm's Research Partner: The Rockefeller

That collaboration, Stirling recalled, "goes back to the early 90s,when we first became involved with each other. Historically, thestrength of the two groups at that time was that Celgene had thechemistry capability plus the clinical side of things, to take advantageof these molecules, whereas The Rockefeller had historicalperspective in the biology."

Since then, he went on, "Celgene has added a biology capability, butwe continue to work with the university for some of the animal work,and help in screening these compounds. And we still have Celgenescientists working in The Rockefeller in New York City.

"The analogues we described in the journal paper," Stirling said,"were like Phase I compounds that got us excited about this wholearea. Now we are pushing the envelope to see how far we can go. Sofar we've gone from several-hundred-fold efficacy quoted in thepaper to several thousand times."

The company has "close to ten primary composition-of-matterpatents pending in the U.S."

Stirling observed, "Quite a spectrum of diseases now have TNF-alphaimplicated in either their symptomology or progression. These rangefrom central nervous system disorders to multiple sclerosis, onthrough the whole variety of autoimmune diseases, like rheumatoidarthritis, diabetes, lupus to infectious diseases in general. Theirinflammatory component," he went on, "include obviouslyHIV/AIDS as well as some chronic infections like tuberculosis."

Clinicals Foreseen in `97

In terms of human trials, Stirling observed that "from a commercialpoint of view, the larger, more chronic diseases, such as rheumatoidarthritis or diabetes, would be of interest. In terms of other unmetneeds, we also would look at acute situations, such as opportunisticinfections in AIDS."

He added, "From a regulatory perspective, something like that mightbe a more rapid route to FDA approval. For that reason, we'relooking for partnering opportunities with a major pharmaceuticalcompany."

He predicted that "assuming nothing goes wrong in terms of toxicity,etcetera, we are hopeful that we will be able to start initial humantoxicology trials early in the new year."

Stirling makes the added point that besides inhibiting inflammation,"another beneficial activity that's been attributed to the parentthalidomide drug is inhibition of angiogenesis _ building bloodvessels to feed growing tumors." He concluded, "Now that we havedeveloped this capability to tease apart the activities of the parentmolecule, and optimize around them, angiogenesis inhibition isanother candidate we're looking at seriously." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.

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