For the second time this year, Merck & Company has abandoned a once-thought-promising weight loss drug in the face of discouraging trial results. But a large phase II trial continues on a more encouraging note of Merck's drug believed similar to Sanofi's diet pill Acomplia (rimonabant).

The latest Merck drug to bite the dust is MK-0557, which turns out to have been a Neuropeptide Y5 receptor (NPY5R) antagonist which entered the brain and bound tightly to a protein that it was designed to inhibit: an appetite-stimulating molecule called neuropeptide Y.

Merck early on had high hopes for this drug. Rodent trials showed that mice ate less when given MK-0557 and human patients in a phase I trial experienced no severe side effects.

But in a year-long multicenter phase II trial involving 1,661 overweight and obese patients, who either received a 1 mg daily dose of MK-0557 or a placebo in addition to following a diet and exercise program, those on the Merck pill lost on average less than 3 pounds more than those on the placebo.

The conclusion of researchers reported in the journal Obesity Reviews: "Pharmacological antagonism of the NPY5R, when used as monotherapy in conjunction with diet and exercise, is not sufficient to obtain clinically
meaningful weight loss in overweight and obese adults."

"Solely targeting the NPY5R in future drug development programs is unlikely to produce therapeutic efficacy," the researchers similarly reported in the October issue of the journal Cell Metabolism.

Or, as Steven Heymsfield, a clinical researcher at Merck who evaluated the drug, put it in a report published Oct. 3rd on the journal Nature's website, "We consider this a negative study."

"The weight loss was about 3 pounds above the placebo group, but that has no commercial viability for a drug company," Heymsfield added.

In March of this year, Merck & Company similarly gave up on the weight-loss nasal spray PYY3-36 after concluding from a "Preliminary Proof of Concept Study" that the drug was not effective.

PYY3-36 is a hormone that occurs naturally in the small intestine after a person consumes food and it is thought to send messages to the brain to signaling fullness.

Merck turned all rights to the drug back to the biotech company Nastech Pharmaceuticals, which has said continues to believe in PYY3-36 and still hopes to press forward with a Phase II clinical trial program.

In the Nature.com article, Heymsfield attributed the disappointing results with MK-0557 to the complexity of the human response to food. Interfering with one pathway, he said, may not have a dramatic effect because there could be other pathways serving as backup systems.

Merck is still moving ahead, however, with a Phase II clinical trial of a CB-1 receptor antagonist that it has identified to participants as "L-000899055." While Merck has declined to discuss this trial with us, this drug almost certainly is MK-0364.

This multicenter, international two-year trial with 2,400 participants is now moving into its second year, at which point participants are being rerandomized into one of six groups.

Some of those who for a year have been on the 6 mg dose (the strongest in the trial) are being switched to a lower dose or a placebo. Those getting a 4 mg dose will continue getting that dose, and those who have been on a placebo will remain on a placebo.

Some of the participants in this trial have told Acomplia Report they have had weight-loss results that are at least equal to, and in some cases better than, results reported in rimonabant clinical trials.

While the scale and length of this study seem unusual for a phase II trial, MK-0364 is now the only obesity drug listed in phase II or beyond in the report on Merck's "pipeline" that the company filed with the U.S. Securities and Exchange Commission on August 7th.

One observer also wondered whether Merck, observing the delays now taking place in FDA approval of Acomplia, concluded that for a drug of this kind that works by affecting brain receptors, longer trials involving more participants might be better.