Bio­gen, Ei­sai fight back against ac­cu­sa­tions their big BAN2401 study was skewed -- but this fight is­n't over yet

Af­ter get­ting slapped hard by crit­ics for the way it han­dled their re­cent tri­al sum­ma­ry for their Alzheimer’s drug BAN2401, Ei­sai and their part­ners at Bio­gen $BI­IB turned up at an Alzheimer’s con­fer­ence in Barcelona to present their de­fense of the da­ta af­ter crunch­ing the num­bers again. But it’s not play­ing their way, with Bio­gen’s stock slid­ing as key an­a­lysts re­fused to for­give or for­get.

The two com­pa­nies man­aged to lose a lot of cred­i­bil­i­ty when an­a­lysts found out that at the re­quest of reg­u­la­tors — deeply con­cerned about the threat of ARIA-E — in­ves­ti­ga­tors pulled high-risk APOE4 car­ri­ers out of the high­est treat­ment arm in their study, cre­at­ing an im­bal­ance be­tween the drug group and place­bo that may have skewed the re­sults in the drug’s fa­vor.

To­day, the re­searchers are back af­ter ex­tract­ing the spe­cif­ic APOE4 re­sults in a close­ly-watched sub­group analy­sis, con­clud­ing:

At the high­est treat­ment dose, APOE4 car­ri­ers treat­ed with BAN2401 saw 63% less de­cline in dis­ease pro­gres­sion, while non-car­ri­ers saw 7% less de­cline, as mea­sured by AD­COMS ver­sus place­bo at 18 months. These re­sults sug­gest that the treat­ment ef­fect for the 10 mg/kg bi-week­ly dose is re­lat­ed to treat­ment with BAN2401 and not due to an im­bal­ance in sub­ject al­lo­ca­tion by APOE4 sta­tus. (Em­pha­sis added.) In ad­di­tion, the pooled 10 mg/kg bi-week­ly and 10 mg/kg month­ly dos­es re­sult in less de­cline on AD­COMS ver­sus place­bo at 18 months (over­all; 21%, APOE4 car­ri­ers; 25%, APOE4 non-car­ri­ers; 6%).

Clin­i­cal Ef­fects in APOE4 Car­ri­ers and Non-car­ri­ers at 18 Months (Page 20, Ei­sai slides)

Bio­gen’s shares dropped 2.6% on the lat­est da­ta. Why?

Both com­pa­nies clear­ly came out of the APOE4 con­tro­ver­sy with lost cred­i­bil­i­ty. Get­ting it back won’t be easy. And that was ev­i­dent in some re­marks from promi­nent an­a­lysts.

Baird’s Bri­an Sko­r­ney:

While the pre­sen­ters claim that this analy­sis re­solves out­stand­ing ques­tions around the mis­matched al­lo­ca­tion of APOE4+ pa­tients be­tween place­bo and treat­ment groups, we con­tin­ue to think that is­sues with tri­al de­sign and the fact of the im­bal­ance make the da­ta im­pos­si­ble to in­ter­pret, hence we find it dif­fi­cult to draw any con­clu­sions, much less the pos­i­tive ones Bio­gen and Ei­sai are in­fer­ring.

Count Ge­of­frey Porges, a skep­tic, as deeply dis­ap­point­ed by what was on dis­play to­day.

In our view this da­ta is con­fus­ing, sug­gest­ing on­ly lim­it­ed val­ue for BAN2401 in the car­ri­er pop­u­la­tion, while the small num­ber of pa­tients re­main­ing on drug at the 18-month time point and lack of clear dose re­spons­es di­min­ish the re­li­a­bil­i­ty of this dataset.

We are sur­prised by the lack of con­sis­tent ef­fect by ApoE4 sub­type, par­tic­u­lar­ly fol­low­ing ad­u­canum­ab da­ta ear­li­er this morn­ing show­ing rel­a­tive­ly con­sis­tent ef­fect in both car­ri­er and non-car­ri­er pop­u­la­tions. Ad­di­tion­al­ly we are dis­ap­point­ed that the ef­fect of low­er BAN2401 dose co­horts was not in­clud­ed in this analy­sis.


Ei­sai showed that the low­er pro­por­tion of ApoE4+ sub­jects in the ac­tive drug arm com­pared to place­bo ac­tu­al­ly di­lut­ed BAN2401’s ef­fect since near­ly all of the ef­fi­ca­cy was dri­ven by the ben­e­fit in the ApoE4+ sub­pop­u­la­tion. How­ev­er, the num­ber of sub­jects re­main­ing in the analy­sis at 18 months was small (n=77 to­tal) and there were just 10 ApoE4+ sub­jects in­clud­ed in this analy­sis.

Ex­pect plen­ty of ad­di­tion­al feed­back on this one. All sub­group analy­sis is sub­ject to ques­tion. Some ob­servers have al­ready not­ed that you can’t pull out these com­par­isons on enough pa­tients to of­fer a clear pic­ture on out­comes rel­a­tive to APOE4. The com­pa­nies al­so came up with a new end­point to as­sess, which isn’t al­ways en­dorsed. And the high dose was clear­ly linked to a much high­er rate of ARIA-E, with 10% and 14% of the pa­tients in the two high­est dos­es suf­fer­ing from brain swelling, which won’t help its chances.

Bio­gen has a tremen­dous amount at stake here. There’s been a grow­ing cho­rus of crit­ics who say the da­ta are in­creas­ing­ly clear that symp­to­matic pa­tients can’t sig­nif­i­cant­ly ben­e­fit from any drug tar­get­ing amy­loid be­ta. And that makes their big play on ad­u­canum­ab in­creas­ing­ly risky.

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.