Af­ter a run of CT­LA-4 com­bo fail­ures, sci­en­tists spot­light a way to make it work — in se­lect pa­tients

CT­LA-4/PD-(L)1 com­bi­na­tions have been one of the El Do­ra­dos of on­col­o­gy, its promise for­ev­er be­hind that next hill but ap­par­ent­ly un­at­tain­able af­ter a se­ries of piv­otal clin­i­cal fail­ures. But re­searchers at New York’s Memo­r­i­al Sloan Ket­ter­ing Can­cer Cen­ter and the Tech­ni­cal Uni­ver­si­ty of Mu­nich think they may know how to fix what’s wrong and boost the dri­ve to next-gen can­cer com­bos.

In a pre­clin­i­cal an­i­mal re­search pro­gram, re­searchers found that with­in a cell, check­points re­ly on a spe­cif­ic mol­e­cule — RNA-sens­ing mol­e­cule RIG-I — to work. If that sounds fa­mil­iar, it’s be­cause it has al­ready been iden­ti­fied as a tar­get for boost­ing im­mune re­spons­es and was sub­ject to at least one Phase I/II tri­al. Pfiz­er in De­cem­ber al­lied it­self with Kine­ta with $15 mil­lion up­front and $505 mil­lion in po­ten­tial mile­stones to de­vel­op RIG-I im­munother­a­pies, and three years ago Mer­ck pur­chased Ger­man up­start Rigontec for $137 mil­lion up­front and over $400 mil­lion in po­ten­tial mile­stones for the same pur­pose.

The sci­ence team’s work helps spot­light what they’re af­ter.

Pub­lish­ing in Sci­ence Im­munol­o­gy, the re­searchers found that high ex­pres­sion of the gene for RIG-I (gene DDX58) her­ald­ed re­spon­sive­ness to CT­LA-4 ther­a­py and sug­gest­ed doc­tors might test for RIG-I ex­pres­sion in tu­mors to pre­dict who will re­spond to the ther­a­py. They could then tai­lor treat­ments to that pop­u­la­tion. The study al­so sug­gests that com­bin­ing  PD-1/CT­LA-4 with a RIG-I ag­o­nist might boost the ef­fec­tive­ness of the hereto­fore of­ten dis­ap­point­ing ther­a­py.

CT­LA-4 and PD-1 ther­a­pies, which won their prin­ci­pal founders 2018’s No­bel Prize in med­i­cine, work by tar­get­ing a re­cep­tor on T cells that stop the cell’s “check­point,” if you will – by block­ing the re­cep­tor, it es­sen­tial­ly re­leas­es the brakes on the im­mune sys­tem and al­lows the body’s T cells to start a full high-speed chase on the tu­mor(s). Sev­er­al such im­munother­a­pies have been ap­proved in the past few years, be­gin­ning with ip­il­i­mum­ab for melanoma in 2011, but the ec­sta­t­ic promise has turned up a lot of dry wa­ter beds of late. Tri­als from the ma­jor play­ers, in­clud­ing Bris­tol-My­ers Squibb, As­traZeneca, and Sanofi,  at­tack­ing small cell lung can­cer, head and neck car­ci­no­ma, and non-small cell lung can­cer with a mix of PD-1 and CT­LA-4 in­hibitors have all failed.

This is not the first study look­ing at how to im­prove and tai­lor CT­LA-4 ther­a­pies. Last year, re­searchers work­ing on mice found that they could “im­age” the re­sponse with a ra­dioac­tive trac­er that latch­es to OX40, a mol­e­cule on­ly found in ac­ti­vat­ed T cells, and thus the­o­ret­i­cal­ly learn ear­ly on if a pa­tient is re­spond­ing to the ther­a­py.

So­cial im­age: Memo­r­i­al Sloan Ket­ter­ing Can­cer Cen­ter

Biotech and Big Phar­ma: A blue­print for a suc­cess­ful part­ner­ship

Strategic partnerships have long been an important contributor to how drugs are discovered and developed. For decades, big pharma companies have been forming alliances with biotech innovators to increase R&D productivity, expand geographical reach and better manage late-stage commercialization costs.

Noël Brown, Managing Director and Head of Biotechnology Investment Banking, and Greg Wiederrecht, Ph.D., Managing Director in the Global Healthcare Investment Banking Group at RBC Capital Markets, are no strangers to the importance of these tie-ups. Noël has over 20 years of investment banking experience in the industry. Before moving to the banking world in 2015, Greg was the Vice President and Head of External Scientific Affairs (ESA) at Merck, where he was responsible for the scientific assessment of strategic partnership opportunities worldwide.

No­var­tis' sec­ond at­tempt to repli­cate a stun­ning can­cer re­sult falls flat

Novartis’ hopes of turning one of the most surprising trial data points of the last decade into a lung cancer drug has taken another setback.

The Swiss pharma announced Monday that its IL-1 inhibitor canakinumab did not significantly extend the lives or slow the disease progression of patients with previously untreated locally advanced or metastatic non-small cell lung cancer when compared to standard of-care alone.

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How Chi­na turned the ta­bles on bio­phar­ma's glob­al deal­mak­ing

Fenlai Tan still gets chills thinking about the darkest day of his life.

Three out of eight lung cancer patients who received a tyrosine kinase inhibitor developed by his company, Betta Pharma, died in the span of a month. Tan, the chief medical officer, was summoned to Peking Union Medical College Hospital, where the head of the clinical trial department told him that the trial investigators would be conducting an autopsy to see if the patients had died of the disease — they were all very sick by the time they enrolled — or of interstitial lung disease, a deadly side effect tied to the TKI class that’s been reported in Japan.

An­gion's or­gan dam­age drug strikes out again, this time in high-risk kid­ney trans­plant pa­tients

After flopping a test in Covid-19 earlier this year, Angion’s lead organ damage drug has now hit the skids again in kidney transplant patients.

Angion and partner Vifor Pharma’s ANG-3777 failed to beat out placebo in terms of improving eGFR, a measure of kidney function, in patients who had received a deceased donor kidney transplant and were at high risk of developing what is known as delayed graft function, according to Phase III results released Tuesday.

An image of Alzheimer's brain tissue. The red show gingipains, a protein from P. gingivalis, intermixing with neurons (yellow) and glial cells (green)

An Alzheimer's dark­horse fails its first big tri­al, but of­fers hope for a long-over­looked hy­poth­e­sis

Three years ago, Cortexyme emerged out of obscurity with some big-name backers and an unorthodox approach to treating Alzheimer’s.

They moved their drug into a pivotal study the next year, offering one of the first major tests for a hypothesis that has fluttered on the outskirts of Alzheimer’s research for decades: that, in many cases, the disease is driven by infectious agents — the havoc they wreak in the brain and the inflammation the body uses to try to fend them off. And that quashing the infection could slow patients’ cognitive decline.

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No­var­tis dumps AveX­is pro­gram for Rett syn­drome af­ter fail­ing re­peat round of pre­clin­i­cal test­ing

Say goodbye to AVXS-201.

The Rett syndrome gene therapy drug made by AveXis — the biotech that was bought, kept separate, then renamed and finally absorbed by Novartis into its R&D division — has been dropped by the biopharma.

In Novartis’ third quarter financial report, the pharma had found that preclinical data did not support development of the gene therapy into IND-enabling trials and beyond. The announcement comes a year after Novartis told the Rett Society how excited it was by the drug — and its potential benefits and uses.

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Peter Nell, Mammoth Biosciences CBO

UP­DAT­ED: Jen­nifer Doud­na spin­out inks a Mam­moth CRISPR deal with Ver­tex worth near­ly $700M

When a company gets its start in gene editing pioneer Jennifer Doudna’s lab, it’s bound to make headlines. But three years in, the fanfare still hasn’t died down for Mammoth Biosciences. Now, the Brisbane, CA-based company is cheering on its first major R&D pact.

Mammoth unveiled a nearly $700 million deal with Vertex on Tuesday morning, good for the development of in vivo gene therapies for two mystery diseases. The stars of the show are Mammoth’s ultra-small CRISPR systems, including two Cas enzymes licensed from Doudna’s lab over the past couple years, Cas14 and Casɸ.

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FDA is much worse than its reg­u­la­to­ry peers at proac­tive­ly dis­clos­ing da­ta, re­searchers find

The European Medicines Agency and Health Canada continue to outpace the FDA when it comes to proactively releasing data on drugs and biologics the agency has reviewed, leading to further questions of why the American agency can’t be more transparent.

In a study published recently in the Journal of Law, Medicine, & Ethics, Yale and other academic lawyers and researchers found that between 2016 and April 2021, the EMA proactively released data for 123 unique medical products, while Health Canada proactively released data for 73 unique medical products between 2019 and April 2021. What’s more, the EMA and Health Canada didn’t proactively release the same data on the same drugs. In stark contrast, the FDA in 2018 only proactively disclosed data supporting one drug that was approved that year.

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NYU surgeon transplants an engineered pig kidney into the outside of a brain-dead patient (Joe Carrotta/NYU Langone Health)

No, sci­en­tists are not any clos­er to pig-to-hu­man trans­plants than they were last week

Steve Holtzman was awoken by a 1 a.m. call from a doctor at Duke University asking if he could put some pigs on a plane and fly them from Ohio to North Carolina that day. A motorcyclist had gotten into a horrific crash, the doctor explained. He believed the pigs’ livers, sutured onto the patient’s skin like an external filter, might be able to tide the young man over until a donor liver became available.