Can a lit­tle known drug in As­traZeneca's pipeline make a come­back as a PARP add-on? Yale sci­en­tists ex­plain how

As­traZeneca’s cedi­ranib may not have made the cut as a sin­gle agent to treat ovar­i­an can­cer, but Yale re­searchers think it could serve as a pow­er­ful add-on to am­pli­fy the ef­fects of PARP in­hibitors.

Pe­ter Glaz­er

The the­o­ry has been that cedi­ranib works by block­ing the for­ma­tion of new blood ves­sels, thus de­priv­ing tu­mors of the nu­tri­tion and oxy­gen nec­es­sary to live and grow. But in a mouse tri­al, a team out of Pe­ter Glaz­er’s lab found that the drug al­so di­rect­ly af­fects path­ways in­volved in DNA re­pair — a po­ten­tial­ly more use­ful func­tion.

The sci­en­tists set out to ex­plain some un­ex­pect­ed re­sults from a re­cent Phase II study, in which a com­bi­na­tion of cedi­ranib with Lyn­parza (ola­parib) im­proved pro­gres­sion-free sur­vival com­pared to Lyn­parza alone (16.5 ver­sus 8.2 months, haz­ard ra­tio 0.50; p = 0.007) in pa­tients with re­lapsed plat­inum-sen­si­tive ovar­i­an can­cer. More im­por­tant­ly, a sub­set of pa­tients in the tri­al with­out doc­u­ment­ed BR­CA1/2 mu­ta­tions demon­strat­ed su­pe­ri­or PFS as well as over­all sur­vival. That’s sur­pris­ing giv­en that a BR­CA mu­ta­tion is of­ten seen as a pre­req­ui­site for As­traZeneca and Mer­ck’s star PARP in­hibitor to work.

Alan­na Ka­plan

Af­ter ex­plor­ing the phe­nom­e­na in mice and cell cul­ture, Glaz­er and his team — in­clud­ing lead in­ves­ti­ga­tor Alan­na Ka­plan — con­clud­ed that cedi­ranib has a di­rect ef­fect on ho­mol­o­gy-di­rect­ed re­pair, a mech­a­nism that can­cer cells can ma­nip­u­late. The down-reg­u­la­tion, they write in Sci­ence Trans­la­tion­al Med­i­cine, hap­pens on­ly in tu­mors but not bone mar­row cells, which has tra­di­tion­al­ly been the dose-lim­it­ing fac­tor for PARP drugs.

“Un­like ola­parib, it doesn’t di­rect­ly block a DNA re­pair mol­e­cule, stop­ping DNA from stitch­ing it­self back to­geth­er. It af­fects the reg­u­la­tion by which DNA re­pair genes are ex­pressed,” Glaz­er added in a state­ment.

More specif­i­cal­ly, cedi­ranib does so through platelet-de­rived growth fac­tor re­cep­tor (PDGFR) in­hi­bi­tion, ac­ti­va­tion of pro­tein phos­phatase 2A (PP2A), and E2F tran­scrip­tion fac­tor 4 (E2F4)/RB tran­scrip­tion­al core­pres­sor like 2 (RB2/p130)–me­di­at­ed re­pres­sion of BR­CA1/2 and RAD51 gene ex­pres­sion.

The ef­fects are not lim­it­ed to Lyn­parza, ei­ther; cedi­ranib al­so sen­si­tized cells to an­oth­er PARP in­hibitor de­vel­oped by Pfiz­er, BMN673 (ta­la­zoparib).

Back in 2016 As­traZeneca pulled an EMA ap­pli­ca­tion for cedi­ranib and axed a monother­a­py pro­gram for the drug. Its web­site now lists a Lyn­parza/cedi­ranib com­bo as a project in a piv­otal phase, with a US fil­ing in ovar­i­an can­cer planned for 2020.

The Yale re­searchers will move on to in­ves­ti­gate whether this new­found syn­thet­ic lethal­i­ty — the idea of killing can­cer cells more ef­fec­tive­ly by tar­get­ing two genes at the same time — in oth­er can­cer types.

Im­age Source: Shut­ter­stock

It’s fi­nal­ly over: Bio­gen, Ei­sai scrap big Alzheimer’s PhI­I­Is af­ter a pre­dictable BACE cat­a­stro­phe rais­es safe­ty fears

Months after analysts and investors called on Biogen and Eisai to scrap their BACE drug for Alzheimer’s and move on in the wake of a string of late-stage failures and rising safety fears, the partners have called it quits. And they said they were dropping the drug — elenbecestat — after the independent monitoring board raised concerns about…safety.

We don’t know exactly what researchers found in this latest catastrophe, but the companies noted in their release that investigators had determined that the drug was flunking the risk/benefit analysis.

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It's not per­fect, but it's a good start: FDA pan­elists large­ly en­dorse Aim­mune's peanut al­ler­gy ther­a­py

Two days after a fairly benign review from FDA staff, an independent panel of experts largely endorsed the efficacy and safety of Aimmune’s peanut allergy therapy, laying the groundwork for approval with a risk evaluation and mitigation strategy (REMS).

Traditionally, peanut allergies are managed by avoidance, but the threat of accidental exposure cannot be nullified. Some allergists have devised a way to dose patients off-label with peanut protein derived from supermarket products to wean them off their allergies. The idea behind Aimmune’s product was to standardize the peanut protein, and track the process of desensitization — so when accidental exposure in the real world invariably occurs, patients are less likely to experience a life-threatening allergic reaction.

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Rit­ter bombs fi­nal PhI­II for sole lac­tose in­tol­er­ance drug — shares plum­met

More than two years ago Ritter Pharmaceuticals managed to find enough silver lining in its Phase IIb/III study — after missing the top-line mark — to propel its lactose intolerance toward a confirmatory trial. But as it turned out, the enthusiasm only set the biotech and its investors up to be sorely disappointed.

This time around there’s little left to salvage. Not only did RP-G28 fail to beat placebo in reducing lactose intolerance symptoms, patients in the treatment group actually averaged a smaller improvement. On a composite score measuring symptoms like abdominal pain, cramping, bloating and gas, patients given the drug had a mean reduction of 3.159 while the placebo cohort saw a 3.420 drop on average (one-sided p-value = 0.0106).

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.

Alex Ar­faei trades his an­a­lyst's post for a new role as biotech VC; Sanofi vet heads to Vi­for

Too often, Alex Arfaei arrived too late. 

An analyst at BMO Capital Markets, he’d meet with biotech or pharmaceutical heads for their IPO or secondary funding and his brain, trained on a biology degree and six years at Merck and Endo, would spring with questions: Why this biomarker? Why this design? Why not this endpoint? Not that he could do anything about it. These execs were coming for clinical money; their decisions had been made and finalized long ago.

Arde­lyx bags its first FDA OK for IBS, set­ting up a show­down with Al­ler­gan, Iron­wood

In the first of what it hopes will be a couple of major regulatory milestones for its new drug, Ardelyx has bagged an FDA approval to market Ibsrela (tenapanor) for irritable bowel syndrome.

The drug’s first application will be for IBS with constipation (IBS-C), inhibiting sodium-hydrogen exchanger NHE3 in the GI tract in such a way as to increase bowel movements and decrease abdominal pain. This comes on the heels of two successful Phase III trials.

Ver­tex deal for Scot­land — no deal for Eng­land

Cystic fibrosis (CF) drug maker Vertex Pharmaceuticals — which is still locked in negotiation with NHS England to endorse the use of its medicines — has successfully negotiated a deal with Scottish authorities.

A month ago, the Scottish Medicines Consortium spurned two of the company’s medicines — Orkambi and Symkevi — citing uncertainty over their long-term efficacy in relation to their cost.

Tony Kulesa, Brian Baynes. Petri

Star founders, in­ves­ti­ga­tors hud­dle around new Boston ac­cel­er­a­tor spot­light­ing young en­tre­pre­neurs

As a widely recognized biotech hub, Boston is undoubtedly one of the best places to start a new company at the frontier of biology and engineering. With a dense network of incubators, venture capitalists and talent, seasoned company founders can have their pick of partners and models launching their latest startups.

But for young, aspiring entrepreneurs, it’s a very different scene.

Big VC firms might hire you to work on their ideas instead of yours, and accelerators may not offer the kind of deep technical expertise and guidance needed to make it in the field.

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From part­ner to knight in shin­ing ar­mor: Cas­tle Creek to buy Fi­bro­cell

In April, Castle Creek swooped in to partner with the embattled gene and cell therapy Fibrocell to shepherd its lead gene therapy for a type of “butterfly” disease into late-stage development. Now, the New Jersey-based dermatology company is acquiring its partner in a deal worth $63.3 million.

Pennsylvania-based Fibrocell last year initiated a review of strategic alternatives, including a sale.