HUMAN GENE THERAPY 25:171–174 (March 2014) ª Mary Ann Liebert, Inc. DOI: 10.1089/hum.2014.2505


Gene Therapy Briefs

The companies uniQure ( and Celladon ( went public in recent weeks, raising a combined $135.8 million through initial public offerings, which reflected tempered investor interest in biotechnology companies, including those focused on developing gene and cell therapies. uniQure saw its first shares begin trading under the symbol ‘‘QURE’’ on February 5, following approval for listing on the NASDAQ Global Select Market. The company raised $91.8 million by selling 5.4 million shares at an initial offering price of $17 per share and said it would retain $81.9 million in net proceeds after deducting underwriting discounts and other estimated offering expenses payable by the company (uniQure, 2014). The estimate also reflects uniQure granting the underwriters of its initial public offering (IPO) a 30-day option to purchase up to an additional 810,000 ordinary shares from the company at the public offering price, less underwriting discounts. The offering was expected to close on or about February 10, subject to customary closing conditions. Jefferies LLC and Leerink Partners LLC are acting as joint book-running managers for the offering. Piper Jaffray & Co. is acting as lead manager for the offering. Additionally, uniQure—which changed its name in 2012 from Amsterdam Molecular Therapeutics—markets its lead product Glybera (alipogene tiparvovec) in the European Union for a subset of patients with lipoprotein lipase deficiency, also known as LPLD or hyperchylomicronemia. Glybera is the first gene therapy approved by regulatory authorities in the Western world. Ultimately, uniQure went public a week after Celladon’s successful IPO, in which the company began trading shares of its common stock on The NASDAQ Global Market January 30, under the symbol ‘‘CLDN.’’ Celladon raised $44 million through its sale of 5.5 million shares of common stock priced at an initial $8 per share. That’s down considerably from the $75 million it hoped to raise when it originally scheduled for November 14 an IPO priced at $15 per share. Instead, the company delayed its offering after investor interest in biotech IPOs started to wane this past fall. The company also granted its IPO underwriters a 30-day option to purchase up to an additional 825,000 shares to cover overallotments (Celladon, 2014). Celladon is a developer of gene therapies and small molecule compounds for diseases characterized by SERCA enzyme deficiency. The company’s most advanced product, MYDICAR, uses gene therapy to target SERCA2a, an enzyme that becomes deficient in patients with heart failure. The company says it has also identified a number of potential first-in-class compounds addressing novel targets in

diabetes and neurodegenerative diseases through its small molecule platform of SERCA2b modulators. Researchers from the University of Oxford (www.ox and Imperial College London (www3.imperial, conducting the first clinical trial of a retinal gene therapy for choroideremia, reported positive initial results on January 16, with two of six enrolled patients able to read more lines on an eye chart after 6 months. Despite undergoing retinal detachment, which normally reduces vision, one of the patients with the inherited cause of progressive blindness was able to read 21 letters or more than four lines of vision, while the other read 11 letters or more than two lines. The other four patients, who enjoyed near-normal best-corrected visual acuity at baseline, showed an average gain in visual acuity overall of between three to eight letters, recovered to within one to three letters. In all patients over 6 months, the increases seen in retinal sensitivity in the treated eyes all correlated with the vector dose administered per mm2 of surviving retina, according to the research team led by Professor Robert MacLaren of Oxford’s Nuffield Laboratory of Ophthalmology. ‘‘To our knowledge, our report is the first in which the effects of retinal gene therapy in patients with good visual acuity of 6/6 or better and before the onset of clinically significant retinal thinning are described. These findings support the development and use of gene therapy to prevent loss of sight in other retinal diseases, such as age-related macular degeneration,’’ the team concluded (MacLaren et al., 2014). Days after publication of the study, Syncona, an independent subsidiary of The Wellcome Trust, announced a £12 million (about $20 million) investment in NightstaRx, a company spun out by Oxford and its research commercialization company Isis Innovation to develop and commercialize gene therapy (Oxford University and Syncona, 2014). Prof. MacLaren, a consultant surgeon at the Oxford Eye Hospital and honorary consultant at Moorfields Eye Hospital, led the development of the clinical trial and the therapy on which it was based. Six men between 35 and 63 years old with choroideremia were administered retinal gene therapy with an adeno-associated viral (AAV) vector encoding REP1 (AAV.REP1). Visual function tests included best-corrected visual acuity, microperimetry, and retinal sensitivity tests to attain a comparison to baseline results 6 months after the surgery. Because of the treatment’s success in the first six patients, three more patients have recently been tested at a higher dose. ‘‘It is still too early to know if the gene therapy treatment will




last indefinitely, but we can say that the vision improvements have been maintained for as long as we have been following up the patients, which is 2 years in one case,’’ Prof. MacLaren said (Imperial College London, 2014a).

addition, Alnylam will receive R&D funding, starting on January 1, 2015, for programs where Genzyme has elected to opt-in for development and commercialization. Alnylam is also eligible to receive milestones and royalties.

Alnylam Pharmaceuticals ( and Genzyme, A Sanofi Company ( said January 13 they formed a more-than-$1 billion alliance— including equity, R&D funding, and potential milestone payments, to develop and commercialize RNAi therapeutics as genetic medicines worldwide. Genzyme agreed to purchase $700 million of Alnylam stock (8.8 million shares at $80/share), becoming approximately a 12% owner of Alynlam, as part of the deal. Alnylam will retain product rights in North America and Western Europe—plus full global product rights for all RNAi therapeutic products outside the genetic medicine field—while Genzyme will obtain the right to access current ‘‘Alnylam 5x15’’ and future genetic medicines pipelines in the rest of the world (ROW), including global product rights for unspecified programs. Alnylam 5x15 is the company’s effort to advance six to seven genetic medicine product candidates into clinical development—including at least two programs in Phase III, and five to six programs with human proof-ofconcept—by the end of 2015. ‘‘In addition, this new collaboration significantly expands our balance sheet to over $1 billion in cash to increase our investment in new RNAi therapeutic programs, while securing a cash runway that we believe will allow us to develop and launch multiple products,’’ John Maraganore, PhD, CEO of Alnylam, said in a statement (Alnylam, 2014). Alnylam and Genzyme began collaborating in 2012 when they formed a partnership to develop and commercialize Alnylam’s lead product, patisiran, which is in Phase III development for the treatment of transthyretin (TTR)familial amyloid polyneuropathy. The expanded relationship between Genzyme and Alnylam includes the following components: First, Genzyme will obtain expanded rights to patisiran. Under the original agreement, Genzyme had rights to commercialize patisiran in Japan and the broader AsiaPacific region. Under the expanded agreement, Genzyme will now commercialize patisiran in all territories outside of North America and Western Europe, which are retained by Alnylam for their commercialization. Second, Genzyme will obtain rights to commercialize worldwide three products in Alnylam’s pipeline. Specifically, Genzyme and Alnylam will co-develop and co-commercialize ALN-TTRsc, a product currently in Phase II development for the treatment of familial amyloid cardiomyopathy, in North America and Western Europe, while Genzyme commercializes the product in the rest of world. Genzyme will have the rights to two additional products after the completion of early clinical trials, and will be able to choose between full global rights or co-commercialization rights, depending on the product. Third, Genzyme will have the option up until 2020, with the possibility of extension through the end of 2021, to develop and commercialize outside of North America and Western Europe all products being developed to treat rare genetic diseases from Alnylam’s pipeline. Alnylam retains its rights to co-develop and co-commercialize its genetic medicine pipeline in North America and Western Europe. In

On January 9, Biogen Idec ( and Sangamo BioSciences ( launched a collaboration that will apply the latter’s genome-editing technology platform to develop treatments targeting sickle cell disease (SCD) and beta thalassemia, in a deal that could net Sangamo up to about $320 million and more. Under their exclusive worldwide collaboration and license agreement, Biogen Idec will pay Sangamo $20 million up front; up to $300 million in payments tied to development, regulatory, commercialization, and sales milestones; as well as double-digit royalties on product sales. In return, Sangamo will oversee all research and development activities through the first clinical proof-of-concept trial in beta thalassemia, while both companies will perform activities designed to enable submission of an investigational new drug (IND) application for SCD. Biogen Idec will be responsible for subsequent worldwide clinical development and commercialization of products arising from the alliance, though Sangamo retains an option to co-promote any licensed product to treat SCD and beta thalassemia in the United States. ‘‘Our collaboration with Sangamo is expected to help us expand our capabilities to develop treatments for people with serious, inherited hematologic conditions,’’ said Douglas E. Williams, PhD, Biogen Idec’s executive vice president (evp) of research and development. ‘‘Building upon emerging science related to fetal hemoglobin regulation, we intend to develop Sangamo’s novel gene-editing technology to create a single approach that has the potential to functionally cure both SCD and beta thalassemia’’ (Biogen Idec and Sangamo, 2014). The companies said the deal has been approved by their boards of directors and is subject to customary closing conditions including expiration of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976 in the United States. The collaboration will use Sangamo’s zinc finger nuclease (ZFN) genome-editing technology, designed to enable multiple approaches to treating SCD and beta thalassemia. Both diseases manifest after birth, when patients switch from producing functional fetal gamma-globin to a mutant form of adult beta-globin. ZFN can precisely target and disrupt key transcriptional regulators to reverse the switch from expression of the mutant adult beta-globin back to the production of functional fetal gamma-globin. Or the technology can be used to precisely insert a new corrected betaglobin gene to replace the defective copy. By engineering a class of DNA-binding proteins called zinc finger DNA-binding proteins (ZFPs) that can recognize a specific DNA sequence, Sangamo has created sequencespecific ZFNs for gene modification and ZFP transcription factors (ZFP TFs) that can control gene expression and, consequently, cell function. Sangamo has ongoing Phase II and Phase I/II clinical trials to assess the safety and efficacy of a new ZFP Therapeutic for HIV/AIDS, as well as a fully enrolled and funded Phase II trial to evaluate NGF-AAV (CERE-110) in Alzheimer’s disease, a program the company acquired as part of its purchase of Ceregene.


The Biogen Idec alliance ‘‘is further validation of our ZFP platform as a transformative technology and accelerates our goal of developing a novel class of therapeutics, which has the potential to revolutionize the treatment of genetic diseases,’’ Edward Lanphier, Sangamo’s president and CEO, said in a statement (Biogen Idec and Sangamo, 2014). Sangamo is also applying its technologies in a separate collaboration with Shire to develop new drugs for hemophilia, Huntington’s disease, and other monogenic diseases, as well as through partnerships with companies in nontherapeutic applications of its technology, including Dow AgroSciences and Sigma-Aldrich. Oxford Biomedica ( said on January 10 that its ProSavin gene therapy for Parkinson’s disease has shown promising first results in human patients, with all 15 trial participants showing significant improvement in their scores on movement tests 6 months and 12 months later. A research team headed by Prof. Nicholas Mazarakis, head of gene therapy at the Division of Brain Sciences, Imperial College London (, published a study detailing the trial results in The Lancet on January 10. Prof. Mazarakis devised the ProSavin therapy while working at Oxford BioMedica in 1997. ProSavin uses a modified virus to deliver three genes into the striatum of the brain, which controls movement. The genes are intended to boost the production of dopamine, a chemical that becomes deficient in patients with Parkinson’s. While current treatments can boost dopamine production temporarily, the cells that produce dopamine continue to degenerate under the disease until treatments are no longer effective. The ProSavin study evaluated three ascending dose levels of ProSavin (1x, 2x, and 5x) in a total of 15 patients with Parkinson’s. Three patients received the 1x dose, six the 2x dose, and six the 5x dose. Patients were treated at the Henri Mondor Hospital in Paris and at Addenbrooke’s Hospital in Cambridge, United Kingdom. Primary endpoints for the Phase I/II study were safety and efficacy as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) assessment. During the first 12 months of follow-up, 54 drug-related adverse events were reported; all but three of them were mild. No serious adverse events related to the study drug or surgical procedure were reported. Favorable tolerability and evidence of continued clinical benefit were seen for up to 4 years post-treatment (Palfi et al., 2014). Another encouraging result was that 11 of the 15 patients realized a reduction in levodopa equivalent daily dose (LEDD) at 12 months compared to baseline. Of the four patients that did not, three showed no change and one had a small increase. The results are considered encouraging given the usual requirement for an increase in LEDD in what is usually a progressively degenerative disease. ‘‘I’m very pleased that it has appeared to work in the clinic,’’ Prof. Mazarakis said. ‘‘It has the potential to move to the next phase. It needs to be done in more people; we have to find the most effective dose, to further increase efficacy, and prove beyond doubt that this is not a placebo effect,’’ (Imperial College London, 2014b). Cardio3 BioSciences ( said January 9 that it received FDA approval for a Phase III pivotal clinical trial of its stem cell therapy. The trial will test the compa-


ny’s proprietary regenerative medicine product C3BS-CQR1, also called C-Cure, as a treatment for heart failure, as well as the discovery by the Mayo Clinic (www.mayoclinic .org) of cardiopoietic stem cells designed to improve heart health in people suffering from heart failure. The multisite U.S. trial, called CHART-2, will seek to recruit 240 patients with chronic advanced symptomatic heart failure to assess the efficacy of C-Cure for heart failure of ischemic origin. CHART-2 will be a multicenter, randomized study comparing the treatment with C-Cure to a placebo. The trial’s primary endpoint will be the Six Minute Walk Test post-procedure. C-Cure involves taking stem cells from a patient’s own bone marrow and re-programming those cells to become heart cells through a process called ‘‘cardiopoiesis.’’ The resulting cardiopoietic cells are then injected back into the patient’s heart through a minimally invasive procedure, with the aim of repairing damaged tissue and improving heart function and patient clinical outcomes. C-Cure was developed through years of research conducted at Mayo. Phase II data published in the Journal of the American College of Cardiology stated that C-Cure showed statistically significant improvement of 77 meters in a 6-minute walk distance for the treated patients compared to the control group, representing a 20% improvement for treated patients versus the control group (Bartunek et al., 2013). ‘‘The files approved by the FDA make us optimistic about our ability to reproduce and potentially amplify the results seen in our Phase II trial,’’ Christian Homsy, CEO of Cardio3 BioSciences, said in a statement. In Europe, Cardio3 BioSciences’ first Phase III study, CHART-1, has been authorized in eight countries. ‘‘We can now consider a potential start to the CHART-2 trial in the second half of 2014. When started, we anticipate that the CHART-2 study will follow a similar timeline to our current European study,’’ Dr. Homsy said (Cardio3 BioSciences, 2014). References

Alnylam (2014). Alnylam and Genzyme form transformational alliance for RNAi therapeutics as genetic medicines. Available at ReleaseID = 818735 (accessed February 3, 2014). Bartunek, J., Behfar, A., Dolatabadi, D., et al. (2013). Cardiopoietic stem cell therapy in heart failure: The C-CURE (Cardiopoietic stem Cell therapy in heart failURE) multicenter randomized trial with lineage-specified biologics. J. Am. Coll. Cardiol. 61, 2329–2338. Biogen Idec and Sangamo (2014). Biogen Idec and Sangamo BioSciences announce global collaboration to develop treatments for hemoglobinopathies. Available at www.biogenidec .com/press_release_details.aspx?ID=14712&Action=1&NewsId= 2276&M=NewsV2&PID=61997 (accessed February 3, 2014). Cardio3 BioSciences (2014). Cardio3 BioSciences receives IND clearance from the FDA for its CHART-2 phase III heart failure clinical trial. Available at files/press/cardio3_biosciences_receives_fda_authorization.pdf (accessed February 5, 2014). Celladon (2014). Celladon announces pricing of initial public offering. Available at ReleaseID=821990 (accessed February 5, 2014). Imperial College London (2014a). Gene therapy for inherited blindness produces promising first results. Available at www3

174 summary/news_16-1-2014-12-31-33 (accessed February 6, 2014). Imperial College London (2014b). Gene therapy for Parkinson’s disease yields promising results in first patients. Available at newssummary/news_9-1-2014-16-19-43 (accessed February 6, 2014). MacLaren, R.E., Groppe, M., Barnard, A.R., et al. (2014). Retinal gene therapy inpatients with choroideremia: initial findings from a phase 1/2 clinical trial. Available at www 2962117-0/fulltext (accessed February 6, 2014). Oxford University and Syncona (2014). Oxford University and Syncona announce the formation of Nightstar, a company


developing retinal gene therapies. Available at www.biospace .com/news_story.aspx?StoryID = 322531 (accessed February 6, 2014). Palfi, S., Gurruchaga, J.M., Ralph, G.S., et al. (2014). Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson’s disease: a dose escalation, openlabel, phase 1/2 trial. Available at lancet/article/PIIS0140-6736%2813%2961939-X/fulltext (accessed February 6, 2014). uniQure (2014). uniQure announces pricing of initial public offering. Available at (accessed February 5, 2014).

—Alex Philippidis

Gene therapy briefs.

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