The newest, $86M Third Rock start­up chas­es the tiny bi­o­log­i­cal ma­chines in­side of you

It took 23 years from the iso­la­tion of the gene for cys­tic fi­bro­sis to the ap­proval of the first drug to tar­get it, and an­oth­er 7 for a drug that could treat the vast ma­jor­i­ty of CF pa­tients. Third Rock Ven­ture’s lat­est start­up thinks they can build sim­i­lar drugs a whole lot faster.

MO­MA Ther­a­peu­tics has raised $86 mil­lion to in­ves­ti­gate and drug a class of en­zymes known as mol­e­c­u­lar ma­chines. These pro­teins in­clude every­thing from en­zymes in­volved in DNA re­pair to the trans­port pro­teins that go awry in cys­tic fi­bro­sis — over 400 dif­fer­ent types, by MO­MA’s count. And yet, MO­MA con­tends, they have been over­looked to date, with re­searchers both fail­ing to un­der­stand them as a co­he­sive group and fail­ing to em­ploy sys­tem­at­ic ways of find­ing and drug­ging them.

Ver­tex’s CF drugs and pro­ton-pump in­hibitors, both of which go af­ter ma­chines, are red her­rings, MO­MA wrote in a blog post ac­com­pa­ny­ing the launch: Their suc­cess is a sign of both the field’s po­ten­tial and bio­phar­ma’s over­all fail­ure.

“Not on­ly do these med­i­cines fur­ther un­der­score the ther­a­peu­tic po­ten­tial of these en­zymes,” MO­MA wrote, “they al­so il­lus­trate bio­phar­ma’s rudi­men­ta­ry ap­proach­es to pros­e­cut­ing them — near­ly all were dis­cov­ered from nat­ur­al prod­ucts, through serendip­i­ty or with­out a sys­tem­at­ic ap­proach to in­ter­ro­gat­ing the bio­chem­istry of the pro­teins them­selves.”

Reid Hu­ber

Al­though the young biotech has yet to an­nounce any tar­gets, the blog post points em­pha­sizes the role of these mol­e­c­u­lar ma­chines in can­cer and rare dis­eases. Like most Third Rock star­tups, it will be led by a firm part­ner: in this case, Reid Hu­ber, who most re­cent­ly served as CSO of In­cyte. And the com­pa­ny’s R&D ef­forts will be led by Blue­print vet­er­ans Christoph Lengauer and Tim Guzi, who step in as CSO and SVP of drug de­vel­op­ment, re­spec­tive­ly.

The com­pa­ny’s ap­proach comes large­ly out of the Howard Hugh­es Med­ical In­sti­tute, where Dorothee Kern, Eva No­gales and Jo­hannes Wal­ter col­lab­o­rat­ed. A fourth founder, Third Rock en­tre­peneur-in-res­i­dence Timur Yusufzai, will head up pro­tein sci­ences at the biotech.

Dorothee Kern

Mol­e­c­u­lar ma­chines are, as the New York Times once put it, the world’s small­est me­chan­i­cal de­vices. Sci­en­tists have just be­gun syn­the­siz­ing ar­ti­fi­cial ones, but hun­dreds of dif­fer­ent types of these puny mo­tors are run­ning in the body at every minute, break­ing down and build­ing DNA, fer­ry­ing salt and wa­ter in­to and out of cells, forc­ing mus­cles to re­lax and con­tract.

Nor­mal­ly, these mo­tors func­tion by shift­ing be­tween iso­forms — dif­fer­ent struc­tures with the same chem­i­cal make­up. But a sin­gle mu­ta­tion, such as those seen on the CFTR mol­e­c­u­lar ma­chine in cys­tic fi­bro­sis, can act like a faulty valve, caus­ing var­i­ous de­grees of mal­func­tion. Tu­mors, mean­while, can some­times de­pend heav­i­ly on one of these mo­tors to grow.

Their struc­tur­al changes are their weak­ness, Hu­ber told End­points News. Al­though all pro­teins change shape, mol­e­c­u­lar ma­chines do so at an un­par­al­leled scale. MO­MA will search for those ma­chines with ge­nom­ic da­ta and try to use small mol­e­cules to in­ter­vene, po­ten­tial­ly cor­rect­ing mal­func­tion in rare dis­eases and crip­pling tu­mors.

Think of it like the dif­fer­ence be­tween walk­ing to the mail­box at the end of the dri­ve­way vs. get­ting in a car and dri­ving to Ohio — mol­e­c­u­lar ma­chines are the lat­ter. They open, they close, they twist, they slide, they un­wind on a mas­sive scale — all in or­der to pro­duce work,” Hu­ber wrote in an email. “This unique de­pen­dence on such large changes in shape pro­vides the key op­por­tu­ni­ty for MO­MA Tx — if we can dis­rupt those changes with small mol­e­cules, we may be able to dis­cov­er nov­el med­i­cines and do it in a sys­tem­at­ic way across the en­tire class.”

The Avance Clinical leadership team: CEO Yvonne Lungershausen, Sandrien Louwaars - Director Business Development Operations, Gabriel Kremmidiotis - Chief Scientific Officer, Ben Edwards - Chief Strategy Officer

How Aus­tralia De­liv­ers Rapid Start-up and 43.5% Re­bate for Ear­ly Phase On­col­o­gy Tri­als

About Avance Clinical

Avance Clinical is an Australian owned Contract Research Organisation that has been providing high-quality clinical research services to the local and international drug development industry for 20 years. They specialise in working with biotech companies to execute Phase 1 and Phase 2 clinical trials to deliver high-quality outcomes fit for global regulatory standards.

As oncology sponsors look internationally to speed-up trials after unprecedented COVID-19 suspensions and delays, Australia, which has led the world in minimizing the pandemic’s impact, stands out as an attractive destination for early phase trials. This in combination with the streamlined regulatory system and the financial benefits including a very favourable exchange rate and the R & D cash rebate makes Australia the perfect location for accelerating biotech clinical programs.

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Paul Hudson, Sanofi CEO (Getty Images)

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