Up­dat­ed: In­ter­change­able biosim­i­lars: FDA fi­nal­izes guid­ance

The FDA on Fri­day fi­nal­ized a long-await­ed guid­ance spelling out how biosim­i­lars can achieve an in­ter­change­able sta­tus, which means they may be sub­sti­tut­ed for the ref­er­ence bi­o­log­ic with­out a pre­scriber in­ter­ven­ing.

No in­ter­change­able biosim­i­lars have been ap­proved in the US yet, and the num­ber of com­pa­nies seek­ing ap­proval for an in­ter­change­able has re­mained at just one, with Boehringer In­gel­heim pub­licly dis­clos­ing that it’s be­gun an in­ter­change­abil­i­ty study for its adal­i­mum­ab (Hu­mi­ra) biosim­i­lar.

But for­mer FDA Com­mis­sion­er Scott Got­tlieb said last month that in­ter­change­able in­sulin prod­ucts are like­ly com­ing to the US in the next cou­ple of years. And fi­nal in­ter­change­abil­i­ty guid­ance will pro­vide spon­sors with more cer­tain­ty on how to de­vel­op in­ter­change­able prod­ucts.

Changes in Fi­nal Guid­ance

The fi­nal guid­ance is sev­en pages short­er than the draft and does not in­clude two ap­pen­dices that were in­clud­ed in the draft on com­par­a­tive use hu­man fac­tors stud­ies.

Com­menters on the draft took is­sue with terms that need­ed fur­ther clar­i­ty, such as “resid­ual un­cer­tain­ty” and “fin­ger­print-like,” which is used in the draft to de­scribe the sim­i­lar­i­ty be­tween the pro­posed in­ter­change­able prod­uct and the ref­er­ence prod­uct.

The fi­nal guid­ance, how­ev­er, no longer us­es the term “fin­ger­print-like” and where­as the draft in­cludes al­most 20 ref­er­ences to “resid­ual un­cer­tain­ty,” the fi­nal guid­ance in­cludes on­ly one. “The agency al­so con­sid­ered the nu­mer­ous com­ments on the draft in­ter­change­abil­i­ty guid­ance and made changes to pro­vide in­creased clar­i­ty to stake­hold­ers,” Act­ing Com­mis­sion­er Ned Sharp­less said.

Chris­tine Sim­mon

Chris­tine Sim­mon, ex­ec­u­tive di­rec­tor of the Biosim­i­lars Coun­cil, ap­plaud­ed the FDA’s “time­ly guid­ance on in­ter­change­abil­i­ty for biosim­i­lars, par­tic­u­lar­ly its stream­lined da­ta and study de­sign re­quire­ments that al­low flex­i­bil­i­ty and the use of glob­al com­para­tor prod­ucts to sup­port ap­pli­ca­tions.”

Com­pa­nies com­ment­ing on the draft al­so took is­sue with the re­quire­ment that they must use US-li­censed ref­er­ence prod­uct in a switch­ing study (or stud­ies). And the FDA has al­tered this re­quire­ment in the fi­nal guid­ance and re­named that sec­tion of the guid­ance.

“If a spon­sor seeks to use da­ta de­rived from a switch­ing study or stud­ies com­par­ing a pro­posed in­ter­change­able prod­uct with a non-U.S.-li­censed com­para­tor prod­uct as part of the demon­stra­tion that the pro­posed in­ter­change­able prod­uct meets the stan­dard de­scribed in sec­tion 351(k)(4)(B) of the PHS Act, the spon­sor should pro­vide ad­e­quate da­ta and in­for­ma­tion to es­tab­lish a ‘bridge’ be­tween the non-U.S.-li­censed com­para­tor and the U.S.-li­censed ref­er­ence prod­uct and there­by jus­ti­fy the rel­e­vance of the da­ta ob­tained us­ing the non-U.S.-li­censed com­para­tor to an eval­u­a­tion of whether the re­quire­ments of sec­tion 351(k)(4)(B) have been met,” the fi­nal guid­ance says, ex­plain­ing more about what the bridge would en­tail.

Oth­er­wise, most of the draft ver­sion was car­ried over in­to the fi­nal guid­ance, in­clud­ing the re­quire­ment that com­pa­nies use so-called “switch­ing stud­ies” to de­ter­mine whether al­ter­nat­ing be­tween a biosim­i­lar and its ref­er­ence prod­uct im­pacts the safe­ty or ef­fi­ca­cy of the treat­ment.

Bern­stein biotech an­a­lyst Ron­ny Gal added in a note to in­vestors: “The main added re­quire­ment is a 2-arm switch­ing tri­al where all pa­tients start on the ref­er­ence prod­uct. In one arm, the pa­tients will re­main on the ref­er­ence prod­uct through­out. On the oth­er, they will switch back and forth twice, end­ing on the biosim­i­lar prod­uct. Crit­i­cal­ly, the main com­par­i­son is on PK/PD mark­ers, not ef­fi­ca­cy mark­ers (which FDA con­sid­ers less sen­si­tive). This will ma­te­ri­al­ly low­er costs of do­ing these tri­als.”

He al­so said he ex­pects this guid­ance will en­able in­sulin in­ter­change­ables and al­low for in­ter­change­able ver­sions of “some of the eas­i­er an­ti­bod­ies to repli­cate like Eylea.”

Con­sid­er­a­tions in Demon­strat­ing In­ter­change­abil­i­ty With a Ref­er­ence Prod­uct: Guid­ance for In­dus­try

Ed­i­tor’s Note: Up­dat­ed with com­ment from Bern­stein’s Gal.

First pub­lished in Reg­u­la­to­ry Fo­cus™ by the Reg­u­la­to­ry Af­fairs Pro­fes­sion­als So­ci­ety, the largest glob­al or­ga­ni­za­tion of and for those in­volved with the reg­u­la­tion of health­care prod­ucts. Click here for more in­for­ma­tion.


Zachary Brennan

managing editor, RAPS

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.

No­var­tis is ax­ing 150 ear­ly dis­cov­ery jobs as CNI­BR shifts fo­cus to the de­vel­op­ment side of R&D

Novartis is axing some 150 early discover jobs in Shanghai as it swells its staff on the drug development side of the equation in China. And the company is concurrently beefing up its investment in China’s fast-growing biotech sector with a plan to add to its investments in local VCs.

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Democratic presidential candidate, U.S. Sen. Elizabeth Warren (D-MA) speaks during the Nevada Democrats' "First in the West" event at Bellagio Resort & Casino on November 17, 2019 in Las Vegas, Nevada (Getty Images)

Eliz­a­beth War­ren pro­pos­es us­ing com­pul­so­ry li­cens­ing, an­titrust ac­tions to break bio­phar­ma’s con­trol of drug pric­ing — and here are the block­busters she’s tar­get­ing first

Nancy Pelosi’s drug pricing bill may have sparked some industrial strength headaches on the money side of biopharma, but Elizabeth Warren seems determined to become biopharma’s Nightmare on Pennsylvania Avenue.
Warren, one of the top-ranked candidates for the Democratic presidential nomination backing Medicare for all, is circulating a new plan that promises to break the industry’s grip on drug prices — and she has some very specific examples of how she would do it.
The Warren plan would rely on the federal government’s compulsory licensing powers to seize the IP of blockbuster drugs like Truvada and Harvoni to provide them at a fraction of what Gilead sells them for in the US. And she would throw some antitrust actions in as needed to rein in the price of Humira, AbbVie’s cash cow that continues to dominate the list of the most profitable therapeutics on the market.
Notably, she plans to rely on the powers already vested in the federal government, rather than suggest remedies that would require the assent of a deeply divided Congress.
In addition to the blockbusters on the list, Warren sends a clear signal that the same tactics would be used to beef up the supply of cheap antibiotics, as needed. And the same action could befall any other therapy patients can’t afford.

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Mer­ck’s $1B cash gam­ble pays off with a sur­pris­ing PhI­II car­dio suc­cess for Bay­er’s heart drug veri­ciguat

More than 3 years after Merck stepped up and paid $1 billion in cold, hard cash to gain the US commercial rights to Bayer’s high-risk heart drug vericiguat in a broad-ranging cardio alliance, the partners say their Phase III study has come through with promising data and a date with regulators.
We don’t have the data, and won’t until they put it out at an upcoming scientific session, but Merck touted the results, saying that their big Phase III VICTORIA study hit the primary endpoint  — with vericiguat combined with available therapies reducing “the risk of the composite endpoint of heart failure hospitalization or cardiovascular death in patients with worsening chronic heart failure with reduced ejection fraction (HFrEF) compared to placebo when given in combination with available heart failure therapies.”
Depending on the hard data, and how it breaks out with the combinations used, this drug could pose a threat to Novartis’ blockbuster drug Entresto, currently at $1.6 billion while analysts expect peak sales to hit $4 billion.
The drug is a soluble guanylate cyclase (sGC) stimulator, which Bayer and Merck have had high hopes for. Evidently, so did cardiologists. Cowen’s last analysis set potential sales at $400 million in 2024, but that number could go up significantly now.
Cowen’s Steve Scala noted this morning:
Vericiguat could be a lucrative product for Merck, and one with potentially under-appreciated value. At Cowen’s Therapeutics Conference in September 2019, 80% of specialists anticipated a positive result from VICTORIA whereas only 51% of investors shared this optimism.
Investigators recruited more than 5,000 patients at more than 600 centers in 42 countries for this study — one of the most expensive propositions in R&D. Millions of people in the US suffer from heart failure with reduced ejection fraction when the failing heart fails to contract properly to eject blood into the system. Bayer holds ex-US rights to the drug and also stands to earn cash from the $1.1 billion in milestones Merck agreed on for their collaboration.
Remarkably, the drug was pushed into Phase III despite failing the mid-stage trial — though investigators flagged a success at the high dose of 10 mg. In VICTORIA, researchers started patients at 2.5 mg and then titrated up to 5 and then 10 mg.

Alk­er­mes forges $950M biotech buy­out deal in a bold bet on an ear­ly-stage CNS drug plat­form

Alkermes $ALKS is investing $100 million cash and committing up to $850 million more in milestones in a big wager on a very early-stage CNS discovery platform. And the biotech is adding $20 million more to fund next year’s new research work on the platform it’s acquiring in today’s buyout with an eye to expanding the research work in oncology.

The biotech, helmed by Richard Pops, is buying Rodin Therapeutics, which had focused early on Alzheimer’s disease. Pops’ buyout, though, isn’t focused solely on the most troublesome sector in pharma R&D.

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Left to right: Arthur Pappas, Robert Nelsen, Peter Kolchinsky Doug Cole and David Beier

In rare po­lit­i­cal for­ay, top biotech in­vestors urge Con­gress to re­ject drug pric­ing bill

Thirteen of the top biotech venture capitalists in the country wrote a letter last week warning lawmakers that if Congress passes a drug pricing bill House Speaker Nancy Pelosi has put before lawmakers, they won’t be able to invest in biomedical research at their current rate, and patients will suffer.

“If policies such as those included within H.R. 3, the Lower Drug Costs Now Act, are passed, our ability to continue to invest in future biomedical innovation will be severely constrained, thus crushing the hopes of millions of patient waiting for the next breakthroughs to treat or cure their cancers, rare genetic diseases, Alzheimer’s, or other serious and life-threatening conditions,” they wrote in a letter addressed to the highest-ranking Democrats and Republicans in the House and Senate and acquired by Endpoints News. 

Dicer­na scores broad, 'rest of liv­er' deal with No­vo Nordisk, bag­ging $225M in cash to hit some 30 tar­gets with RNAi plat­form

Turns out Dicerna wasn’t done with deals yet after locking in $200 million upfront from Roche for a hepatitis B cocktail two weeks ago.

Novo Nordisk has signed on as the latest partner to its GalXC RNAi platform, handing over $175 million in cash to claim any and all targets of interest in liver-related cardio-metabolic diseases that are not already reserved in previous pacts. The Danish drugmaker — which has signaled its interest to expand considerably beyond its core diabetes franchise into areas like NASH — is also purchasing $50 million worth of Dicerna’s equity at a 25% premium of $21.93 per share. More research payments and milestones extending to the billions are on the line.

Gene ther­a­py wins the in­side track at EMA; PPD files for IPO

→ Gene therapy maker Orchard Therapeutics has been granted an accelerated assessment for OTL-200 by the EMA’s Committee for Medicinal Products for Human Use (CHMP). The gene therapy — in development in partnership with the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) in Milan, Italy — being used towards the treatment of metachromatic leukodystrophy.

→ Pharmaceutical Product Development has announced that its parent company, PPD, Inc has submitted a draft to the SEC relating to the proposal of an IPO of the parent company’s common stock. Number of shares and price range have not yet been determined.

Pfiz­er gets biosim­i­lar ap­proved for Hu­mi­ra, set­ting up com­pe­ti­tion — in 2023

In the story lawmakers and drug pricing reform advocates have told about the drug industry, there are perhaps few greater villains than Humira and its maker AbbVie.

Between 2012 and 2018, AbbVie upped the drug’s annual after-rebates cost from $19,000 to $38,000 in the US, with sticker prices now over $60,000 per year — increases that led to accusations of price gouging, most recently from Democratic presidential frontrunner Elizabeth Warren.