A $25 million Series B financing disclosed Wednesday morning will bring the total amount invested in Rhythm Pharmaceuticals Inc. to $65 million, according to Bart Henderson, founder and president of the Boston-based company.

"This really comes on the strength of significant clinical progress in both programs," Henderson told BioWorld Today, referring to clinical-stage peptide drugs RM-131 and RM-493.

The round included all of Rhythm's existing investors: MPM Capital, New Enterprise Associates and Third Rock Ventures, plus new investor Paris-based Ipsen SA.

Proceeds will support the advancement of ghrelin agonist RM-131 through Phase II trials for diabetic gastroparesis and melanocortin 4 receptor (MC4R) agonist RM-493 through Phase I testing in obesity and diabetes. The two programs were licensed from Ipsen in 2010 in exchange for 17 percent equity in Rhythm and up to $80 million in milestone payments, plus royalties.

Both peptides are involved in food intake, energy homeostasis and gastrointestinal (GI) function.

Ghrelin is a hunger-stimulating hormone thought by some to be the key to obesity, along with its counterpart, leptin, the satiety hormone. Ghrelin agonists have been identified as potential therapies for gastrointestinal motility disorders like postoperative ileus and diabetic gastroparesis, and for cachexia (muscle loss) resulting from multiple causes, including cancer.

RM-131 is derived from the natural ghrelin sequence and engineered to stimulate GI motility, weight gain and anti-inflammatory activity while retaining good stability and pharmacokinetics. In animal models, it has been shown to reverse both surgical and opioid-induced ileus and to reverse cachexia.

Rhythm recently started a Phase II trial of RM-131 in gastroparesis in patients with Type I and Type II diabetes. The trial will assess doses from 10 mcg to 100 mcg in about 100 patients, with endpoints measuring effects on GI motility, symptoms of gastroparesis and safety.

Previous Phase I trials showed a highly prokinetic effect on gastric emptying.

Diabetic gastroparesis is a highly debilitating illness, affecting up to 30 percent of people with diabetes in the U.S. It causes chronic nausea, vomiting, malnutrition and has a high rate of hospitalization.

"There are very limited treatment options available," said Keith Gottesdiener, CEO of Rhythm. "There's really no safe and effective way to treat it."

Reglan (metoclopramide) is used to treat diabetic gastroparesis, but it carries a black-box warning for Parkinsonian side effects, and is limited to three months of use.

Rhythm's second clinical program for RM-493 is complementary to its work in the ghrelin space. MC4R agonists have potential for obesity, diabetes and related metabolic disorders.

"For diabetes, one of the pressing needs is for effective weight-loss drugs. That's why MC4 is so appealing. It has an effect not only on weight regulation, but also insulin sensitivity," Henderson said.

Gottesdiener called the MC4 receptor a "robust target for obesity," and said Rhythm has established the target as being highly validated for obesity indications based on two scientific studies. One study showed that between 1 percent and 2 percent of obese people are heterozygous for a mutation of the MC4 receptor gene. Those individuals tend to be overweight, with a stronger effect if they are homozygous for the gene. That result established the role of the MC4 receptor in obesity.

Another study in obese rhesus monkeys showed an average loss of 13 percent of body weight "without evidence of any toxicities," according to Gottesdiener.

If borne out in human trials, those results would beat the pants off late-stage obesity contenders such as lorcaserin (Arena Pharmaceuticals Inc.), which scored a thumbs up from the FDA's Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) in May and seems likely to win FDA approval upon its upcoming June 27 PDUFA date. (See BioWorld Today, May 11, 2012.)

In clinical trials, 35 percent of patients taking lorcaserin lost at least 5 percent of their body weight, about double the comparable number in the placebo group, and that weight loss led to trends toward improved cardiovascular risk, glycemic control and quality of life.

Lorcaserin could be a weight loss blockbuster, along with Contrave (naltrexone HCl/bupropion HCl, Orexigen Therapeutics Inc.) and Qnexa (phentermine/topiramate, Vivus Inc.), but there's clearly room for stronger efficacy results and more robust safety profiles for weight-loss drugs, as the FDA is giving the current batch extreme scrutiny. (See BioWorld Insight, May 29, 2012.)

The new cash infusion will allow Rhythm to explore RM-493's potential in Phase I studies.

Rhythm is not projecting a timeline for its cash runway, but it expects the funds to substantially support its planned Phase I and Phase II studies. "We currently expect that the financing will take us through Phase II programs," Gottesdiener said.