Award-win­ning sep­sis project gets $13M and a shot at re­open­ing an R&D av­enue as FDA pitch­es out old gold stan­dard

As chair of the British Heart Foun­da­tion’s trans­la­tion­al awards com­mit­tee, David Grainger was pow­er­ful­ly at­tract­ed to some re­search that Glas­gow Uni­ver­si­ty pro­fes­sor James Leiper was do­ing on a com­mon symp­tom of sep­tic shock, a ma­jor killer that is re­spon­si­ble for more than a quar­ter mil­lion deaths in the US each year.

That was good for an award.

David Grainger

But now Grainger, a part­ner at Medicxi, has fol­lowed through with an $13 mil­lion ven­ture round to cre­ate a vir­tu­al com­pa­ny called Crit­i­cal Pres­sure that could take this as­set through ear­ly-stage stud­ies and in­to the hands of com­mer­cial buy­er.

And this time, it’s per­son­al.

Sep­sis is a se­vere, of­ten life threat­en­ing bac­te­r­i­al in­fec­tion that is fought off with an­tibi­otics. Dur­ing that fight the hu­man body can ex­pe­ri­ence tox­ic shock af­ter gen­er­at­ing ni­tric ox­ide, which dri­ves down blood pres­sure to a crit­i­cal point. For years now, doc­tors have fought back with no­ra­dren­a­line to con­strict blood ves­sel tis­sue and dri­ve the pres­sure back up, which can al­so be harm­ful.

So in re­search pri­mar­i­ly at Uni­ver­si­ty Col­lege Lon­don, Leiper de­vel­oped CPL001, a chem­i­cal com­pound that in­hibits an en­zyme called DDAH1.

James Leiper

“In­hibit­ing DDAH1 pre­vents the dra­mat­ic loss of blood pres­sure that of­ten ac­com­pa­nies sep­sis,” said the pro­fes­sor. “The body nat­u­ral­ly pro­duces a chem­i­cal, ni­tric ox­ide, that kills bac­te­ria but al­so low­ers blood pres­sure. Block­ing DDAH1 pre­vents the drop in blood pres­sure, with­out los­ing the abil­i­ty to fight the in­fec­tion.”

“It is try­ing to sta­bi­lize the pa­tient so that the at­tempts to deal with the un­der­ly­ing in­fec­tion have the time to be ef­fec­tive,” Grainger tells me. It’s some­thing he’s seen first hand, when his moth­er died from sep­sis sev­er­al years ago.

Even so, Grainger says that sep­sis as a fo­cus in R&D has been as qui­et as a grave­yard in biotech, al­most en­tire­ly be­cause of the high bar set by the FDA in gain­ing new ap­provals for the con­di­tion. Reg­u­la­tors have de­mand­ed a 28-day all cause mor­tal­i­ty ben­e­fit as the gold stan­dard for the last 25 years.

“The FDA has set the bar so high that no one has been able to achieve it,” he says. “It’s on­ly in the last 6 to 9 months that the FDA changed their po­si­tion.”

In pre-IND talks with the FDA, reg­u­la­tors — in writ­ing — backed off that stan­dard, in­stead turn­ing to a much more pli­ant no­ra­dren­a­line-spar­ing stan­dard for the piv­otal end­point.

The next step is straight­for­ward. Start­ing with healthy vol­un­teers but quick­ly loop­ing in some sep­sis pa­tients, Grainger has es­tab­lished a com­plete­ly vir­tu­al com­pa­ny which will take the drug through an ear­ly-stage pro­gram. In about two years, he says, the mon­ey in the start­up round will de­liv­er proof-of-prin­ci­ple da­ta that a com­mer­cial bio­phar­ma can use to see if this is some­thing that could be quick­ly shep­herd­ed in­to the mar­ket, per­haps af­ter a small piv­otal study to con­firm the ear­li­er find­ing.

Grainger isn’t known as a high roller in the de­vel­op­ment world. He and Medicxi are known for ruth­less­ly cut­ting costs to a bone, and there will be no full timers on board to spend mon­ey. He’s ex­ec­u­tive chair­man, the sin­gle-as­set com­pa­ny will be based un­der an um­brel­la group in Babra­ham in Cam­bridge, UK, and a part-time COO will man­age the day-to-day.

It’s not com­pli­cat­ed, he adds. This is some­thing that should be quick­ly ap­par­ent if it’s work­ing and safe to use.

Con­quer­ing a silent killer: HDV and Eiger Bio­Phar­ma­ceu­ti­cals

Hepatitis delta, also known as hepatitis D, is a liver infection caused by the hepatitis delta virus (HDV) that results in the most severe form of human viral hepatitis for which there is no approved therapy.

HDV is a single-stranded, circular RNA virus that requires the envelope protein (HBsAg) of the hepatitis B virus (HBV) for its own assembly. As a result, hepatitis delta virus (HDV) infection occurs only as a co-infection in individuals infected with HBV. However, HDV/HBV co-infections lead to more serious liver disease than HBV infection alone. HDV is associated with faster progression to liver fibrosis (progressing to cirrhosis in about 80% of individuals in 5-10 years), increased risk of liver cancer, and early decompensated cirrhosis and liver failure.
HDV is the most severe form of viral hepatitis with no approved treatment.
Approved nucleos(t)ide treatments for HBV only suppress HBV DNA, do not appreciably impact HBsAg and have no impact on HDV. Investigational agents in development for HBV target multiple new mechanisms. Aspirations are high, but a functional cure for HBV has not been achieved nor is one anticipated in the forseeable future. Without clearance of HBsAg, anti-HBV investigational treatments are not expected to impact the deadly course of HDV infection anytime soon.

UP­DAT­ED: In a land­mark first glimpse of hu­man da­ta from Ver­tex, CRISPR/Cas9 gene ther­a­py sig­nals ear­ly ben­e­fit

Preliminary data on two patients with blood disorders that have been administered with Vertex and partner CRISPR Therapeutics’ gene-editing therapy suggest the technology is safe and effective, marking the first instance of the benefit of the use of CRISPR/Cas9 technology in humans suffering from disease.

Patients in these phase I/II studies give up peripheral blood from which hematopoietic stem and progenitor cells are isolated. The cells are tinkered with using CRISPR/Cas9 technology, and the edited cells — CTX001 — are infused back into the patient via a stem cell transplant. The objective of CTX001 is to fix the errant hemoglobin gene in patents with two blood disorders: beta-thalassemia and sickle cell disease, by unleashing the production of fetal hemoglobin.

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UP­DAT­ED: Make that 2 ap­proved RNAi drugs at Al­ny­lam af­ter the FDA of­fers a speedy OK on ul­tra-rare dis­ease drug

Seventeen years into the game, Alnylam’s pivot into commercial operations is picking up speed.
The bellwether biotech $ALNY has nabbed their second FDA OK for an RNAi drug, this time for givosiran, the only therapy now approved for acute hepatic porphyria. This second approval came months ahead of the February deadline — even after winning priority review following their ‘breakthrough’ title earlier.
AHP is an extremely rare disease, with some 3,000 patients in Europe and the US, not all diagnosed, and analysts have projected peak revenue of $600 million to $700 million a year. The drug will be sold as Givlaari.

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David Ricks. Eli Lilly

Eli Lil­ly touts $400M man­u­fac­tur­ing ex­pan­sion, 100 new jobs to much fan­fare in In­di­anapo­lis — even though it's been chop­ping staff

Eli Lilly is pouring in $400 million to beef up manufacturing facilities at its home base of Indianapolis. The investment, which was lauded by the city’s mayor, is expected to create 100 new jobs.

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Am­gen chops 172 more staffers in R&D, op­er­a­tions and sales amid neu­ro­science ex­it, rev­enue down­turn

Neuroscience wasn’t the only unit that’s being hit by a reorganization underway at Amgen. As well as axing 149 employees in its Cambridge office, the company has disclosed that 172 others nationwide, including some from its Thousand Oaks, CA headquarters, are being let go.

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Stephen Hahn (via Senate HELP Committee)

Stephen Hahn gets through Sen­ate’s soft­ball job in­ter­view — but most­ly plays dodge­ball on the is­sues fac­ing the FDA

Anyone looking for fresh insights on what kind of FDA commissioner Stephen Hahn will be got precious few clues during Wednesday’s Senate hearing on the nomination.

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Op­di­vo/Yer­voy com­bo for melanoma fails in key pa­tient pop­u­la­tion

Bristol-Myers Squibb’s efforts to expand their checkpoint inhibitor combination have run into another recalcitrant cancer.

The NJ-based pharma announced that a combination of Yervoy and Opdivo didn’t beat out Opdivo alone in patients with resected high-risk melanoma who had very low levels of PD-L1. The drug combo couldn’t improve recurrence-free survival in these post-surgery patients.

Ver­tex's stel­lar quar­ter car­ries on with French re­im­burse­ment deal

Vertex’s golden quarter just got brighter. About a month after the US drugmaker finally clinched a deal with UK authorities to cover its slate of cystic fibrosis (CF) drugs following years of protracted negotiations, the company on Wednesday secured a deal with France for its CF therapy, Orkambi.

After the UK, France has one of the largest CF populations outside the United States. Achieving French reimbursement unlocks an ~7000-patient CF population, around ~2500-3000 of which will likely be eligible to receive (and be reimbursed for) Orkambi, Stifel’s Paul Matteis wrote in a note.

Nello Mainolfi, Kymera via Youtube

Kymera hands the helm to No­var­tis vet — and found­ing CSO — Nel­lo Main­olfi

Kymera Therapeutics is turning to a co-founder to run the company.
The protein degradation specialist with a deep-pocket syndicate behind them has opted to give the helm officially to Nello Mainolfi. The new CEO is a veteran of the Novartis Institutes for Biomedical Research. He joined Atlas Venture in their entrepreneur-in-residence program and helped launch Kymera as the CSO three years ago with Atlas’ Bruce Booth.
The boast at Kymera is that they’re angling to create a new class of protein degraders, a popular field where there’s been a variety of startups. One of its chief advocates is NIBR head Jay Bradner, who launched C4 just ahead of joining Novartis, where he’s also been doing new work in the field.