CEO Jason Coloma (Maze)

Ex­clu­sive: Maze un­veils their $191M pipeline, tak­ing on Ver­tex and two long-sought con­di­tions

More than two years af­ter emerg­ing from stealth mode with $191 mil­lion, a guild of pres­ti­gious sci­en­tif­ic founders and sup­port from some top-flight VCs, Maze Ther­a­peu­tics is fi­nal­ly ready to un­veil what they’ve been up to.

Maze CEO Ja­son Colo­ma walked End­points News through their de-stealthed pipeline Mon­day, show­cas­ing three pro­grams that are still ear­ly stage but pro­gressed since the com­pa­ny’s 2019 launch. They in­clude a new small mol­e­cule ap­proach for the rare lyso­so­mal dis­or­der Pompe dis­ease, a chron­ic kid­ney dis­ease tar­get that will put them in square com­pe­ti­tion with Ver­tex, and an ALS gene ther­a­py that the­o­ret­i­cal­ly could be mar­ket­ed for the en­tire pa­tient pop­u­la­tion.

The tar­gets all come from the ini­tial batch of pro­grams the Maze’s founders seed­ed the com­pa­ny with at the start, but they al­so an­nounced new di­rec­tions for their ear­li­er stage re­search, with plans to broad­ly fo­cus on car­dio/re­nal, car­dio­vas­cu­lar, neu­rol­o­gy, eye and meta­bol­ic dis­eases and use a num­ber of tech­nolo­gies. Even­tu­al­ly, that could give them 10 to 15 pro­grams be­tween them­selves and their part­ners.

To plan for that ex­pan­sion, they’ve hired At­ul Dan­dekar, who led oph­thal­mol­o­gy at Roche and Genen­tech, as chief strat­e­gy of­fi­cer.

“In or­der to ex­e­cute on that strat­e­gy, of course, it’s not triv­ial,” Colo­ma said of the 10-15 pro­gram plan. “For a small com­pa­ny to try to be in­di­ca­tion ag­nos­tic and modal­i­ty ag­nos­tic, how do you make those trade-offs be­tween dif­fer­ent lev­els of in­vest­ments? And to have some­one who has seen pro­grams not on­ly get in­to the clin­ic but in­to the mar­ket­place I think is im­por­tant.”

Al­though Maze launched with a stat­ed goal of find­ing new so-called ge­net­ic mod­i­fiers — un­der­ap­pre­ci­at­ed genes that can change the sever­i­ty of a mono­genet­ic dis­ease like sick­le cell — all of the com­pa­ny’s ini­tial pro­grams go af­ter genes that have been stud­ied pre­vi­ous­ly, in­clud­ing, in one case, to the ex­tent that a ri­val com­pa­ny put a drug for it in Phase II last year. But Colo­ma said that each re­lies on tech­niques Maze col­lect­ed and de­vel­oped to turn those genes in­to drugs.

“Some of these tar­gets have been known for a while,” he said. “But it took many, many years to fig­ure out how do we uti­lize all the dif­fer­ent tech­nolo­gies at our dis­pos­al to ac­tu­al­ly turn that in­to a drug­ging pro­gram.”

The Pompe dis­ease pro­gram, for in­stance, goes af­ter a gene called Gys1 that is re­spon­si­ble for mak­ing glyco­gen in cells. The rare mus­cle-wast­ing con­di­tion aris­es when glyco­gen builds up in the cells of pa­tients who don’t have a func­tion­ing copy of the en­zyme for dis­pos­ing the sug­ary mol­e­cule, and drug pro­grams have large­ly ei­ther in­fused ar­ti­fi­cial copies of that en­zyme or sought to de­liv­er a gene for a healthy one. For years, though, re­searchers the­o­rized you could al­so in­hib­it Gys1 and pre­vent glyco­gen from build­ing up in the first place.

Maze fig­ured out two pieces of the puz­zle to make such a pro­gram pos­si­ble. First, Colo­ma claimed, Maze be­came the first com­pa­ny to crack the crys­tal struc­ture of the en­zyme Gys1 codes for. Sec­ond, he said, they used tis­sue and ge­net­ic da­ta from thou­sands of pa­tients at the UK biobank to find that peo­ple who hap­pen to have mu­tat­ed Gys1 genes func­tion­al nor­mal­ly, mean­ing that it should be safe to knock out.

Maze is now de­vel­op­ing a dai­ly pill for pa­tients with late-on­set stage of the dis­ease. It would be the first oral ther­a­py in a field dom­i­nat­ed by in­fused pro­teins and ex­per­i­men­tal gene ther­a­pies.

“That would be par­a­digm-chang­ing,” Colo­ma said.

The sec­ond pro­gram is for APOL1, a gene that has long been linked to a great­ly in­creased risk of kid­ney dis­ease. Ver­tex now has a mol­e­cule in Phase II for the APOL1-linked kid­ney con­di­tions. Colo­ma ar­gued that the com­pa­ny’s func­tion­al ge­nomics plat­form could give them new in­sights and give them a best-in-class drug, but he didn’t of­fer specifics on what those in­sights were or might be.

He not­ed that Ver­tex has yet to pub­lish their an­i­mal da­ta.

“I think you see that quite a bit in car­dio-re­nal,” Colo­ma said. “It’s not an area where you want to be nec­es­sar­i­ly first-in-class.”

Last­ly, they’ll de­vel­op a gene ther­a­py for ALS that tar­gets a gene called ATXN2. Biotechs de­vel­op­ing ALS gene ther­a­pies have un­der­stand­ably large­ly fo­cused on sin­gle genes that dri­ve ALS, but those genes on­ly ac­count for a small sub­set of pa­tients. De­vel­op­ing an ap­proach pi­o­neered by co-founder Aaron Gitler, Maze will look to knock out a gene whose ab­sence can help pro­tect against the buildup of dan­ger­ous plaques.

The first pro­gram, for pompe dis­ease, is slat­ed for the clin­ic in 2022.

No­var­tis reshuf­fles its wild cards; Tough sell for Bio­gen? Googling pro­teins; Ken Fra­zier's new gig; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

If you enjoy the People section in this report, you may also want to check out Peer Review, my colleagues Alex Hoffman and Kathy Wong’s comprehensive compilation of comings and goings in biopharma.

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Demis Hassabis, DeepMind CEO (Qianlong/Imaginechina via AP Images)

Google's Deep­Mind opens its pro­tein data­base to sci­ence — po­ten­tial­ly crack­ing drug R&D wide open

Nearly a year ago, Google’s AI outfit DeepMind announced they had cracked one of the oldest problems in biology: predicting a protein’s structure from its sequence alone. Now they’ve turned that software on nearly every human protein and hundreds of thousands of additional proteins from organisms important to medical research, such as fruit flies, mice and malaria parasite.

The new database of roughly 350,000 protein sequences and structures represents a potentially monumental achievement for the life sciences, one that could hasten new biological insights and the development of new drugs. DeepMind said it will be free and accessible to all researchers and companies.

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Vas Narasimhan, Novartis CEO (Jason Alden/Bloomberg via Getty Images)

No­var­tis dis­cards one of its ‘wild card’ drugs af­ter it flops in key study. But it takes one more for the hand

Always remember just how risky it is to gamble big on small studies.

A little more than 4 years ago, Novartis reportedly put up a package worth up to $1 billion for the dry eye drug ECF843 after a small biotech called Lubris put it through its paces in a tiny study of 40 moderate to severe patients, tracking some statistically significant markers of efficacy.

By last fall, the program had risen up to become one of CEO Vas Narasimhan’s top “wild card” programs in line for a potential breakthrough year in 2021. These drugs were all considered high-risk, high-reward efforts. And in this case, risk won.

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6 top drug­mak­ers of­fer per­spec­tives on FDA's new co­vari­ates in RCTs guid­ance

Back in May, the FDA revised and expanded a 2019 draft guidance that spells out how to adjust for covariates in the statistical analysis of randomized controlled trials.

Building on the ICH’s E9 guideline on the statistical principles for clinical trials, the 3-page draft was transformed into an 8-page draft, with more detailed recommendations on linear and nonlinear models to analyze the efficacy endpoints in RCTs.

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In­side Bio­gen's scram­ble to sell Aduhelm: Pro­ject 'Javelin' and pres­sure to ID as many pa­tients as pos­si­ble

In anticipation of Aduhelm’s approval for Alzheimer’s in June, Biogen employees were directed to identify and guarantee treatment centers would administer the drug through a program called “Javelin,” a senior Biogen employee told Endpoints News.

The program identified about 800 centers for use, he said, and Biogen now pays for the use of bioassays to identify beta amyloid in potential patients having undergone a lumbar puncture procedure, the employee said — and one center preparing to administer the drug confirmed its participation in the bioassay program.

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EMA re­jects FDA-ap­proved Parkin­son's drug, signs off on Mod­er­na vac­cine use in ado­les­cents ahead of FDA

The European Medicines Agency on Friday rejected Kyowa Kirin’s Parkinson’s disease drug Nouryant (istradefylline), which the US FDA approved in 2019 under the brand name Nourianz.

EMA said it considered that the results of the clinical studies used to support the application “were inconsistent and did not satisfactorily show that Nouryant was effective at reducing the ‘off’ time. Only four out of the eight studies showed a reduction in ‘off’ time, and the effect did not increase with an increased dose of Nouryant.”

Laurent Fischer, Adverum CEO

Ad­verum faces murky fu­ture af­ter re­view turns up deep­er safe­ty is­sues for gene ther­a­py

Three months after revealing that a patient lost significant vision in one eye after receiving its experimental gene therapy, Adverum announced it found the safety issues were more widespread: Five of 12 patients who received a high dose of the therapy saw “similar clinically-relevant events.”

Three required surgery on their treated eye. And all 12 are being recommended “aggressive immunomodulatory treatments” to prevent further injury.

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Al Sandrock, Biogen R&D chief (Biogen via YouTube)

Bio­gen has a shaky end to H1 with a $542M write-off adding to its woes — but an­a­lysts see big rev­enue ahead for Aduhelm

All eyes at Biogen’s Q2 earnings call Thursday were on Aduhelm, but investors also got a glimpse of what Biogen would have faced had the FDA not opted to approve their controversial Alzheimer’s drug.

That glimpse, revealing a combination of declining sales, growing competition and failed medicines, underscores the stakes of the big biotech’s Aduhelm efforts, as execs punch back at the criticism they’ve engendered in the political and medical world and vigorously pushes its sales staff to roll out the drug as fast as possible.

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Mol­e­c­u­lar Di­ag­nos­tics Can Trans­form Can­cer Care. Let’s Make It Hap­pen.

Like so many people around the world, my life has been profoundly shaped by cancer. Those personal experiences, along with a deep love of clinical laboratory science and a passion to apply the power of genomics in medicine, motivated me to launch a company that would improve cancer care through better diagnostics. Thirteen years later, I am proud that we are delivering more accurate information at multiple points along the patient journey, with a focus on eight of the 10 cancers that are most commonly diagnosed in the United States.