VIEWS & REVIEWS

. '.,',

-Gill Higgins-

Leptin, a hormone involved in bodyweight control, hit the pages of Jnpluuma® for the first time in August 1995.* Since then, it has led to excitement and disappointment for researchers and the public alike. In this week's issue, Jnpluuma® keeps you up to date with this fast-moving field of research, and describes some of the key studies that may eventually lead to a new treatment for obesity and other bodyweight disorders.

The story began last year with the cloning of the mouse ob gene by Dr Jeffrey Friedman and colleagues at the Rockefeller University. US.1 This gene encodes for the hormone leptin. Dr Friedman and colleagues then showed that it was possible to induce bodyweight loss and reduce food intake in genetically obese mice. which had 2 faulty copies of the ob gene. by administering leptin. This news inspired hope for a new treatment for obesity.

Further research conducted in Canada concentrated on the expression of the human version of the ob gene. It was found that the gene was expressed in much higher quantities in adipose tissue of obese patients than in controls.2 With high levels of ob gene expression. but few signs of leptin's regulatory activity, the researchers speculated that the ob gene in obese patients might be producing defective leptin, or that patients with obesity are insensitive to the hypothesised regulatory function of leptin. This paved the way for pharmaceutical companies to jump in and grab the chance to develop treatments that could somehow activate the leptin pathway, or sensitise patients to leptin.

As indicated by Amgen's $US20 million deal for an exclusive license to develop leptin-based products, this was being viewed as big business.

Millennium is front runner ... The beginning of this year saw another chapter

begin to unfold in the leptin story. Millennium Pharmaceuticals made the headlines in January by announcing the successful cloning of a gene for the leptin receptor. ** At first, Drs Louis Tartaglia and Robert Tepper from Millennium were unsure whether the cloned gene encoded for a receptor that transported leptin across the blood:brain barrier, or one that is responsible for intracellular signalling.

But 2 other groups, both from Rockefeller University, have now confirmed the identification of the receptor as one that mediates leptin signalling. In fact, it has been confirmed that Dr Tartaglia's leptin receptor is a product of a gene called db. For years, researchers had thought that the db gene was involved in bodyweight control. Now they have their proof.

By identifying the gene that encodes for the receptor involved in leptin signalling, the race to develop new agonist drugs is sure to gain pace. The discovery has certainly provided a significant boost to research in this area.

And it appears that Millennium has received a boost of its own, as a partnership deal has been struck with Hoffmann-La Roche with the aim of beginning clinical trials with a leptin receptor agonist within 3 years.

* See Inpharma 1001: 12, 26Aug 1995; lKXJ314619

** See Inpharma 1020: 10, 20 Jan 1996; 8lXJ416340

0156·270319611033-0003l$01 .00'' Adl. International Umlted 1H6. All rlghta r~

... but Interneuron is in on the chase However, as is often the case, the road to success is

not always smooth, and Millennium's file for a patent for the discovery of the leptin receptor has been challenged by a file for worldwide patents by Progenitor Inc., a majority-owned subsidiary of Interneuron Pharmaceuticals Inc., reports the Wall Street Journal. 3 In response to this, George Gould,

Inphanna· 20 Apr 1H6 No. 1033

3

4 VIEWS &; REVIEWS

Hoffmann-La Roche's chief patent counsel, has claimed that Interneuron only discovered a molecule related to the leptin receptor, and not the receptor itself.

Several unknown factors make it difficult to say which company has the better claim, notes the Wall Street Journal. Interneuron may already be one up on Millennium as the former company filed a patent application in Europe in September 1994. However, a 'glaring weakness' in Interneuron's application is that it focuses on using its discovery as a receptor for proteins that stimulate red blood cell growth, rather than as having a possible role in the development of antiobesity drugs.

Fat chance? Apparently, developing organic compounds that

can mimic the effects of protein hormones is one of the most difficult quests in pharmaceutical research. Many scientists are pessimistic about the chances of a successful outcome with a synthetic form of leptin, but only time and further research will tell.

Yet more pessimism comes from scientists in the US who have published a study in the NEJM showing that there is no defect in leptin production in obese patients.4 As with the ob gene, levels of leptin appear to be positively correlated with percentage of body fat. In the US study, the mean serum leptin level in obese individuals was 31.3 nglml, compared with 7.5 nglml in lean individuals. This suggests that developing a leptin mimic may be of little use.

However, as knowledge of the leptin receptor increases, researchers may discover other ways of amplifying the leptin signal. It seems that the problem is decreased sensitivity to leptin, rather than reduced plasma levels of the protein. Indeed, no mutation of the human ob gene, similar to the one found in mice, has been established for obese people.

Now, researchers are likely to concentrate on identifying mutations in the db receptor gene. Mutant forms have already been found in mice db genes and in the rat counterpart, the fatty gene. One known db gene mutation produces a receptor molecule that is shorter than normal. Accordingly, it cannot cross the cell membrane into the cytoplasm, and fails to transmit signals from leptin into the cell.

Leptin studies still likely to proceed Although a number of discouraging findings have

been made regarding the potential of leptin or a leptin mimic to exert control over bodyweight gain in humans, no direct evidence is available. Thus, researchers have not yet been dissuaded from pursuing this idea.

Amgen is keen to discover the truth on this matter and to discover it quickly - researchers there are planning to conduct a clinical study within the next few months to examine the effects of leptin administration, according to Amgen chief executive Gordon Binder. t

Inpharma- 20 Apr 1996 No. 1033

Encouragement is available in the torm ot an animal study in which obese mice injected with human leptin were seen to lose bodyweight. 'The fact that human leptin reduces weight in the mice raises the possibility that giving leptin to people might have similar effects', said Dr Friedman.

Obviously, the safety of this approach is a prime concern, and Amgen researchers will proceed cautiously with tolerability studies.

If leptin administration did prove effective, it is likely that treatment would involve daily injections or a drug implant under the skin. The animal studies involving leptin administration to obese mice showed that the mice began to regain bodyweight as soon as the injections were discontinued. t See Inphanna 1023: 10, 10 Feb 1996; lnJ314910

1. Barinaga M. Obese protein slims mice. Science 269: 475-476. 28 Jul 1995

2. Hamilton BS, et aI. Increased obese mRNA expression in omental fat cells

from massively obese humans. Nature Medicine I: 953-956, Sep 1995

3. Johannes L. Interneuron is cballensing Millennium for patents tied to obesity

discoveries. Wall Street Journal : B 10. 26 Mar 1996 4. Considine RV, et aI. Serum

immunoreactive.leptin concentrations in normal-weight and obese humans. New England Journal of Medicine 334: 292-295. I Feb 1996 10001'"

0156-2703196/1033-00041$01.00° Adialnternational Limited 1996. All rights reMrVed