Mer­ck­'s Keytru­da builds a com­mand­ing lead in front­line lung can­cer with da­ta from two more land­mark tri­als

CHICA­GO — Mer­ck came to AS­CO as the dom­i­nant in­dus­try play­er in front­line lung can­cer. It’s go­ing to leave AS­CO with that rep in­tact — at the ex­pense of its heavy­weight ri­vals in the field still play­ing catch-up.

Roy Baynes

In two key stud­ies out this morn­ing, the phar­ma gi­ant spelled out pos­i­tive, crit­i­cal­ly im­por­tant da­ta un­der­scor­ing Keytru­da’s abil­i­ty to fight a broad seg­ment of the cas­es in the first-line lung can­cer field as a monother­a­py, with the Keytru­da/chemo com­bo the best op­tion (so far) in front­line squa­mous cas­es, where Roche tried — and large­ly failed — to el­bow ahead this week­end.

“If you think of the whole front­line lung can­cer field (ex­cept for EGFR and ALK mu­ta­tion cas­es),” says Mer­ck head of glob­al clin­i­cal de­vel­op­ment Roy Baynes, “for pret­ty much every­body there is a Keytru­da-based ther­a­py that makes sense for those pa­tients. It would be fair to say, all things be­ing equal, the chemo com­bi­na­tion is a very rea­son­able first-line op­tion.”

But not every­one is go­ing to be able to take the chemo com­bo, in­clud­ing pa­tients with high co-mor­bidi­ties. 

“Giv­en the sit­u­a­tion of all things be­ing equal, the chemo com­bo would be a pre­ferred ther­a­py,” says Baynes. “And if there are cir­cum­stances where chemo is not a pre­ferred ther­a­py, monother­a­py is a rea­son­able op­tion.”

In its monother­a­py study dubbed Keynote-042, pa­tients in the Keytru­da arm hit a me­di­an over­all sur­vival rate of 20 months, a clear­ly promis­ing out­come com­pared to 12.2 months for chemo-so­lo pa­tients with a PD-L1 tu­mor pro­por­tion score (TPS) of ≥50 per­cent. In pa­tients with a TPS of less than 20%, the OS rate was re­duced to 17.7 vs 13 months, and 16.7 vs 12.1 months for the over­all study pop­u­la­tion of pa­tients with a TPS of ≥1%.

The ‘042 study was the longer take of an ear­li­er, faster tri­al num­bered ‘024. And Mer­ck views it as a more thor­ough con­fir­ma­tion of what it saw in that quick take.  

Then there’s Keynote-407, a com­bi­na­tion of Keytru­da and chemo for front­line squa­mous NSCLC  which had es­sen­tial­ly the same de­sign as Roche’s IM­pow­er131, with Tecen­triq. Mer­ck’s team post­ed an im­pres­sive 36% re­duc­tion in the risk of death, a haz­ard ra­tio that won’t es­cape the at­ten­tion of spe­cial­ists. The Keytru­da com­bi­na­tion hit a me­di­an OS of 15.9 months com­pared to 11.3 months in the chemother­a­py-alone group. The me­di­an PFS was 6.4 months for the Keytru­da com­bi­na­tion com­pared with 4.8 months for chemother­a­py alone. 

And at the sec­ond in­ter­im read­out, the ORR was 57.9% for the com­bo com­pared to 38.4% for the chemother­a­py group. 

Roche has yet to see an OS ad­van­tage, but the PFS was close at 6.3 months for the Roche check­point vs 5.6 months for the con­trol — just a 3 week ad­van­tage. As al­ways when you com­pare da­ta on drugs that were not in a head-to-head tri­al, it’s prob­lem­at­ic to as­sess ri­val ther­a­pies. But with­out com­pet­i­tive OS re­sults, Roche is left with a small ad­van­tage in PFS that won’t com­pare well for an­a­lysts cov­er­ing the area.

The new da­ta sets will al­so in­evitably draw com­par­isons with Bris­tol-My­ers Squibb’s work with Op­di­vo. Bris­tol-My­ers has faced some stiff crit­i­cism for its set­backs as well as its tri­al de­signed in lung can­cer, where they’ve been a con­sis­tent run­ner up to Mer­ck.

The re­sults build on the re­cent­ly re­leased da­ta from Keynote-189 for non­squa­mous non-small cell lung can­cer, where re­searchers say that their com­bo of Keytru­da and chemo clear­ly beat out chemo alone on over­all sur­vival, though the fi­nal OS rate for the com­bi­na­tion has not yet been reached.

For Mer­ck, it’s an­oth­er chance to cel­e­brate pos­i­tive out­comes as ri­vals strug­gle to make their case for their drugs.

“As we look at the lung can­cer are­na,” Baynes adds, “we com­plet­ed 5 ran­dom­ized, con­trolled tri­als, with sur­vival ben­e­fits in all 5. It’s quite re­mark­able.”

Not every­one is pro­vid­ing Mer­ck with a stand­ing ova­tion, though. Some prac­ti­tion­ers in the field feel that those groups with a low­er TPS score on PD-L1 are def­i­nite­ly not get­ting a tremen­dous amount of help from Keytru­da. Here’s a note from lung can­cer ex­pert Jack West — a tho­racic on­col­o­gist at the Swedish Can­cer In­sti­tute at Swedish Med­ical Cen­ter — about my sto­ry:

Though I com­plete­ly agree that re­sults over­all are im­pres­sive and that Mer­ck is more or less run­ning the ta­ble with pem­bro in ad­vanced NSCLC, I need to high­light that the re­sults are not as fa­vor­able as your lan­guage would syggest for the pa­tients with low PD-L1 on KEYNOTE-042. The num­bers you use for pa­tients with low­er tu­mor PD-L1 ex­pres­sion in­clude the pa­tients with high PD-L1, who prop up the re­sults for the en­tire tri­al. When the re­sults of the 042 tri­al are looked at for pa­tients with PD-L1 1-49%, there is no ef­fi­ca­cy ad­van­tage for pem­bro. This doesn’t mean that on­col­o­gists and pa­tients won’t fa­vor it for com­pa­ra­ble ef­fi­ca­cy and more fa­vor­able tol­er­a­bil­i­ty than chemo, but it’s im­por­tant to clar­i­fy that the num­bers you’re pre­sent­ing for the “PD-L1 less than 20%” are ac­tu­al­ly not the num­bers for that sub­set alone but the num­bers for that sub­set com­bined with the larg­er num­ber of pa­tients with high­er tu­mor PD-L1 ex­pres­sion. The re­sults are pooled and mere­ly don’t “de-se­lect” the low PD-L1 group when they present “PD-L1 <50%” or “PD-L1 < 20%”, but they al­ways in­clude the pa­tients with high­er PD-L1 who are prop­ping up the tri­al over­all. And this is the sub­group for whomp pem­bro alone has been the stan­dard of care for more than 18 months, for whom we’d al­ready con­sid­er chemo alone an es­tab­lished in­fe­ri­or ap­proach in the US and wouldn’t en­roll on KN-042 these days.

Mer­ck has been pour­ing bil­lions of dol­lars in­to its Keytru­da pipeline, and the in­vest­ment has paid off hand­some­ly with a block­buster fran­chise and a col­lec­tion of more than 750 tri­als — an ex­plo­sion of clin­i­cal re­search. Five years ago, says Baynes, Mer­ck was at AS­CO with one pre­sen­ta­tion. For AS­CO 2018, it’s pre­sent­ing 140.

Con­quer­ing a silent killer: HDV and Eiger Bio­Phar­ma­ceu­ti­cals

Hepatitis delta, also known as hepatitis D, is a liver infection caused by the hepatitis delta virus (HDV) that results in the most severe form of human viral hepatitis for which there is no approved therapy.

HDV is a single-stranded, circular RNA virus that requires the envelope protein (HBsAg) of the hepatitis B virus (HBV) for its own assembly. As a result, hepatitis delta virus (HDV) infection occurs only as a co-infection in individuals infected with HBV. However, HDV/HBV co-infections lead to more serious liver disease than HBV infection alone. HDV is associated with faster progression to liver fibrosis (progressing to cirrhosis in about 80% of individuals in 5-10 years), increased risk of liver cancer, and early decompensated cirrhosis and liver failure.
HDV is the most severe form of viral hepatitis with no approved treatment.
Approved nucleos(t)ide treatments for HBV only suppress HBV DNA, do not appreciably impact HBsAg and have no impact on HDV. Investigational agents in development for HBV target multiple new mechanisms. Aspirations are high, but a functional cure for HBV has not been achieved nor is one anticipated in the forseeable future. Without clearance of HBsAg, anti-HBV investigational treatments are not expected to impact the deadly course of HDV infection anytime soon.

No­var­tis is ax­ing 150 ear­ly dis­cov­ery jobs as CNI­BR shifts fo­cus to the de­vel­op­ment side of R&D

Novartis is axing some 150 early discover jobs in Shanghai as it swells its staff on the drug development side of the equation in China. And the company is concurrently beefing up its investment in China’s fast-growing biotech sector with a plan to add to its investments in local VCs.

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No­var­tis is eye­ing a multi­bil­lion-dol­lar Med­Co buy­out as Jer­sey biotech nears NDA — re­ports

To get from Novartis’ US headquarters to the Medicines Company, you make a left out of a square concrete building on NJ-Route 10, follow it past the sun orange veranda of Jersey’s Hot Bagels and the inexplicable green Vermont cabin that houses the Whippany Railway Museum until you turn right and immediately arrive at a rectangular glass building. It should take you about 12 minutes.

Reports are out that Novartis may be making that trip. Amid a torrent of Phase III data burnishing MedCo’s chances at a blockbuster cholesterol drug,  Bloomberg News is reporting that Novartis is looking to acquire the Jersey-based biotech.

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UP­DAT­ED: In a land­mark first glimpse of hu­man da­ta from Ver­tex, CRISPR/Cas9 gene ther­a­py sig­nals ear­ly ben­e­fit

Preliminary data on two patients with blood disorders that have been administered with Vertex and partner CRISPR Therapeutics’ gene-editing therapy suggest the technology is safe and effective, marking the first instance of the benefit of the use of CRISPR/Cas9 technology in humans suffering from disease.

Patients in these phase I/II studies give up peripheral blood from which hematopoietic stem and progenitor cells are isolated. The cells are tinkered with using CRISPR/Cas9 technology, and the edited cells — CTX001 — are infused back into the patient via a stem cell transplant. The objective of CTX001 is to fix the errant hemoglobin gene in patents with two blood disorders: beta-thalassemia and sickle cell disease, by unleashing the production of fetal hemoglobin.

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Badrul Chowdhury. FDA via Flickr

As­traZeneca los­es an­oth­er ex­ec­u­tive to biotech, as Badrul Chowd­hury moves to Savara

Another executive is migrating from the echelons of Big Pharma to the corridors of small biotech.

In April 2018, Badrul Chowdhury took his more than two decades of experience at the FDA to AstraZeneca, where he took on the role of senior vice president and chief physician-scientist for respiratory, inflammation and autoimmunity late-stage development in biopharmaceuticals R&D.

After about a year and a half in this role, Chowdhury is moving to a small Texas biotech called Savara, where he will serve as chief medical officer.

Yiannis Kiachopoulos and Artur Saudabayev, co-founders of Causaly

Lon­don AI up­start, which counts No­var­tis as a cus­tomer, can teach your com­put­er to read

When Amazon developed a machine-learning tool to make its recruitment process more efficient — the man-made system absorbed the gender-bias of its human makers, and the project was aborted. In the field of biopharmaceuticals, the way researchers train their machine learning algorithms can skew the outcome of predictions. But before those predictions can be made, the engine must learn to read to make sense of explosive volume of knowledge out there.

Burt Adelman. Novo Ventures

Here's a $25M seed fund aimed at back­ing some brash new drug ideas out of the Broad

As a former academic and a seasoned drug developer, Burt Adelman knew when he was recruited as a senior advisor to Novo Ventures in 2017 that one of his key priorities needs to be introducing the fund to the network he was so deeply embedded in.

“I was thinking long and hard on how can I, as a Boston insider, help Novo really get inside the ecosystem of Boston biotech?” he recalled in an interview with Endpoints News.

Welling­ton lines up a $393M bankroll for its next round of pri­vate biotech bets — and they’re like­ly think­ing big

Wellington Management made some uncustomary waves at the beginning of the year when it threw its considerable weight against Bristol-Myers Squibb’s $74 billion Celgene buyout. But after Bristol-Myers’ biggest investor conceded that game to the influential proxy firms involved, they’re now going to end the year by rolling out a big new investment fund for a new stable of fledgling biotechs on the private side of the industry.

As uter­ine race with Ab­b­Vie heats up, My­ovant eyes FDA ap­proval with tri­al re­sults from prostate can­cer

Myovant has long had a secret weapon in its uterine rivalry with AbbVie: Men.

While the small Swiss biotech has jockeyed with the Illinois-based giant for a foothold in the endometriosis and uterine fibroid therapy market, the company has been developing the same lead compound, relugolix, for use in one of the most common cancers for the uterus-less: prostate cancer. Today, Myovant is out with positive topline results from its big Phase III trial on the gonadotropin-releasing hormone (GnRH) antagonist. They say they’ve reached every primary and secondary endpoint with p values less than .0001.