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.”

The FDA on Tuesday released a warning letter sent earlier this month to the Mason, OH-based site of Procter & Gamble Manufactura, raising questions about the list of ingredients on the label and in the electronic filing.

The warning says that for P&G’s over-the-counter Vicks Nyquil Severe Hot Remedy Cold and Flu Plus Congestion, there’s a “mismatched” list of active ingredients between the labeling and the electronic listing file. The listing file for the active ingredients did not match the active ingredients in the electronic file.

The Federal Trade Commission has gotten involved in a patent feud over Supernus’ Parkinson’s drug Apokyn, a case the agency said may have ‘‘significant implications” for patients who rely on the drug.

Sage Chemical won the first generic approval for its Apokyn formulation (also known as apomorphine hydrochloride injection) back in 2022. The non-ergoline dopamine agonist is approved to treat Parkinson’s symptoms during “off episodes,” such as difficulty moving, tremors and intense cramping. However, regulators specified that the approval pertained to the generic drug cartridges only, not the injector pen required for administration.