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Through the lymph nodes it goes — re­searchers de­vel­op a can­cer drug that avoids tox­i­c­i­ties by skirt­ing the liv­er

PI3K is a pro­tein that is part of a path­way that reg­u­lates cell growth, sur­vival and me­tab­o­lism — earn­ing it the in­scrip­tion of mas­ter reg­u­la­tor for can­cer. How­ev­er, while a num­ber of PI3K in­hibitor drugs have been ap­proved since 2014, the class as a whole has dwin­dled, as it has been plagued by tox­i­c­i­ty is­sues in var­i­ous blood can­cers.

For ex­am­ple, the FDA hit Se­cu­ra Bio’s PI3K in­hibitor Copik­tra, which earned ac­cel­er­at­ed ap­proval in 2018, with an in­creased death warn­ing in June fol­low­ing the re­sults of its con­fir­ma­to­ry Phase III tri­al. That warn­ing came af­ter a num­ber of com­pa­nies, in­clud­ing Se­cu­ra, Gilead and In­cyte, with­drew their ac­cel­er­at­ed ap­provals for their PI3K in­hibitors af­ter fail­ing to com­plete con­fir­ma­to­ry tri­als. The FDA now re­quires ran­dom­ized tri­als to be con­duct­ed for PI3K in­hibitors in blood can­cers.

Bri­an Ross

But what if a PI3K in­hibitor some­how avoid­ed those tox­i­c­i­ties? In a pa­per pub­lished in Na­ture Com­mu­ni­ca­tions Wednes­day, re­searchers from the Uni­ver­si­ty of Michi­gan de­scribe a dual PI3K and MAPK in­hibitor that lim­it­ed tox­i­c­i­ties and ex­tend­ed sur­vival time in mice through what lead in­ves­ti­ga­tor Bri­an Ross called an “unan­tic­i­pat­ed” mech­a­nism — go­ing through the lymph nodes.

Six years ago, when Ross — a ra­di­ol­o­gy pro­fes­sor at Michi­gan — start­ed this project, he was not look­ing for a can­cer drug that was ab­sorbed through the lymph nodes. In­stead, his pro­pos­al to the NCI was for a mul­ti-tar­get­ed ki­nase in­hibitor, for which he was giv­en a spe­cial sev­en-year grant to, in his own words, do any­thing he want­ed, “but make it high risk, high re­ward.”

Over those six years, Ross’ lab has been look­ing at un­con­ven­tion­al struc­tures for and pub­lish­ing about mul­ti­func­tion­al in­hibitors. But when it came to this drug, a PI3K and MAPK in­hibitor dubbed LP-182, they no­ticed it was be­hav­ing dif­fer­ent­ly and that it was be­ing ab­sorbed at a dif­fer­ent rate. “Af­ter talk­ing to col­leagues, we thought per­haps this is a lym­phat­i­cal­ly ab­sorbed drug. So we re­tooled the group, re­tooled the lab … and we found it, in fact, was lym­phat­i­cal­ly ab­sorbed,” Ross said. “It was quite as­ton­ish­ing, ac­tu­al­ly.”

“To my mind, it’s the world’s first ki­nase in­hibitor that’s lym­phat­i­cal­ly ab­sorbed,” he said.

Most oral drugs are ab­sorbed through the blood, mean­ing they first pass through the liv­er, where some drugs are me­tab­o­lized. The bro­ken-down parts of those drugs can con­tribute to liv­er dam­age, but their drug avoid­ed that by go­ing through the lymph sys­tem, ac­cord­ing to Ross. In­stead, the lymph nodes were “sort of like a gas can that you fill up in your car,” Ross said. “The drug is fill­ing up this big reser­voir — it’s be­ing se­questered away from the en­tire body by the [lym­phat­ic] ab­sorp­tion, and then slow­ly drain­ing over a day in­to a neck vein.”

And that slow drip from the lym­phat­ic sys­tem means that the drug doesn’t cause an ini­tial spike like tra­di­tion­al oral drugs.

When the re­searchers put the drug in­to mice with myelofi­bro­sis, a form of blood can­cer where scar tis­sue builds up in the bone mar­row, they saw that all the mice treat­ed with their drug sur­vived to 28 days af­ter treat­ment — the planned cut­off for the study — while con­trol group mice had pro­gres­sive dis­ease, “reach­ing hu­mane end­points” be­fore 21 days.

The catch, how­ev­er, is that Ross and his team are still fig­ur­ing out how ex­act­ly their drug works. They are cur­rent­ly test­ing po­ten­tial hy­poth­e­sis, Ross said, not­ing that it’s a process that takes time.

Ross has spun his lab’s find­ing off in­to a new biotech, named Lym­phar­ma, where he is both co-founder and CEO. Oth­er biotechs and re­searchers are al­so toy­ing with the con­cept of a lym­phat­i­cal­ly ab­sorbed can­cer drug, al­beit with dif­fer­ent ap­proach­es. In a pa­per pub­lished ear­li­er this week in PNAS, re­searchers from Tufts Uni­ver­si­ty de­scribe an mR­NA can­cer vac­cine tar­get­ed to the lymph nodes that boosts T cell re­sponse in skin can­cer.

And Eli­cio Ther­a­peu­tics, found­ed based on work done in Dar­rell Irvine’s lab at MIT, is work­ing on “amph-lig­ands,” in which some drug or pro­tein is bound to a lymph node-tar­get­ing lipid. The biotech has a Phase I/II study on­go­ing for an amph-lig­and can­cer vac­cine for KRAS-mu­tat­ed can­cers. More sim­i­lar to Ross’ ap­proach, PureTech has a plat­form search­ing for an oral pro­drug that can evade the liv­er by go­ing through the lymph nodes.

When asked when he thought his drug for blood can­cer could be in the clin­ic, Ross not­ed that there was still a ways to go, re­spond­ing, “op­ti­misti­cal­ly, with­in two years.”

Image courtesy of The Janssen Pharmaceutical Companies of Johnson & Johnson.

Pro­tect­ing the glob­al phar­ma­ceu­ti­cal in­no­va­tion ecosys­tem – what’s at stake?

We are living in a new era of healthcare that is rapidly advancing progress impacting patient outcomes and experiences. We’ve seen a remarkable pace of transformational innovation, applied research, and advanced clinical development over the last decade.

Despite this tremendous progress, there is much more work to be done, and patients are counting on us – now more than ever – to continue that momentum. At the heart of our industry is a focus on developing and delivering medicines for some of the world’s most challenging diseases, including those that have few or no effective treatments today.

Mi­rati’s drug sitra­va­tinib flops PhI­II in com­bo with Op­di­vo for cer­tain lung can­cer

Mirati Therapeutics’ path to a second drug approval will likely have to wait. The San Diego biotech company said Wednesday that its investigational lung cancer drug failed a Phase III trial testing it in combination with Bristol Myers Squibb’s Opdivo.

The drug, sitravatinib, and Opdivo weren’t better than the chemo drug docetaxel at keeping patients alive, Mirati said in a press release. The spectrum-selective kinase inhibitor missed the primary goal of overall survival in patients with second- or third-line advanced non-squamous, non-small cell lung cancer.

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End­points 20(+2) un­der 40, 2023; Bio­phar­ma's high­est-paid CEOs; N-of-1 CRISPR sto­ry goes on af­ter tragedy; 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.

We will be off Monday in observance of Memorial Day — and when we get back, it will be a straight march to ASCO, BIO and more. Enjoy the (long) weekend!

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Rich Horgan (R) with his late brother, Terry

Rich Hor­gan spear­head­ed a gene ther­a­py for his broth­er. The tri­al end­ed in tragedy, but the work con­tin­ues for more pa­tients

Rich Horgan’s quest to create a custom gene therapy for his brother, Terry, ended in tragedy. But Horgan doesn’t believe it’s the end of the story.

Terry, a 27-year-old patient with Duchenne muscular dystrophy, died last October just eight days after receiving the therapy in a clinical trial in which he was the only participant. The case raised questions about the safety of certain gene therapies and what would happen to other drug programs under a nonprofit that Horgan created, called Cure Rare Disease.

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Bio­phar­ma's 20 high­est-paid CEOs of 2022, each bring­ing in $20M+ pay­days

Even in a down year for much of the biopharma market, 20 CEOs brought in pay packages valued at more than $20 million, an Endpoints News analysis found.

Endpoints collected data on more than 350 CEO compensation packages, covering a wide range of pharma, biotech, and life sciences companies. All told, the 20 largest earners made over $725 million in 2022 — an average package of $36.4 million. Three brought in paydays over $50 million, and one CEO broke the $100 million mark.

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The 20(+2) un­der 40: Your guide to the next gen­er­a­tion of biotech lead­ers

This year’s list of 20 biotech leaders under the age of 40 includes a huge range of ambitions. Some of our honorees are planning to create the next big drug giant. Others are pushing the bounds of AI. One is working to revolutionize TB testing. All are compelling talents who are still young in age, but already far along in achievement.

And, as in years past, we went over. The 20 are actually 22 because of two double profiles that reflect how important teamwork is in the industry. As one of our honorees, Joe Illingworth of DJS Antibodies, told me in our interview, “It takes a village to raise a biotech.”

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Teresa Bitetti, Takeda's president of the global oncology business unit

Take­da wins pri­or­i­ty re­view for $400M col­orec­tal can­cer drug, li­censed from Hutchmed in Jan­u­ary

Takeda and Hutchmed scored a priority review Thursday afternoon for a colorectal cancer drug, the companies announced.

The experimental drug in question is fruquintinib, previously approved in China in 2018 to treat metastatic colorectal cancer. Takeda and Hutchmed are aiming to bring fruquintinib to the US and other countries outside China in the same indication, and the FDA set its decision date for Nov. 30 of this year.

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David Ricks, Eli Lilly CEO (Carolyn Kaster/AP Images)

Lil­ly gears up trio of PhI­II tri­als for its oral GLP-1 amid No­vo Nordisk, Pfiz­er com­pe­ti­tion

As Novo Nordisk and Pfizer disclose some data on their oral weight loss drugs in Phase III and II, respectively, Eli Lilly is beefing up its stance in the obesity field with three late-stage clinical trials of its next-generation GLP-1 agonist orforglipron.

The moves, disclosed in updates to the federal clinical trials database this week, put the Indianapolis drugmaker ahead of Pfizer, whose science chief has said the company will “cherry-pick” which of its mid-stage candidates to take deeper into the clinic after data late this year or early next.

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Douglas Love, Annexon CEO

An­nex­on’s GA drug miss­es on pri­ma­ry goal but win on vi­su­al acu­ity will be fo­cus of planned late-stage tri­al

Annexon’s complement inhibitor didn’t prove better than sham at reducing lesion growth in a leading cause of blindness, but the biotech still plans to move forward on the back of secondary endpoints showing visual acuity preservation, which will “certainly” be the primary goal in a late-stage trial to be discussed shortly with the FDA, CEO Douglas Love told Endpoints News. 

The California biotech’s ANX007 was not statistically significant compared to pooled sham, the comparator, at 12 months in patients with geographic atrophy, per a Wednesday presentation. In every-month dosing, the GA lesion area changed about 6.2% from baseline (p=0.526) and 1.3% (p=0.896) in the every-other-month group. In a March note, Jefferies analyst Suji Jeong said a reduction of 20% to 30% would be “encouraging.”

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