Ness Bermingham (file photo)

What uni­fies Hunt­ing­ton's, spin­ocere­bel­lar atax­ia and my­oton­ic dy­s­tro­phy? Ness Berming­ham's new start­up looks to drug that

Ness Berming­ham’s lat­est ven­ture brings throw­backs to some of his ear­li­est work in bio­phar­ma. Part of his PhD work at Im­pe­r­i­al Col­lege Lon­don re­volved around triplet re­peat dis­or­ders, a group of 40 or so ge­net­ic dis­eases char­ac­ter­ized by the rep­e­ti­tion and ex­pan­sion of spe­cif­ic trin­u­cleotide se­quences. Dur­ing his ear­ly years at At­las Ven­ture — way be­fore he be­came known as a co-founder of pi­o­neer­ing CRISPR play­er In­tel­lia — he helped cre­ate a biotech, Prest­wick Phar­ma­ceu­ti­cals, that cre­at­ed a Hunt­ing­ton’s drug dubbed tetra­benazine.

Back then — and un­til very re­cent­ly — even though Hunt­ing­ton’s and oth­er dis­eases such as spin­ocere­bel­lar atax­ia and my­oton­ic dy­s­tro­phy fell un­der the same um­brel­la, they were con­strued as sep­a­rate af­flic­tions. A po­ten­tial­ly uni­fy­ing the­o­ry, as it turned out, lay in one ques­tion: Why don’t pa­tients born with the same re­peats al­ways be­gin to see symp­toms at the same age?

“For quite some time peo­ple had known that there are these ge­net­ic mod­i­fiers that re­al­ly seem to pro­found­ly im­pact these dis­eases and the on­set and pro­gres­sion of these dis­eases,” Berming­ham told End­points News.

Triplet Ther­a­peu­tics, which is do­ing the rounds to­day with $59 mil­lion in launch cash from At­las, MPM Cap­i­tal and Pfiz­er Ven­tures, be­lieves the key to that mech­a­nism is the DNA dam­age re­sponse path­way.

Iri­na An­toni­je­vic

The DNA dam­age re­sponse path­way, or DDR, is a cru­cial way for cells to re­pair ge­net­ic ma­te­r­i­al. But in pa­tients with re­peat ex­pan­sion dis­or­ders, when their DDR ma­chine goes in to fix the kinks dur­ing DNA repli­ca­tion, they al­so in­sert mul­ti­ple re­peat­ing se­quences — in turn blow­ing up the size of the DNA so much that it’s more prone to dam­age, cre­at­ing a snow­ball ef­fect, ac­cord­ing to Berming­ham.

Out of about 100 genes in­volved in the DDR path­way, Triplet has iden­ti­fied a cou­ple key dri­vers that they can tar­get to stop the in­ser­tion of re­peats, there­by hold­ing the dis­ease at bay.

Bri­an Bet­ten­court

That has al­lowed to shift their think­ing from a dis­ease stand­point to a tis­sue stand­point, Berming­ham said, and the first tis­sue they will go af­ter is the brain: Hunt­ing­ton’s, mul­ti­ple sub­types of spin­ocere­bel­lar atax­ia, den­ta­torubral–pal­li­doluysian at­ro­phy, my­oton­ic dy­s­tro­phy, and so on.

“As you move from tis­sue to tis­sue, it opens up dif­fer­ent drugs of dif­fer­ent for­mu­la­tions that hit the same tar­get,” he said.

Un­like at Ko­r­ro Bio, the RNA edit­ing out­fit Berming­ham has re­cent­ly un­veiled as ex­ec­u­tive chair­man, Triplet is not look­ing to new tools. Rather, the goal is to home in on a “fun­da­men­tal dri­ver” of dis­ease up­stream of what ri­vals like Roche/Io­n­is and Wave are knock­ing out in Hunt­ing­ton’s.

David Mor­risey

The can­di­dates they are now test­ing in non-hu­man pri­mates for CNS dis­or­ders are an­ti­sense oligonu­cleotides, but for oth­er tis­sues such as mus­cles, the eye or even the kid­ney, they al­so plan to use small in­ter­fer­ing RNA. These tools were cho­sen as they pro­vide more spe­cif­ic tar­get­ing and less safe­ty is­sues than, say, small mol­e­cules, Berming­ham said.

The CEO added that us­ing ASO and siR­NA has al­lowed his team of 29 to move quick­ly, ready to en­ter the clin­ic with­in two years — the run­way that the Se­ries A (al­so fea­tur­ing In­vus, Part­ners In­no­va­tion Fund and Alexan­dria Ven­ture In­vest­ments) is pro­vid­ing. In the process he’s look­ing to grow the com­pa­ny to some­where be­tween 45 to 60.

Cur­rent­ly help­ing Berming­ham run the op­er­a­tions are some sea­soned ex­ecs in the space: Iri­na An­toni­je­vic, SVP of de­vel­op­ment, pre­vi­ous­ly led trans­la­tion­al med­i­cine and ear­ly de­vel­op­ment at Wave; Bri­an Bet­ten­court, SVP of com­pu­ta­tion­al bi­ol­o­gy & sta­tis­tics, spe­cial­ized in mod­el­ing and de­sign of oligonu­cleotide and mR­NA at Trans­late Bio; David Mor­ris­sey, SVP of tech­nol­o­gy, and Pe­ter Blalek, head of trans­la­tion­al sci­ences, are both old col­leagues from In­tel­lia; Head of phar­ma­col­o­gy Pei Ge led the Hunt­ing­ton’s pro­gram at Al­ny­lam be­fore mov­ing to Iron­wood; Er­ic Sul­li­van, CFO, was for­mer­ly of Gem­i­ni Ther­a­peu­tics and blue­bird bio; and Jef­frey Ce­rio, gen­er­al coun­sel, has served at Mod­er­na.

Shinichi­ro Fuse of MPM and Las­z­lo Kiss of Pfiz­er Ven­tures are join­ing the board, chaired by At­las part­ner Jean-François Formela, along­side Dou­glas Kerr, chief de­vel­op­ment of­fi­cer at Gen­er­a­tion Bio. Then there’s the sci­en­tif­ic ad­vi­so­ry board com­pris­ing three aca­d­e­m­ic ex­perts, in­clud­ing Vanes­sa Wheel­er at Mass­a­chu­setts Gen­er­al Hos­pi­tal, who hap­pened to be a PhD mate of Berming­ham’s.

Ramp­ing up would mean spend­ing the ma­jor­i­ty of his time with Triplet at the new Kendall Square of­fices they are mov­ing in­to in Jan­u­ary, slight­ly de­tached from At­las — which he re­joined as ven­ture part­ner less than two years ago in the wake of his ex­it from the helm of In­tel­lia.

“It’s my in­tent to stay here and see this com­pa­ny through,” he said. “I’m trained as a hu­man ge­neti­cist orig­i­nal­ly, and then fur­ther spe­cial­ized down to mol­e­c­u­lar bi­ol­o­gy. So this is ab­solute­ly in my sweet spot.”

2019 Trin­i­ty Drug In­dex Eval­u­ates Ac­tu­al Com­mer­cial Per­for­mance of Nov­el Drugs Ap­proved in 2016

Fewer Approvals, but Neurology Rivals Oncology and Sees Major Innovations

This report, the fourth in our Trinity Drug Index series, outlines key themes and emerging trends in the industry as we progress towards a new world of targeted and innovative products. It provides a comprehensive evaluation of the performance of novel drugs approved by the FDA in 2016, scoring each on its commercial performance, therapeutic value, and R&D investment (Table 1: Drug ranking – Ratings on a 1-5 scale).

How to cap­i­talise on a lean launch

For start-up biotechnology companies and resource stretched pharmaceutical organisations, launching a novel product can be challenging. Lean teams can make setting a launch strategy and achieving your commercial goals seem like a colossal undertaking, but can these barriers be transformed into opportunities that work to your brand’s advantage?
We spoke to Managing Consultant Frances Hendry to find out how Blue Latitude Health partnered with a fledgling subsidiary of a pharmaceutical organisation to launch an innovative product in a
complex market.
What does the launch environment look like for this product?
FH: We started working on the product at Phase II and now we’re going into Phase III trials. There is a significant unmet need in this disease area, and everyone is excited about the launch. However, the organisation is still evolving and the team is quite small – naturally this causes a little turbulence.

Aymeric Le Chatelier, Ipsen

A $1B-plus drug stum­bles in­to an­oth­er big PhI­II set­back -- this time flunk­ing fu­til­i­ty test -- as FDA hold re­mains in ef­fect for Ipsen

David Meek

At the time Ipsen stepped up last year with more than a billion dollars in cash to buy Clementia and a late-stage program for a rare bone disease that afflicts children, then CEO David Meek was confident that he had put the French biotech on a short path to a mid-2020 launch.

Instead of prepping a launch, though, the company was hit with a hold on the FDA’s concerns that a therapy designed to prevent overgrowth of bone for cases of fibrodysplasia ossificans progressiva might actually stunt children’s growth. So they ordered a halt to any treatments for kids 14 and under. Meek left soon after to run a startup in Boston. And today the Paris-based biotech is grappling with the independent monitoring committee’s decision that their Phase III had failed a futility test.

Endpoints News

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Roche's check­point play­er Tecen­triq flops in an­oth­er blad­der can­cer sub­set

Just weeks after Merck’s star checkpoint inhibitor Keytruda secured FDA approval for a subset of bladder cancer patients, Swiss competitor Roche’s Tecentriq has failed in a pivotal bladder cancer study.

The 809-patient trial — IMvigor010 — tested the PD-L1 drug in patients with muscle-invasive urothelial cancer (MIUC) who had undergone surgery, and were at high risk for recurrence.

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UP­DAT­ED: Eli Lil­ly’s $1.6B can­cer drug failed to spark even the slight­est pos­i­tive gain for pa­tients in its 1st PhI­II

Eli Lilly had high hopes for its pegylated IL-10 drug pegilodecakin when it bought Armo last year for $1.6 billion in cash. But after reporting a few months ago that it had failed a Phase III in pancreatic cancer, without the data, its likely value has plunged. And now we’re getting some exact data that underscore just how little positive effect it had.

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UP­DAT­ED: FDA’s golodirsen CRL: Sarep­ta’s Duchenne drugs are dan­ger­ous to pa­tients, of­fer­ing on­ly a small ben­e­fit. And where's that con­fir­ma­to­ry tri­al?

Back last summer, Sarepta CEO Doug Ingram told Duchenne MD families and investors that the FDA’s shock rejection of their second Duchenne MD drug golodirsen was due to some concerns regulators raised about the risk of infection and the possibility of kidney toxicity. But when pressed to release the letter for all to see, he declined, according to a report from BioPharmaDive, saying that kind of move “might not look like we’re being as respectful as we’d like to be.”

He went on to assure everyone that he hadn’t misrepresented the CRL.

But Ingram’s public remarks didn’t include everything in the letter, which — following the FDA’s surprise about-face and unexplained approval — has now been posted on the FDA’s website and broadly circulated on Twitter early Wednesday.

The CRL raises plenty of fresh questions about why the FDA abruptly decided to reverse itself and hand out an OK for a drug a senior regulator at the FDA believed — 5 months ago, when he wrote the letter — is dangerous to patients. It also puts the spotlight back on Sarepta $SRPT, which failed to launch a confirmatory study of eteplirsen, which was only approved after a heated internal controversy at the FDA. Ellis Unger, director of CDER’s Office of Drug Evaluation I, notes that study could have clarified quite a lot about the benefit and risks associated with their drugs — which can cost as much as a million dollars per patient per year, depending on weight.

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Gilead dusts off a failed Ebo­la drug as coro­n­avirus spreads; Ex­elix­is boasts pos­i­tive Ph I/II da­ta

→ Less than a year ago Gilead’s antiviral remdesivir failed to make the cut as investigators considered a raft of potential drugs that could be used against an Ebola outbreak. But it may gain a new mission with the outbreak of the coronavirus in China, which is popping up now around the world.

Gilead put out a statement saying that they’re now in discussions with health officials in the US and China about testing their NUC against the virus. It’s the latest in a growing lineup of biopharma companies that are marshaling R&D forces to see if they can come up with a vaccine or therapy to blunt the spread of the virus, which has now sickened hundreds, killed at least 17 people and led the Chinese government to start quarantining cities.

Alex Karnal (Deerfield)

Deer­field vaults to the top of cell and gene ther­a­py CD­MO game with $1.1B fa­cil­i­ty at Philadel­phi­a's newest bio­phar­ma hub

Back at the beginning of 2015, Deerfield Management co-led a $10 million Series C for a private gene therapy startup, reshaping the company and bringing in new leaders to pave way for an IPO just a year later.

Fast forward four more years and the startup, AveXis, is now a subsidiary of Novartis marketing the second-ever gene therapy to be approved in the US.

For its part, Deerfield has also grown more comfortable and ambitious about the nascent field. And the investment firm is now putting down its biggest bet yet: a $1.1 billion contract development and manufacturing facility to produce everything one needs for cell and gene therapy — faster and better than how it’s currently done.

Tri­fec­ta of sick­le cell dis­ease ther­a­pies ex­tend life ex­pectan­cy, but are not cost-ef­fec­tive — ICER

Different therapeutic traits brandished by the three approved therapies for sickle cell disease all extend life expectancy, but their impact on quality of life is uncertain and their long-term cost-effectiveness is not up to scratch according to the thresholds considered reasonable by ICER, the non-profit concluded in a draft guidance report on Thursday.

Sickle cell disease (SCD), which encompasses a group of inherited red blood cell disorders that typically afflict those of African ancestry, impacts hemoglobin — and is characterized by episodes of searing pain as well as organ damage.