For tai­lored, sin­gle-per­son an­ti­sense oligonu­cleotides, FDA of­fers guid­ance on non­clin­i­cal test­ing

Over the last sev­er­al years, a new wave of hy­per-per­son­al­ized ther­a­pies have quick­ly made their way in­to peo­ple, just one at a time, and of­ten tai­lored to a spe­cif­ic ge­net­ic vari­ant.

Suc­cess sto­ries with these ex­pen­sive to make, so-called “n-of-1” ther­a­pies – from 6-year-old Mi­la Makovec with Bat­ten dis­ease, a rare, in­her­it­ed neu­ro­log­i­cal con­di­tion to 3-year-old Ipek Kuzu with atax­ia telang­iec­ta­sia, a rare in­her­it­ed dis­or­der that af­fects the ner­vous and oth­er sys­tems – have caused the FDA to take no­tice, par­tic­u­lar­ly as both are an­ti­sense oligonu­cleotide (ASO) treat­ments.

As part of ef­forts to help re­searchers de­vel­op­ing these ther­a­pies, the FDA in Jan­u­ary re­leased its first guid­ance ex­plain­ing how to sub­mit INDs for the in­di­vid­u­al­ized ASOs. On Mon­day, the agency re­leased ad­di­tion­al draft guid­ance on non­clin­i­cal test­ing for these ASOs for se­vere­ly de­bil­i­tat­ing or life-threat­en­ing dis­eases.

The two guid­ance doc­u­ments are im­por­tant be­cause much of the de­vel­op­ment work for these in­di­vid­ual ther­a­pies is done by aca­d­e­m­ic in­ves­ti­ga­tors, many of whom will nev­er seek to com­mer­cial­ize these ther­a­pies, but who al­so may not be fa­mil­iar with the way that the FDA reg­u­lates them.

In the lat­est guid­ance, the agency ex­plains how a sin­gle, 3-month tox­i­c­i­ty study is con­sid­ered ad­e­quate to as­sess the safe­ty for ini­ti­at­ing hu­man dos­ing, dose es­ca­la­tion, and chron­ic treat­ment for ASOs.

But for a ther­a­py for some­one who is rapid­ly pro­gress­ing to death or to sub­stan­tial ir­re­versible mor­bid­i­ty with­in one year, FDA said, “The IND sub­mis­sion should in­clude at least 2 weeks of in-life da­ta gen­er­at­ed from an on­go­ing 3-month tox­i­c­i­ty study.”

Be­cause the time­lines for de­vel­op­ing these ther­a­pies can be much faster than typ­i­cal drug de­vel­op­ment time­lines, the FDA al­so warns that some prob­lems may not be de­tect­ed ear­ly on.

“The prob­a­bil­i­ty of iden­ti­fy­ing tox­i­c­i­ty non­clin­i­cal­ly may be re­duced in com­par­i­son to stan­dard non­clin­i­cal safe­ty test­ing, and the po­ten­tial for clin­i­cal­ly sig­nif­i­cant ad­verse ef­fects may there­fore be in­creased,” FDA notes. But it al­so ex­plains that as long as there are ap­pro­pri­ate dis­clo­sures in the in­formed con­sent, “this in­creased risk is con­sid­ered ac­cept­able to FDA at this time in the con­text of an in­ves­ti­ga­tion­al an­ti­sense oligonu­cleotide cov­ered by this guid­ance.”

Re­searchers al­so have to ex­plain and jus­ti­fy to the FDA their meth­ods for se­lect­ing the start­ing dose of any ad­min­is­tered ther­a­py, in­clud­ing the ba­sis for cal­cu­lat­ing safe­ty mar­gins be­tween dos­es test­ed in an­i­mals and the dose or dos­es se­lect­ed for hu­mans.

FDA al­so said it would con­sid­er, on a case-by-case ba­sis, ex­pand­ing this ap­proach from the guid­ance “to oth­er oligonu­cleotide chemistries or mech­a­nisms of ac­tion (e.g., siR­NA), or to oth­er treat­ment modal­i­ties (e.g., in­di­vid­u­al­ized bi­o­log­ics) should be sup­port­ed by a non­clin­i­cal ap­proach that pro­vides a sim­i­lar un­der­stand­ing of the chem­istry and mech­a­nism of ac­tion suf­fi­cient to al­low for safe FIH [first in hu­man] dose se­lec­tion, po­ten­tial dose es­ca­la­tion, and an abil­i­ty to pre­dict the like­ly ad­verse ef­fects that could oc­cur, and how these can be clin­i­cal­ly mon­i­tored.”

Mov­ing Out of the Clin­ic with Dig­i­tal Tools: Mo­bile Spirom­e­try Dur­ing COVID-19 & Be­yond

An important technology in assessing lung function, spirometry offers crucial data for the diagnosis and monitoring of pulmonary system diseases, as well as the ongoing measurement of treatment efficacy. But trends in the healthcare industry and new challenges introduced by the COVID-19 pandemic are causing professionals in clinical practice and research to reevaluate spirometry’s deployment methods and best practices.

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Sanofi, Glax­o­SmithK­line jump back in­to the PhI­II race for a Covid vac­cine — as the win­ners con­gre­gate be­hind the fin­ish line

Sanofi got out early in the race to develop a vaccine using more of a traditional approach, then derailed late last year as their candidate failed to work in older people. Now, after likely missing the bus for the bulk of the world’s affluent nations, they’re back from that embarrassing collapse with a second attempt using GSK’s adjuvant that may get them back on track — with a potential Q4 launch that the rest of the world will be paying close attention to.

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SCO­TUS de­clines to re­view En­brel biosim­i­lar case, tee­ing up 30+ years of ex­clu­siv­i­ty and $20B more for Am­gen’s block­buster

As the House Oversight Committee is set to grill AbbVie CEO Richard Gonzalez on Tuesday over tactics to block competition for its best-selling drug of all time, another decision on Capitol Hill on Monday opened the door for billions more in Amgen profits over the next eight years.

The Supreme Court on Monday denied Novartis subsidiary Sandoz’s petition to review a Federal Circuit’s July 2020 decision concerning its biosimilar Erelzi (etanercept-szzs), which FDA approved in 2016 as a biosimilar to Amgen’s Enbrel (etanercept). Samsung’s Enbrel biosimilar Eticovo also won approval in 2019 and remains sidelined.

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How to man­u­fac­ture Covid-19 vac­cines with­out the help of J&J, Pfiz­er or Mod­er­na? Bi­ol­yse sees the dif­fi­cul­ties up close

When Biolyse, an Ontario-based manufacturer of sterile injectables, forged a deal with Bolivia last week to manufacture up to 50 million J&J Covid-19 vaccine doses, the agreement kicked off what will prove to be a test case for how difficult the system of compulsory licenses is to navigate.

The first problem: When Biolyse asked J&J, via a March letter, to license its Covid-19 vaccine, manufacture it in Canada and pay 5% royalties on shipments to needy, low-income countries, J&J rejected the offer, refusing to negotiate. J&J also did not respond to a request for comment.

Tim Mayleben (L) and Sheldon Koenig (Esperion)

On the heels of a sting­ing Q1 set­back, Es­pe­ri­on's long­time cham­pi­on is ex­it­ing the helm and turn­ing the wheel over to a mar­ket­ing pro

Just days after getting stung by criticism from a badly disappointed group of analysts, there’s a big change happening today at the helm of Esperion $ESPR.

Longtime CEO Tim Mayleben, who championed the company for 9 years from early clinical through a lengthy late-stage drive to successfully get their cholesterol drug approved for a significant niche of patients in the US, is out of the C suite, effective immediately. Sheldon Koenig — hired at the end of 2020 with a resume replete with Big Pharma CV sales experience —  is stepping into his place, promising to right a badly listing commercial ship that’s been battered by market forces.

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No­var­tis' En­tresto takes its 2nd fail­ure of the week­end at ACC, show­ing no ben­e­fit in most dire heart fail­ure pa­tients

Novartis’ Entresto started the ACC weekend off rough with a trial flop in heart attack patients, slowing the drug’s push into earlier patients. Now, an NIH-sponsored study is casting doubt on Entresto’s use in the most severe heart failure patients, another black mark on the increasingly controversial drug’s record.

Entresto, a combination of sacubitril and valsartan, could not beat out valsartan alone in an outcomes head-to-head for severe heart failure patients with a reduced ejection fraction (HFrEF), according to data presented Monday at the virtual American College of Cardiology meeting.

Matt Gline (L) and Vivek Ramaswamy

In­sid­er ac­count of Roivan­t's SPAC deal — and that $7.3B val­u­a­tion — re­veals a few se­crets as Matt Gline po­si­tions the com­pa­ny as the new ‘Big Phar­ma’

It was Oct. 7, 2020, and Matt Gline wasn’t wasting any time.

The CEO of Roivant had word that KKR vet Jim Momtazee’s SPAC had priced late the night before, triggering a green light for anyone interested in pursuing a big check for future operations and riding the financial instrument to Nasdaq. So he wrote a quick email congratulating Momtazee, whom he knew, for the launch.

Oh, and maybe Momtazee would like to schedule something with Gline and his executive chairman, Roivant founder Vivek Ramaswamy, to chat about Roivant and its business?

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$DNA is once again on NYSE; FDA clears Soliris chal­lenger for the mar­ket; Flag­ship’s think­ing big again with eR­NA; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

I still remember the uncertainty in the air last year when nobody was sure whether ASCO would cancel their in-person meeting. But it’s now back again for the second virtual conference, and Endpoints News is here for it. Check out our 2-day event reviewing the landscape of cancer R&D and send news our way.

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John­son & John­son do­nates Ebo­la vac­cine amid new out­break; Ji Xing promis­es more than $127M for Mile­stone's nasal spray for rapid heart rate

As Johnson & Johnson continues to roll out its Covid-19 shot, the company is also focused on another vaccine.

J&J is donating up to 200,000 doses of its Ebola vaccine regimen developed with Bavarian Nordic to help health authorities deal with a new outbreak in Sierra Leone. The regimen, Zabdeno and Mvabea, was granted prequalification by the WHO in April, which will help accelerate its registration in countries where Ebola is a threat.