Check­point com­bos for can­cer are all the rage as tri­al spon­sors line up hun­dreds of new stud­ies — re­port

Num­ber of An­ti-PD-1/PD-L1 MAb com­bi­na­tion stud­ies 2015 vs. 2017
Full Re­port: Eval­u­ate Ltd. May 2017


Over the last few months it hasn’t been un­usu­al to see new com­bi­na­tion stud­ies be­ing an­nounced on a dai­ly ba­sis, match­ing one of the 5 ap­proved PD-(L)1 check­point drugs with an­oth­er can­cer ther­a­py. Some morn­ings they come in pairs.

It’s not hard to see why. The check­points typ­i­cal­ly work as a monother­a­py — though there have been some nasty set­backs over the past 6 months. And some of the big play­ers are hap­py to con­tribute their drug to stud­ies spon­sored by oth­ers look­ing to ad­vance a pi­lot Phase I/II ex­plorato­ry study. There are al­so re­cent ex­am­ples of some big tie-ups be­tween Mer­ck (Keytru­da) and Bris­tol-My­ers Squibb (Op­di­vo) check­points with In­cyte in Phase III.

In­cyte has its own PD-1 in the clin­ic as it lines up these ag­nos­tic late-stage tri­als to po­si­tion its lead­ing IDO1 drug.

Now EP Van­tage has tal­lied the whole score on these com­bo tri­als, not co­in­ci­den­tal­ly just ahead of AS­CO, and found a stun­ning 765 com­bi­na­tion stud­ies list­ed on clin­i­cal­tri­als.gov. Keytru­da leads the pack, with 268 — up from 70 just 18 months ago. For Bris­tol-My­ers it’s 242, more than three times the num­ber EP Van­tage’s ed­i­to­r­i­al team found in 2015.

Any­one even mod­er­ate­ly in­ter­est­ed in this field will want to check it out di­rect­ly. There’s a lot of de­tail on what’s now in the clin­ic.

Don’t ex­pect the ris­ing trend lines to start to plateau any­time soon, ei­ther, as Pfiz­er/Mer­ck KGaA (Baven­cio) and As­traZeneca (Imfinzi) start to gain trac­tion on the com­bo front. Roche al­ready emerged as the num­ber three play­er in the field with Tecen­triq, though its re­cent Phase III fail­ure for its check­point may chill oth­er would-be part­ners.

Mean­while, new check­point play­ers like BeiGene and Lil­ly are mov­ing along, the re­port notes, while No­var­tis has been ad­vanc­ing its own in-house check­point pro­grams. The sec­ond wave of PD-(L)1 ther­a­pies will be large.

One of the key next steps in this field is in As­traZeneca’s hands. It has a com­bo of Imfinzi with an in-house CT­LA-4 check­point dubbed treme­li­mum­ab in the MYS­TIC study that will read out soon for lung can­cer. An­a­lysts are wait­ing ea­ger­ly to see if it can beat out the com­pe­ti­tion, or get side­lined by some well-known tox­i­c­i­ty con­cerns.

One thing is ab­solute­ly cer­tain. Bris­tol-My­ers Squibb start­ed as the dom­i­nant play­er in PD-(L)1, then got checked by a surg­ing Mer­ck when it made the wrong clin­i­cal move on non-small cell lung can­cer. As­traZeneca, the last of the big 5 to land an ap­proval, just days ago stunned vir­tu­al­ly every­one with pos­i­tive Phase III da­ta for Imfinzi in un­re­sectable lung can­cer, pro­vid­ing ear­ly dom­i­nance in a sig­nif­i­cant niche mar­ket.

The Big Phar­ma’s stock soared as an­a­lysts be­gan to cal­cu­late what that is worth.

Just at a time when check­points should start get­ting more pre­dictable, the field seems to be ripe for fresh sur­pris­es of all kinds. And that will con­tin­ue to at­tract fresh waves of com­bi­na­tion stud­ies tack­ling all kinds of can­cers.

UP­DAT­ED: Clay Sie­gall’s $614M wa­ger on tu­ca­tinib pays off with solid­ly pos­i­tive piv­otal da­ta and a date with the FDA

Back at the beginning of 2018, Clay Siegall snagged a cancer drug called tucatinib with a $614 million cash deal to buy Cascadian. It paid off today with a solid set of mid-stage data for HER2 positive breast cancer that will in turn serve as the pivotal win Siegall needs to seek an accelerated approval in the push for a new triplet therapy.

And if all the cards keep falling in its favor, they’ll move from 1 drug on the market to 3 in 2020, which is shaping up as a landmark year as Seattle Genetics prepares for its 23rd anniversary on July 15.

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UP­DAT­ED: The FDA sets a reg­u­la­to­ry speed record, pro­vid­ing a snap OK for Ver­tex's break­through triplet for cys­tic fi­bro­sis

The FDA has approved Vertex’s new triplet for cystic fibrosis at a record-setting speed.

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IM­brave150: Roche’s reg­u­la­to­ry crew plans a glob­al roll­out of Tecen­triq com­bo for liv­er can­cer as PhI­II scores a hit

Just weeks after Bristol-Myers Squibb defended its failed pivotal study pitting Opdivo against Nexavar in liver cancer, Roche says it’s beat the frontline challenge with a combination of their PD-L1 Tecentriq with Avastin. And now they’re rolling their regulatory teams in the US, Europe and China in search of a new approval — badly needed to boost a trailing franchise effort.
Given their breakthrough and Big Pharma status as well as the use of two approved drugs, FDA approval may well prove to be something of a formality. And the Chinese have been clear that they want new drugs for liver cancer, where lethal disease rates are particularly high.
Researchers at their big biotech sub, Genentech, say that the combo beat Bayer’s Nexavar on both progression-free survival as well as overall survival — the first advance in this field in more than a decade. We won’t get the breakdown in months of life gained, but it’s a big win for Roche, which has lagged far, far behind Keytruda and Opdivo, the dominant PD-1s that have captured the bulk of the checkpoint market so far.
Researchers recruited hepatocellular carcinoma — the most common form of liver cancer — patients for the IMbrave150 study who weren’t eligible for surgery ahead of any systemic treatment of the disease.
Roche has a fairly low bar to beat, with modest survival benefit for Nexavar, approved for this indication 12 years ago. But they also plan to offer a combo therapy that could have significantly less toxicity, offering patients a much easier treatment regimen.
Cowen’s Steven Scala recently sized up the importance of IMbrave150, noting:

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That $335M JV Bay­er set up on CRISPR/Cas9? They’re let­ting the biotech part­ner car­ry on

Bayer committed $300 million to set up a joint venture on CRISPR/Cas9 tech with CRISPR Therapeutics $CRSP. But they’re handing off control now to the smaller biotech while retaining a couple of opt-ins for programs nearing an IND.

Bayer $BAY made much of the fact that they were going all-in on gene editing when they did their deal 3 years ago with CRISPR Therapeutics, which pitched $35 million in on their end. This was the cornerstone of their plan to set up new JVs that could make some serious leap forwards in hot new R&D spaces. Now CRISPR will have full management control of Casebia as they pursue programs in hemophilia, ophthalmology and autoimmune diseases.
Samarth Kulkarni, the CEO at CRISPR, made it sound like a natural progression.

J&J's block­buster Ste­lara wins US ap­proval for ul­cer­a­tive col­i­tis

J&J’s Stelara, which is set to be in the top ten list of blockbusters come 2025, is now cleared by the FDA for use in ulcerative colitis (UC), an inflammatory disease of the large intestine.

The biologic targets interleukin (IL)-12 and IL-23 cytokines, which are known to play a key role in inflammatory and immune responses. Stelara, which generated about $4.7 billion in the first nine months of 2019, is a key player in the crowded marketplace of drugs to treat autoimmune disorders such as psoriasis, rheumatoid arthritis and Crohn’s disease. AbbVie’s star therapy, Humira, continues to dominate, despite its looming patent cliff in the United States, while others including J&J’s $JNJ own anti-IL23 Tremfya, Lilly’s $LLY anti-IL-17 Taltz and AbbVie’s $ABBV recently approved anti-IL-23 antibody Skyrizi carve out a slice of market share.

Drug com­pa­nies reach $260M set­tle­ment just ahead of opi­oid tri­al; Oys­ter Point set terms for $85M IPO

→ Hours before the first federal opioid trial was set to begin, three drug distributors and an opioid manufacturer agreed to a $260 million agreement settlement, the Wall Street Journal was the first to report. The deal — which will see McKesson, Cardinal Health and AmerisourceBergen pay $215 million to Summit and Cuyahoga counties, and Teva deal out $35 million in cash and addiction treatments — does not resolve the pending, nationwide litigation that may result in a settlement worth upwards of $40 billion. Negotiators in that case, brought by 2,300 tribes, counties and cities nationwide and led by several states’ attorneys general, worked through much of Friday without success. Josh Stein, the attorney general for North Carolina, said they were trying to put together a $48 billion deal.

GSK of­floads two vac­cines in $1.1B deal as it works to re­vive the pipeline

GlaxoSmithKline is leaving the deep dark woods and its viruses behind.

GSK has agreed to divest its vaccines for rabies, RabAvert, and tick-born encephalitis vaccine, Encepur, to Bavarian Nordic, part of the company’s broader efforts to narrow its pipeline and focus on oncology and immunology.

The deal is worth up to nearly $1.1 billion, with a $336 million upfront payment. GSK acquired the vaccines from Novartis as part of an exchange for their late-stage oncology programs in 2015 under former chief Sir Andrew Witty.

Pfiz­er gets some en­cour­ag­ing PhI­II news on a fran­chise sav­ior, but is a dos­ing ad­van­tage worth the $295M up­front?

Close to 3 years after Opko tried to defend itself as shares tumbled on the news that its long-acting growth hormone had failed to outperform a placebo, the Pfizer partner $PFE is back. And this time they’re pitching Phase III data that demonstrate their drug is non-inferior — or maybe a tad better — than their well-known but fading standard in the field.
The comparator drug here is Genotropin, which earned a marginal $142 million for Pfizer last year — down 9% from the year before. Approved 24 years ago, biosimilars are now in development that Pfizer would like to stay out in front of. The market leader here is Norditropin, a growth hormone from Novo Nordisk that uses the same basic ingredient as Genotropin, which the Danish company sells with a kid-friendly self-injectable pen. That would also present some big competition if the new therapy from Opko/Pfizer makes it to the market.
The new data, says researchers, underscore that a weekly injection of somatrogon performed as well or slightly better than Genotropin (somatropin) in young children with growth hormone deficiency. Investigators tracked height velocity at 10.12 cm/year, edging out the older drug’s 9.78 cm/year. That 0.33 difference may not prove compelling to payers, though, who have been known to overlook dosing advantages in favor of lower costs.
That message may have weighed on the stock reaction this morning, with a 30%-plus hike $OPK giving way to more marginal gains.
Back in late 2016, Opko had to defend itself against a devastating Phase III setback as their initial late-stage trial failed against a sugar pill. Opko later blamed that setback on outliers in the study, though it wasn’t able to expunge the failure.

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As­traZeneca's Farx­i­ga scores FDA nod to cut risk of hos­pi­tal­iza­tion for heart fail­ure in di­a­bet­ics

While the FDA recently spurned an application to allow AstraZeneca’s blockbuster drug Farxiga for type 1 diabetes that cannot be controlled by insulin, citing safety concerns — the US regulator has endorsed the use of the SGLT2 treatment to reduce the risk of hospitalisation for heart failure in patients with type-2 diabetes and established cardiovascular disease or multiple CV risk factors.