By David N. Leff
Last Thursday's domino-driven plunge on the world's stock exchanges generated waves of anxiety and depression among people, from stockbrokers to small investors, from Hong Kong to Wall Street.
Actually, these emotions are endemic in large parts of the world's populations. The U.S. National Institute of Mental Health (NIMH) estimates that 10 percent of Americans suffer from some kind of anxiety disorder. Other statistics estimate 50 million in the U.S., 100 million worldwide.
Last Friday in New Orleans, NIMH sponsored a satellite symposium on the theme, "The Neuroscience of Fear and Anxiety," as a warm-up to this week's 27th Annual Meeting of the Society for Neuroscience. In opening the event, NIMH associate director Michael Huerta pointed out that "this area of neuroscience has important clinical implications, since fear and anxiety are key elements of several brain disorders."
Neuroscientist Errol De Souza reported to the symposium on "CRF [corticotropin releasing factor] Antagonists and Anxiety." De Souza is executive vice president of Neurocrine Biosciences Inc., in San Diego, and an adjunct professor at the University of California, San Diego. As he told his audience, CRF is a lead candidate compound under development by the company, with Phase I clinical trials due to start during the fourth quarter of 1997.
"We're looking at an orally active, selective CRF-1 antagonist for treatment of anxiety and depression," De Souza told his symposium audience.
Neurocrine's research and development corporate partner for its mood-ameliorating drug is Janssen Pharmaceutica N.V., of Beerse, Belgium. In February 1995, that firm made a $1-million equity investment in Neurocrine, and selected its CRF drug for clinical development.
Janssen is expected to conduct the impending human safety studies in Belgium or the Netherlands, De Souza told BioWorld Today, "before the end of this year."
He added, "We have projected to be in the clinic in the fourth quarter, which is where we're at now, and I think that's very much on target. We have completed the toxicology, and there are no red flags to stop us from moving forward in terms of planning to initiate the Phase I trials."
Janssen is designing the studies, which are expected to enroll normal, healthy volunteers, rather than people actually suffering from anxiety.
"We have very good preclinical data," De Souza said, "suggesting that increased levels of CRF in the brain contribute not just to the primary symptoms associated with anxiety and depression, but to a great extent with the secondary symptoms also. They mediate in particular the reduced appetite, the sedation and depressed libido and diazepam addiction that you see in these disorders."
Next-Generation Valium? Prozac?
On that point, he added: "The rationale right now for our CRF receptor antagonist is that, from an anxiety standpoint, it will have the same efficacy as diazepams, such as Valium, but without their sedative properties or the abuse liability."
As for antidepressant drugs, De Souza continued, "The advantage of the CRF mechanism over Prozac is that it takes care more of those secondary symptoms related to depression, in terms of normalizing the decreased appetite and libido. The Prozac-like compounds, if anything, exacerbate the reduced appetite that you see in these individuals."
De Souza presented the symposium with data from animal models showing that in CRF transgenic mice the compound normalized diminished sexual function. "The other major advantage seen in our preclinical data," he added, "which won't be proven until we do the clinical trials, is that CRF may be a fast-acting antidepressant." He pointed out that "current drugs against depression usually take three to four weeks to reach therapeutic effectiveness."
At this week's full neuroscience meeting, Neurocrine is presenting seven posters detailing preclinical CRF research. They report results in animal models of the hormone's mechanisms in the brain, plus effects on learning and memory, cocaine addiction and obesity.
In the symposium, DeSouza pointed out that four receptor target variants of CRF have now been identified, and described the one he regards as critical. "What we have done in a fairly systematic manner," he said, "is determine that the CRF-1 receptor is the one involved in the hormone's anxiety-related effects. So we have developed a very selective small molecule block to inhibit the effects of just that one receptor, but then we minimize the side-effect profile related to generalized suppression of these receptors."
The "Three Fs" Of Stress Control
Corticotropin releasing factor is the designated hormonal hitter for honchoing the body's response to stress, whether physical or emotional, external or internal. The human crf gene sits on the long arm of chromosome 8. It expresses its 41-amino-acid, single-chain peptide in the brain's hypothalamus. There, CRF begets ACTH, the adrenocorticotrophic hormone from the anterior pituitary gland. This in turn begets hormones, notably epinephrine, in the body's adrenal glands (atop the kidneys). These kick on the well-known "flight, fight or fornicate" syndrome to mobilize circulatory, muscular and psychological responses for dealing with the stress. (See BioWorld Today, April 17, 1995, p. 1.)
An injection of epinephrine produces the physical symptoms of a sudden attack of anxiety — sweating, trembling, rocketing heartbeat.
In rats, very low doses of CRF set off locomotor activity, which is dramatically decreased by higher doses. Administered directly into the brain, the hormone produces additional behavioral effects. In a familiar environment, these take the form of increased sniffing, grooming and rearing; in a strange setting, heightened "emotionality" and a freeze posture, as well as decreased feeding and sexual activity, plus increased conflict behavior.
In clinical anxiety, depression and panic, human patients show greatly elevated secretion of CRF. Therapeutic strategies to check this excess include inhibiting the hormone's synthesis and, as in Neurocrine's drug candidate, antagonizing its effects through receptor blockade. High-throughput screening of chemical libraries and structural modifications has identified several classes of nonpeptide CRF receptor antagonists.
The fact that the number of CRF binding sites decrease in the cerebral cortex of suicide victims bears out the hypothesis that CRF is hypersecreted in major depression.
De Souza found at the NIMH symposium "a lot of excitement in the industry — both biotech and big pharma — in looking at this as really the next-generation approach, a newer Prozac, a newer Valium." He concluded: "So Neurocrine is in major competition with just about every big pharmaceutical company, and holding its own with our partner, Janssen, in terms of rapidly moving the CRF hypothesis into the clinic." *