Adrian Hayday. Crick

Adri­an Hay­day re­futes chal­lenge on in­flu­en­tial au­toan­ti­body pa­per by Karolin­s­ka sci­en­tists

Back in 2016, Adri­an Hay­day and his col­leagues at King’s Col­lege Lon­don — to­geth­er with some col­lab­o­ra­tors in Ger­many and Es­to­nia — made a splash in the im­munol­o­gy world with a pa­per, pub­lished in Cell, sug­gest­ing that pa­tients with a par­tic­u­lar ge­net­ic de­fect pro­duce more au­toan­ti­bod­ies than pre­vi­ous­ly known. These self-gen­er­at­ed an­ti­bod­ies, they pro­posed, of­fered ther­a­peu­tic po­ten­tial for au­toim­mune dis­eases, most promi­nent­ly Type 1 di­a­betes.

The re­sults formed the foun­da­tion of a Ger­man biotech dubbed Im­muno­Qure, which lat­er inked a part­ner­ship with France’s Servi­er to pur­sue an au­toan­ti­body that found to neu­tral­ize in­ter­fer­on-α. Servi­er pledged up to €164 mil­lion to the deal.

Nils Lan­de­gren

It al­so piqued the in­ter­est of Nils Lan­de­gren, a pro­fes­sor at the Karolin­s­ka In­sti­tute who’s spent years de­cod­ing the au­toim­mune reg­u­la­tor gene (AIRE) and its de­fi­cien­cy. While he’s helped iden­ti­fy a num­ber of bona fide au­toanti­gens in au­toim­mune poly­en­docrine syn­drome type 1, the vast num­ber of au­toan­ti­bod­ies iden­ti­fied in the Cell pa­per caught him by sur­prise. And he want­ed to see if there was re­al­ly a link be­tween one of the known au­toanti­gens to Type 1 di­a­betes. So he took a cou­ple of ex­ist­ing datasets and then ran his own analy­sis with a team from Swe­den and the US.

Long sto­ry short: They couldn’t repli­cate the re­sults.

“We could show that us­ing ran­dom da­ta, we got ba­si­cal­ly the same re­sult they did,” Lan­de­gren told Med­Scape. “We have a very strong case their re­sults are false.”

In a re­sponse to the pa­per, Hay­day stood by his re­sults and the meth­ods brought in­to ques­tion, coun­ter­ing that “flaws in de­sign and im­ple­men­ta­tion in­val­i­date this chal­lenge.”

“While we wel­come open, con­struc­tive dis­course about sci­ence, we are dis­ap­point­ed by this dis­pute be­cause we be­lieve it re­flects sim­ple but im­por­tant dif­fer­ences be­tween our ap­proach­es that could have been eas­i­ly re­solved, had Lan­de­gren and co-work­ers ap­proached us di­rect­ly,” his team wrote.

The dis­putes are two-pronged. The first has to do with the num­ber of au­toan­ti­bod­ies APS1 pa­tients har­bor. Hay­day’s group — with Stef­fen Mey­er and Mar­tin Wood­ward — as co-first au­thors found that col­lec­tive­ly hit over more than 3,700 hu­man pro­teins out of the 9,000 screened. But when Lan­de­gren’s team ran their sam­ples against the same as­say, they found “on­ly a very re­strict­ed set of pro­teins (<1% of the pro­tein pan­el) are tar­get­ed by au­toan­ti­bod­ies in mul­ti­ple APS1 pa­tients.”

The sta­tis­ti­cal method de­ployed for the pa­tient group ver­sus the con­trol, Lan­de­gren wrote, skewed the re­sults to show high­er lev­els of au­toan­ti­body sig­nals than in re­al­i­ty.

To bet­ter de­ter­mine how the an­a­lyt­i­cal bias in­flu­enced the over­all re­sults, we ap­plied a re­versed cut­off to our dataset based on the val­ues ob­tained for the 51 APS1 pa­tients in­stead of those for the 21 healthy con­trols. The healthy con­trols now turned out to show greater num­bers of high-lev­el (Z ≥ 5) au­toan­ti­body sig­nals than the APS1 pa­tients, re­veal­ing that the skew­ing ef­fect of the da­ta analy­sis was dom­i­nat­ing the re­sults.

To be sure, the 2016 pa­per had a stat­ed in­ter­est in find­ing pa­tients’ “pri­vate au­toan­ti­body reper­toire” — which might not be shared with oth­ers.

“When you un­der­take a sta­tis­ti­cal treat­ment of da­ta, there is no sil­ver bul­let, you have to use what makes sense,” he said to Med­Scape.

Even if they ap­ply a more con­ser­v­a­tive sta­tis­ti­cal ap­proach, he wrote in his re­sponse, they “iden­ti­fied re­ac­tiv­i­ties over­lap­ping 81% with our orig­i­nal study: again, these com­prised broad­ly shared au­toanti­gens and from ~30 to~100 pri­vate speci­fici­ties that col­lec­tive­ly com­posed a sub­stan­tial frac­tion of the pro­teome.”

Per­haps more point­ed­ly, Lan­de­gren’s team at­tempt­ed to poke holes in the cor­re­la­tion be­tween hav­ing neu­tral­iz­ing au­toan­ti­bod­ies of in­ter­fer­on-α and be­ing free of Type 1 di­a­betes. Hay­day’s the­o­ry was that an­ti-IFNα an­ti­bod­ies ap­peared to pro­tect APS1 pa­tients from ul­ti­mate­ly de­vel­op­ing that dis­ease, sup­port­ing pre­vi­ous claims that type I IFN con­tributes to Type 1 di­a­betes,

Writ­ing in eLife — where they went af­ter get­ting turned down by Cell — Lan­de­gren re­port­ed strong neu­tral­iza­tion of type 1 IFN in all APS1 sam­ples, not just the ones from di­a­bet­ics (a find­ing that Hay­day dis­missed as a re­sult of a “shod­dy ex­per­i­ment” con­duct­ed with less sen­si­tive meth­ods.)

“[A]t high con­cen­tra­tions, the sera of pa­tients with and with­out T1D showed com­pa­ra­ble ac­tiv­i­ties, but at low­er, sub-sat­u­ra­tion con­cen­tra­tions [50-fold di­lu­tions], the co­hort with­out T1D showed sig­nif­i­cant­ly greater ca­pac­i­ty to lim­it IFNα ac­tiv­i­ty,” Hay­day et al wrote in their re­sponse.

They added that the oth­er cen­tral ob­ser­va­tions from their 2016 pa­per re­mained un­chal­lenged: that APS1 pa­tients share nat­u­ral­ly aris­ing au­toan­ti­bod­ies to a small sub­set of pro­teins that are of ex­treme­ly high affin­i­ty.

Im­muno­Qure is still in the CMC stage for its drug can­di­date tar­get­ing IFN-α, but they won’t ex­act­ly be the first. As­traZeneca re­cent­ly con­ced­ed a Phase III de­feat for an­i­frol­um­ab in lu­pus, an an­ti­body that hits the re­cep­tors for IFN-α, IFN-β and IFN-ω. The hope is that by hit­ting the cy­tokines di­rect­ly — a “very dif­fer­ent modal­i­ty” — their nov­el pan an­ti-Type I IFN neu­tral­iz­ing an­ti­body will work “far more ef­fec­tive­ly” than the ex­ist­ing mAbs pro­duced by As­traZeneca or Genen­tech, Hay­day added.

The FDA will hus­tle up an ex­pe­dit­ed re­view for As­traZeneca’s next shot at a block­buster can­cer drug fran­chise

AstraZeneca paid a hefty price to partner with Daiichi Sankyo on their experimental antibody drug conjugate for HER2 positive breast cancer. And they’ve been rewarded with a fast ride through the FDA, with a straight shot at creating another blockbuster oncology franchise.

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Sean Parker, AP

Sean Park­er helps cre­ate a CRISPRed cell ther­a­py 2.0 play — and he’s got a high-pro­file set of lead­ers on the team

You can rack up one more high-profile debut effort in the wave of activity forming around cell therapy 2.0. It’s another appealing Bay Area group that’s attracted some of the top hands in the business to a multi-year effort to create a breakthrough. And they have $85 million in hand to make that first big step to the clinic.

Today it’s Ken Drazan and the team at South San Francisco-based ArsenalBio that are coming from behind the curtain for a public bow, backed by billionaire Sean Parker and a collection of investors that includes Beth Seidenberg’s new venture investment operation based in LA.
Drazan — a J&J Innovation vet with a long record of entrepreneurial endeavors — exited the stage in 2018 when his last mission ended as he stepped aside as president of Grail. It wasn’t long, though, before he was helping out with a business plan for ArsenalBio that revolved around the work of a large group of interconnected scientists supported by the Parker Institute for Cancer Immunology.
The biotech started by putting together an “arsenal” of technologies aimed at making cell therapies for cancer much, much better than the rather crude first-generation drugs that hit the market from Novartis and Kite.
Their drugs have become the baseline against which all others are being measured.
“The technology set we’re developing is independent of the chassis,” Drazan tells me. “It doesn’t have to be autologous (extracted from the patient) or allogeneic (off the shelf). It doesn’t have to be a T cell, it could be a B cell.” But they are starting out on the autologous side, where they have the most knowledge and insight into manufacturing techniques.
It also doesn’t have to be close to the clinic.
Drazan expects the biotech will be working its way through preclinical operations for “a few years,” with enough money from the $85 million launch round to get into humans.
By today’s superheated fundraising standards, that’s not a huge amount of cash. Lyell, another cell therapy 2.0 startup we featured last week, raised $600 million in a year, including a big chunk of cash from GlaxoSmithKline. Drazan is interested in dealmaking as well, but he also knows he has the cash necessary to support the company for a good run — a key part of what it takes to bring together a stellar team of top players.

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Eli Lil­ly’s first PhI­II show­down for their $1.6B can­cer drug just flopped — what now?

When Eli Lilly plunked down $1.6 billion in cash to acquire Armo Biosciences a little more than a year ago, the stars seemed aligned in its favor. The jewel in the crown they were buying was pegilodecakin, which had cleared the proof-of-concept stage and was already in a Phase III trial for pancreatic cancer.

And that study just failed.

Lilly reported this morning that their cancer drug flopped on overall survival when added to FOLFOX (folinic acid, 5-FU, oxaliplatin), compared to FOLFOX alone among patients suffering from advanced pancreatic cancer.

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Swamy Vijayan. Plexium

San Diego up­start de­buts dis­cov­ery en­gine that puts a twist to pro­tein degra­da­tion

For years, the idea of protein degradation — utilizing the cell’s natural garbage disposal system to mark problematic proteins for destruction — remained an elegant but technically difficult concept. But now established as a promising clinical strategy, with major biopharma players such as Bayer, Gilead and Vertex trying to grab a foothold via partnership deals, a San Diego startup is looking to exploit it and push its limits.

CSL ac­cus­es ri­val Pharm­ing of par­tic­i­pat­ing in a scheme to rip off IP on HAE while re­cruit­ing se­nior R&D staffer

Pharming has landed in the middle of a legal donnybrook after recruiting a senior executive from a rival R&D team at CSL. The Australian pharma giant slapped Pharming with a lawsuit alleging that the Dutch biotech’s new employee, Joseph Chiao, looted a large cache of proprietary documents as he hit the exit. And they want it all back.
Federal Judge Juan Sanchez in the Eastern District Pennsylvania court issued an injunction on Tuesday prohibiting Chiao from doing any work on HAE or primary immune deficiency in his new job and demanding that he return any material from CSL that he may have in his possession. And he wants Pharming to tell its employees not to ask for any information on the forbidden topics.
For its part, Pharming fired off an indignant response this morning denying any involvement in extracting any kind of IP from CSL, adding that it’s cooperating in the internal probe that CSL has underway.

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Hal Barron, GSK's president of R&D and CSO, speaks to Endpoints News founder and editor John Carroll in London at Endpoints' #UKBIO19 summit on October 8, 2019

[Video] Cel­e­brat­ing tri­al fail­ures, chang­ing the cul­ture and al­ly­ing with Cal­i­for­nia dream­ers: R&D chief Hal Bar­ron talks about a new era at GSK

Last week I had a chance to sit down with Hal Barron at Endpoints’ #UKBIO19 summit to discuss his views on R&D at GSK, a topic that has been central to his life since he took the top research post close to 2 years ago. During the conversation, Barron talked about changing the culture at GSK, a move that involves several new approaches — one of which involves celebrating their setbacks as they shift resources to the most promising programs in the pipeline. Barron also discussed his new alliances in the Bay Area — including his collaboration pact with Lyell, which we covered here — frankly assesses the pluses and minuses of the UK drug development scene, and talks about his plans for making GSK a much more effective drug developer.

This is one discussion you won’t want to miss. Insider and Enterprise subscribers can log-in to watch the video.

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Med­ical an­i­ma­tion: Mak­ing it eas­i­er for the site and the pa­tient to un­der­stand

Medical animation has in recent years become an increasingly important tool for conveying niche information to a varied audience, particularly to those audiences without expertise in the specialist area. Science programmes today, for example, have moved from the piece-to-camera of the university professor explaining how a complex disease mechanism works, to actually showing the viewer first-hand what it might look like to shrink ourselves down to the size of an ant’s foot, and travel inside the human body to witness these processes in action. Effectively communicating a complex disease pathophysiology, or the novel mechanism of action of a new drug, can be complex. This is especially difficult when the audience domain knowledge is limited or non-existent. Medical animation can help with this communication challenge in several ways.
Improved accessibility to visualisation
Visualisation is a core component of our ability to understand a concept. Ask 10 people to visualise an apple, and each will come up with a slightly different image, some apples smaller than others, some more round, some with bites taken. Acceptable, you say, we can move on to the next part of the story. Now ask 10 people to visualise how HIV’s capsid protein gets arranged into the hexamers and pentamers that form the viral capsid that holds HIV’s genetic material. This request may pose a challenge even to someone with some virology knowledge, and it is that inability to effectively visualise what is going on that holds us back from fully understanding the rest of the story. So how does medical animation help us to overcome this visualisation challenge?

UP­DAT­ED: Alex­ion pays $930M to buy out Achillion and its promis­ing com­pan­ion drug to Soliris

After a series of stock-crunching setbacks over the years, Achillion enjoyed a turn in the sun a few weeks ago as the FDA blessed their lead drug danicopan (ACH-4471) — a complementary therapy for PNH patients taking Alexion’s Soliris — with a breakthrough drug designation after taking a look at some solid supporting Phase II data.

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The $102B club: The top 15 R&D spenders in the glob­al bio­phar­ma busi­ness — 2019 edi­tion

Over the past few years, the deluge of capital into biotech has helped lead to a dramatic shift in focus on new drug approvals, as startups are now able to raise enough cash to get through a pivotal and onto the market. But the top 15 players still account for $102 billion in spending, and their successes and failures continue to determine just how productive the industry is.

Recently we’ve seen a number of new R&D chiefs take their places at the Big 15, either setting the stage for a more focused R&D strategy — often playing more heavily in oncology. That’s true for AstraZeneca, which has had some landmark successes, and GSK, which is in search of its own turnaround in pharma R&D. HIV and vaccines are separate from that group, now led by Hal Barron.

I’ve made a point of watching their track record every year for more than a decade now. What follows is intended as a broad gauge of their activity. You don’t have to have a lot of major successes to score a winning record here, but it’s virtually impossible without a blockbuster or three in the pipeline.

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