GSK presents case to ex­pand use of its lu­pus drug in pa­tients with kid­ney dis­ease, but the field is evolv­ing. How long will the mo­nop­oly last?

In 2011, Glax­o­SmithK­line’s Benlysta be­came the first bi­o­log­ic to win ap­proval for lu­pus pa­tients. Nine years on, the British drug­mak­er has un­veiled de­tailed pos­i­tive re­sults from a study test­ing the drug in lu­pus pa­tients with as­so­ci­at­ed kid­ney dis­ease — a post-mar­ket­ing re­quire­ment from the ini­tial FDA ap­proval.

Al Roy Lu­pus Al­liance Re­search

Lu­pus is a drug de­vel­op­er’s night­mare. In the last six decades, there has been just one FDA ap­proval (Benlysta), with the field re­sem­bling a grave­yard in re­cent years with a string of fail­ures in­clud­ing UCB and Bio­gen’s late-stage flop, as well as de­feats in Xen­cor and Sanofi’s pro­grams. One of the main rea­sons the suc­cess has elud­ed re­searchers is be­cause lu­pus, akin to can­cer, is not just one dis­ease — it re­al­ly is a dis­ease of many dis­eases, not­ed Al Roy, ex­ec­u­tive di­rec­tor of Lu­pus Clin­i­cal In­ves­ti­ga­tors Net­work, an ini­tia­tive of New York-based Lu­pus Re­search Al­liance that claims it is the world’s lead­ing pri­vate fun­der of lu­pus re­search, in an in­ter­view.

Un­der­stand­ing the dis­ease at the mol­e­c­u­lar lev­el will help re­searchers un­der­stand that cer­tain drugs will be ap­pro­pri­ate for cer­tain pa­tients, he said. “I think our in­abil­i­ty to sort of bet­ter seg­ment the pa­tients is a domi­no ef­fect for us not to bet­ter iden­ti­fy the drugs, and then test them in the right pop­u­la­tion…so right now it’s sort of a hodge­podge ap­proach, we sort of throw spaghet­ti at a wall, and hope that some­thing sticks.”

Giv­en lu­pus is an au­toim­mune dis­ease, im­mune cells such as B cells and T cells are im­pli­cat­ed in its man­i­fes­ta­tion, which is why some can­cer drugs such as Roche’s Gazy­va that share some of the same mech­a­nisms of ac­tion are be­ing test­ed for lu­pus.

Richard Fu­rie North­well Health

GSK’s Benlysta, which in­hibits the repli­ca­tion of B cells, was ini­tial­ly al­so be­ing pur­posed for use in a host of au­toim­mune dis­eases such as rheuma­toid arthri­tis, but the lu­pus da­ta emerged most com­pelling, sug­gest­ed Richard Fu­rie, chief of the di­vi­sion of rheuma­tol­ogy and pro­fes­sor at the Fe­in­stein In­sti­tutes at New York State’s largest health­care provider North­well Health, who has in­ves­ti­gat­ed the use of the drug for over two decades.

Fu­rie is al­so the lead in­ves­ti­ga­tor of BLISS-LN, the tri­al that tracked Benlysta’s im­pact on the rough­ly 60% of pa­tients with the sys­temic au­toim­mune dis­ease who de­vel­op lu­pus nephri­tis (of which 1 in 4 progress to end-stage re­nal dis­ease) for two years. In the 448 adult pa­tient-tri­al, the in­tra­venous for­mu­la­tion (one-hour IV in­fu­sion month­ly) of the drug plus stan­dard care was com­pared to stan­dard care alone. The topline re­sults were first dis­closed last De­cem­ber.

De­tailed da­ta, pre­sent­ed at a med­ical con­fer­ence on Thurs­day, showed that 43% of lu­pus nephri­tis pa­tients in the Benlysta arm achieved pri­ma­ry ef­fi­ca­cy re­nal re­sponse—a mea­sure of kid­ney func­tion de­fined by re­duc­tion in pro­tein in urine —com­pared with 32.3% of pa­tients in the con­trol arm at 104 weeks. A key sec­ondary goal, com­plete re­sponse rate was al­so sta­tis­ti­cal­ly sig­nif­i­cant­ly in fa­vor of the Benlysta arm at 30%, ver­sus 19.7% in the con­trol arm. Oth­er end­points, such as time to death or re­nal-re­lat­ed event, all point­ed to Benlysta’s su­pe­ri­or­i­ty.

For now, with stan­dard care on­ly about a third of pa­tients are get­ting com­plete re­spons­es and so its key to get that com­plete re­sponse rate up — and com­pa­nies have been try­ing to do that for some 20 odd years, but it’s been fail­ure af­ter fail­ure af­ter fail­ure, not­ed Fu­rie.

“So this is re­fresh­ing be­cause it works,” he said. “So 11 per­cent­age points was the ef­fect size. And when any­body would ask me what kind of ef­fect size would I like to see or what min­i­mum ef­fect size would I’d like to see? My an­swer was al­ways 10%. Con­sid­er­ing how many pa­tients I’ve sent on dial­y­sis and how many pa­tients have got­ten kid­ney trans­plants. I will take that bar­ring any safe­ty is­sues. And there re­al­ly were no safe­ty is­sues in this study.”

While the re­sults are en­cour­ag­ing, and Benlysta en­joys its mo­nop­oly in the lu­pus space for now rak­ing in £613 mil­lion in sales last year, ri­vals are stack­ing up, es­pe­cial­ly in lu­pus nephri­tis (LN). Com­peti­tors have al­so pub­lished their own Phase III da­ta, but with­out head-to-head tri­als, com­par­isons are tricky.

For in­stance, Au­rinia’s oral drug, vo­closporin, gen­er­at­ed pos­i­tive piv­otal da­ta last De­cem­ber. When added to stan­dard-of-care the drug, which is de­signed to in­hib­it an en­zyme that ac­ti­vates T-cells called cal­cineurin, in­duced re­nal re­sponse of 40.8%, while those on the con­trol arm ex­pe­ri­enced a rate of 22.5% at 52 weeks. Al­though a pre­vi­ous mid-stage study brought up safe­ty con­cerns with the drug, af­ter more deaths in the vo­closporin arm were record­ed, the Phase III tri­al put those fears to rest with rough­ly sim­i­lar rates of se­ri­ous ad­verse events across both arms.

“De­spite pro­vid­ing Benlysta treat­ment for twice as long as vo­closporin, and set­ting the bar for re­nal re­sponse sub­stan­tial­ly low­er, Benlysta still on­ly man­aged to bare­ly hit sta­tis­ti­cal sig­nif­i­cance. In light of these re­sults, we re­gard the ben­e­fit of Benlysta in LN to be mar­gin­al, at best, sim­i­lar to its ben­e­fit in sys­temic lu­pus ery­the­mato­sus (SLE),” HC Wain­wright an­a­lyst Ed Arce wrote in a De­cem­ber note.

Last No­vem­ber, Roche’s Gazvya al­so gen­er­at­ed pos­i­tive mid-stage da­ta when com­bined with stan­dard care in LN pa­tients. The drug — en­gi­neered to at­tach to CD20, a pro­tein found on cer­tain B-cells — met the main goal of in­duc­ing a sta­tis­ti­cal­ly su­pe­ri­or com­plete re­nal re­sponse of 40% at week 76, ver­sus 18% in pa­tients giv­en stan­dard treat­ment, Roche said.

A num­ber of oth­er au­toim­mune and can­cer drugs are al­so be­ing re­pur­posed for use in LN and in the larg­er lu­pus pa­tient pop­u­la­tion. But for Lu­pus Re­search Al­liance’s Roy, a sin­gle tar­get ap­proach will not gar­ner the type of im­pact that could trans­form the lives of pa­tients, but a bis­pe­cif­ic strat­e­gy that is be­ing test­ed in ear­li­er stage tri­als from com­pa­nies just might.

“I think a B cell or a T cell sort of drug mech­a­nism is too my­opic, and I think that’s been borne out in the tri­als. Even in Benlysta, the ef­fect size was very small. So I think one sort of ther­a­py ei­ther tar­get­ing a B or T cell pop­u­la­tion is not go­ing to be enough,” he said. “And un­for­tu­nate­ly, be­cause we have a lack of ap­proved drugs, com­bi­na­tion ther­a­pies aren’t re­al­ly some­thing that we can em­ploy in lu­pus as you can em­ploy in oth­er dis­eases, par­tic­u­lar­ly can­cer.”

So some com­pa­nies such as Bris­tol My­ers and Am­gen are try­ing to ad­dress the het­ero­gene­ity of the dis­ease with­out know­ing how we strat­i­fy pa­tients at a mol­e­c­u­lar lev­el, rec­og­niz­ing that monother­a­pies at­tack­ing a sin­gle path­way aren’t very ef­fec­tive, he not­ed. “So the next best bet is to re­al­ly look at de­vel­op­ing a com­bo ther­a­py by virtue of hav­ing mul­ti­ple mech­a­nisms.”

Donald and Melania Trump watch the smoke of fireworks from the South Lawn of the White House on July 4, 2020 (via Getty)

Which drug de­vel­op­ers of­fer Trump a quick, game-chang­ing ‘so­lu­tion’ as the pan­dem­ic roars back? Eli Lil­ly and Ab­Cellera look to break out of the pack

We are unleashing our nation’s scientific brilliance and will likely have a therapeutic and/or vaccine solution long before the end of the year.

— Donald Trump, July 4

Next week administration officials plan to promote a new study they say shows promising results on therapeutics, the officials said. They wouldn’t describe the study in any further detail because, they said, its disclosure would be “market-moving.”

— NBC News, July 3

Something’s cooking. And it’s not just July 4 leftovers involving stale buns and uneaten hot dogs.

Over the long weekend observers picked up signs that the focus in the Trump administration may swiftly shift from the bright spotlight on vaccines being promised this fall, around the time of the election, to include drugs that could possibly keep patients out of the hospital and take the political sting out of the soaring Covid-19 numbers causing embarrassment in states that swiftly reopened — as Trump cheered along.

So far, Gilead has been the chief beneficiary of the drive on drugs, swiftly offering enough early data to get remdesivir an emergency authorization and into the hands of the US government. But their drug, while helpful in cutting stays, is known for a limited, modest effect. And that won’t tamp down on the hurricane of criticism that’s been tearing at the White House, and buffeting the president’s most stalwart core defenders as the economy suffers.

We’ve had positive early-stage vaccine data, most recently from Pfizer and BioNTech, playing catchup on an mRNA race led by Moderna — where every little sign of potential trouble is magnified into a lethal threat, just as every advance excites a frenzy of support. But that race still has months to play out, with more Phase I data due ahead of the mid-stage numbers looming ahead. A vaccine may not be available in large enough quantities until well into 2021, which is still wildly ambitious.

So what about a drug solution?

Trump’s initial support for a panacea focused on hydroxychloroquine. But that fizzled in the face of data underscoring its ineffectiveness — killing trials that aren’t likely to be restarted because of a recent population-based study offering some support. And there are a number of existing drugs being repurposed to see how they help hospitalized patients.

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Elias Zerhouni (Photo by Vincent Isore/IP3/Getty Images)

Elias Zer­houni dis­cuss­es ‘am­a­teur hour’ in DC, the de­struc­tion of in­fec­tious dis­ease R&D and how we need to prep for the next time

Elias Zerhouni favors blunt talk, and in a recent discussion with NPR, the ex-Sanofi R&D and ex-NIH chief had some tough points to make regarding the pandemic response.

Rather than interpret them, I thought it would be best to provide snippets straight from the interview.

On the Trump administration response:

It was basically amateur hour. There is no central concept of operations for preparedness, for pandemics, period. This administration doesn’t want to or has no concept of what it takes to protect the American people and the world because it is codependent. You can’t close your borders and say, “OK, we’re going to be safe.” You’re not going to be able to do that in this world. So it’s a lack of vision, basically just a lack of understanding, of what it takes to protect the American people.

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Sec­ond death trig­gers hold on Astel­las' $3B gene ther­a­py biotech's lead pro­gram, rais­ing fresh con­cerns about AAV

Seven months after Astellas shelled out $3 billion to acquire the gene therapy player Audentes, the biotech company’s lead program has been put on hold following the death of 2 patients taking a high dose of their treatment. And there was another serious adverse event recorded in the study as well, with a total of 3 “older” patients in the study affected.

The incidents are derailing plans to file for a near-term approval, which had been expected right about now.

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George Yancopoulos (Regeneron)

UP­DAT­ED: Re­gen­eron co-founder George Yan­copou­los of­fers a com­bat­ive de­fense of the po­lice at a high school com­mence­ment. It didn’t go well

Typically, the commencement speech at Yorktown Central School District in Westchester — like most high schools — is an opportunity to encourage students to face the future with confidence and hope. Regeneron president and co-founder George Yancopoulos, though, went a different route.

In a fiery speech, the outspoken billionaire defended the police against the “prejudice and bias against law enforcement” that has erupted around the country in street protests from coast to coast. And for many who attended the commencement, Yancopoulos struck the wrong note at the wrong time, especially when he combatively challenged someone for interrupting his speech with a honk for “another act of cowardness.”

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Tesla and SpaceX founder Elon Musk gestures to the audience after being recognized by President Trump following the successful launch of a Falcon 9 rocket at the Kennedy Space Center. (via Getty Images)

Tes­la chief Elon Musk teams up with Covid-19 play­er Cure­Vac to build 'R­NA mi­cro­fac­to­ries'

Elon Musk has joined the global tech crusade now underway to revolutionize vaccine manufacturing — now aimed at delivering billions of doses of a new mRNA vaccine to fight Covid-19. And he’s cutting right to the front.

In a late-night tweet Wednesday, the Tesla chief announced:

Tesla, as a side project, is building RNA microfactories for CureVac & possibly others.

That’s not a lot to go on. But the tweet comes a year after Tesla’s German division in Grohmann and CureVac filed a patent on a “bioreactor for RNA in vitro transcription, a method for RNA in vitro transcription, a module for transcribing DNA into RNA and an automated apparatus for RNA manufacturing.” CureVac, in the meantime, has discussed a variety of plans to build microfactories that can speed up the whole process for a global supply chain.

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An ex­pe­ri­enced biotech is stitched to­geth­er from transpa­cif­ic parts, with 265 staffers and a fo­cus on ‘new bi­ol­o­gy’

Over the past few years, different teams at a pair of US-based biotechs and in labs in Japan have labored to piece together a group of cancer drug programs, sharing a single corporate umbrella with research colleagues in Japan. But now their far-flung operations have been knit together into a single unit, creating a pipeline with 10 cancer drug development programs — going from early-stage right into Phase III — and a host of discovery projects managed by a collective staff of some 265 people.

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Pfiz­er shares surge on pos­i­tive im­pact of their mR­NA Covid-19 vac­cine — part­nered with BioN­Tech — in an ear­ly-stage study

Pfizer and their partners at the mRNA specialist BioNTech have published the first glimpse of biomarker data from an early-stage study spotlighting the “robust immunogenicity” triggered by their Covid-19 vaccine, which is one of the leaders in the race to vanquish the global pandemic.

Researchers selected 45 healthy volunteers 18-55 years of age for the study. They were randomized to receive 2 doses, separated by 21 days, of 10 µg, 30 µg, or 100 µg of BNT162b1, “a lipid nanoparticle-formulated, nucleoside-modified, mRNA vaccine that encodes trimerized SARS-CoV-2 spike glycoprotein RBD.” Their responses were compared against the effect of a natural, presumably protective defense offered by a regular infection.

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New stan­dard of care? FDA hands Pfiz­er, Mer­ck KGaA an OK for Baven­cio in blad­der can­cer

The breakthrough therapy designation Pfizer and Merck KGaA notched for Bavencio in bladder cancer has quickly paved way for a full approval.

The PD-L1 drug is now sanctioned as a first-line maintenance treatment for patients with locally advanced or metastatic urothelial carcinoma, applicable in cases where cancer hasn’t progressed after platinum-containing chemotherapy.

Petros Grivas, the principal investigator of the supporting Phase III JAVELIN Bladder 100, called the approval “one of the most significant advances in the treatment paradigm in this setting in 30 years.”

Joseph Kim, Inovio CEO (Andrew Harnik, AP Images)

Pos­i­tive Covid-19 vac­cine da­ta? New mouse study? OWS in­clu­sion? Yep, but some­how, the usu­al tid­bits from In­ovio back­fire

You don’t go more than 40 years in biotech without ever getting a product to market unless you can learn the art of writing a promotional press release. And Inovio captures the prize in baiting the hook.

Tuesday morning Inovio, which has been struggling to get its Covid-19 vaccine lined up for mass manufacturing, put out a release that touched on virtually every hot button in pandemic PR.

There was, first and foremost, an interim snapshot of efficacy from their Phase I program for INO-4800.