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

FDA commissioner Stephen Hahn at the White House (AP Images)

Un­der fire, FDA to is­sue stricter guid­ance for Covid-19 vac­cine EUA this week — re­port

The FDA has been insisting for months that a Covid-19 vaccine had to be at least 50% effective – a measure of transparency meant to shore public trust in the agency and in a vaccine that had been brought forward at record speed and record political pressure. But now, with concerns of a Trump-driven authorization arriving before the election, the agency may be raising the bar.

The FDA is set to release new guidance that would raise safety and efficacy requirements for a vaccine EUA above earlier guidance and above the criteria used for convalescent plasma or hydroxychloroquine, The Washington Post reported. Experts say this significantly lowers the odds of an approval before the election on November 3, which Trump has promised despite vocal concerns from public health officials.

Blueprint CEO Jeff Albers (file photo)

Blue­print plots re­turn to FDA with new Ay­vak­it da­ta in rare con­di­tion — and the an­a­lysts cheer

Over a decade after launch, Blueprint Medicines nabbed the first approval for their first drug earlier this year. Now, as they move forward with a Roche-partnered global launch, they’re touting data that could push them into more patients.

The Jeff Albers-led Cambridge biotech released their full pivotal data for Ayvakit in patients with advanced systemic mastocytosis. In one 53-person study, they showed that 76% of patients responded to the drug, 36% had complete responses and that on average their responses lasted for just over 3 years. A smaller, 32-patient study had a 75% response rate and most were still responding after 10.4 months, the last follow-up.

Secretary of health and human services Alex Azar speaking in the Rose Garden at the White House (Photo: AFP)

Trump’s HHS claims ab­solute au­thor­i­ty over the FDA, clear­ing path to a vac­cine EUA

The top career staff at the FDA has vowed not to let politics overrule science when looking at vaccine data this fall. But Alex Azar, who happens to be their boss’s boss, apparently won’t even give them a chance to stand in the way.

In a new memorandum issued Tuesday last week, the HHS chief stripped the FDA and other health agencies under his purview of their rule making ability, asserting all such power “is reserved to the Secretary.” Sheila Kaplan of the New York Times first obtained and reported the details of the September 15 bulletin.

Samit Hirawat (Bristol Myers Squibb)

Af­ter bruis­ing re­jec­tion, blue­bird and Bris­tol My­ers Squibb land ide-cel pri­or­i­ty re­view. But will it mat­ter for the CVR?

With the clock all but up, the FDA accepted and handed priority review to Bristol Myers Squibb and bluebird bio’s BCMA CAR-T, keeping a narrow window open for Celgene investors to still cash in on the $9 CVR from the $63 billion Celgene merger.

The acceptance comes five months after the two companies weres slammed with a surprise refuse-to-file that threatened to foreclose the CVR entirely. Today’s acceptance sets the FDA decision date for March 27, 2021 – or precisely 4 days before the CVR deadline of March 31. Given the breakthrough designation and strong pivotal data — 81.5% response rate, 35.2% complete response rate — priority review was largely expected.

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Anthony Coyle (Repertoire)

Flag­ship's merged biotech Reper­toire nets ex-Pfiz­er CSO An­tho­ny Coyle as R&D chief

Flagship is building a big-name C-suite at its new, $220 million merged biotech.

Repertoire Immune Medicines, which already boasts former Bioverativ chief John Cox as its CEO, announced yesterday that Anthony Coyle, the former Pfizer CSO and the founding CEO of Pandion, will join as their head of R&D.

“As we progress clinical trials for our multi-clonal T cell candidates in immuno-oncology, Tony’s deep expertise in cellular immunology and novel therapeutic development will help us achieve our vision of creating a new class of transformative medicines for patients,” Cox said in a statement.

#ES­MO20: Push­ing in­to front­line, Mer­ck and Bris­tol My­ers duke it out with new slate of GI can­cer da­ta

Having worked in parallel for years to move their respective PD-1 inhibitors up to the first-line treatment of gastrointestinal cancers, Merck and Bristol Myers Squibb finally have the data at ESMO for a showdown.

Comparing KEYNOTE-590 and CheckMate-649, of course, comes with the usual caveats. But a side-by-side look at the overall survival numbers also offer some perspective on a new frontier for the reigning checkpoint rivals, both of whom are claiming to have achieved a first.

President Donald Trump (via AP Images)

Signs of an 'Oc­to­ber Vac­cine Sur­prise' alarm ca­reer sci­en­tists. HHS con­tin­ues to claim Azar “will de­fer com­plete­ly to the FDA"

President Donald Trump, who seems intent on announcing a Covid-19 vaccine before Election Day, could legally authorize a vaccine over the objections of experts, officials at the FDA and even vaccine manufacturers, who have pledged not to release any vaccine unless it’s proved safe and effective.

In podcasts, public forums, social media and medical journals, a growing number of prominent health leaders say they fear that Trump — who has repeatedly signaled his desire for the swift approval of a vaccine and his displeasure with perceived delays at the FDA — will take matters into his own hands, running roughshod over the usual regulatory process.

Can a mag­net­ic cell ther­a­py re­place corneal trans­plan­ta­tion? As eight-year jour­ney leads to the clin­ic, two broth­ers un­veil bold vi­sion

Jeff Goldberg was getting acquainted with a brand new way to do corneal transplants when an even newer, even bolder idea hit him.

It was almost 10 years ago, and Goldberg was in his first faculty position at Bascom Palmer Eye Institute at the University of Miami. Scientists had developed a new way to do cornea transplants where instead of sewing a whole donor cornea — a decades-old practice — they were just engrafting the inner layer of cells.

News brief­ing: Tiny Vac­cinex's drug flops in PhII Hunt­ing­ton's tri­al, stock craters; Siol­ta nabs $30M Se­ries B to de­vel­op mi­cro­bio­me drug

Siolta Therapeutics, a microbiome company targeting allergic diseases, raked in a $30 million Series B to develop its lead candidate, STMC-103H. The drug, which has been FDA fast-tracked, is headed for proof-of-concept trials, according to the company. Its various indications include allergic asthma, food allergies, atopic dermatitis, allergic rhinitis, and allergy prevention.

The news comes just after the California-based biotech added a prominent biopharma veteran as an advisor: 20-year Gilead CEO John Martin. The biotech also gained Richard Shames as CMO, who came by way of Protagonist Therapeutics.