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.

Forge Bi­o­log­ics’ cGMP Com­pli­ant and Com­mer­cial­ly Vi­able Be­spoke Affin­i­ty Chro­matog­ra­phy Plat­form

Forge Biologics has developed a bespoke affinity chromatography platform approach that factors in unique vector combinations to streamline development timelines and assist our clients in efficiently entering the clinic. By leveraging our experience with natural and novel serotypes and transgene conformations, we are able to accelerate affinity chromatography development by nearly 3-fold. Many downstream purification models are serotype-dependent, demanding unique and time-consuming development strategies for each AAV gene therapy product1. With the increasing demand to propel AAV gene therapies to market, platform purification methods that support commercial-scale manufacturing of high-quality vectors with excellent safety and efficacy profiles are essential.

Cy­to­ki­net­ics’ ALS drug fails PhI­II, leav­ing the biotech with a sin­gle late-stage prospect

Cytokinetics’ candidate for the muscle disease amyotrophic lateral sclerosis, or ALS, failed a Phase III trial, the Bay Area biotech announced Friday morning.

At a second interim analysis of the trial, an independent review committee recommended that Cytokinetics discontinue its COURAGE-ALS trial for reldesemtiv, as it “found no evidence of effect” compared to placebo on the primary or key secondary endpoints.

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CHMP gives thumbs-up for We­govy use in ado­les­cents, along with nine new drug rec­om­men­da­tions

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) recommended nine drugs for approval this week while also giving thumbs up for six expanded indications, including Novo Nordisk’s approved obesity medication Wegovy for younger people. Wegovy is already approved as an obesity treatment in the EU for adults, and the new indication would allow prescriptions for adolescents aged 12 and older.

Austin biotech Mol­e­c­u­lar Tem­plates lays off more than 100 staffers as pipeline nar­rows

Molecular Templates is ridding itself of a Phase I HER2 asset and fine-tuning its pipeline to focus on three programs and a preclinical Bristol Myers Squibb collaboration. With the narrowed scope on its so-called engineered toxin bodies, the Austin, TX biotech is laying off about half of its staff.

That’s a little more than 100 employees, per an SEC filing. Molecular’s layoffs, approved by its board Wednesday, add to the dozens of pullbacks in the industry in the first three months of 2023.

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Green­Light re­ceives buy­out of­fer; Apol­lomics com­pletes SPAC merg­er

RNA biotech GreenLight Biosciences has been handed an offer for potential acquisition.

GreenLight said in a release that it has received a non-binding “indication of interest” from Fall Line Endurance Fund to acquire GreenLight’s capital stock for $0.60 per share in cash. The release said any potential agreement between the two parties would depend on certain conditions.

Through a special committee, the biotech will evaluate the offer but added there’s no certainty a deal will go forward. GreenLight will also not make any more announcements until a deal comes through or “otherwise determines” a statement is necessary.

Mathai Mammen, FogPharma's next CEO

Math­ai Mam­men hands in J&J's R&D keys to lead Greg Ver­dine’s Fog­Phar­ma 

In the early 1990s, Mathai Mammen was a teaching assistant in Greg Verdine’s Science B46 course at Harvard. In June, the former R&D head at Johnson & Johnson will succeed Verdine as CEO, president and chair of FogPharma, the same month the seven-year-old biotech kickstarts its first clinical trial.

After leading R&D at one of the largest drugmakers in the world, taking the company through more than half a dozen drug approvals in the past few years, not to mention a Covid-19 vaccine race, Mammen departed J&J last month and will take the helm of a Cambridge, MA biotech attempting to go after what Verdine calls the “true emperor of all oncogenes” — beta-catenin.

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TScan Therapeutics' departing CEO David Southwell and CSO/COO Gavin MacBeath

TCR up­start an­nounces CEO ex­it, with CSO now act­ing re­place­ment

A public T cell biotech’s chief executive has decided to leave the company.

TScan Therapeutics said Friday morning that CEO David Southwell stepped down earlier this week, leaving both his chief executive and board member roles. Filling in is Gavin MacBeath, the company’s CSO and COO. He became the acting CEO on Tuesday, and will continue to remain CSO and COO, TScan’s announcement read.

Aptinyx eval­u­ates fu­ture of the com­pa­ny fol­low­ing two failed tri­als, 60% lay­offs

This year has been tough for Aptinyx — two failed trials, a 60% cut in its workforce, and now the company has brought on a firm to help evaluate the future of the company.

The press release noted it’s working with the firm Ladenburg Thalmann as its financial advisor to assist in exploring and evaluating “strategic alternatives” — a process that a growing group of struggling biotechs has embarked on, sometimes ending in a merger, asset sale or wind-down.

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Sar­to­rius to ac­quire French man­u­fac­tur­er for $2.6B+ in cell and gene ther­a­py play

The German life science group Sartorius will be picking up French contract manufacturer Polyplus for the price of €2.4 billion, or $2.6 billion.

On Friday, Sartorius announced the acquisition through its French subgroup, Sartorius Stedim Biotech, which will be acquiring Polyplus from private investors ARCHIMED and WP GG Holdings IV. Polyplus has 270 employees and produces materials and components that go into making viral vectors that are used in cell and gene therapies. This includes DNA/RNA reagents as well as plasmid DNA. Polyplus has locations in France, Belgium, China and the US.