Chris Varma, Frontier Medicines CEO

Months af­ter Am­gen's land­mark KRAS ap­proval, Chris Var­ma bags a crossover round for next-gen can­di­date

For years, mu­tant, can­cer-fu­el­ing KRAS pro­teins were con­sid­ered “un­drug­gable.” That all changed in May, when Am­gen’s KRAS-block­ing drug Lumakras snagged the FDA’s first ap­proval in the field. And now a slate of in­vestors are bet­ting $88.5 mil­lion on a Bay Area start­up’s next-gen­er­a­tion can­di­date.

Fron­tier Med­i­cines has closed a hefty Se­ries B round, co-led by Wood­line Part­ners and RA Cap­i­tal Man­age­ment, the com­pa­ny said on Mon­day. Deer­field Man­age­ment, Deep Track Cap­i­tal, Ar­row­Mark Part­ners, Driehaus Cap­i­tal Man­age­ment, Sphera Health­care, DCVC’s Bio fund, Droia Ven­tures and MPM Cap­i­tal al­so chimed in. With the lat­est round, it’s pos­si­ble CEO Chris Var­ma has an IPO on the mind.

Var­ma launched Fron­tier back in 2019 with $67 mil­lion in launch mon­ey and a mis­sion to drug pre­vi­ous­ly “un­drug­gable” pro­teins. Since then, the 10-per­son team has grown to about 60 staffers. Var­ma — who has al­so co-found­ed Blue­print Med­i­cines and built com­pa­nies at Third Rock and Flag­ship — says the team is like­ly a cou­ple years away from the clin­ic.

“We’re pro­gress­ing rapid­ly to IND-en­abling stud­ies,” he told End­points News on Mon­day morn­ing.

Back in De­cem­ber, Ab­b­Vie shelled out $55 mil­lion up­front to part­ner with Fron­tier on pro­tein degra­da­tion work, promis­ing to re­im­burse the start­up for its pre­clin­i­cal R&D costs.

Mean­while, the B round will be used to ad­vance the com­pa­ny’s pre­clin­i­cal pipeline of pre­ci­sion med­i­cines against dri­vers of can­cer. Its lead pro­gram is fo­cused on block­ing ac­tive and in­ac­tive forms of KRAS G12C, the same mu­ta­tion tar­get­ed by Am­gen’s Lumakras for non-small cell lung can­cer. What dif­fer­en­ti­ates Fron­tier’s can­di­date is that it tar­gets both ac­tive and in­ac­tive forms of the pro­tein. A ma­jor­i­ty of pa­tients who are treat­ed with in­hibitors tar­get­ing in­ac­tive forms of KRAS G12C don’t re­spond, Var­ma added.

“The abil­i­ty to tar­get both forms of KRASG12C, which in­cludes the ac­tive and in­ac­tive states of the pro­tein, with a small mol­e­cule ther­a­py would be a long-await­ed sci­en­tif­ic break­through,” said Frank Mc­Cormick, a pro­fes­sor of the UCSF He­len Diller Fam­i­ly Com­pre­hen­sive Can­cer Cen­ter, in a state­ment.

“Im­por­tant­ly for pa­tients, a drug with this dual in­hi­bi­tion may be more ef­fi­ca­cious than a drug that tar­gets just the in­ac­tive form of KRASG12C by ad­dress­ing the large ma­jor­i­ty of pa­tients who are non-re­spon­ders to first gen­er­a­tion sin­gle-form KRASG12C in­hibitors, as well as those pa­tients whose tu­mors be­come re­sis­tant to the first-gen­er­a­tion mol­e­cules,” he con­tin­ued.

At the core of Fron­tier’s plat­form is ma­chine learn­ing paired with some­thing the com­pa­ny calls chemo­pro­teomics, or find­ing new ways to bind tar­gets by ex­am­in­ing tem­po­rary pock­ets in pro­teins.

Up­on the com­pa­ny’s launch back in 2019, Var­ma told End­points that “drug­gable” pro­teins are like coat hang­ers — they have cor­ners that drugs can dock in­to. “Un­drug­gable” pro­teins on the oth­er hand ap­pear — fig­u­ra­tive­ly — more like a string.

“If you shake the string, you wig­gle it, then you see that ac­tu­al­ly curves do form and with­in those curves are cor­ners and you could imag­ine dock­ing a small mol­e­cule drug in­to those,” he said.

Fron­tier is work­ing on tech that would al­low sci­en­tists to put a co­va­lent bind there, cre­at­ing a per­ma­nent lock in a tran­sient cor­ner.

A hand­ful of oth­er drug­mak­ers are pur­su­ing KRAS in­hibitors, in­clud­ing Mi­rati, which snagged break­through ther­a­py des­ig­na­tion for its ada­gra­sib in non-small cell lung can­cer back in June. Eli Lil­ly jumped in­to the hunt back in March, and said it planned to put a new small mol­e­cule in Phase I lat­er this year. And back in Oc­to­ber 2019, Boehringer In­gel­heim ad­vanced its pan-KRAS in­hibitor in­to the clin­ic.

In ad­di­tion to the fi­nanc­ing, Fron­tier has an­nounced that it’s adding a new site in Boston to com­ple­ment its South San Fran­cis­co head­quar­ters, where it will “build its em­ploy­ee ex­per­tise across re­search and de­vel­op­ment, in­clud­ing dis­cov­ery, pre-clin­i­cal de­vel­op­ment, trans­la­tion­al med­i­cine, and ear­ly clin­i­cal de­vel­op­ment.” The new site is ex­pect­ed to open be­fore the end of the year, and will be home to about 60 or so more em­ploy­ees — and Var­ma added that he’s look­ing to hire.

*A cor­rec­tion has been made to note that DCVC’s in­vest­ment came from their Bio fund.

The Fac­tors Dri­ving a Rapid Evo­lu­tion of Gene & Cell Ther­a­py and CAR-T Clin­i­cal Re­search in APAC

APAC is the fastest growing region globally for cell & gene therapy trials representing more than a third of all cell & gene studies globally, with China leading in the region. 

APAC is the leading location globally for CAR-T trials with China attracting ~60% of all CAR-T trials globally between 2015-2022. The number of CAR-T trials initiated by Western companies has rapidly increased in recent years (current CAGR of about 60%), with multiple targets being explored including CD19, CD20, CD22, BCMA, CD30, CD123, CD33, CD38, and CD138.

The End­points 11; blue­bird's $3M gene ther­a­py; Bio­gen tout new neu­ro da­ta; Harsh re­views for can­cer drugs; 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.

Reading about John Carroll’s pick of biotech’s most promising startups has become a treasured tradition. If you ever get curious about previous classes of the Endpoints 11, you can find all of them (plus a number of our other regular specials) here.

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EMA warns of short­ages of two Boehringer heart drugs due to a spike in de­mand

The EMA is putting EU member states on alert over the shortage of two drugs that counter heart attacks due to an uptick in demand.

On Friday, the EMA sent out a warning that two Boehringer Ingelheim drugs are experiencing a shortage: Actilyse and Metalyse. The drugs are used as emergency treatments for adults experiencing acute myocardial infarction, or a heart attack, by dissolving blood clots that have formed in the blood vessels.

The End­points 11: The top pri­vate biotechs in pur­suit of new drugs. Push­ing the en­ve­lope with pow­er­ful new tech­nolo­gies

Right around the beginning of the year, we got a close-up look at what happens after a boom ripples through biotech. The crash of life sciences stocks in Q1 was heard around the world.

In the months since, we’ve seen the natural Darwinian down cycle take effect. Reverse mergers made a comeback, with more burned out shells to go public at a time IPOs and road shows are out of favor. And no doubt some of the more recent arrivals on the investing side of the business are finding greener pastures.

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Solicitor General Elizabeth Prelogar

Should SCO­TUS hear Am­gen's Repatha case? So­lic­i­tor gen­er­al says no

Back in April, Amgen said it was encouraged by the solicitor general’s anticipated review of its Supreme Court petition to rehear a Repatha patent case. They’re likely much less optimistic about the outcome now.

Solicitor General Elizabeth Prelogar wrote in a recent 27-page brief that Amgen’s arguments “lack merit and further review is not warranted.”

The case traces back to a suit filed in 2014 against Sanofi and Regeneron’s Praluent, which ended up beating Amgen’s PCSK9 blockbuster Repatha to market by a month just a year later.

As­traZeneca, Mer­ck cull one Lyn­parza in­di­ca­tion in heav­i­ly pre­treat­ed ovar­i­an can­cer pa­tients

Just one day after blockbuster Lynparza got access to another indication in China, its Big Pharma owners have decided to withdraw it in certain patients after reviewing Phase III data.

The two companies that work together on Lynparza decided to recall one of the indications several weeks ago in a specific type of ovarian cancer, Lynparza’s first indication when it was first FDA-approved in 2014. Initial data showed that rates of overall survival in patients with at least three rounds of chemo before getting on the PARP inhibitor were lower than in patients with less previous chemo treatment.

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Fu­ji­film con­tin­ues CD­MO ex­pan­sion, break­ing ground on $435M UK site

Fujifilm’s CDMO arm, Fujifilm Diosynth, has been on a roll this month as the company has recently broken ground on a major project in Europe and it appears to be keeping up the momentum.

Fujifilm Diosynth announced that it has kicked off an expansion project for its microbial manufacturing facility at its campus in the town of Billingham, UK, in the northeast of England.

The 20,000 square-foot, £400 million ($435 million) expansion will add clean rooms, purification suites and a packing area along with more space for the manufacturing itself.

An­oth­er Cipla site lands a Form 483 over clean­ing is­sues and QC con­trols

A Cipla drug manufacturing site in India has once again landed in the crosshairs of FDA inspectors.

The facility in question is Cipla’s drug manufacturing facility in the village of Verna, in the state of Goa in India’s southwest. In a sign that foreign inspections might ramp up again, the FDA’s visit from Aug. 16 to Aug. 22 uncovered six observations.

The 11-page report noted that environmental monitoring at the site did not properly ensure that microbial contaminants were not making any impact in the aseptic filling areas. It also found that procedures meant to stop microbial contamination were not adequately conducted in aseptic areas of the facility.

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FDA ad­comm takes down Se­cu­ra Bio's leukemia drug af­ter fi­nal tri­al re­sults show po­ten­tial OS detri­ment

The FDA’s Oncologic Drugs Advisory Committee on Friday voted 8-4 against the benefit-risk profile of Secura Bio’s PI3K inhibitor Copiktra (duvelisib), which won approval in September 2018 as a third-line treatment for relapsed or refractory CLL or SLL, but updated pivotal trial results raised safety questions.

In addition to the serious and fatal toxicities of duvelisib, FDA speakers at the ODAC meeting pointed to an evolved treatment landscape for CLL and SLL, with targeted BTK or BCL2 inhibitors (front-line or second-line), and data pointing to a “potential detriment” in overall survival for duvelisib. But some ODAC members noted that the detriment was likely small and that there is some efficacy even as the data are difficult to interpret.

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