Cerulean crash­es af­ter lead nano drug flubs its sec­ond PhII can­cer study

Cerulean Phar­ma’s lead nan­otech can­cer drug has run in­to an­oth­er stone wall in the clin­ic. The Waltham, MA-based biotech $CERU says that CR­LX101 com­bined with Avastin flubbed a Phase II study, fail­ing to pro­vide ev­i­dence of an im­prove­ment in pro­gres­sion-free sur­vival when com­pared against stan­dard of care ther­a­pies for re­nal cell car­ci­no­ma.

Cerulean’s shares were slammed on the news, plung­ing 62% and wip­ing out the li­on’s share of its $75 mil­lion mar­ket cap.

The drug com­bo group ac­tu­al­ly per­formed worse than the con­trol arm, with in­ves­ti­ga­tors re­port­ing a 3.7 month me­di­an PFS for Cerulean’s drug com­pared with 3.9 months for stan­dard of care. The ob­jec­tive re­sponse rate was even worse: 5% for the CR­LX101 com­bi­na­tion against 14% for stan­dard of care.

This wasn’t the first fail­ure for Cerulean. The drug, which com­bines tiny amounts of the an­ti­cancer tox­in camp­tothecin with a poly­mer mol­e­cule in or­der to in­fil­trate leaky tu­mors, al­so failed a study for non-small cell lung can­cer in 2014 that raised se­ri­ous doubts about the tech­nol­o­gy.

The set­back marks the end of a the­o­ry that CR­LX101 could play a key role in can­cer cell sur­vival by in­hibit­ing hy­pox­ia-in­ducible fac­tor-1α (HIF-1α). The fo­cus now will shift en­tire­ly to in­hibit­ing topoi­so­merase 1 (topo 1), which is in­volved in cel­lu­lar repli­ca­tion. The biotech has sev­er­al oth­er on­go­ing stud­ies.

“We are con­vinced that CR­LX101 is an ac­tive drug,” CMO Adri­an Senderow­icz told an­a­lysts in a call Wednes­day af­ter­noon, ze­ro­ing in on ear­ly clin­i­cal ev­i­dence of monother­a­py ac­tiv­i­ty for pan­creas and col­orec­tal can­ncer.

The stock crunch comes at a bad time. The biotech re­port­ed that it had $47 mil­lion in its cof­fers at the end of Q2, giv­ing it enough cash to make it through Q2 2017. CFO Gregg Beloff told an­a­lysts the com­pa­ny has op­tions to ex­tend the run­way in­to Q3 of next year, while ex­ecs look to some in­ter­im cat­a­lysts with on­go­ing pro­grams to fu­el a new fundrais­ing ef­fort. Cerulean took out a loan from Her­cules in ear­ly 2015, which won’t ease any con­cerns among the an­a­lysts about its cash po­si­tion fol­low­ing a hard set­back like this.

The biotech en­list­ed MIT’s pro­lif­ic nan­otech ex­pert Bob Langer for its sci­en­tif­ic ad­vi­so­ry board. The IPO boom of the past few years took a few nan­otech com­pa­nies like Cerulean on­to Nas­daq. But at least one – Bind Ther­a­peu­tics, a Langer lab spin­out – foundered and was re­cent­ly bought out of a bank­rupt­cy auc­tion by Pfiz­er.

Michael Schmidt at Leerink is tak­ing a more skep­ti­cal view of Cerulean’s fu­ture now. His com­ment:

“CR­LX-101 is be­ing al­so stud­ied in plat­inum-re­sis­tant ovar­i­an can­cer; how­ev­er with mod­er­ate sin­gle agent ac­tiv­i­ty in this topo1-sen­si­tive can­cer, we think it’s dif­fi­cult to in­ter­pret the ear­ly stage sin­gle-arm com­bi­na­tion da­ta. CR­LX-101 gen­er­at­ed 16% re­spons­es in 19 plat­inum re­sis­tant pa­tients sin­gle agent, 17% ORR in com­bi­na­tion w/ Avastin in 18 pts, and 5/9 (56%) in com­bi­na­tion with week­ly pa­cli­tax­el. Based on our pri­or MEDA­Corp KOL checks, we think more than 20-30% ORR would be re­quired to be con­sid­ered dif­fer­en­ti­at­ed in this in­di­ca­tion. Longer term we are more op­ti­mistic on the on­go­ing com­bi­na­tion study with Lyn­parza giv­en the stronger pre­clin­i­cal ra­tio­nale, but we think it’s still too ear­ly to as­sign val­ue to this opp’ty.”

Christo­pher D. T. Guiffre, Cerulean Pres­i­dent & CEO

“We are dis­ap­point­ed with this out­come and will un­der­take a thor­ough analy­sis of the da­ta to un­der­stand why CR­LX101 plus Avastin un­der­per­formed com­pared to the re­sults we saw in an ear­li­er in­ves­ti­ga­tor-spon­sored tri­al,” said Christo­pher D. T. Guiffre, Pres­i­dent and Chief Ex­ec­u­tive Of­fi­cer of Cerulean, in a state­ment. “This out­come did not sup­port our hy­poth­e­sis that tar­get­ing hy­pox­ia in­ducible fac­tor (HIF) in com­bi­na­tion with VEGF in­hibitor in RCC, a HIF-over­ex­press­ing tu­mor type, would be ben­e­fi­cial, so we will not pur­sue HIF as a tar­get go­ing for­ward. We will con­tin­ue to fo­cus on the po­tent topoi­so­merase 1 in­hi­bi­tion of CR­LX101’s pay­load, camp­tothecin, in topoi­so­merase 1-sen­si­tive tu­mors. Our com­bi­na­tions with week­ly pa­cli­tax­el and LYN­PARZA (ola­parib) are ex­am­ples of on­go­ing tri­als that lever­age CR­LX101’s topoi­so­merase 1 in­hi­bi­tion in com­bi­na­tion with chemother­a­pies and DNA dam­age re­pair agents.”

UP­DAT­ED: In a stun­ning turn­around, Bio­gen says that ad­u­canum­ab does work for Alzheimer's — but da­ta min­ing in­cites con­tro­ver­sy and ques­tions

Biogen has confounded the biotech world one more time.

In a stunning about-face, the company and its partners at Eisai say that a new analysis of a larger dataset on aducanumab has restored its faith in the drug as a game-changer for Alzheimer’s and, after talking it over with the FDA, they’ll now be filing for an approval of a drug that had been given up for dead.

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Vas Narasimhan. Getty Images

UP­DAT­ED: Failed PhI­II fe­vip­iprant tri­als pour more cold wa­ter on No­var­tis' block­buster R&D en­gine — and briefly spread the chill to a high-pro­file biotech

Back in July, during an investor call where Novartis execs ran through an upbeat assessment of their Q2 performance, CEO Vas Narasimhan and development chief John Tsai were pressed to predict which of the two looming Phase III readouts — involving cardio drug Entresto and asthma therapy fevipiprant, respectively — had a higher likelihood of success. Tsai gave the PARAGON-HF study with Entresto minimally better odds, but Narasimhan emphasized that their strategy of giving fevipiprant to more severe patients gave them confidence.

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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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David Liu, Liu Group

David Liu un­veils newest ad­vance­ment in CRISPR tech: Prime edit­ing

The researcher behind base-editing is out with what some scientists are hailing as the biggest advancement in CRISPR technology since that 2016 breakthrough: “prime editing.” The new molecular gadget is capable of erasing any base pair and stenciling in another and cutting or adding long segments of DNA without breaking both strands of the helix.

David Liu, base editing pioneer and founder of Beam Therapeutics, published the findings in Nature alongside Andrew Anzalone. They estimated that the breakthrough “in principle” puts 89% of human diseases in purview — although experts cautioned that human therapies were a long way off.

Bhaskar Chaudhuri. Frazier Healthcare Partners

Fra­zier Health­care Part­ner­s' der­ma­tol­ogy up­start at­tracts a mar­quee syn­di­cate, $94M+ for 'in-be­tween' top­i­cal drug

For the past three years Frazier Healthcare Partners’ Bhaskar Chaudhuri has been carefully and quietly grooming Arcutis Therapeutics, a new dermatology play he co-founded to deliver topical formulations of well-known drugs. Now that the biotech is poised to enter Phase III, he’s being joined by a marquee syndicate for its $94.5 million Series C.

HBM Healthcare Investments, Vivo Capital, BlackRock, Omega Funds, Pivotal BioVentures, and Goldman Sachs jumped on board, joining Bain Capital Life Sciences, OrbiMed and RA Capital Management in backing Arcutis’ lead topical cream for plaque psoriasis.

A new com­pa­ny en­ters the Tec­fidera fight, of­fer­ing to kill two birds

The remedy for the most common side effect for one of the most common multiple sclerosis drugs is simple: aspirin.

Taking aspirin with Biogen’s Tecfidera will reduce the flush, a sometimes painful form of red skin irritation, many patients experiences. The problem is that the aspirin has to be taken at least 30 minutes before Tecfidera, turning a simple twice-a-day, one-dose oral drug into a staggered two-drug regimen.

UP­DAT­ED: Bris­tol-My­ers makes Op­di­vo pitch for front­line lung can­cer with open la­bel PhI­II study

Despite a head start, when Bristol-Myers Squibb and its pioneering checkpoint inhibitor Opdivo suffered a key lung cancer setback in 2016, they found themselves relegated to the backseat as Merck’s Keytruda seized the wheel on the road to immunotherapy stardom. Bristol-Myers has since suffered blow after blow in its quest to take a big slice of the lucrative market, peppered with some small successes. On Tuesday, the New Jersey drugmaker touted positive data from a Phase III open-label study in a bid to carve itself a piece of the frontline lung cancer market.

Take­da tees up $420M deal for celi­ac an­ti­dote, con­tin­u­ing R&D re­fo­cus

Sometime in the 1st century AD, a patient presented to Arataeus looking like a varicose ghost. He was “emaciated and atrophied, pale, feeble and incapable of performing any of his accustomed works,” the Greek physician wrote, with hollow temples and huge veins running all over his body.

A dysfunctional digestive system, Arataeus concluded – an imbalance he attributed to a “heat” deficiency in a system he and other Greeks regarded as functioning similarly to an oven – and coined a term: coeliac disease, after the Greek word for abdomen.

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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