Biogen CEO Michel Vounatsos

Biogen saw its shares surge nearly 40% in morning trading today after surprising analysts by announcing that it plans to file for FDA approval of the Alzheimer’s disease candidate aducanumab, being co-developed with Eisai, despite halting two failed Phase III studies of the drug in March.

Biogen and Eisai now assert that one of those trials, the EMERGE Study (NCT02484547) met its primary endpoint showing a significant reduction in clinical decline—a result the companies now say is supported by results from a subset of patients in the other halted Phase III study, ENGAGE (NCT02477800).

That subset of patients received “sufficient” exposure to aducanumab at the trial’s high dose, and as a result “experienced significant benefits on measures of cognition and function such as memory, orientation, and language,” according to Biogen and Eisai.

“Patients also experienced benefits on activities of daily living including conducting personal finances, performing household chores such as cleaning, shopping, and doing laundry, and independently traveling out of the home,” the companies added.

Biogen said it plans to file a BLA in early 2020 based on talks with the FDA, and will also continue dialogue with regulators in international markets that include Europe and Japan. The BLA submission will include the complete set of data from the Phase III studies, as well as data from the Phase I/Ib studies.

If approved, aducanumab would be the first therapy indicated for reducing clinical decline in people with Alzheimer’s disease, and would also be the first therapy to tie improved clinical outcomes to removing amyloid beta.

Investors responded to the planned FDA filing by sending shares of Biogen (BIIB) on NASDAQ zooming at the start of trading today to $310 a share—up 39% from yesterday’s closing price of $223.51—before the price dipped to $286.88 as of 3:20 p.m., still up 28%.

New analysis

Biogen and Eisai said their about-face followed a new analysis of a larger dataset from EMERGE and ENGAGE, both of which were ended in March after a futility analysis. That initial futility analysis was based on data available as of December 26, 2018, from 1,748 patients who had the opportunity to complete the 18-month study period and predicted that both studies were unlikely to meet their primary endpoint upon completion.

After EMERGE and ENGAGE were ended, additional data from the studies became available, Biogen said, resulting in a larger dataset of 3,285 patients, of whom 2,066 had the opportunity to complete the full 18 months of treatment.

A new analysis of the larger dataset showed effective pharmacological and clinical activity, according to Biogen—namely, that aducanumab showed dose-dependent effects in reducing brain amyloid and in reducing clinical decline as assessed by the pre-specified primary endpoint Clinical Dementia Rating-Sum of Boxes (CDR-SB) as of week 78 following treatment. Patients treated with high dose aducanumab showed a significant 23% reduction of clinical decline from baseline in CDR-SB scores at 78 weeks compared with placebo.

EMERGE trial patients treated with high-dose aducanumab also showed a consistent reduction of clinical decline as measured by three pre-specified secondary endpoints:

  • The Mini-Mental State Examination (MMSE; 15% versus placebo)
  • The AD Assessment Scale-Cognitive Subscale 13 Items (ADAS-Cog 13; 27% versus placebo)
  • The AD Cooperative Study-Activities of Daily Living Inventory Mild Cognitive Impairment Version (ADCS-ADL-MCI; 40% versus placebo.

Imaging of amyloid plaque deposition in EMERGE showed that amyloid plaque burden was reduced with low and high dose aducanumab compared to placebo at 26 and 78 weeks. Additional biomarker data of tau levels in the cerebrospinal fluid supported these clinical findings, Biogen said.

“Providing new hope”

“This large dataset represents the first time a Phase III study has demonstrated that clearance of aggregated amyloid beta can reduce the clinical decline of Alzheimer’s disease, providing new hope for the medical community, the patients, and their families,” stated Anton Porsteinsson, MD, William B. and Sheila Konar professor of psychiatry, neurology and neuroscience, director of the University of Rochester Alzheimer’s Disease Care, Research and Education Program (AD-CARE), and principal investigator.

Biogen added that data from a subset of ENGAGE supported the findings from EMERGE, while acknowledging that ENGAGE did not meet its primary endpoint, which was also change from baseline in CDR-SB score as of week 78 after treatment.

“With such a devastating disease that affects tens of millions worldwide, today’s announcement is truly heartening in the fight against Alzheimer’s. This is the result of groundbreaking research and is a testament to Biogen’s steadfast determination to follow the science and do the right thing for patients,” Biogen CEO Michel Vounatsos said in a statement. “We are hopeful about the prospect of offering patients the first therapy to reduce the clinical decline of Alzheimer’s disease and the potential implication of these results for similar approaches targeting amyloid beta.”

One analyst, however, expressed caution until additional details about the data emerge at an upcoming conference: “We would like to wait until BIIB presents a fuller data set at the Clinical Trials in Alzheimer’s Disease (CTAD) conference in San Diego, CA [set for December 4-7] before we may be able to recommend a more active position,” Canaccord Genuity biotechnology analyst Sumant Kulkarni wrote in a note to investors.

Biogen and Eisai hope to succeed where numerous other drug developers have failed in the long struggle to create successful new drugs for Alzheimer’s disease. Only a handful of drug successes have ever reached the market, and even they have merely slowed progression of symptoms by 6 to 12 months.

A 2014 Cleveland Clinic study found a 99.6% failure rate of clinical trials for Alzheimer’s disease drug candidates between 2002 and 2012. That study found high attrition rates for Alzheimer’s disease treatments, with 72% of agents failing in Phase I, 92% failing in Phase II, and 98% failing in Phase III.

Eisai joined Biogen in partnering on aducanumab in 2017—10 years after Biogen (then called Biogen Idec) began developing the drug under license from its original developer, Zurich-based Neurimmune. “Today’s news marks a substantial advancement in neuroscience. This is long-awaited progress in finding a treatment for Alzheimer’s disease,” said Roger Nitsch, CEO and president of Neurimmune, said in a company statement.

Analyst calls for clarity

Biogen announced its planned filing for aducanumab a day after Kulkarni voiced concerns that the biotech giant needed to give investors clearer insight into its longer-range planning and development efforts beyond quarterly results.

“Investors need to see clearer articulation of specifics or action on strategy/offense,” Kulkarni commented. “We believe most investors will not be focused on 3Q performance, unless it is perceived to be ‘bad’ by investors.”

In results also released today, Biogen said it ended the third quarter with a 7% increase in net income, to $1.546 billion from $1.444 billion in Q3 2018, on revenue that rose 5% over the year-ago quarter, to $3.6 billion. Among drivers of third-quarter revenue growth:

  • Multiple sclerosis drugs including the Genentech (Roche)-marketed Ocrevus® (ocrelizumab), for which Biogen received $188 million in royalties, up 37% from $137 million in the year-ago quarter.
  • The continued global launch of spinal muscular atrophy (SMA) treatment Spinraza® (nusinersen), which contributed $547 million in revenues in Q3 2019, up 17% from $468 million in July–September 2018.
  • Biosimilars revenues, which rose 36% to $184 million, from $135 million in Q3 2018, primarily driven by IMRALDI, a biosimilar to AbbVie’s Humira® (adalimumab).

In a research note, Kulkarni and Canaccord Genuity associate Jia Min, CFA, expressed what they said was a consensus view among investors: “We think a majority of investors believe BIIB needs to do something (anything?) to step out of the rut that the stock is in after the failure of aducanumab, followed to a lesser extent by elenbecestat,” another Biogen-Eisai Alzheimer’s disease candidate.

Last month, Eisai and Biogen halted a pair of Phase III trials of elenbecestat—MISSION AD1 (NCT02956486) and MISSION AD2 (NCT03036280)—at the recommendation of the trials’ Data Safety Monitoring Board.

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