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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.”

Clin­i­cal tri­al di­ver­si­ty da­ta show mis­match be­tween en­roll­ment and dis­ease preva­lence, GSK says

A lack of diversity in clinical trials has persisted despite decades of initiatives to try to turn the tide.

In a recent review of 17 years of clinical trials, drugmaker GSK found that there were some mismatches between the demographics of its US-based trials and how prevalent diseases were in those populations.

The results, the company says, will help GSK and others design studies that better represent epidemiological rates within races and ethnicities.

The Big Phar­ma dis­card pile; Lay­offs all around while some biotechs bid farewell; New Roche CEO as­sem­bles top team; 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.

With earnings seasons in full swing, we’ve listened in on all the calls so you don’t have to. But news is popping up from all corners, so make sure you check out our other updates, too.

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Ma­gen­ta halts stem cell work and may sell it­self fol­low­ing pa­tient death, clin­i­cal hold

Magenta Therapeutics said it is halting work on its stem cell transplant drug pipeline and may sell itself, a week after the company reported the death of a patient in an early stage trial of its antibody-drug conjugate.

The Cambridge, MA-based company said it will conduct a “review of strategic alternatives,” and that could include an “acquisition, merger, business combination, or other transaction.”

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How to use ex­ter­nal con­trols: FDA spells out think­ing in new draft guid­ance

The use of real-world evidence to inform the FDA’s decision-making continues apace, with the agency releasing new draft guidance yesterday on how sponsors can compare outcomes of trial participants receiving a test treatment with outcomes in a group of people external to the trial.

The practice of externally controlled trials is common, particularly in oncology or other difficult areas where it’s not ethical or feasible to use internal controls.

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The Big Phar­ma axe: Mer­ck cuts chikun­gun­ya vax, Bris­tol My­ers drops Cy­tomX-part­nered pro­gram, and more

As fourth quarter earnings come in, Big Pharmas are disclosing changes to their pipelines during their investor calls, and sometimes more quietly in presentation appendices.

Merck dropped its chikungunya vaccine candidate, which completed a Phase II study. Merck acquired the vaccine through its purchase of Themis Bioscience in 2020. In developing a vaccine for chikungunya, a mosquito-borne virus, Valneva is the frontrunner, as it submitted its vaccine to the FDA at the end of December.

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Goldfinch Bio CEO Tony Johnson (L) and Karuna Therapeutics CEO Bill Meury

Karuna li­cens­es Goldfinch as­sets to com­pete with Boehringer In­gel­heim in neu­ro­science

Karuna Therapeutics is looking to compete with Boehringer Ingelheim on depression and anxiety with a new license to Goldfinch Bio’s assets, starting with $15 million to the shuttered biotech.

Karuna steps into an arena already being tested by Boehringer in multiple Phase II studies — the two are targeting transient receptor potential canonical 4 and 5, or TRPC4/5, which is thought to have a role in neuroscience indications. Goldfinch’s asset went through a Phase II in kidney diseases, but Karuna’s sights are set on mood and anxiety disorders for now.

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Roche's headquarters in Basel, Switzerland (Kyle LaHucik for Endpoints News)

Roche ditch­es fi­nal PhI­II for can­cer hope­ful, re­ports set­back for key drug in $1.4B buy­out

Over the past few years, Roche has released news about its AKT inhibitor ipatasertib in drips — most of them negative. The drug yielded mixed data in a key prostate cancer trial, Phase III flops in triple-negative breast cancer forced the pharma giant to pull the plug there, and in mid-2022 Roche trimmed two more early-stage indications in prostate cancer after completing the trials.

Now, the last piece of the program is gone.

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Simba Gill, Evelo Biosciences CEO

Sim­ba Gill stay­ing on at Evelo to weath­er lay­offs and a PhII fail

Simba Gill will be staying put as CEO of Evelo Biosciences for now.

Gill announced last year that he would be leaving the head position at Evelo to take on the role of executive partner at Flagship Pioneering. He was aiming to stay on until a successor was selected, but there’s a new course of action in the wake of a Phase II miss and a reduced headcount.

“I want to emphasize that I remain personally committed to Evelo and staying on to lead the organization. I continue to believe that Evelo is a remarkable opportunity in terms of the science, the platform, the type of products that we’re able to produce, and most importantly, the potential of millions of patients suffering from all stages of inflammatory disease,” Gill said on a conference call.

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Sen. Ron Wyden (D-OR) (Francis Chung/E&E News/Politico via AP Images)

In­fla­tion re­bates in­com­ing: Wyden calls on CMS to move quick­ly as No­var­tis CEO pledges re­ver­sal

Senate Finance Chair Ron Wyden (D-OR) this week sent a letter to the head of the Centers for Medicare & Medicaid Services seeking an update on how and when new inflation-linked rebates will take effect for drugs that see major price spikes.

The newly signed Inflation Reduction Act requires manufacturers to pay a rebate to Medicare when they increase drug prices faster than the rate of inflation.

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