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.

Un­de­terred by a pan­dem­ic, Gilde Health­care rais­es their largest fund yet

When Pieter van der Meer started raising the capital for Gilde Healthcare’s fifth fund in the waning months of 2019, he had his eyes on a different chain of events that could change the healthcare system and perhaps even play to his firm’s advantage: The US presidential election.

Since raising their third fund in 2011, the 34-year-old Dutch firm had focused on value-based care. They chose late-stage biotechs that came up with new devices and delivery systems for de-risked established compounds, and when they chose preclinical biotechs, they spoke with potential pharma partners, payers and regulators to ask where and at what prices the drug made sense. As the Democratic primary became a contest over how to lower healthcare costs, it looked like a strategy that could pay off.

In a stun­ning set­back, Amarin los­es big patent fight over Vas­cepa IP. And its high-fly­ing stock crash­es to earth

Amarin’s shares $AMRN were blitzed Monday evening, losing billions in value as reports spread that the company had lost its high-profile effort to keep its Vascepa patents protected from generic drugmakers.

Amarin had been fighting to keep key patents under lock and key — and away from generic rivals — for another 10 years, but District Court Judge Miranda Du in Las Vegas ruled against the biotech. She ruled that:
(A)ll the Asserted Claims are invalid as obvious under 35 U.S.C.§ 103. Thus, the Court finds in favor of Defendants on Plaintiff’s remaining infringementclaim, and in their favor on their counterclaims asserting the invalidity of the AssertedClaims under 35 U.S.C. § 103.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 77,000+ biopharma pros reading Endpoints daily — and it's free.

Brii Bio gets all hands on deck for Covid-19 an­ti­body hunt, lever­ag­ing Chi­nese part­ner­s' work with re­cov­ered pa­tients

A preprint paper describing 206 monoclonal antibodies against SARS-Cov-2 isolated from eight Covid-19 patients in China attracted a small rally on Twitter a few days ago, when Broad investigator David Liu dubbed it “very good news.

Now Brii Bio is unveiling some more good news: It’s partnering with the researchers behind that paper from Tsinghua and 3rd People’s Hospital of Shenzhen to bring some of those antibodies to the clinic.

Covid-19 roundup: J&J, BAR­DA set ear­ly 2021 fin­ish line for $1B vac­cine race; FDA al­lows emer­gency drug use, ahead of piv­otal da­ta

J&J has zeroed in on a Covid-19 vaccine candidate that it hopes to begin testing in humans by September this year — with the extraordinary goal of getting it ready for emergency use in early 2021. And together with BARDA, it’s committing $1 billion to make it happen.

That kind of accelerated timeline would fall on the fast side of NIAID director Anthony Fauci’s well-publicized prediction that it would be another 12 to 18 months before a vaccine can be available for public use. A Phase I trial of Moderna’s mRNA vaccine began two weeks ago, and both the biotech and fellow mRNA player CureVac have discussed similar, if not even faster, timelines for emergency use among healthcare workers.

Mene Pangalos via YouTube

As­traZeneca says its block­buster Farx­i­ga proved to be a game-chang­er in CKD — wrap­ping PhI­II ear­ly

If the FDA can still hold up its end of the bargain, AstraZeneca is already on a short path to scooping up a cutting-edge win with a likely approval for their SGLT2 drug Farxiga in cutting the risk of heart failure. Now the pharma giant says it can point to solid evidence that the drug — initially restricted to diabetes — also works for chronic kidney disease, potentially adding a blockbuster indication for the franchise.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 77,000+ biopharma pros reading Endpoints daily — and it's free.

Daniel O'Day (AP Images)

Gilead CEO Dan O'­Day of­fers a de­tailed ex­pla­na­tion on remde­sivir ac­cess — re­as­sur­ing an­a­lysts that Covid-19 da­ta are com­ing fast

After coming under heavy fire from consumer groups ready to pummel them for grabbing the FDA’s orphan status for remdesivir — reserved to encourage the development of rare disease therapies — Gilead CEO Daniel O’Day had some explaining to do about the company’s approach to providing access to this drug to patients suffering from Covid-19. And he set aside time over the weekend to patiently explain how they are making their potential pandemic drug available in a new program — one he feels can better be used to address a growing pack of infected patients desperately seeking remdesivir under compassionate use provisions.

In addition to trying to reassure patients that they will once again have an avenue to pursue access, O’Day also reassured some analysts who had been fretting that China’s quick comeback from the coronavirus outbreak could derail its ultra-fast schedule for testing the drug in patients. The data are still expected in a few weeks, he says in the letter, putting the readout in April.

O’Day emphasizes that Gilead intends to pursue a pricing approach that will make this drug widely available — if it proves effective and safe. But no one is quite sure just what the longterm value would be, given the work being done on a variety of vaccines that may be rolled out as early as this fall — at least to the most heavily threatened groups.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 77,000+ biopharma pros reading Endpoints daily — and it's free.

Covid-19 roundup: Doud­na's ge­nomics crew launch­es di­ag­nos­tic lab; More biotechs dis­close tri­al dis­rup­tions

CRISPR pioneer Jennifer Doudna and her team at UC Berkeley’s Innovative Genomics Institute are pitching in to an industry-wide effort of casting a wide net to diagnose and track Covid-19 within the US.

While the US has rapidly ramped up its testing capacity from an abysmal level — fewer than 100 a day and all conducted by the CDC — in February to tens of thousands daily, governors have warned that they’re still facing shortages. The lack of fast, accurate and widespread testing creates a barrier to building a nationwide surveillance system, which many believe is needed to both understand how the coronavirus is spreading across the country and make key public health decisions.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 77,000+ biopharma pros reading Endpoints daily — and it's free.

Eli Lil­ly antes up $60M gam­ble on a dis­cov­ery deal with GSK-backed biotech

GSK-backed Sitryx has scored another illustrious partner: Eli Lilly.

The Oxford, UK-based company, which is focused on regulating immune cell metabolism to treat cancer and autoimmune diseases, has secured $50 million upfront from the US drugmaker in a deal that will make way for the two companies to collaborate on preclinical autoimmune disease targets identified by Sitryx.

Lilly, which already has its JAK inhibitor Olumiant and IL-17A antagonist Taltz in its immunology portfolio, will also make a $10 million equity investment in Sitryx, and is also on the hook for potential development milestone payments of up to $820 million, as well as commercialization milestones and royalty payments on potential sales.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 77,000+ biopharma pros reading Endpoints daily — and it's free.

Un­fazed by dis­rup­tions, Cowen backs AM-Phar­ma's $176M piv­otal plan around lethal con­di­tion

It may not be the best time to start up a late-stage study unrelated to Covid-19, but AM-Pharma isn’t letting a slight delay derail its overall plan.

The Dutch biotech has been singularly focused on recAP, an anti-inflammatory recombinant human form of an enzyme originally found in cows called alkaline phosphatase.

The one Phase III it believes it needs for approval was scheduled for this summer, funded by a $133 million round last July. Having pushed study initiation to after the summer, AM-Pharma is adding $52 million for the regulatory work needed to prepare for launch, including CMC validation and commercial supply.