Ear­ly snap­shot of Ad­verum's eye gene ther­a­py sparks con­cern about vi­sion loss

An ear­ly-stage up­date on Ad­verum Biotech­nolo­gies’ in­trav­it­re­al gene ther­a­py has trig­gered in­vestor con­cern, af­ter pa­tients with wet age-re­lat­ed mac­u­lar de­gen­er­a­tion (AMD) saw their vi­sion de­te­ri­o­rate, de­spite signs that the treat­ment is im­prov­ing reti­nal anato­my.

Ad­verum, on Wednes­day, un­veiled 24-week da­ta from the OP­TIC tri­al of its ex­per­i­men­tal ther­a­py, AD­VM-022, in six pa­tients who have been ad­min­is­tered with one dose of the ther­a­py. On av­er­age, pa­tients in the tri­al had se­vere dis­ease with an av­er­age of 6.2 an­ti-VEGF in­jec­tions in the eight months pri­or to screen­ing and an av­er­age an­nu­al­ized in­jec­tion fre­quen­cy of 9.3 in­jec­tions.

Over the six month pe­ri­od, pa­tients did not re­quire any an­ti-VEGF res­cue in­jec­tions — and five of six pa­tients saw a com­plete re­sponse with a to­tal res­o­lu­tion of flu­id fol­low­ing the Ad­verum in­jec­tion. There were no se­ri­ous ad­verse events, and the ma­jor­i­ty of side-ef­fects were mild.

How­ev­er, pa­tients lost vi­su­al acu­ity by two let­ters on av­er­age, with a 90% con­fi­dence in­ter­val of -9.1 let­ters to +5.1 let­ters.

Mani Foroohar

“The range of in­di­vid­ual pa­tient da­ta were not pre­sent­ed, though the wide con­fi­dence in­ter­val sug­gests that some pa­tients may have ex­pe­ri­enced a loss of more than 10 let­ters dur­ing the course of the tri­al – lack of res­cue in­jec­tions is dif­fi­cult to square with de­clin­ing vi­sion.” SVB Leerink’s Mani Foroohar wrote in a note.

“How­ev­er, the study in­ves­ti­ga­tor in­sist­ed no loss in vi­sion was due to wet AMD pathol­o­gy and ob­served loss of vi­su­al acu­ity is due to nor­mal vari­abil­i­ty…in a small set of pa­tients – an as­ser­tion that, if proved out with ad­di­tion­al fol­low-up, would very sub­stan­tial­ly im­prove the im­plied qual­i­ty of this dataset.”

Shares of the com­pa­ny — which spec­tac­u­lar­ly failed years ago when it was chris­tened Avalanche Biotech­nolo­gies — $AD­VM were down about 6.8% to $5.56 in Fri­day pre­mar­ket trad­ing. The stock sank on Thurs­day, evap­o­rat­ing mil­lions from its mar­ket val­ue.

“This da­ta sug­gest AD­VM-022 is po­ten­tial­ly ac­tive in de­liv­er­ing an ex­press­ible gene cas­sette in wet AMD, but mixed sig­nals in this small dataset should lift some of the com­pet­i­tive over­hang on RGNX shares,” Foroohar added. Re­genexBio ex­per­i­men­tal gene ther­a­py for wet AMD, RGX-314, is cur­rent­ly in a Phase I/II tri­al.

Wet AMD, which is char­ac­ter­ized by blurred vi­sion or a blind spot in an in­di­vid­ual’s vi­su­al field, is typ­i­cal­ly caused by ab­nor­mal growth of blood ves­sels that leak flu­id or blood in­to the mac­u­la. Mac­u­lar de­gen­er­a­tion is the lead­ing cause of se­vere, ir­re­versible vi­sion loss in the el­der­ly. An­ti-VEGF in­jec­tions such as Re­gen­eron’s $REGN flag­ship Eylea, as well as Roche’s $RHB­BY Lu­cen­tis and Avastin, are com­mon­ly used to treat wet AMD.

In April, the FDA im­posed a clin­i­cal hold on an ap­pli­ca­tion to test AD­VM-022 in hu­mans, ask­ing for ad­di­tion­al da­ta on Ad­verum’s chem­istry, man­u­fac­tur­ing and con­trol process. In May, the hold was lift­ed. Late last year, the biotech aban­doned its then lead ex­per­i­men­tal drug, AD­VM-043, for the treat­ment of A1AT de­fi­cien­cy.

Jake Van Naarden, Josh Bilenker, Nisha Nanda (Credit: Loxo, Aisling Capital)

Josh Bilenker and his Loxo crew are tak­ing the reins on on­col­o­gy R&D at Eli Lil­ly, culling the weak and map­ping a new path

Josh Bilenker, Jake Van Naarden and Nisha Nanda came out of Eli Lilly’s $8 billion Loxo Oncology buyout with a bundle of cash and plenty of choices on what they could do next. Start a new company, go public. Live on the beach in 5-star luxury. Contemplate the stars — in their own observatory.

So what are they doing?

They formed a new executive team that is taking over the management of Eli Lilly’s hundreds-strong oncology R&D group — essentially using Loxo as a base for a bold new experiment in Big Pharma R&D in an attempt to create a true biotech environment with the deep pockets of a top-15 industry player. They’ve recruited David Hyman from Memorial Sloan Kettering to join the team as chief medical officer. And the mandate includes culling out the oncology pipeline, highlighting their star prospects and going after new programs wherever they can find the best prospects.

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Samit Hirawat. Bristol-Myers Squibb

Bris­tol-My­ers is mak­ing a bee-line to the FDA with pos­i­tive liso-cel da­ta — but is it too late in the CAR-T game?

Bristol-Myers Squibb came to ASH this past weekend with a variety of messages on the new cancer drugs they had acquired in the big Celgene buyout, including liso-cel, the lead CAR-T program picked up in the $9 billion Juno acquisition. And one of the most important was that they had the pivotal efficacy and safety data needed to snag an approval from the FDA next year, with the BLA on track for a filing this month.
Provided there are no snafus or even modest stumbles now, they should get an OK within the 2020 timeline lined out in their $9 CVR for Celgene — the first in a trifecta of approvals required for a payout.
Whether they can go on to make it into a viable commercial therapy, though, is a whole other thing.
At first glance, there isn’t anything about the safety and efficacy data that would force a CRL or delay. In a large trial of patients with relapsed/refractory large B-cell lymphomas investigators tracked an outstanding 73% response rate and 53% complete response rate in heavily pretreated patients with few options.
That’s in line with Yescarta from Gilead’s Kite, which snagged an approval more than 2 years ago, just after Novartis’ Kymriah came through.
Then there’s safety. To be sure, the drug has safety issues. There were 4 patients in the study who died after treatment. Several others died for unrelated issues. But…with only a 2% rate of cytokine release syndrome, Bristol-Myers has a shot at a differentiated safety profile.
“There is a potential these patients can be treated on an outpatient basis,” says Samit Hirawat, the chief medical officer at Bristol-Myers. He noted that 23% of patients were never admitted, while 73% were admitted 4 days or later after therapy. The key is to treat them at a hospital with the infrastructure to provide care 24/7, so a patient can be admitted at any time later if needed.
How that will fly with payers after rivals have been on the market for about 3 years, with new evidence that earlier use of steroids can dramatically reduce CRS and considerable durability of response, will have to be seen.
But time is not on Bristol-Myers’ side. Liso-cel is the long delayed followup to the disastrous JCAR015, which killed a number of patients. Their setback threw them years off schedule. And rivals are advancing off-the-shelf alternatives or other new approaches that could knock the pioneers completely out of the game. In the meantime, Bristol-Myers is gathering its own durability data and will gradually see if their mix of CD4 and CD8 cells can do better.
The main interest now is in the timeline around the approval. Hirawat says they’ll ask for priority review, and there’s every reason to believe that regulators will move swiftly — barring a nasty surprise.

J&J team shows off 'break­through' BC­MA CAR-T da­ta, and that could cause a big headache at blue­bird and Bris­tol-My­ers

Just hours after J&J’s oncology team bragged about scoring a breakthrough therapy designation for their BCMA CAR-T drug, they pulled the wraps off of the multiple myeloma data for JNJ-4528 that impressed the FDA. And it’s easy to see why they may well be on a short path to a landmark approval — which may well be making the rival team at bluebird/Bristol-Myers more than a little nervous.

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J&J's Mathai Mammen at an Endpoints News event in Boston, June 2018 (Photo: Rob Tannenbaum for Endpoints News)

J&J fronts $750M cash to grab a failed can­cer drug that’s been re­pur­posed as a pow­er­ful an­ti-in­flam­ma­to­ry

J&J has stepped up with one of its blockbuster drug buys, agreeing to pay Austin-based XBiotech $XBIT $750 million in cash and up to $600 million more in milestones for their late stage-ready anti-inflammatory drug bermekimab — which some longtime biotech observers may recognize as a failed cancer therapy with a disaster-prone past.

The drug targets the IL-1a pathway. J&J $JNJ R&D chief Mathai Mammen is cutting a check for a drug that has produced positive mid-stage data in patients suffering from a skin condition called hidradenitis suppurativa with another mid-stage program underway for atopic dermatitis.

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Sangamo CEO Sandy Macrae

Pa­tient #9 has been a con­cern, but Sang­amo and Pfiz­er are bull­ish about win­ning the marathon he­mo­phil­ia A gene ther­a­py race

Patient number 9 has given Sangamo and its partners at Pfizer some heart palpitations in their high profile hemophilia A gene therapy program.

After watching his Factor VIII level rise following treatment like the rest, the crucial efficacy gauge they track saw a sudden and significant plunge. At week 13, the FVIII level had dropped below normal. Then it began to rise again.

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Un­lock the full End­points ex­pe­ri­ence for your com­pa­ny — and sup­port our mis­sion of in­de­pen­dent bio­phar­ma re­port­ing

I want to give readers a quick update on the most important part of our business model — premium subscriptions. We have some crucial financial goals we hope to achieve by the end of the year, and the team here in Lawrence is ready to ship some swag to kick off this limited December promotion.

We offer two premium plans — Enterprise for companies ($1,000/year, unlimited people), and Insider for individuals ($200/year). This month of December will be the last chance to enroll at the original rates — which have remained flat since we launched them in 2017.

One of Wall Street’s most high-pro­file hedge funds push­es Alex­ion's CEO to the auc­tion block — and he's not budg­ing

Fresh off buying Barnes & Noble and prodding AT&T with some heavy-handed criticism after picking up a $3.2 billion stake in the company, the activist — and supremely high profile — hedge fund Elliott Management has stepped up with some M&A advice for Alexion’s management team.
And the execs on the team $ALXN are giving them a polite — but very firm — stiff arm Friday morning.
In a release out early Friday, the big biotech said that the Elliott team had been in touch to encourage them to sell the company. But that’s not on the agenda.

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Samantha Budd Haeberlein. Biogen via YouTube

UP­DAT­ED: Skep­tics pounce as Bio­gen de­tails pos­i­tive sub­group analy­sis on ad­u­canum­ab — and both sides are dig­ging in

“Exhilarating.” “A major advance.” “A milestone achievement.” If one had just tuned into the panel comments on Biogen’s presentation at CTAD, it would seem that the biotech had an impressive, disease-modifying Alzheimer’s drug in aducanumab.

But off the stage, reactions to their admittedly complicated dataset and the biotech’s explanation for resurrecting a drug that failed its futility analysis were a lot more mixed, with analysts continuing to question whether the evidence is substantial enough to warrant an FDA approval and raising new doubts on the safety side.

In an investor call later in the day, execs noted that they are not planning another study and stood by their intention, publicized in October to much surprise, to submit regulatory filings based on what they have.

“We don’t file willy nilly,” said Al Sandrock, head of R&D. “We only go to filing when we believe that there is a benefit-risk argument based on science, based on data. And if you look at our history, we haven’t done filings right and left without good reason.”

Biogen had a theory going into the Clinical Trials on Alzheimer’s Disease meeting.

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Vas Narasimhan, Getty Images

No­var­tis CEO Vas Narasimhan's R&D up­date spot­lights next wave of drug stars as well as late-stage fa­vorites

As one of the biggest spenders in biopharma R&D, Novartis execs love to tout the scope of its late-stage pipeline, spotlighting the winners most likely to create blockbuster revenue streams in the near future.

Building on the 5 drug approvals the pharma giant expects to end the year with, Novartis CEO Vas Narasimhan — who’s done a slate of acquisitions topped by the recent $9.7 billion MedCo buyout — tapped the top emerging drugs as:

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