KalVis­ta's di­a­bet­ic mac­u­lar ede­ma da­ta falls short — will Mer­ck walk away?

Mer­ck’s 2017 bet on KalVista Phar­ma­ceu­ti­cals may have soured, af­ter the UK/US-based biotech’s lead drug failed a mid-stage study in pa­tients with di­a­bet­ic mac­u­lar ede­ma (DME).

Two dos­es of the in­trav­it­re­al in­jec­tion, KVD001, were test­ed against a place­bo in a 129-pa­tient tri­al. Pa­tients who con­tin­ued to ex­pe­ri­ence sig­nif­i­cant in­flam­ma­tion and di­min­ished vi­su­al acu­ity, de­spite an­ti-VEGF ther­a­py, were re­cruit­ed to the tri­al. Typ­i­cal­ly pa­tients with DME — the most fre­quent cause of vi­sion loss re­lat­ed to di­a­betes — are treat­ed with an­ti-VEGF ther­a­pies such as Re­gen­eron’s flag­ship Eylea or Roche’s Avastin and Lu­cen­tis.

An­drew Crock­ett

KVD001 is en­gi­neered to in­hib­it an en­zyme called plas­ma kallikrein and was de­vel­oped on the ba­sis of re­search that in­di­cat­ed en­hanced lev­els of the pro­tein are present in the vit­re­ous flu­id in the eyes of peo­ple with DME. Pre­clin­i­cal da­ta sug­gest plas­ma kallikrein in­hi­bi­tion is key to a de­cline in reti­nal thick­en­ing and bet­ter pro­cess­ing of vi­su­al sig­nals, ac­cord­ing to KalVista.

How­ev­er, nei­ther dose of KVD001 met the main goal of the Phase II study, which was to in­duce a sta­tis­ti­cal­ly sig­nif­i­cant change in best-cor­rect­ed vi­su­al acu­ity (BC­VA) at 16 weeks ver­sus place­bo (6 μg = +2.6 let­ters or 3 μg = +1.5 let­ters; p=0.465). No sig­nif­i­cant dif­fer­ences from place­bo emerged on any of the sec­ondary end­points in­clud­ing cen­tral sub­field thick­ness or the di­a­bet­ic retinopa­thy sever­i­ty scale, the com­pa­ny said, adding that the drug was gen­er­al­ly safe and well-tol­er­at­ed.

The com­pa­ny’s stock tum­bled $KALV more than 17% to $11.88 in pre­mar­ket trad­ing.

Still, KalVista high­light­ed some sil­ver lin­ings from sub­group analy­ses that chief An­drew Crock­ett said could jus­ti­fy fur­ther study of the drug in the DME pop­u­la­tion.

Pa­tients giv­en the high­er dose of KVD001 saw a slow­er re­duc­tion in vi­sion loss at 32.5% ver­sus place­bo at 54.5%, al­though the dif­fer­ence was not deemed sta­tis­ti­cal­ly sig­nif­i­cant (p=0.042). Af­ter ex­clud­ing pa­tients with the most se­vere lev­els of vi­sion loss, the re­main­ing 70% of the to­tal pa­tient pop­u­la­tion showed a dif­fer­ence in BC­VA com­pared to place­bo of 4.9 let­ters at the 6 μg dose, al­though again the dif­fer­ence was not sta­tis­ti­cal­ly sig­nif­i­cant (p=0.056).

“From a look at the da­ta and var­i­ous sec­ondary/sub­group analy­ses it does ap­pear that there were some trends to­wards ben­e­fit in the study, but we doubt it will gain cred­it from in­vestors in the ab­sence of an­oth­er cor­rob­o­rat­ing tri­al,” Stifel’s Paul Mat­teis wrote in a note, in­di­cat­ing that the fail­ure is not a huge sur­prise.

In 2017, Mer­ck paid $8.50 a share for a 10% stake in KalVista and a fur­ther $37 mil­lion up­front for an op­tion to buy KVD001.

“We think in­vestors buy­ing the stock to­day should large­ly as­sume that this pro­gram won’t move for­ward. If Mer­ck pass­es on the as­set it’s pos­si­ble KALV could look for an­oth­er part­ner, but again, fig­ur­ing out the next steps here, if there are any, may take time,” Mat­teis said.

End­points News has con­tact­ed Mer­ck for com­ment.

KalVista has an­oth­er plas­ma kallikrein in­hibitor in its ar­se­nal, the oral ther­a­py KVD900, un­der de­vel­op­ment for hered­i­tary an­gioede­ma (HAE). Da­ta from a Phase II tri­al are ex­pect­ed next year.

“(W)e see no readthrough on­to KVD900: in HAE plas­ma kallikrein is a val­i­dat­ed tar­get, and in DME it is an in­ter­est­ing tar­get that, un­like in HAE, has nev­er be­fore been the foun­da­tion for ap­proved/ef­fec­tive drugs,” Mat­teis not­ed. “In turn, we con­tin­ue to gain op­ti­mism in the prospects for KVD900, based on the suc­cess of oth­er med­ica­tions in the space, and our work…based on the tri­an­gu­la­tion of PK/PD da­ta which we think sup­port ‘900 as an oral res­cue med with po­ten­tial “in­jec­tion-like” ef­fi­ca­cy.”

Michel Vounatsos, Biogen CEO (via YouTube)

UP­DAT­ED: Bio­gen spot­lights a pair of painful pipeline set­backs as ad­u­canum­ab show­down looms at the FDA

Biogen has flagged a pair of setbacks in the pipeline, spotlighting the final failure for a one-time top MS prospect while scrapping a gene therapy for SMA after the IND was put on hold due to toxicity.

Both failures will raise the stakes even higher on aducanumab, the Alzheimer’s drug that Biogen is betting the ranch on, determined to pursue an FDA OK despite significant skepticism they can make it with mixed results and a reliance on post hoc data mining. And the failures are being reported as Biogen was forced to cut its profit forecast for 2020 as a generic rival started to erode their big franchise drug.

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A new chap­ter in the de­cen­tral­ized clin­i­cal tri­al ap­proach

Despite the promised decentralized trial revolution, we haven’t yet moved the needle in a significant way, although we are seeing far bolder commitments to this as we continue to experience the pandemic restrictions for some time to come. The vision of grandeur is one thing, but operationalizing and execution are another and recognising that change, particularly mid-flight on studies, is worthy of thorough evaluation and consideration in order to achieve success. Here we will discuss one of the critical building blocks of a Decentralized and Remote Trial strategy: TeleConsent; more than paper under glass, it is a paradigm change and key digital enabler.

Stephen Hahn, FDA commissioner (AP Images)

As FDA sets the stage for the first Covid-19 vac­cine EUAs, some big play­ers are ask­ing for a tweak of the guide­lines

Setting the stage for an extraordinary one-day meeting of the Vaccines and Related Biological Products Advisory Committee this Thursday, the FDA has cleared 2 experts of financial conflicts to help beef up the committee. And regulators went on to specify the safety, efficacy and CMC input they’re looking for on EUAs, before they move on to the full BLA approval process.

All of this has already been spelled out to the developers. But the devil is in the details, and it’s clear from the first round of posted responses that some of the top players — including J&J and Pfizer — would like some adjustments and added feedback. And on Thursday, the experts can offer their own thoughts on shaping the first OKs.

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UP­DAT­ED: CRISPR Ther­a­peu­tics gets a snap­shot of off-the-shelf CAR-T suc­cess in B-cell ma­lig­nan­cies — marred by the death of a pa­tient

Just days after scientific founder Emmanuelle Charpentier shared the Nobel prize for her work on CRISPR/Cas9, CRISPR Therapeutics $CRSP is showing off a snapshot of success in their early-stage study for an off-the-shelf CAR-T approach to CD19+ B cell malignancies — a snapshot marred by the death of a patient who had been given a high dose of the treatment.

Using their gene editing tech, researchers for CRISPR engineered cells from healthy donors into an attack vehicle aimed at cancer, something that has been achieved with great success using patients’ own cells — the autologous approach. But autologous CAR-T is hampered by the more complex vein-to-vein requirement that delays treatment, and now CRISPR Therapeutics along with other players like Allogene are determined to replace the pioneers with CAR-T 2.0.

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RBC's Bri­an Abra­hams holds a mock ad­comm on Bio­gen's iffy ad­u­canum­ab da­ta — and most of these ex­perts don't see a path to an ap­proval

As catalysts go, few loom larger than the aducanumab adcomm slated for Nov. 6.

With its big franchise under assault, Biogen is betting the ranch that its mixed late-stage Alzheimer’s data can squeak past the experts and regulators and get onto the market. And the topic — after a decade of Alzheimer’s R&D disasters in what still represents the El Dorado of drug markets — remains in the center ring of discussions around late-stage pipeline prospects.

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Philipp Spycher

Promis­ing bet­ter link­er tech to ADC field, Araris has 'very, very am­bi­tious' plans for the clin­ic

A couple months after raising CHF 2.5 million ($2.76 million) in initial seed funding, one-year-old Araris Biotech is topping off the round with another CHF 12.7 million ($14 million).

The Paul Scherrer Institute and ETH Zurich spinout now has CHF 15.2 million to work with, and CEO Philipp Spycher has big plans. He hopes to bring one of the company’s antibody-drug conjugates (ADC) to the clinic by late 2022 or early 2023. “It’s very, very ambitious, but we are very optimistic that we actually can make it,” he said.

David Hung (file photo)

Mas­ter deal­mak­er David Hung re­tools a SPAC sedan in­to a fi­nanc­ing mus­cle ve­hi­cle that leaves his can­cer start­up with $850M and a place on Wall Street

It’s only right that one of the industry’s top dealmakers just completed one of the biggest SPAC-related deals in the pipeline.

David Hung, of Medivation fame, has completed a back flip into the market, merging with EcoR1 Capital’s SPAC Panacea and landing neatly on Wall Street with an $NUVB stock ticker after filling out the blank check in his name. In addition to the $144 million held in the SPAC — provided none of the investors opt out — Hung is getting ahold of $500 million more being chipped in by a slate of institutional investors who feel that Hung could have the keys to another Medivation-style success.

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Years af­ter a ma­jor tri­al set­back, No­var­tis switch­es gears with SMA drug. This time they're try­ing it for Hunt­ing­ton's

Four years after a Phase I/II setback in spinal muscular atrophy (SMA), Novartis is hoping its drug branaplam will find more success in a new neurological indication: Huntington’s disease.

The decision was announced a year after the head of research, Jay Bradner, said he did not see a “big opportunity” in SMA, according to Reuters. Novartis says it has preclinical data showing that branaplam reduces levels of mutant huntingtin protein, and SMA data showing patients on the drug had reductions in huntingtin mRNA. The FDA gave branaplam their orphan drug designation, and Novartis plans to move forth with a Phase IIb trial next year.

Glax­o­SmithK­line's vac­cines group aims for a first as it kicks off PhI­II RSV stud­ies

One of GlaxoSmithKline’s big projects at its global vaccine R&D center in Rockville, MD is set to enter Phase III after passing early-stage tests with flying colors.

Eyeing the wide-open respiratory syncytial virus (RSV) space, GSK is pushing two different vaccine candidates: GSK3888550A is designed to confer protection to infants via maternal immunization, while GSK3844766A is meant for the elderly.