Biogen Inc. (NASDAQ:BIIB) shares seesawed Thursday and Friday, propelled upward by data showing that aducanumab (BIIB037) cleared amyloid plaques and improved cognition in an exploratory analysis of a Phase Ib study to treat Alzheimer's disease, but then tempered by safety concerns after the data were presented at the Clinical Trials on Alzheimer's Disease (CTAD) meeting.
Investors' views of Biogen's data also were affected by a separate presentation late Thursday showing that beta amyloid-binding antibody solanezumab (LY2062430) from Eli Lilly and Co. (NYSE:LLY) failed to clear amyloid plaques in the Phase III EXPEDITION3 trial. Last month, Lilly said it would abandon solanezumab after it missed EXPEDITION3's primary endpoint, which measured cognitive decline. However, data presented Thursday evening showed the mAb did lead to a significant improvement in Clinical Dementia Rating-Sum of Boxes (CDR-SB) (p=0.004), the same endpoint Biogen is using in its ongoing Phase III study of aducanumab (see BioCentury Extra, Nov. 23).
Biogen added $4.24 to $289.54 on Thursday, rising sharply after abstracts containing some of the data were leaked. The shares continued to rise to as much as $306.98 on Friday before the safety data were presented, and Biogen ended the day off $1.79 to $287.75.
In one presentation at CTAD in San Diego, Biogen said each of four doses of aducanumab significantly reduced amyloid plaques vs. placebo after 54 weeks, as did a titration arm in which doses were increased. In an exploratory endpoint, the highest dose significantly improved CDR-SB scores over 54 weeks, as did the titration (p<0.05 vs. placebo for both). The top dose also significantly improved clinical decline as measured by Mini-Mental State Examination (MMSE) scores at 52 weeks.
The presentation disclosed three deaths in the 197-patient dose-escalation study, none of which were ruled treatment-related. Two were in the placebo arm. The most common serious adverse event was amyloid-related imaging abnormalities-edema (ARIA-E), which occurred in 55% of apolipoprotein E (APOE) epsilon 4 carriers receiving the top dose.
In a separate presentation on a 24-month extension of the study, Biogen reported five cases of ARIA-E in patients who switched from placebo or the lowest dose of aducanumab to a higher dose, including one subject with concurrent seizure and loss of pulse. The company said there were two deaths in the first year of the extension study, neither ruled treatment-related.
Biogen did not respond to inquiries regarding the SAEs. In 2014, the company said ARIA incidence was higher in the treatment arm of a Phase Ib study of aducanumab, particularly in patients expressing APOE4 (see BioCentury Extra, Dec. 2, 2014).
The company expects results in 2018 from the Phase III study of aducanumab.
Lilly's presentation showed that solanezumab did not significantly reduce amyloid deposition compared to placebo, although it did reduce plasma amyloid beta. On the study's primary endpoint, cognitive decline as measured by the 14-item AD Assessment Scale-Cognitive (ADAS-Cog14) scores at 80 weeks, solanezumab failed to show statistical significance vs. placebo (p=0.95). The mAb, which binds to soluble beta amyloid, did lead to a significant improvement of MMSE scores (p=0.014), as well as CDR-SB.
During a panel discussion at CTAD, Lilly consultant and University of Southern California Professor Paul Aisen called the data "our strongest evidence to date" to support the amyloid hypothesis. Although the EXPEDITION3 failure followed two previous studies that missed their primary endpoints, Aisen said the three studies showed a consistent but small benefit (see BioCentury Extra, Aug. 24, 2012).
Meanwhile, shares of AC Immune S.A (NASDAQ:ACIU) jumped sharply Friday after it released safety data for its crenezumab (RG7412) anti-amyloid beta mAb just before market close. It gained $2.88 (24%) to $14.93 on the day.
AC Immune said it observed no incidences of ARIA-E in a Phase Ib trial of crenezumab. The company also said an exposure-response model predicted that a 60 mg/kg dose of the mAb every four weeks would improve outcomes compared to smaller doses in previous studies.
Partner Roche (SIX:ROG; OTCQX:RHHBY) is evaluating the 60 mg/kg dose to treat prodromal or mild AD in the Phase III CREAD trial. AC Immune expects those results in 2020.
In 2014, Roche said crenezumab missed the primary endpoints of two Phase II trials to treat AD. The studies used what the pharma called a "high" dose of 15 mg/kg every four weeks and a "low" dose of 300 mg subcutaneously every other week (see BioCentury Extra, July 16, 2014).
Last month, John Hardy of University College London, a co-author of the amyloid hypothesis in 1992, told BioCentury the best test of the hypothesis will occur in mid-2017 when data read out from a Phase II/III study of verubecestat (MK-8931) from Merck & Co. Inc. (NYSE:MRK) to treat mild to moderate disease. The beta-site APP-cleaving enzyme 1 (BACE1) inhibitor acts upstream in the pathway and is thought to prevent production of amyloid rather than clear it (see BioCentury, Nov. 14).
AstraZeneca plc (LSE:AZN; NYSE:AZN) and Eli Lilly and Co. (NYSE:LLY) said they partnered to co-develop MEDI1814, a mAb against beta amyloid 42 which is in Phase I testing. Lilly will pay AstraZeneca $30 million up front.
The companies said the collaboration will build on their 2014 deal to co-develop AZD3293 (LY3314814), a beta-site APP-cleaving enzyme (BACE) inhibitor which is in Phase III for mild Alzheimer's dementia (see BioCentury Extra, Sept. 16, 2014).
Late Thursday, Lilly said its anti-amyloid beta mAb solanezumab (LY2062430) failed to clear amyloid plaques in the Phase III EXPEDITION3 study. The company had previously reported solanezumab missed the study's primary endpoint of improving cognition (see above).
AstraZeneca plc (NYSE:AZN; LSE:AZN) said FDA accepted and granted Priority Review to a BLA for durvalumab (MEDI4736) to treat locally advanced or metastatic urothelial carcinoma in patients who have progressed after one standard platinum-based regimen. Its PDUFA date is in 2Q17.
The human IgG1 mAb targeting PD-L1 has breakthrough therapy designation to treat PD-L1-positive inoperable or metastatic urothelial carcinoma.
AstraZeneca based the submission on data from the bladder cancer cohort of the Phase I/II Study 1108 to treat solid tumors. The company expects data in 2018 from the Phase III DANUBE trial, which is evaluating durvalumab alone and in combination with tremelimumab (CP-675) as first-line treatment of metastatic bladder cancer. Tremelimumab is a human mAb against cytotoxic T-lymphocyte associated protein 4 (CTLA4; CD152).
In May, FDA granted accelerated approval to rival PD-L1 inhibitor Tecentriq atezolizumab from the Genentech Inc. unit of Roche (SIX:ROG; OTCQX:RHHBY) to treat locally advanced or metastatic urothelial carcinoma that has progressed on or after platinum-based chemotherapy (see BioCentury Extra, May 18).
GlaxoSmithKline plc (LSE:GSK; NYSE:GSK) said Deborah Waterhouse will succeed Dominique Limet at CEO of Viiv Heathcare, its HIV-focused joint venture with Pfizer Inc. (NYSE:PFE) and Shionogi & Co. Ltd. (Tokyo:4507). Limet is to step down in March 2017. Waterhouse is SVP of primary care at GSK's U.S. Pharmaceuticals subsidiary.
Gene therapy company Spark Therapeutics Inc. (NASDAQ:ONCE) hired John Furey as COO, a newly created position. He was SVP and head of global operations at Baxalta Inc., which was acquired by Shire plc (LSE:SHP; NASDAQ:SHPG).
Cancer company OncoMed Pharmaceuticals Inc. (NASDAQ:OMED) said SVP and CMO Jakob Dupont will resign, effective on or about Jan. 1, 2017. The company is searching for a successor.
Neurodegeneration company Asceneuron S.A. (Lausanne, Switzerland) named J. Michael Ryan CMO. He was VP in the neuroscience development franchise and therapeutic area head for neurodegeneration at Novartis AG (NYSE:NVS; SIX:NOVN).
Sequencing company Illumina Inc. (NASDAQ: ILMN) named Sam Samad SVP and CFO, effective Jan. 6, 2017. He was SVP and corporate treasurer at Cardinal Health Inc. (NYSE:CAH).
Microbiome company Enterome Bioscience S.A. (Paris, France) named Jai Patel CMO. He was CMO and CSO at NephroGenex Inc. (Pink:NRXGQ).
Hematological company Kiadis Pharma N.V. (Euronext:KDS) named Arthur Lahr COO and CEO designate, effective Jan. 1. 2017. He is to succeed CEO Manfred Ruediger on April 1, 2017. Lahr has held several advisory and director roles since serving as chief strategy officer at Crucell N.V., which Johnson & Johnson (NYSE:JNJ) acquired in 2011.
Antifungal company F2G Ltd. (Manchester, U.K.) named John Rex CMO. He was SVP and head of infection, global medicines development at AstraZeneca plc (LSE:AZN; NYSE:AZN).
On Monday, Bayer AG (Xetra:BAYN) and Versant Ventures are expected to announce the launch of stem cell company BlueRock Therapeutics with an initial joint funding of $225 million. The company will develop therapies to treat Parkinson's disease and for regeneration of heart muscles after heart attacks.
BlueRock, which hasn't announced its headquarters, has licensed stem cell IP from Kyoto University. Shinya Yamanaka, a professor at the university's Institute for Integrated Cell-Material Sciences, shared the Nobel Prize in Physiology or Medicine in 2012 for his discovery that mature cells can be reprogrammed to become pluripotent. The newco also has partnered with researchers from the McEwen Center for Regenerative Medicine in Toronto and Memorial Sloan Kettering Cancer Center.
Only two biotech companies have been formed with at least $200 million in initial funding. Immunocore Ltd. (Abingdon, U.K.) raised $320 million in a series A round to develop its T cell receptor (TCR) targeting technology (see BioCentury Extra, July 16, 2015).
Also in 2015, neurodegenerative disease company Denali Therapeutics Inc. (San Francisco, Calif.) raised $217 million in an untranched series A round (see BioCentury Extra, May 14, 2015).
BlueRock is the second newco Bayer has formed to develop a potentially transformational technology. Last year, the pharma partnered with CRISPR Therapeutics AG (NASDAQ:CRSP) to form Casebia Therapeutics (Cambridge, Mass.). The JV aims to discover, develop and commercialize therapeutics based on the CRISPR-Cas9 gene editing technology to treat blood disorders, blindness and congenital heart disease, including hemophilia and Stargardt's disease (see BioCentury Extra, Dec. 21, 2015).
Clearside Biomedical Inc. (NASDAQ:CLSD), which had hoped to raise $75 million, settled for $36 million through the sale of 4 million shares at $9 in a follow-on underwritten by JPMorgan, Cowen, Stifel and Wedbush. The price is a 38% discount to Clearside's close of $14.43 on Wednesday, before the offering was announced after market.
Clearside lost 20% on Thursday, and slipped another $2.48 (22%) to $9.05 at 3:10p on Friday.
The company expects Phase III data in 2H17 for Zuprata (CLS-1001) to treat with non-infectious uveitis-associated macular edema, and plans to start Phase III testing in 1H17 of Zuprata in combination with Eylea aflibercept to treat retinal vein occlusion-associated macular edema.
Zuprata is a triamcinolone acetonide formulation delivered using Clearside's suprachoroidal space microinjector. Regeneron Pharmaceuticals Inc. (NASDAQ:REGN) markets Eylea, a human fusion protein that binds all forms of VEGF-A and placental growth factor (PGF; PlGF).
In June, Clearside priced its IPO at $7. It had hoped to price at $14-$16 (see BioCentury Extra, June 2).
EMA defended its Adaptive Pathways program on Thursday amid concerns from payers and technology assessment bodies that it could lower the evidentiary standards for drug approvals.
In 2014, EMA launched a pilot of Adaptive Pathways, which allows companies to market new products for limited, high unmet need populations based on promising early data, followed by iterative approvals for additional populations based on postmarket trials and real-world data.
At a workshop of stakeholders, representatives from European payers and HTA bodies said EMA's willingness to accept and review observational data as part of the iterative review process could weaken standards.
In response, EMA Senior Medical Officer Hans-Georg Eichler reiterated the agency was not lowering the evidentiary bar for its benefit-risk assessment of new drugs. He said Adaptive Pathways uses existing regulatory tools such as conditional approval and parallel EMA-HTA scientific advice to help companies and regulators plan ahead for how stakeholders will handle uncertainty.
Eichler also cautioned the workshop participants against taking "militant positions" on the usefulness of observational data when making decisions about efficacy or comparative effectiveness.
EMA is still accepting proposals for products that may fit into the program.
In its final report on the pilot, published in August, EMA said patients and payers should be more involved in early discussions, and more work was needed to develop a methodology for using real-world data (see BioCentury, August 15).
During Thursday's workshop, a European Commission representative said the agency would start discussions next year with European member states about the potential to create a pan-European HTA system. A proposal is expected by YE17.
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