Rev­o­lu­tion­iz­ing obe­si­ty treat­ment: Could mi­to­chon­dria hold the key to un­lock­ing fat-spe­cif­ic weight loss?

Glob­al­ly, ap­prox­i­mate­ly 300 mil­lion peo­ple are grap­pling with obe­si­ty, a com­plex dis­ease that has a pro­found im­pact on a per­son’s qual­i­ty of life and in­creas­es their risk of a host of se­ri­ous car­diometa­bol­ic dis­or­ders. Obe­si­ty man­age­ment has long been dom­i­nat­ed by ap­proach­es fo­cused on reg­u­lat­ing ap­petite and re­duc­ing food in­take. These in­clude the ap­proved GLP-1 re­cep­tor ag­o­nists, which have be­come an es­tab­lished part of the treat­ment par­a­digm. How­ev­er, these ther­a­pies, known for their rapid and sub­stan­tial to­tal weight loss, have nu­mer­ous well-rec­og­nized lim­i­ta­tions, in­clud­ing the need for week­ly in­jec­tions, sig­nif­i­cant mus­cle loss, poor ad­her­ence over the long-term, and rapid weight re­bound up­on dis­con­tin­u­a­tion.

As ex­perts con­tin­ue to sound the alarm on obe­si­ty, with the World Health Or­ga­ni­za­tion deem­ing it a glob­al epi­dem­ic, bio­phar­ma com­pa­nies are rac­ing to ex­plore new ap­proach­es – in­clud­ing ones that fo­cus on in­creas­ing en­er­gy ex­pen­di­ture – that can over­come the lim­i­ta­tions of cur­rent ap­proach­es.

Pi­o­neer­ing con­trolled meta­bol­ic ac­cel­er­a­tors 

Mi­to­chon­dr­i­al un­cou­pling, a nat­ur­al meta­bol­ic process that sup­ports me­tab­o­lism and reg­u­la­tion of body tem­per­a­ture, has long been an al­lur­ing tar­get for weight loss ther­a­pies. Pre­clin­i­cal stud­ies show that mi­to­chon­dr­i­al un­cou­pling ac­counts for up to 50% of dai­ly en­er­gy ex­pen­di­ture. How­ev­er, for decades, sci­en­tists in both acad­e­mia and in­dus­try have strug­gled to de­vel­op ther­a­peu­tics that ef­fec­tive­ly lever­age this mech­a­nism with­out caus­ing in­tol­er­a­ble side ef­fects.

En­ter Rivus Phar­ma­ceu­ti­cals, a trail­blaz­er in the field of mi­to­chon­dr­i­al bi­ol­o­gy. The com­pa­ny has pi­o­neered a new class of in­ves­ti­ga­tion­al ther­a­pies called Con­trolled Meta­bol­ic Ac­cel­er­a­tors (CMAs). These nov­el oral com­pounds are pur­pose­ly de­signed to in­crease a pa­tient’s me­tab­o­lism in an im­per­cep­ti­ble way, re­sult­ing in in­creased en­er­gy ex­pen­di­ture, pri­mar­i­ly from fat, while pre­serv­ing mus­cle mass. Un­like caloric-re­stric­tion strate­gies, such as those in­volv­ing GLP-1 re­cep­tor ag­o­nists, which re­duce en­er­gy in­put and re­sult in mus­cle loss, CMAs pro­vide an ef­fi­ca­cy tri­fec­ta. They in­crease the meta­bol­ic rate in a con­trolled and con­sis­tent man­ner to ox­i­dize fat and glu­cose, re­duce sys­temic in­flam­ma­tion, and main­tain mus­cle mass and qual­i­ty.

Clin­i­cians are in­creas­ing­ly rec­og­niz­ing the im­por­tance of main­tain­ing mus­cle in weight man­age­ment. Mus­cle is the body’s largest con­sumer of calo­ries and en­er­gy. When an in­di­vid­ual with obe­si­ty los­es lean mus­cle, their meta­bol­ic rate de­creas­es, re­sult­ing in low­er base­line en­er­gy ex­pen­di­ture, rapid weight re­gain when they dis­con­tin­ue GLP-1 ther­a­py, poor­er meta­bol­ic health, and po­ten­tial­ly se­ri­ous long-term health is­sues. El­der­ly obese pa­tients may be at even greater risk of neg­a­tive con­se­quences from loss of mus­cle, in­clud­ing hip and pelvis frac­tures, falls and hos­pi­tal­iza­tions – thus high­light­ing the crit­i­cal role of pre­serv­ing mus­cle mass in the bat­tle against obe­si­ty. Ad­di­tion­al­ly, due to the high dis­con­tin­u­a­tion rates ob­served in re­al-world us­age, ex­ist­ing agents are im­per­fect long-term ther­a­pies for chron­ic con­di­tions. As such, the abil­i­ty to keep off the weight that has been lost re­mains elu­sive to­day.

Rapid­ly ad­vanc­ing the clin­i­cal de­vel­op­ment of CMAs

Ini­tial clin­i­cal da­ta showed that CMAs can pro­vide fat-spe­cif­ic weight loss, im­prove in­sulin sen­si­tiv­i­ty and sig­nif­i­cant­ly re­duce ox­ida­tive stress and in­flam­ma­tion – key fac­tors in ad­dress­ing car­diometa­bol­ic dis­or­ders.

Rivus’ lead CMA pro­gram, HU6, is cur­rent­ly in Phase 2 clin­i­cal de­vel­op­ment and has the po­ten­tial to be a foun­da­tion­al monother­a­py for the treat­ment of obe­si­ty as well as re­sult­ing car­diometa­bol­ic dis­eases. The com­pa­ny is fo­cus­ing the clin­i­cal de­vel­op­ment of HU6 on obe­si­ty and the re­lat­ed car­diometa­bol­ic dis­eases with the high­est mor­bid­i­ty and great­est treat­ment needs.

To date, more than 450 pa­tients have been treat­ed with HU6 in the clin­i­cal de­vel­op­ment pro­gram. Promis­ing re­sults demon­strat­ing fat-spe­cif­ic weight loss with pre­served mus­cle mass have been ob­served in two Phase 2a clin­i­cal tri­als – one in pa­tients with a high body mass in­dex (BMI) and meta­bol­ic dys­func­tion-as­so­ci­at­ed steatot­ic liv­er dis­ease (MASLD) and the oth­er in pa­tients with obe­si­ty-re­lat­ed heart fail­ure with pre­served ejec­tion frac­tion (HF­pEF).

Im­por­tant­ly, HU6 was well tol­er­at­ed in pa­tients with HF­pEF, even though they are gen­er­al­ly old­er and have sig­nif­i­cant car­dio­vas­cu­lar co-mor­bidi­ties. Both body weight and to­tal fat mass were sig­nif­i­cant­ly re­duced with on­ly 19 weeks of HU6 treat­ment (by 2.86 kg and 2.96 kg [p<0.003] re­spec­tive­ly), with no change in mus­cle mass. Across clin­i­cal stud­ies to date, fat-spe­cif­ic weight loss with HU6 has been ac­com­pa­nied by low­er blood pres­sure and im­proved lipid pro­files, as well as re­duced mark­ers of sys­temic in­flam­ma­tion.

“By har­ness­ing the pow­er of mi­to­chon­dr­i­al un­cou­pling, CMAs are paving the way for a new era in obe­si­ty treat­ment – one that pri­or­i­tizes both weight loss and mus­cle preser­va­tion,” said Sha­har­yar Khan, Ph.D., co-founder and Chief Sci­en­tif­ic Of­fi­cer of Rivus. “As we con­tin­ue the clin­i­cal de­vel­op­ment of HU6, the po­ten­tial for this ground­break­ing ther­a­py to trans­form the lives of mil­lions of peo­ple around the world is noth­ing short of rev­o­lu­tion­ary.”

Rivus is look­ing ahead to fur­ther ex­pand the clin­i­cal da­ta for HU6, with up­com­ing da­ta from a six-month Phase 2b tri­al in pa­tients with meta­bol­ic dys­func­tion-as­so­ci­at­ed steato­hep­ati­tis (MASH) on the hori­zon. MASH is caused by an ac­cu­mu­la­tion of ex­cess fat cells in the liv­er and is close­ly linked to obe­si­ty. In fact, weight loss and the re­duc­tion of sys­temic in­flam­ma­tion are con­sid­ered part of an ef­fi­cient treat­ment strat­e­gy, high­light­ing the po­ten­tial for HU6 to have a mean­ing­ful im­pact on this pro­gres­sive and dif­fi­cult to man­age dis­ease. Fur­ther clin­i­cal ex­pan­sion of HU6 is in the works, in­clud­ing a planned obe­si­ty de­vel­op­ment pro­gram that will kick off lat­er this year.

Pur­su­ing a new era in the treat­ment of obe­si­ty

In or­der to con­tin­ue the evo­lu­tion of ther­a­pies for obe­si­ty and its con­tin­u­um of car­diometa­bol­ic dis­eases, Rivus has al­so de­vel­oped a pro­pri­etary ma­chine learn­ing mod­el that pow­ers an AI dis­cov­ery plat­form. As a re­sult, the com­pa­ny is de­vel­op­ing an ap­proach that would syn­er­gis­ti­cal­ly tar­get both sides of the en­er­gy bal­ance equa­tion, en­abling both con­trolled meta­bol­ic ac­cel­er­a­tion and GLP-1 ag­o­nism in a sin­gle, non-pep­tide small mol­e­cule. This pro­gram is al­so de­liv­er­ing stand-alone non-pep­tide oral sub-max­i­mal GLP-1 ag­o­nists.

These in­ves­ti­ga­tion­al treat­ments could hold promise for over­com­ing sig­nif­i­cant draw­backs of cur­rent ther­a­pies for obe­si­ty and re­lat­ed car­diometa­bol­ic dis­eases. In a world cur­rent­ly dom­i­nat­ed by mul­ti-phar­ma­col­o­gy, in­jectable pep­tides, Rivus imag­ines a fu­ture in which there is a choice of well tol­er­at­ed oral agents that are ef­fec­tive long-term ther­a­peu­tic op­tions for this clus­ter of chron­ic dis­eases.

Learn more about Rivus Phar­ma­ceu­ti­cals here.