KRAS analy­sis vaults Mer­ck­'s flag­ship Keytru­da back in­to the spot­light

The jew­el in Mer­ck’s crown — Keytru­da — just got more pre­cious.

On Thurs­day, the US drug­mak­er broke out an ex­plorato­ry analy­sis show­ing the check­point in­hibitor helped pa­tients live longer as the first line of de­fense in pa­tients with a form of non-small cell lung can­cer (NSCLC) whose tu­mors ex­pressed PD-L1, re­gard­less of KRAS sta­tus.

Jonathan Cheng Mer­ck

KRAS mu­ta­tions oc­cur in rough­ly a fifth of pa­tients di­ag­nosed with non-small cell lung can­cer, and da­ta sug­gest that these mu­ta­tions are as­so­ci­at­ed with poor re­sponse to treat­ment, not­ed Jonathan Cheng, vice pres­i­dent of on­col­o­gy clin­i­cal re­search at Mer­ck Re­search Lab­o­ra­to­ries, in a state­ment.

The ex­plorato­ry analy­sis was con­duct­ed on the KEYNOTE-042 tri­al, which pit­ted the block­buster ther­a­py Keytru­da against chemother­a­py in metasta­t­ic non­squa­mous NSCLC whose tu­mors ex­pressed PD-L1. Of the 1,274 pa­tients in the tri­al — 301 pa­tients had KRAS evalu­able da­ta (n=232 with­out any KRAS mu­ta­tion; n=69 with any KRAS mu­ta­tion, in­clud­ing n=29 with the KRAS G12C mu­ta­tion).

Keytru­da re­duced the risk of death by 58% in pa­tients with any KRAS mu­ta­tion, and by 72% in pa­tients with the KRAS G12C mu­ta­tion, ver­sus chemother­a­py, the com­pa­ny said.

For decades, sci­en­tists have scratched their heads about KRAS, the no­to­ri­ous can­cer-caus­ing pro­tein. “Some have de­scribed KRAS as the beat­ing heart of can­cer,” Dar­ryl Mc­Connell, Boehringer’s head of dis­cov­ery re­search not­ed in an in­ter­view with End­points News ear­li­er this year.

Dar­ryl Mc­Connell

KRAS’ smooth ter­rain long elud­ed ma­nip­u­la­tion, large­ly due to the ab­sence of a dis­tinct pock­et for a drug to latch on to. How­ev­er, the process of tri­al and er­ror fi­nal­ly yield­ed progress — trig­ger­ing a flock of com­pa­nies, in­clud­ing Mer­ck, Am­gen, J&J, and As­traZeneca, to en­gi­neer com­pounds de­signed to an­nex the oft’ mu­tat­ed onco­gene. Re­cent­ly, Ger­many’s Boehringer In­gel­heim en­tered the fold. An­a­lysts have been in­tox­i­cat­ed with the po­ten­tial of KRAS drugs for use in can­cer pa­tients with few op­tions at their dis­pos­al — fore­cast­ing ap­proved drugs will reap bil­lions in peak sales.

The first KRAS pock­et es­tab­lished by Am­gen for at­tack is G12C, al­though small­er ri­val Mi­rati is at the large drug­mak­er’s heels. The KRAS G12C mu­ta­tion is found in rough­ly 14% of NSCLC pa­tients and 5% of col­orec­tal can­cer pa­tients. Un­like Am­gen and Mi­rati — Boehringer’s ear­ly-stage drug is a pan-KRAS in­hibitor hits SOS1 as well as G12C. SOS1 is a pro­tein that turns KRAS from an “off” to “on” state.

Am­gen’s keen­ly watched AMGN510 made a splash at the AS­CO con­fer­ence this year af­ter a small, ear­ly study showed five out of 10 pa­tients suf­fer­ing from ad­vanced, drug-re­sis­tant NSCLC saw a par­tial re­sponse to the ex­per­i­men­tal treat­ment, in­clud­ing one who went on to achieve a com­plete re­sponse af­ter the da­ta cut­off point. In Sep­tem­ber, those da­ta were up­dat­ed at the World Con­fer­ence on Lung Can­cer. Re­searchers tracked a 54% par­tial tu­mor re­sponse, and ob­served tu­mors shrink­ing in sev­en of 13 NSCLC pa­tients.

Mean­while, en­cour­ag­ing Phase I/II da­ta em­a­nat­ing from Mi­rati’s ex­per­i­men­tal drug, MRTX849, for ad­vanced sol­id tu­mors that har­bor KRAS G12C mu­ta­tions were un­veiled in late Oc­to­ber. The lit­tle biotech has tied up with No­var­tis — and the two are look­ing at com­bin­ing the G12C drug with a ther­a­py that tar­gets SHP2, which func­tions as a key reg­u­la­tor of cell cy­cle con­trol.

Rev­o­lu­tion Med­i­cines has the same po­ten­tial com­bo in-house. Oth­er KRAS con­tenders in­clude Mod­er­na and Mer­ck’s mR­NA-5671; J&J’s col­lab­o­ra­tion with Well­spring on ARS-3248, a G12C tar­get­ed small mol­e­cule; and AZD4785, li­censed by As­traZeneca from Io­n­is — al­though the com­pound has been dis­con­tin­ued af­ter a poor show­ing in clin­i­cal tri­als.

As an onco­gene, KRAS has the po­ten­tial to ren­der nor­mal cells can­cer­ous. Akin to HRAS and NRAS, it be­longs to the RAS fam­i­ly of onco­genes and plays a key role in cell di­vi­sion, cell dif­fer­en­ti­a­tion, and apop­to­sis.

Is a pow­er­house Mer­ck team prepar­ing to leap past Roche — and leave Gilead and Bris­tol My­ers be­hind — in the race to TIG­IT dom­i­na­tion?

Roche caused quite a stir at ASCO with its first look at some positive — but not so impressive — data for their combination of Tecentriq with their anti-TIGIT drug tiragolumab. But some analysts believe that Merck is positioned to make a bid — soon — for the lead in the race to a second-wave combo immuno-oncology approach with its own ambitious early-stage program tied to a dominant Keytruda.

Endpoints Premium

Premium subscription required

Unlock this article along with other benefits by subscribing to one of our paid plans.

Pfiz­er’s Doug Gior­dano has $500M — and some ad­vice — to of­fer a cer­tain breed of 'break­through' biotech

So let’s say you’re running a cutting-edge, clinical-stage biotech, probably public, but not necessarily so, which could see some big advantages teaming up with some marquee researchers, picking up say $50 million to $75 million dollars in a non-threatening minority equity investment that could take you to the next level.

Doug Giordano might have some thoughts on how that could work out.

The SVP of business development at the pharma giant has helped forge a new fund called the Pfizer Breakthrough Growth Initiative. And he has $500 million of Pfizer’s money to put behind 7 to 10 — or so — biotech stocks that fit that general description.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 82,200+ biopharma pros reading Endpoints daily — and it's free.

BiTE® Plat­form and the Evo­lu­tion To­ward Off-The-Shelf Im­muno-On­col­o­gy Ap­proach­es

Despite rapid advances in the field of immuno-oncology that have transformed the cancer treatment landscape, many cancer patients are still left behind.1,2 Not every person has access to innovative therapies designed specifically to treat his or her disease. Many currently available immuno-oncology-based approaches and chemotherapies have brought long-term benefits to some patients — but many patients still need other therapeutic options.3

President Donald Trump (left) and Moncef Slaoui, head of Operation Warp Speed (Alex Brandon, AP Images)

White House names fi­nal­ists for Op­er­a­tion Warp Speed — with 5 ex­pect­ed names and one no­table omis­sion

A month after word first broke of the Trump Administration’s plan to rapidly accelerate the development and production of a Covid-19 vaccine, the White House has selected the five vaccine candidates they consider most likely to succeed, The New York Times reported.

Most of the names in the plan, known as Operation Warp Speed, will come as little surprise to those who have watched the last four months of vaccine developments: Moderna, which was the first vaccine to reach humans and is now the furthest along of any US effort; J&J, which has not gone into trials but received around $500 million in funding from BARDA earlier this year; the joint AstraZeneca-Oxford venture which was granted $1.2 billion from BARDA two weeks ago; Pfizer, which has been working with the mRNA biotech BioNTech; and Merck, which just entered the race and expects to put their two vaccine candidates into humans later this year.

UP­DAT­ED: Es­ti­mat­ing a US price tag of $5K per course, remde­sivir is set to make bil­lions for Gilead, says key an­a­lyst

Data on remdesivir — the first drug shown to benefit Covid-19 patients in a randomized, controlled trial setting — may be murky, but its maker Gilead could reap billions from the sales of the failed Ebola therapy, according to an estimate by a prominent Wall Street analyst. However, the forecast, which is based on a $5,000-per-course US price tag, triggered the ire of one top drug price expert.

FDA de­lays de­ci­sion on No­var­tis’ po­ten­tial block­buster MS drug, wip­ing away pri­or­i­ty re­view

So much for a speedy review.

In February, Novartis announced that an application for their much-touted multiple sclerosis drug ofatumumab had been accepted and, with the drug company cashing in on one of their priority review vouchers, the agency was due for a decision by June.

But with June less than 48 hours old, Novartis announced the agency has extended their review, pushing back the timeline for approval or rejection to September. The Swiss pharma filed the application in December, meaning their new schedule will be nearly in line with the standard 10-month window period had they not used the priority voucher.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 82,200+ biopharma pros reading Endpoints daily — and it's free.

Credit: AP Images

Covid-19 roundup: BAR­DA sup­ports Op­er­a­tion Warp Speed with big $628M con­tract to ser­vice Amer­i­ca's vac­cine pro­duc­tion needs

Another BARDA contract designed to service America’s Covid-19 vaccine needs has been deployed.

The White House-led initiative designed to bankroll development to bring a vaccine to the American public by this fall — Operation Warp Speed — has via BARDA handed a meaty contract to the maker of an FDA-licensed anthrax vaccine to open up its manufacturing apparatus to shore up production of Covid-19 vaccines.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 82,200+ biopharma pros reading Endpoints daily — and it's free.

Ken Frazier, AP Images

Why Mer­ck wait­ed, and what they now bring to the Covid-19 fight

Nicholas Kartsonis had been running clinical infectious disease research at Merck for almost 2 years when, in mid-January, he got a new assignment: searching the pharma giant’s vast libraries for something that could treat the novel coronavirus.

The outbreak was barely two weeks old when Kartsonis and a few dozen others got to work, first in small teams and then in a larger task force that sucked in more and more parts of the sprawling company as Covid-19 infected more and more of the globe. By late February, the group began formally searching for vaccine and antiviral candidates to license. Still, while other companies jumped out to announce their programs and, eventually and sometimes controversially, early glimpses at human data, Merck remained silent. They made only a brief announcement about a data collection partnership in April and mentioned vaguely a vaccine and antiviral search in their April 28 earnings call.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 82,200+ biopharma pros reading Endpoints daily — and it's free.

A low-pro­file biotech bests Re­gen­eron in high-pro­file patent suit

For nearly a decade now, the low-profile Cambridge biotech Kymab has been battling in US, UK, Japanese and Australian courts with the biotech behemoth Regeneron.

Regeneron has turned itself into a $70 billion company off of a platform of transgenically humanized mice they can use to make antibodies for anything from Ebola to colorectal cancer. The technology took decades and billions to build, 20 years from the company’s founding to the first approved drug. And the company guards and touts it zealously, breaking their production process down into various branded components — Velocimmune, Velocigene, Velocimouse and four other Velocis — and sometimes suing would-be copycats. In 2014, most notably, they sued two Pfizer-backed entities for patent infringement.