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.

What Will it Take to Re­al­ize the Promise and Po­ten­tial of Im­mune Cell Ther­a­pies?

What does it take to get to the finish line with a new cancer therapy – fast? With approvals in place and hundreds of immune cell therapy candidates in the pipeline, the global industry is poised to create a fundamental shift in cancer treatments towards precision medicine. At the same time, unique challenges associated with cell and process complexity present manufacturing bottlenecks that delay speed to market and heighten cost of goods sold (COGS) — these hurdles must be overcome to make precision treatments an option for every cancer patient. This series of articles highlights some of the key manufacturing challenges associated with the production of cell-based cancer therapies as well as the solutions needed to transcend them. Automation, process knowledge, scalability, and assured supply of high-quality starting material and reagents are all critical to realizing the full potential of CAR-based therapies and sustaining the momentum achieved in recent years. The articles will highlight leading-edge technologies that incorporate these features to integrate across workflows, accelerate timelines and reduce COGS – along with how these approaches are enabling the biopharmaceutical industry to cross the finish line faster with new treatment options for patients in need.

The biggest ques­tions fac­ing gene ther­a­py, the XLMTM com­mu­ni­ty, and Astel­las af­ter fourth pa­tient death

After three patients died last year in an Astellas gene therapy trial, the company halted the study and began figuring out how to safely get the program back on track. They would, executives eventually explained, cut the dose by more than half and institute a battery of other measures to try to prevent the same thing from happening again.

Then tragically, Astellas announced this week that the first patient to receive the new regimen had died, just weeks after administration.

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Lat­est news: It’s a no on uni­ver­sal boost­ers; Pa­tient death stuns gene ther­a­py field; In­side Tril­li­um’s $2.3B turn­around; 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.

Next week is shaping up to be a busy one, as our editor-in-chief John Carroll and managing editor Kyle Blankenship lead back-to-back discussions with a great group of experts to discuss the weekend news and trends. John will be spending 30 minutes with Jake Van Naarden, the CEO of Lilly Oncology, and Kyle has a brilliant panel lined up: Harvard’s Cigall Kadoch, Susan Galbraith, the new head of cancer R&D at AstraZeneca, Roy Baynes at Merck, and James Christensen at Mirati. Don’t miss out on the action — sign up here.

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Mi­rati's KRAS drug looks like the fa­vorite in colon can­cer with new da­ta, putting the pres­sure square on Am­gen

With Amgen already providing proof-of-concept for KRAS inhibitors with its sotorasib, Mirati Therapeutics is piecing together a follow-up effort in lung cancer with data it thinks are superior. But in colon cancer, where solo sotorasib has turned in a dud, Mirati may now have a strong case for superiority.

Mirati’s adagrasib, dosed solo or in combination with chemotherapy cetuximab, showed response rates grater than sotorasib solo  and as part of combination study in a similar patient population also revealed this week at #ESMO21. Mirati’s data were presented as part of a cohort update from the Phase II KRYSTAL-1 study testing adagrasib in a range of solid tumors harboring the KRAS-G12C mutation.

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President Biden and Pfizer CEO Albert Bourla (Patrick Semansky/AP Images)

Chaot­ic ad­comm sees Pfiz­er/BioN­Tech boost­ers re­ject­ed for gen­er­al pop­u­la­tion, but rec­om­mend­ed for old­er and high-risk pop­u­la­tions

With just days before President Joe Biden’s Covid-19 booster rollout is set to go into effect, an FDA advisory committee appeared on the verge of not recommending boosters for anyone in the US before a last-minute change of wording laid the groundwork for older adults to have access to a third dose.

The FDA’s adcomm on Vaccines and Related Biological Products (VRBPAC) roundly rejected Pfizer/BioNTech booster shots for all individuals older than 16 by a 16-2 vote Friday afternoon. Soon after, however, the agency posed committee members a new question limiting booster use to the 65-and-older population and individuals at high risk of disease due to occupational exposure or comorbidities.

The best of the rest: High­lights from the be­low-the-fold pre­sen­ta­tions at #ES­MO21

This year’s ESMO Congress has had a major focus on Big Pharma drugs — most notably candidates from Merck and AstraZeneca — but there have also been updates from smaller biotechs with data looking to challenge the big-name drugmakers.

Today, we’re highlighting some of the data releases that flew under the radar at #ESMO21 — whether from early-stage drugs looking to make a mark or older stalwarts with interesting follow-up data.

As­traZeneca, Dai­ichi Sanky­o's ADC En­her­tu blows away Roche's Kad­cy­la in sec­ond-line ad­vanced breast can­cer

AstraZeneca and Japanese drugmaker Daiichi Sankyo think they’ve struck gold with their next-gen ADC drug Enhertu, which has shown some striking data in late-stage breast cancer trials and early solid tumor tests. Getting into earlier patients is now the goal, starting with Enhertu’s complete walkover of a Roche drug in second-line breast cancer revealed Saturday.

Enhertu cut the risk of disease progression or death by a whopping 72% (p=<0.0001) compared with Roche’s ADC Kadcyla in second-line unresectable and/or metastatic HER2-positive breast cancer patients who had previously undergone treatment with a Herceptin-chemo combo, according to interim data from the Phase III DESTINY-Breast03 head-to-head study presented at this weekend’s #ESMO21.

Merck Research Laboratories CMO Roy Baynes

Mer­ck­'s Keytru­da un­corks full da­ta on lat­est ad­ju­vant win — this time in melanoma — adding bricks to ear­ly can­cer wall

In recent months, the battle for PD-(L)1 dominance has spilled over into early cancer with Merck’s Keytruda and Bristol Myers Squibb’s Opdivo all alone on the front lines. Keytruda now has another shell in its bandolier, and it could spell a quick approval.

Keytruda cut the risk of relapse or death by 35% over placebo (p=0.00658) in high-risk, stage 2 melanoma patients who had previously undergone surgery to remove their tumors, according to full data from the Phase III KEYNOTE-716 presented Saturday at #ESMO21.

Mer­ck flesh­es out Keytru­da win in first-line cer­vi­cal can­cer, adding more fire­pow­er to its ear­ly can­cer push

Merck has worked hard to bring its I/O blockbuster Keytruda into earlier and earlier lines of therapy, and now the wonder drug appears poised to make a quick entry into early advanced cervical cancer.

A combination of Keytruda and chemotherapy with or without Roche’s Avastin cut the risk of death by 33% over chemo with or without Avastin (p=<0.001) in first-line patients with persistent, recurrent or metastatic cervical cancer, according to full data from the Phase III KEYNOTE-826 study presented Saturday at #ESMO21.