BOSTON—Rhythm Pharmaceuticals Inc., a biopharmaceutical company aimed at developing and commercializing therapies for the treatment of rare genetic disorders of obesity, announced at the beginning of April that it has acquired exclusive worldwide rights from Takeda Pharmaceutical Co. Ltd. to develop and commercialize T-3525770 (now RM-853).
RM-853 is a potent, orally available ghrelin o-acyltransferase (GOAT) inhibitor currently in preclinical development for Prader-Willi syndrome (PWS). PWS is a rare genetic disorder that results in hyperphagia and early-onset, life-threatening obesity—it is a condition for which there are no approved therapeutic options.
“We’ve had a long-standing scientific relationship with Takeda, and they came to us due to our strong expertise in rare genetic disorders of obesity,” Dr. Keith Gottesdiener, CEO of Rhythm Pharmaceuticals, tells DDNews. “We have already advanced our lead product candidate, a first-in-class MC4R agonist called setmelanotide, into late-stage clinical trials for six of these disorders, two of which we have been granted Breakthrough Therapy Designation and Orphan Drug Designation by the FDA.
“The exciting opportunities we are positioned to deliver on as we continue to progress with the setmelanotide development program, along with our overall expertise and familiarity with the metabolic space, gave both sides confidence to move forward with the licensing agreement. We both recognized that RM-853 has tremendous potential for the treatment of Prader-Willi syndrome.”
“While this is our first collaboration with Takeda, we’ve had both professional and personal relationships with Takeda for many years … I have had strong personal and professional ties to key R&D leaders at Takeda, going back to my previous roles at Merck,” Gottesdiener notes. “As a result, the collaboration and eventual deal went extremely quickly and smoothly, going from negotiation of the term sheet to final deal within one month. The Takeda team was a pleasure to work with and joined us in trying to find a good ‘home’ for an excellent program that has the potential to address a large unmet need.”
“First, it is important to understand the mechanisms that contribute to an unrelenting hunger, known as hyperphagia, which leads to severe obesity in people living with PWS. Ghrelin is an orexigenic peptide, secreted by the stomach and proximal small intestine in response to a negative energy balance,” Gottesdiener points out. “Ghrelin plays a key physiological role in stimulating appetite and promoting food intake, thereby maintaining overall energy balance. In people living with PWS, levels of active ghrelin are elevated, leading to the hypothesis that the high levels of ghrelin might contribute to the hyperphagia they experience.”
RM-853 is designed to block GOAT, the key enzyme involved in the production of the active form of ghrelin, with the expected effect of lowering active ghrelin levels. This blockage increases the levels of des-acyl-ghrelin (DAG), a ghrelin precursor. High levels of DAG are believed to have independent beneficial effects on the control of appetite and tissue homeostasis, which might add to the potential efficacy of RM-853 in PWS.
In preclinical research, RM-853 prevented body weight gain and reduced fat mass in high fat-fed mice, with a favorable pharmacokinetic, pharmacodynamic and safety profile. “We plan to complete preclinical studies of RM-853 and file an Investigational New Drug application with the U.S. Food and Drug Administration in the first quarter of 2020,” Gottesdiener notes.
“Our team has a deep understanding of the complex pathways involved in regulating bodyweight and appetite and is experienced in working with specialized endocrinologists and physicians to design and execute clinical trials that evaluate therapeutic options for people living with PWS,” said Dr. Lex H.T. Van der Ploeg, chief scientific officer of Rhythm Pharmaceuticals. “We believe this knowledge, coupled with our focus on rare genetic disorders of obesity, positions Rhythm well to seek to effectively develop RM-853.”
Under the terms of the agreement, Rhythm will assume sole responsibility for the global product development and commercialization of RM-853. Takeda will receive an upfront payment of $5 million in Rhythm common stock, back-end development milestones and single-digit royalties on future RM-853 sales.
“With RM-853, we have the opportunity to develop a first-in-class therapy with a likely dual mechanism of action, which may more effectively mediate the hyperphagia and weight gain associated with PWS. We are also planning to further evaluate setmelanotide in PWS in parallel with the development of RM-853. Given setmelanotide and RM-853’s distinct mechanisms of action, we will explore opportunities to evaluate the two compounds in combination, as there may be complementary effects. We look forward to broadening our ongoing efforts in PWS and to advancing RM-853 through preclinical studies,” Gottesdiener reports.
