FDA in-house re­view spot­lights an is­sue with one of Hori­zon's end­points but notes ef­fi­ca­cy for lead drug

The FDA in-house re­view high­lights a dis­agree­ment of in­ves­ti­ga­tors’ use of a key end­point by Hori­zon Phar­ma in the late-stage tri­al for the top drug in its pipeline, but large­ly agreed that the an­ti­body was ef­fec­tive.

Hori­zon sub­mit­ted a BLA for thy­roid eye dis­ease (TED) drug tepro­tu­mum­ab in March, less than two years af­ter they bought the drug (and the rest of a di­vi­sion) from Nar­row Riv­er for $145 mil­lion up­front. With break­through sta­tus, pri­or­i­ty re­view, or­phan des­ig­na­tion and in-house sales pro­jec­tions of up to $750 mil­lion, the one-time Roche re­ject be­came the mar­quee pipeline as­set for a com­pa­ny that’s de­vel­oped some of the world’s most ex­pen­sive drugs.

Hori­zon sub­mit­ted their ap­pli­ca­tion based on a Phase II and a Phase III study, tout­ing pos­i­tive re­sults on pri­ma­ry end­points in both tri­als. But the FDA re­ject­ed their pri­ma­ry end­point in the Phase II and sec­ondary end­point in Phase III: Clin­i­cal Ac­tiv­i­ty Score, or CAS. They not­ed that CAS com­piles mul­ti­ple forms of clin­i­cal ac­tiv­i­ty and weighs them equal­ly.

“FDA’s clin­i­cal team does not con­sid­er these fac­tors to be of equal clin­i­cal weight ei­ther to the pa­tients or to physi­cians treat­ing these pa­tients,” they wrote.

Rather, they fo­cused on pa­tients’ re­sponse in prop­to­sis, or the dis­lo­ca­tion of the eye from its or­bit, ar­gu­ing that this was the main symp­tom that af­flicts TED pa­tients. They not­ed an im­prove­ment by week 6 in both tri­als that con­tin­ued through the treat­ment pe­ri­od, and that 60% of pa­tients did not re­lapse in the year fol­low­ing treat­ment.

For pa­tients, prop­to­sis of­ten leads to diplop­ia — more pop­u­lar­ly called “dou­ble-vi­sion” — and de­spite less than eye-pop­ping re­sults in pa­tients’ sub­jec­tive re­spons­es, the FDA said Hori­zon showed im­prove­ment.

The FDA had few warn­ings about ad­verse ef­fects be­sides a slight in­crease in gas­tro-in­testi­nal events, but not­ed the lim­it­ed pa­tient pop­u­la­tion. With less than 90 pa­tients who re­ceived the treat­ment, they said, ad­verse ef­fects can be ex­pect­ed to oc­cur in up to 3% of pa­tients with­out show­ing up in the tri­al.

TED is an au­toim­mune dis­or­der that large­ly af­fects women in mid­dle age and can lead to blind­ness if not treat­ed with surgery ear­ly on. Hori­zon projects to treat around 15,000 to 20,000 peo­ple.

Tim­o­thy Wal­bert Hori­zon

The PDU­FA date is set for March 8. An ap­proval would mark one end of a long road for the drug. It be­gan at Gen­mab, be­fore Roche li­censed it as a treat­ment for sol­id tu­mors. It proved in­ef­fec­tive, and was lat­er test­ed at Nar­row Riv­er in di­a­bet­ic mac­u­lar ede­ma — the an­ti­body af­fects the in­sulin-like growth fac­tor-1 re­cep­tor — be­fore show­ing promise in TED.

In their lat­est earn­ings call on Sep­tem­ber 30, the com­pa­ny ap­peared to ful­ly ex­pect ap­proval.

“We are ag­gres­sive­ly prepar­ing for the po­ten­tial US launch with our tepro­tu­mum­ab com­mer­cial and med­ical teams ful­ly in place,” CEO Tim­o­thy Wal­bert said.

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.

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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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.

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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: 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 claims Tru­va­da patents in HHS’ com­plaint are in­valid

Back in November, the Department of Health and Human Services took the rare step of filing a complaint against Gilead for infringing on government-owned patents related to the HIV drug Truvada (emtricitabine/tenofovir disoproxil fumarate) for pre-exposure prophylaxis (PrEP).

But on Thursday, Gilead filed its own retort, making clear that it does not believe it has infringed on the Centers for Disease Control and Prevention’s (CDC) Truvada patents because they are invalid.

Stephen Hahn, AP

The FDA has de­val­ued the gold stan­dard on R&D. And that threat­ens every­one in drug de­vel­op­ment

Bioregnum Opinion Column by John Carroll

A few weeks ago, when Stephen Hahn was being lightly queried by Senators in his confirmation hearing as the new commissioner of the FDA, he made the usual vow to maintain the gold standard in drug development.

Neatly summarized, that standard requires the agency to sign off on clinical data — usually from two, well-controlled human studies — that prove a drug’s benefit outweighs any risks.

Over the last few years, biopharma has enjoyed an unprecedented loosening over just what it takes to clear that bar. Regulators are more willing to drop the second trial requirement ahead of an accelerated approval — particularly if they have an unmet medical need where patients are clamoring for a therapy.

That confirmatory trial the FDA demands can wait a few years. And most everyone in biopharma would tell you that’s the right thing for patients. They know its a tonic for everyone in the industry faced with pushing a drug through clinical development. And it’s helped inspire a global biotech boom.

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UP­DAT­ED: New play­ers are jump­ing in­to the scram­ble to de­vel­op a vac­cine as pan­dem­ic pan­ic spreads fast

When the CNN news crew in Wuhan caught wind of the Chinese government’s plan to quarantine the city of 11 million people, they made a run for one of the last trains out — their Atlanta colleagues urging them on. On the way to the train station, they were forced to skirt the local seafood market, where the coronavirus at the heart of a brewing outbreak may have taken root.

And they breathlessly reported every moment of the early morning dash.

In shuttering the city, triggering an exodus of masked residents who caught wind of the quarantine ahead of time, China signaled that they were prepared to take extreme actions to stop the spread of a virus that has claimed 17 lives, sickened many more and panicked people around the globe.

CNN helped illustrate how hard all that can be.

The early reaction in the biotech industry has been classic, with small-cap companies scrambling to headline efforts to step in fast. But there are also new players in the field with new tech that has been introduced since the last of a series of pandemic panics that could change the usual storylines. And they’re volunteering for a crash course in speeding up vaccine development — a field where overnight solutions have been impossible to prove.

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