Why Biogen/Eisai's Aducanumab Failure Is Not The End Of Amyloid Hypothesis

Biogen and Eisai still have multiple programs testing amyloid-targeting therapies in the treatment of Alzheimer's disease, but pressure for Biogen to focus its efforts elsewhere are mounting after the partners discontinued Phase III studies for aducanumab.

Biogen and Eisai Co. Ltd. will continue to test anti-amyloid agents in the treatment of Alzheimer's disease even after the failure of their most advanced and highest-profile candidate aducanumab in Phase III, but suggestions that Biogen should focus its resources elsewhere are mounting after this latest setback.

The partners said on March 21 that they will discontinue the Phase III ENGAGE and EMERGE clinical trials testing aducanumab in patients with mild cognitive impairment due to Alzheimer's disease and in patients with mild Alzheimer's disease dementia based on a futility analysis by an independent data monitoring committee, which found that the trials were unlikely to meet their primary endpoints.

A Phase II safety study and a long-term extension of the Phase Ib study that convinced Biogen to take aducanumab into Phase III also will be terminated. The company and its partner will determine after looking at the ENGAGE and EMERGE data whether to initiate a planned Phase III study for the anti-amyloid-beta antibody in secondary prevention of Alzheimer's.

Biogen closed down 29.2% at $226.88 per share on March 21 after the announcement that its most advanced and closely watch late-stage development program will be discontinued, wiping out $18.6bn worth of the company's value.

The failure of aducanumab to significantly affect even mild cognitive impairment in early-stage Alzheimer's disease patients is not particularly surprising, since several anti-amyloid antibody candidates similarly have failed in previous clinical trials. However, Biogen has projected so much confidence in its program – and Alzheimer's disease has so much unmet need – that there was a lot of hope despite multiple sets of evidence to the contrary that aducanumab would work.

"Aducanumab now joins a long list of Alzheimer’s therapies that have failed to change the course of the disease, particularly those targeting beta-amyloid," William Blair analyst Matt Phipps wrote in a March 21 note.

"Despite the concerns with the amyloid hypothesis, we had hoped the Phase I data with aducanumab, particularly the correlation between removal of amyloid plaque as measured by PET scan and slowing of cognitive decline, would prove aducanumab could succeed where others have failed, but this hypothesis was obviously wrong," Phipps continued. "This is a setback for the Alzheimer’s field and patients, but will hopefully catalyze increased investment in novel targets to treat the devastating disease."

Biogen Pipeline Doesn't Excite Analysts, Investors

Aducanumab's failure leaves Biogen with a research and development pipeline that analysts describe as unexciting – including multiple amyloid-targeting agents – at a time when its multiple sclerosis (MS) franchise is projected to see sales decline and when its top-selling drug, Tecfidera (dimethyl fumarate), is facing patent challengers seeking to launch generics of the MS drug, though probably not before 2020. (Also see "Going Generic: Big Brands Poised To Lose Marketing Exclusivity In The US In 2019 " - Scrip, 15 Mar, 2019.) 

Even its much-hyped spinal muscular atrophy (SMA) drug Spinraza (nusinersen), partnered with Ionis Pharmaceuticals Inc., could see its blockbuster status challenged when the Novartis AG gene therapy Zolgensma for SMA launches later this year. (Also see "Novartis Pharma CEO Sees Zolgensma Supplanting Spinraza" - Scrip, 1 Feb, 2019.) Roche also is closing in on Biogen's SMA franchise with plans for mid-year filings seeking approvals of ridisplam. (Also see "Roche Makes Case For Its Oral SMA Drug Risdiplam As Filings Beckon" - Scrip, 6 Feb, 2019.)

Analysts expect Biogen to engage in more aggressive business development as a result of the aducanumab failure on top of the company's other challenges to build up a more interesting pipeline.

"Aducanumab was the key pipeline drug, and beyond it there was [elenbecestat (E2609)] and BAN2401, two other beta-amyloid related compounds," Mizuho Securities analyst Salim Syed said in a March 21 note. He added that the amyloid hypothesis in Alzheimer's disease is now dead, so investors should take elenbecestat, which inhibits beta-secretase cleaving enzyme (BACE) to block amyloid production, and the anti-amyloid beta protofibril antibody BAN2401 out of their models assessing Biogen's value.

Both candidates plus aducanumab are being developed in partnership with Eisai and the three assets are the foundation upon which Biogen has built its Alzheimer's-lead neurology focus. Biogen recently revealed that BAN2401 was moved from Phase II into Phase III development despite mixed mid-stage results. (Also see "Biogen To Launch Phase III Alzheimer’s Prevention Study " - Scrip, 29 Jan, 2019.) and (Also see "Biogen, Eisai Report BAN2401 Seemingly Positive In Alzheimer's; Others Skeptical" - Scrip, 26 Jul, 2018.)

Eisai announced after the aducanumab Phase III trial discontinuations were disclosed that the company and Biogen have initiated the Phase III ClarityAD /Study 301 testing BAN2401 versus placebo in 1,566 patients with mild cognitive impairment due to Alzheimer's disease.

"BACE inhibitors (like E2609) have not worked historically to further this argument, and BAN2401, is another beta-amyloid targeting compound," Syed noted. (Also see "Eisai/Biogen Remain In BACE Race As Alzheimer's Contenders Dwindle" - Scrip, 6 Jun, 2018.)

Who Might Biogen Buy – Or Buy Biogen?

Syed suggested several companies that are potential acquisition targets for Biogen, including Sage Therapeutics Inc., which won US FDA approval on March 19 for its first drug, the postpartum depression (PPD) therapy Zulresso (brexanolone). Sage also has a promising oral drug in Phase III development with a similar mechanism of action, SAGE-217, for PPD and major depressive disorder (MDD). (Also see "Zulresso Is Sage’s First Step In Postpartum Depression Treatment" - Scrip, 19 Mar, 2019.)

Among other companies with late-stage and commercial neurology assets that Biogen investors may see as favorable acquisition targets, Syed named Neurocrine Biosciences Inc., Acadia Pharmaceuticals Inc., Biohaven Pharmaceutical Holding Co. Ltd., Alder BioPharmaceuticals Inc. and Sarepta Therapeutics Inc. The company previously has noted that it wants to increase its investments in gene therapy, even after the recently announced deal to acquire Nightstar Therapeutics PLC for $877m in cash. (Also see "Biogen By Buying Nightstar Targets Ophthalmology As Emerging Growth Area" - Scrip, 4 Mar, 2019.)

"Investors wanted Biogen to buy assets ahead of this [aducanumab] news for this very scenario. The company admittedly wasn't too active on this front, at least not enough to move the needle," he wrote. "Today's news definitely weakens Biogen's seat at the negotiation table, and any strategics that Biogen engages with at this point will know that."

Syed said Biogen may be a more attractive acquisition target itself with the aducanumab risk removed from its pipeline, but noted the Tecfidera intellectual property risk and coming Spinraza competition as issues that may also impact the company's value in the eyes of purchasers.

Morningstar analyst Karen Andersen was more optimistic about Biogen's prospects going forward, however, pointing to multiple 2019 catalysts in a March 21 note – approval for the MS drug Vumerity (diroximel fumarate), which may show better gastrointestinal tolerability versus Tecfidera in an ongoing head-to-head trial, and Phase II data in treatment-resistant epilepsy for Tysabri (natalizumab) and for the anti-tau antibody BIIB092 in progressive supranuclear palsy.

BTIG analyst Thomas Shrader pointed to Vumerity and other R&D programs as well, but wasn't particularly enthusiastic about any of the assets in a March 21 note.

"We like the GI friendly Tecfidera (GI news mid-year) and the stroke drug (BIIB093; in P3), but neither is really exciting. Most of the rest of the pipeline is novel and high-risk medicine – remyelination [in MS] and such," Shrader wrote. "We expect BAN2401 (always weaker data) will be stopped as well." (Also see "Alzheimer's Early Approval? Skepticism Over Biogen/Eisai's BAN2401 Data Clouds Chances" - Pink Sheet, 26 Jul, 2018.)

Amyloid Hypothesis Remains In Play Despite Setbacks

In addition to Biogen and Eisai's partnered programs for the amyloid-targeting antibody BAN2401 and BACE inhibitor elebecestat, the Phase III Alzheimer's disease pipeline includes two other amyloid-focused programs. They are ALZT-01, a small molecule designed to block amyloid beta aggregation and polymerization in the brain from AZTherapeutics Inc., and Roche's anti-amyloid antibody gantenerumab, developed in partnership with MorphoSys AG. (Also see "Roche In New Phase III Bet On MorphoSys' Anti-Amyloid Agent" - Scrip, 7 Mar, 2017.)

However, Roche's amyloid-targeting antibody crenezumab developed in collaboration with AC Immune SA recently came to the same end as aducanumab. The partners discontinued two Phase III studies for crenezumab in January after an interim analysis found that the antibody was unlikely to succeed if the trials were continued to their conclusion. (Also see "AC Immune/Roche Drop Crenezumab After Phase III CREAD Alzheimer's Failure" - Scrip, 30 Jan, 2019.)

Aducanumab and crenezumab joined 26 other antibodies, vaccines, peptides and small molecules seeking to block amyloid formation or clear it from the brain, which were all suspended at various stages of preclinical through Phase III development, according to a review of the Biomedtracker database.

The Biogen/Eisai and Roche/AC Immune candidates followed the same path as other high-profile, late-stage antibody therapeutics. Eli Lilly & Co.'s solanezumab flopped in Phase III in 2016. (Also see "Lilly’s Solanezumab Fails, But The Surprise Would Have Been Success" - Scrip, 23 Nov, 2016.) Pfizer Inc., Johnson & Johnson and partners pulled the plug on bapineuzumab in 2012. (Also see " Pfizer and partners pull plug on bapineuzumab for Alzheimer's after second Phase III failure " - Scrip, 7 Aug, 2012.)

Also, development has been suspended for 15 different compounds targeting BACE, including three late-stage drugs whose development ended in 2018 – Merck & Co. Inc.'s verubecestat in February, J&J and Shionogi & Co. Ltd.'s atabecestat in May, and AstraZeneca PLC and Lilly's lanabecestat in June. (Also see "M&A Pressure Mounts For Merck & Co After Alzheimer's Drug Dismissed" - Scrip, 14 Feb, 2018.) and (Also see "More Alzheimer's Pain As J&J Pulls Plug On BACE Inhibitor" - Scrip, 18 May, 2018.)

Alternative Amyloid, Alzheimer's Approaches

ProMIS Neurosciences Inc. Chief Medical Officer James Kupiec, who worked on the clinical trials for bapineuzumab during his tenure at Pfizer, said in an interview with Scrip that the now-failed amyloid-targeting antibodies, including BACE inhibitors, all went after the wrong amyloid target.

Kupiec, who was vice president and global clinical leader for Parkinson’s disease as well as clinical head of the Neuroscience Research Unit at Pfizer before he joined ProMIS last year, noted that the late-stage and discontinued anti-amyloid candidates targeted amyloid plaques. (Also see "Executives On The Move: Defectors From GSK, Pfizer, Shire, Dr Reddy's Get New Posts" - Scrip, 27 Sep, 2018.) Those antibodies were created before research showed amyloid oligomers may be a better target and before there were technology platforms, like the one used by ProMIS, that could develop antibodies capable of precisely targeting toxic amyloid oligomers, he said.

That's what ProMIS' lead candidate PMN310, which is in preclinical development, is designed to do. The company is "hoping to get into the clinic as soon as possible" and is in "serious discussions with a lot of large pharma companies," Kupiec said.

Meanwhile, AgeneBio Inc. is in Phase III testing a drug with a completely different mechanism of action altogether. The private company has a $20m National Institutes of Health (NIH) grant to help fund its 830-patient Phase III trial for AGB101, which enrolled its first patient in January.

The drug is a low dose of the anti-epileptic therapy levetiracetam, which targets SV2A, a synaptic vesicle membrane protein. AGB101 is a proprietary, extended-release, once-daily formulation of levetiracetam dosed at one-twelfth of what's given to treat epilepsy.

AgeneBio's candidate is being studied in the treatment of mild cognitive impairment in Alzheimer's disease based on research from the lab of company CEO and founder Michela Gallagher at Johns Hopkins University that hypothesizes a restoration of normal brain function with AGB101 may significantly slow the progression of Alzheimer's.

AgeneBio is talking to investors and pharma partners in an effort to secure more funding for the Phase III study, which may be registrational, since AGB101 is based on a known, approved drug, Gallagher told Scrip in an interview.