One of the quarter's most eagerly anticipated data events came up short, as Celladon Corp. (NASDAQ:CLDN) plummeted $11.04 (81%) to $2.64 on Monday after its Mydicar gene therapy missed the primary and secondary endpoints vs. placebo in the CUPID2 Phase IIb trial to treat heart failure.
The recombinant adeno-associated viral (AAV) vector containing the gene for ATPase Ca++ transporting cardiac muscle slow twitch 2 (ATP2A2; SERCA2A) missed the primary endpoint of reducing time to heart failure-related hospitalizations or ambulatory treatment (HR 0.93; 95%CI: 0.53, 1.65, p=0.81). Mydicar also missed the trial's secondary endpoint, time to all-cause death or need for a heart transplant or circulatory support device. Celladon is conducting PCR analysis of patient biopsies to determine whether Mydicar was present in cardiomyocytes, which could signal what role the delivery mechanism may have played in the study results.
Multiple buysiders previously told BioCentury the Phase IIb data would either be a home-run or a strikeout (see BioCentury, April 6).
Celladon had $84.9 million in cash on Dec. 31, 2014. The company said it is still evaluating whether to advance Mydicar in heart failure; it will continue a Phase II trial of a higher dose of Mydicar to treat heart failure, and has run preclinical studies to treat pulmonary hypertension. The company also has a preclinical stem cell therapy candidate for myocardial infarction.
Monday's broader biotech selloff makes it impossible to discern the effect -- if any -- Celladon's news had on other gene therapy stocks. uniQure N.V. (NASDAQ:QURE) lost $0.36 to $25.73, bluebird bio (NASDAQ:BLUE) shed $4.14 to $132.12 and Spark Therapeutics Inc. (NASDAQ:ONCE) lost $7.46 (12%) to $53.93. Those companies aim primarily to treat monogenic diseases, while Mydicar was tested to treat a complex condition.
Overall on Monday the BioCentury 100 index shed 4.3%. The NASDAQ slipped 0.6% and the DJIA lost 0.2%.
Before it reported data on Sunday, Celladon shares had already fallen by more than 50% to Friday's close of $13.68 from a 52-week high of $28.25 in intraday trading March 20 (see BioCentury, April 27).
Celgene Corp. (NASDAQ:CELG) exercised its option to acquire Quanticel Pharmaceuticals Inc. (San Francisco, Calif.) for $100 million up front. Celgene gains Quanticel's platform to perform single-cell genomic analysis of tumors along with preclinical oncology candidates that target undisclosed epigenetic modifiers.
Celgene received the option to acquire Quanticel under a 2011 deal that also gave it an undisclosed equity stake. Quanticel's shareholders, including founding investor Versant Ventures, are eligible for $385 million in R&D and regulatory milestones (see BioCentury, Nov. 14, 2011).
Multiple candidates from Quanticel's pipeline are due to enter clinical testing in early 2016. Quanticel CEO Steve Kaldor declined to provide further details but said its pipeline aligns with Celgene's more mature epigenetic portfolio.
The acquisition is slated to close this year and Celgene expects the deal to be neutral to its 2015 guidance. The company was off $4 to $114.71 on Monday.
Shenzhen Hepalink Pharmaceutical Co. Ltd. (Shenzhen, China) gained exclusive development and commercialization rights to RVX-208 from Resverlogix Corp. (TSX:RVX) in greater China.
Resverlogix President and CEO Donald McCaffrey told BioCentury the deal offers an opportunity to enter the China market with a global partner and enough capital to pursue several new indications for RVX-208. Shenzhen Hepalink will be responsible for all development costs in China, Hong Kong, Taiwan and Macau.
Next half, Resverlogix plans to begin a Phase III trial of the inhibitor of the BET family of bromodomain-containing proteins, including bromodomain containing 4 (BRD4), to treat cardiovascular disease in patients with diabetes and low HDL. McCaffrey said the company plans to complete regulatory submissions by 2020 for RVX-208 in China to reduce major adverse cardiac events (MACE) in diabetes patients. RVX-208 also is in development for chronic kidney disease (CKD), Alzheimer's disease (AD) and an undisclosed Orphan indication.
Shenzhen Hepalink agreed to price RVX-208 at 110% of the manufacturing cost. Resverlogix also granted Shenzhen Hepalink an option to manufacture and distribute products outside greater China that include RVX-208.
Hepalink will take a C$35 million (US$28.7 million) equity stake in Resverlogix through the purchase of 13.3 million shares and 1 million warrants at C$2.67. Hepalink is entitled to nominate one member for Resverlogix's board.
Existing shareholder Eastern Capital Ltd. also will take an additional C$15 million (US$12.3 million) equity stake in Resverlogix through the purchase of shares and warrants at C$2.67.
Resverlogix is eligible for more than $400 million in sales milestones and royalties from Hepalink. The deal is expected to close in June.
Resverlogix gained C$0.18 to C$2.87 on Monday.
Roche (SIX:ROG; OTCQX:RHHBY) partnered with 4D Molecular Therapeutics LLC (San Francisco, Calif.) to use 4D's Directed Vector Evolution platform to develop next-generation adeno-associated viral (AAV) vectors.
4D co-founder and CEO David Kirn said the partners will target a series of undisclosed monogenic diseases. Kirn said 4D will generate the vectors and optimize them for specific tissue types and transgene payloads, while Roche will perform preclinical and clinical studies, and is responsible for global commercialization.
Kirn would not disclose financial terms but said 4D received an upfront cash payment, and is eligible for milestones and royalties. He said 4D expects to deliver patented vectors to Roche within one year.
4D uses its platform to generate vectors that can evade host immunity and are designed to target and penetrate specific tissues (see BioCentury, July 14, 2014).
BioMarin Pharmaceutical Inc. (NASDAQ:BMRN) completed the submission of a rolling NDA to FDA for drisapersen (PRO051) to treat a genetically defined subset of patients with Duchenne muscular dystrophy (DMD).
Drisapersen, an antisense oligoribonucleotide that induces exon 51 skipping on the dystrophin gene, has Fast Track and breakthrough therapy designations from FDA, and Orphan Drug designation in the U.S. and EU. BioMarin said that in about 13% of DMD patients, skipping of exon 51 restores the proper dystrophin reading frame.
The candidate was central to BioMarin's acquisition of Prosensa Holding N.V., which was announced last November and completed in January. Prosensa had regained rights to drisapersen from GlaxoSmithKline plc (LSE:GSK; NYSE:GSK) after it missed the primary endpoint in a Phase III study in 2013 (see BioCentury, Dec. 8, 2014).
BioMarin expects to submit an MAA to EMA for drisapersen this summer. BioMarin was off $3.31 to $116.97 on Monday.
The board of Mylan N.V. (NASDAQ:MYL) unanimously rejected an unsolicited bid from Teva Pharmaceutical Industries Ltd. (NYSE:TEVA) to acquire the company for $82 per share, or $40.1 billion in cash and stock. Mylan said the offer "grossly undervalues" the company, reiterated concerns that the combination may violate anti-trust regulations, and stood by its existing offer to acquire Perrigo Co. plc (NYSE:PRGO; Tel Aviv:PRGO), which Perrigo has rejected. Teva said it remains committed to its offer, which it said is contingent on Mylan not acquiring Perrigo. Mylan dipped $4.34 to $71.72 on Monday, while Teva lost $2.78 to $61.63 and Perrigo shed $4.61 to $188.28 in New York amid a broader selloff for biotechs.
Swedish Orphan Biovitrum AB (SSE:SOBI) rose SEK21.70 (19%) to SEK133.40 after confirming it received a takeover bid from an undisclosed company. Swedish Orphan has partnerships with Pfizer Inc. (NYSE:PFE) and Biogen Inc. (NASDAQ:BIIB) in hemophilia. Pfizer and Biogen declined to comment on the takeover bid.
Aerocrine AB (SSE:AERO) confirmed it is discussing the sale of the company with an undisclosed third party but did not comment on terms of a potential offer. The diagnostics company lost SEK0.04 to SEK2.05 on Monday.
Diagnostics company Invitae Corp. (NYSE:NVTA) named Robert Nussbaum CMO, effective Aug. 1. Nussbaum was chief of the division of genomic medicine at the University of California San Francisco Medical Center; he will continue clinical activities as a volunteer physician at UCSF.
Gene editing company Editas Medicine (Cambridge, Mass.) hired Vic Myer as CTO, a newly created position. Myer was an executive director and the Cambridge site head for the developmental and molecular pathways department at the Novartis Institutes for BioMedical Research (NIBR).
Rare disease play Amicus Therapeutics Inc. (NASDAQ:FOLD) named David Allsop SVP of international, effective Monday. Allsop was SVP of the Europe and Canada commercial teams at Biogen Inc. (NASDAQ:BIIB).
Cancer company Synta Pharmaceuticals Corp. (NASDAQ:SNTA) promoted EVP and COO Chen Schor to president, CEO and director, effective May 7. Schor succeeds Anne Whitaker.
Autoimmune play La Jolla Pharmaceutical Co. (NASDAQ:LJPC) named Lakhmir Chawla CMO, effective July 1. Chawla is an associate professor of medicine at The George Washington University.
Healthcare services company BioScrip Inc. (NASDAQ:BIOS) appointed Jeffrey Kreger SVP, CFO and treasurer, effective April 27. Kreger was SVP of finance at LHC Group Inc. (NASDAQ:LHCG).
Research services company SynGen Inc. (Sacramento, Calif.) hired Chuck Novak as CFO and Paul Hoseit as SVP of R&D. Novak was CFO at ConQuip Inc. (Rancho Cordova, Calif.), while Hoseit was VP of system R&D at Volcano Corp. (Rancho Cordova, Calif.).
FDA reviewers questioned "both the existence and the magnitude of an overall benefit" of talimogene laherparepvec from Amgen Inc. (NASDAQ:AMGN) in briefing documents posted in advance of an April 29 joint meeting of its Cellular, Tissue, and Gene Therapies Advisory Committee and Oncologic Drugs Advisory Committee.
The modified herpes simplex virus type 1 (HSV-1) carrying GM-CSF is under FDA review to treat metastatic melanoma, with an Oct. 27 PDUFA date. Amgen based its BLA primarily on a Phase III open-label trial comparing talimogene to GM-CSF; the latter was under investigation to treat melanoma when the study began. BioVex Inc. began the Phase III trial in 2009; Amgen acquired the company in 2011.
In the trial, talimogene met the primary endpoint of showing a higher durable response rate vs. GM-CSF (15.6% vs. 1.4%; p<0.0001), but not the secondary endpoint of overall survival (23.3 months vs. 18.9 months, p=0.051).
Reviewers cited concerns with the study design and results, and questioned the appropriateness of the comparator, the potential for investigator bias, clinical meaningfulness of the primary endpoint, lack of clear effect on OS and limited evidence of a systemic effect.
The reviewers asked the committees to vote on "only whether the available evidence would support traditional approval" because they said Amgen's BLA did not explain how the data could support accelerated approval.
Along with the briefing documents, the agency published two patient testimonials and a letter from the National Patient Advocate Foundation in support of talimogene.
Researchers at the Salk Institute for Biological Studies have used gene editing to eliminate mutations in mitochondrial DNA in mice. The findings are likely to fuel the debate about germline gene editing, which has raised concerns about the ethics of altering DNA that is passed to future generations, even for heritable diseases for which no treatment is available (see BioCentury Innovations, March 26).
In the study, published in Cell, researchers used two techniques, involving either mitochondrially-targeted restriction nucleases or transcription activator-like effector nucleases (TALENs), to eliminate specific mitochondrial DNA sequences in mouse oocytes and, separately, in one-cell mouse embryos. The mitochondrial changes were transmitted to the first generation of mice. In addition, the Salk group used the technique in mammalian oocytes to edit mutations in human mitochondrial genes responsible for the mitochondrial diseases Leber's hereditary optic neuropathy and dystonia and neurogenic muscle weakness, ataxia and retinitis pigmentosa.
In February, the U.K. became the first country to legalize the use of mitochondrial replacement techniques, which involve using healthy donor mitochondrial DNA to replace mutated mitochondrial DNA during IVF. The authors of the Cell study claim the gene editing approach is technically simpler than mitochondrial replacement, and avoids the ethical concerns of using donor oocytes.
Manipulating mitochondrial DNA in human oocytes has met with similar controversy to editing of nuclear DNA in germline cells, and is not legal in the U.S. for use in IVF.
On May 19, the Institute of Medicine will hold a forum for public comments to its Committee on Ethical and Social Policy Considerations of Novel Techniques for Prevention of Maternal Transmission of Mitochondrial DNA Diseases. The Institute intends to incorporate the comments into a study to inform FDA about genetic modification of eggs and zygotes for the prevention of transmission of mitochondrial DNA disease.
Molecular diagnostics company Biocartis Group N.V. (Euronext:BCART) gained EUR 1.50 (13%) to EUR 13 in its first day of trading Monday after it raised EUR 100 million ($107.8 million) in an IPO on Euronext Brussels last week. The company ended Monday with a market cap of EUR 525 million ($569.9 million). Underwriters were KBC Securities; Kempen; and Petercam (see BioCentury Extra, April 24).
Investment bank Roth Capital Partners hired Michael Higgins as a senior research analyst for biotechnology and specialty pharmaceuticals. Higgins was a managing director and a senior specialty pharmaceuticals analyst at Rodman & Renshaw.
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