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.

And…

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.

Biotech Half­time Re­port: Af­ter a bumpy year, is biotech ready to re­bound?

The biotech sector has come down firmly from the highs of February as negative sentiment takes hold. The sector had a major boost of optimism from the success of the COVID-19 vaccines, making investors keenly aware of the potential of biopharma R&D engines. But from early this year, clinical trial, regulatory and access setbacks have reminded investors of the sector’s inherent risks.

RBC Capital Markets recently surveyed investors to take the temperature of the market, a mix of specialists/generalists and long-only/ long-short investment strategies. Heading into the second half of the year, investors mostly see the sector as undervalued (49%), a large change from the first half of the year when only 20% rated it as undervalued. Around 41% of investors now believe that biotech will underperform the S&P500 in the second half of 2021. Despite that view, 54% plan to maintain their position in the market and 41% still plan to increase their holdings.

How to col­lect and sub­mit RWD to win ap­proval for a new drug in­di­ca­tion: FDA spells it out in a long-await­ed guid­ance

Real-world data is messy. There can be differences in the standards used to collect different types of data, differences in terminologies and curation strategies, and even in the way data is exchanged.

While acknowledging this somewhat controlled chaos, the FDA is now explaining how biopharma companies can submit study data derived from real-world data (RWD) sources in applicable regulatory submissions, including new drug indications.

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David Lockhart, ReCode Therapeutics CEO

Pfiz­er throws its weight be­hind LNP play­er eye­ing mR­NA treat­ments for CF, PCD

David Lockhart did not see the meteoric rise of messenger RNA and lipid nanoparticles coming.

Thanks to the worldwide fight against Covid-19, mRNA — the genetic code that can be engineered to turn the body into a mini protein factory — and LNPs, those tiny bubbles of fat carrying those instructions, have found their way into hundreds of millions of people. Within the biotech world, pioneers like Alnylam and Intellia have demonstrated just how versatile LNPs can be as a delivery vehicle for anything from siRNA to CRISPR/Cas9.

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No­vo CEO Lars Fruer­gaard Jør­gensen on R&D risk, the deal strat­e­gy and tar­gets for gen­der di­ver­si­ty

 

I kicked off our European R&D summit last week with a conversation involving Novo Nordisk CEO Lars Fruergaard Jørgensen. Novo is aiming to launch a new era of obesity management with a new approval for semaglutide. And Jørgensen had a lot to say about what comes next in R&D, how they manage risk and gender diversity targets at the trendsetting European pharma giant.

John Carroll: I’m here with Lars Jørgensen, the CEO of Novo Nordisk. Lars, it’s been a really interesting year so far with Novo Nordisk, right? You’ve projected a new era of growing sales. You’ve been able to expand on the GLP-1 franchise that was already well established in diabetes now going into obesity. And I think a tremendous number of people are really interested in how that’s working out. You have forecast a growing amount of sales. We don’t know specifically how that might play out. I know a lot of the analysts have different ideas, how those numbers might play out, but that we are in fact embarking on a new era for Novo Nordisk in terms of what the company’s capable of doing and what it’s able to do and what it wants to do. And I wanted to start off by asking you about obesity in particular. Semaglutide has been approved in the United States for obesity. It’s an area of R&D that’s been very troubled for decades. There have been weight loss drugs that have come along. They’ve attracted a lot of attention, but they haven’t actually ever gained traction in the market. My first question is what’s different this time about obesity? What is different about this drug and why do you expect it to work now whereas previous drugs haven’t?

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Pascal Soriot, AstraZeneca CEO (via Getty images)

UP­DAT­ED: FDA slaps As­traZeneca's MCL-1 can­cer drug with a hold af­ter safe­ty is­sue — 2 years af­ter Am­gen axed a trou­bled ri­val

There are new questions being posed about a class of cancer drugs in the wake of the second FDA-enforced clinical hold in the field.

Two years after the FDA hit Amgen with a clinical hold on its MCL-1 inhibitor AMG 397 following signs of cardiac toxicity, AstraZeneca says that regulators hit them with a hold on their rival therapy of the same class.

The pharma giant noted on clinicaltrials.gov that its Phase I/II study for the MCL-1 drug AZD5991 “has been put on hold to allow further evaluation of safety related information.”

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Sur­geons suc­cess­ful­ly at­tach pig kid­ney to a hu­man for the first time, us­ing tech from Unit­ed's Re­vivi­cor

In a first, researchers reportedly successfully transplanted a pig kidney into a human without triggering an immediate immune response this week. And the technology came from the biotech United Therapeutics.

Surgeons spent three days attaching the kidney to the patient’s blood vessels, but when all was said and done, the kidney appeared to be functioning normally in early testing, Reuters and the New York Times were among those to report. The kidney came from a genetically altered pig developed through United’s Revivicor unit.

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Leen Kawas (L) has resigned as CEO of Athira and will be replaced by COO Mark Litton

Ex­clu­sive: Athi­ra CEO Leen Kawas re­signs af­ter in­ves­ti­ga­tion finds she ma­nip­u­lat­ed da­ta

Leen Kawas, CEO and founder of the Alzheimer’s upstart Athira Pharma, has resigned after an internal investigation found she altered images in her doctoral thesis and four other papers that were foundational to establishing the company.

Mark Litton, the company’s COO since June 2019 and a longtime biotech executive, has been named full-time CEO. Kawas, meanwhile, will no longer have ties to the company except for owning a few hundred thousand shares.

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Sen. Richard Durbin (D-IL, foreground) and Sen. Richard Blumenthal (D-CT) (Patrick Semansky/AP Images)

Sen­a­tors back FDA's plan to re­quire manda­to­ry pre­scriber ed­u­ca­tion for opi­oids

Three Senate Democrats are backing an FDA plan to require mandatory prescriber education for opioids as overdose deaths have risen sharply over the past decade, with almost 97,000 American opioid-related overdose deaths in the past year alone.

While acknowledging a decline in overall opioid analgesic dispensing in recent years, the FDA said it’s reconsidering the need for mandatory prescriber training through a REMS given the current situation with overdoses, and is seeking input on the aspects of the opioid crisis that mandatory training could potentially mitigate.

Bris­tol My­ers pledges to sell its Ac­celeron shares as ac­tivist in­vestors cir­cle Mer­ck­'s $11.5B buy­out — re­port

Just as Avoro Capital’s campaign to derail Merck’s proposed $11.5 billion buyout of Acceleron gains steam, Bristol Myers Squibb is leaning in with some hefty counterweight.

The pharma giant is planning to tender its Acceleron shares, Bloomberg reported, which add up to a sizable 11.5% stake. Based on the offer price, the sale would net Bristol Myers around $1.3 billion.

To complete its deal, Merck needs a majority of shareholders to agree to sell their shares.