HUMAN GENE THERAPY 25:679–681 (August 2014) ª Mary Ann Liebert, Inc. DOI: 10.1089/hum.2014.2531
Briefs
Gene Therapy Briefs
The U.S. Food and Drug Administration (FDA) has issued a draft guidance spelling out when sponsors of investigational new drug (IND) applications, and applicants for a biologics license application (BLA) or a supplement to a BLA, will be required to file an environmental assessment (EA) for gene therapies, vectored vaccines, and related recombinant viral or microbial products (GTVVs). INDs are ordinarily categorically excluded from the requirement to submit an EA absent extraordinary circumstances: ‘‘FDA believes that, in most cases, agency action on an IND for a clinical study using a GTVV will not significantly affect the quality of the environment because, in brief, these clinical trials are closely monitored and are limited to a designated study group’’ (U.S. Food and Drug Administration, 2014). Extraordinary circumstances for GTVVs are those that the FDA finds may significantly affect environmental quality based on the degree to which environmental effects are likely to be highly controversial; are highly uncertain or involve unique or unknown risks; may adversely affect an endangered or threatened species or its habitat; or threaten to violate federal, state, or local environment protection laws. A categorical exclusion from EA requirements is also allowed for BLAs involving substances that occur naturally in the environment when the FDA determines that its action does not significantly alter the concentration or distribution of the substance, its metabolites, or degradation products in the environment (Gaffney, 2014). According to the draft guidance, most GTVVs are considered to be substances that do not occur naturally because they include functional protein-coding sequences from a genus that differs from the organism that is expressing the sequences—unlike GTVVs that include functional protein-coding sequences from one or more species within a single genus. ‘‘Applications requesting agency action for GTVVs that are engineered to express one or more proteins from a different genus should include an EA,’’ the draft guidance concluded (U.S. Food and Drug Administration, 2014). The FDA added that it generally considers GTVVs that differ from a wild-type substance only in attenuating point mutations or deletions to be substances that occur naturally in the environment. Such mutations can occur as natural variants during replication/propagation and can remain exempt if the changes were introduced to reduce virulence, or to restrict the ability of the product to replicate in humans. GTVVs killed or inactivated through a specific manufacturing step designed to eliminate their ability to replicate are generally considered to be naturally occurring substances, and thus EA-exempt. Such GTTVs were not viable and have degraded into substances that occur naturally in the environment, the FDA stated. Also exempt from EA requirements, according
to the FDA, are GTVVs that consist of genetically modified human cells, since they have stringent nutritional requirements for survival and replication and are therefore not viable in the environment, causing them to degrade into naturally occurring substances. The draft guidance also contains recommendations on information that should be included in an EA and what sponsors can expect once an EA is filed. When finalized, the draft will supplement ‘‘Guidance for Industry: Environmental Assessment of Human Drug and Biologics Applications,’’ finalized in July 1998 (63 FR 40127), and supersede its recommendations for GTVVs in assessing toxicity to environmental organisms. Generx [Ad5FGF-4], an angiogenic gene therapy product candidate being developed by Cardium Therapeutics (www .cardiumtx.com; San Diego, CA) for patients with myocardial ischemia caused by coronary artery disease, reported positive phase III interim results on June 24. Cardium said Ad5FGF-4 met the primary endpoint of the ASPIRE clinical study, namely, improvement in blood flow compared with a control group. At 8 weeks, Ad5FGF-4 treatment resulted in a 24% improvement in reversible perfusion defect size (RPDS) as determined by singlephoton emission computed tomography—a result Cardium said was consistent with RPDS improvement previously reported in the 52-patient Ad5FGF-4 AGENT phase II trial, where 88% of patients were men. ‘‘This represents another important step forward in the development of an innovative biology-based microvascular gene therapy tool for the interventional cardiologist designed to broaden the cycle of care for a large number of patients worldwide with myocardial ischemia,’’ said Timothy Henry, MD, FACC, chief of cardiology at the Cedars-Sinai Heart Institute, in a company statement (Cardium Therapeutics, 2014). Cardium added that the RPDS improvements reported by patients in the ASPIRE and AGENT trials were similar to either bypass surgery or angioplasty involving the right coronary artery, the left anterior descending artery, and the left circumflex artery. ASPIRE is a 100-patient randomized, multicenter study conducted at medical centers in the Russian Federation. Following ASPIRE’s successful completion, Cardium will seek marketing and sales authorization in the federation, and is expected to seek similar approvals elsewhere in the Commonwealth of Independent States. Cardium also plans to pursue FDA approval and seek a ‘‘breakthrough therapy’’ designation, as well as discuss the harmonization of the U.S. and international clinical study protocols. Ad5FGF-4 alferminogene tadenovec uses an adenovirus serotype 5 delivery vector that is replication-deficient and
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nonintegrating and drives short-term transient expression of the fibroblast growth factor-4 (FGF-4) transgene. Ad5FGF-4 is designed to stimulate the body’s natural healing response to ischemic coronary artery disease by promoting microvascular angiogenesis and arteriogenesis, and enhancing blood flow. Cardium Therapeutics is a drug developer whose holding company is publicly traded Taxus Cardium Pharmaceuticals Group. Christopher Reinhard, Taxus Cardium’s CEO and Cardium Therapeutics’s cofounder, presented the results from ASPIRE at the Biotechnology Industry Organization 2014 International Convention in San Diego. Bayer HealthCare (www.healthcare.bayer.com; Leverkusen, Germany) will use the adeno-associated virus (AAV) technology of Dimension Therapeutics (www.dimensiontx.com; Cambridge, MA) under a collaboration by the companies to develop and commercialize a new gene therapy for hemophilia A. The deal could net Dimension up to $252 million. The AAV vector technology is designed to allow for systemic intravenous administration of the clotting factor gene in vivo. The technology has been shown in preclinical studies to target the liver, resulting in long-lasting expression of the FVIII protein at therapeutic levels. Dimension’s vectors apply the NAV technology platform of co-owner ReGenX Biosciences (http://regenxbio.com; Washington, DC). NAV includes novel AAV vectors such as rAAV7, rAAV8, rAAV9, and rAAVrh10. The company says that NAV provides further advantages over traditional AAV vectors, including greater efficiency for delivering genes in vivo, faster onset of gene expression, high tissue selectivity, and high-titer manufacture. The technology was discovered in the lab of ReGenX’s scientific founder James M. Wilson, MD, PhD, director of the gene therapy program at the University of Pennsylvania. Dr. Wilson also chairs Dimension’s Scientific and Technical Advisory Board, and is the editor-in-chief of Human Gene Therapy. In October, Dimension entered into an exclusive license and collaboration with ReGenX that gave Dimension preferred access to NAV vector technology and rights in ReGenX product programs in multiple rare disease indications. ‘‘We are proud to partner with Bayer, a leader in the treatment of hemophilia A, to develop a therapy with the potential to significantly change the treatment landscape,’’ Thomas R. Beck, MD, Dimension’s CEO, said in a statement (Dimension Therapeutics, 2014). Dimension will receive $20 million upfront from Bayer, and is eligible for up to $232 million in payments tied to development and commercialization milestones. Dimension will oversee all preclinical development activities and the phase I/IIa clinical trial, with funding from Bayer. Depending on results of the phase I/IIa trial, Bayer will advance the gene therapy to a phase III trial, make all regulatory submissions, and hold worldwide rights to commercialize the potential treatment for hemophilia A. Dimension is also eligible for tiered royalties based on product sales. Separately, Dimension said that it closed on a $30 million financing, with new investor OrbiMed joining existing investor Fidelity Biosciences in the round. Fidelity—whose partners include Beck and Dimension Chairman Ben Auspitz—joined ReGenX in launching the company last year, focusing on developing gene therapies for rare diseases. Dimension con-
GENE THERAPY BRIEFS
tinues to advance a wholly owned hemophilia B program toward clinical development. The program has progressed past candidate selection toward IND-enabling work in advance of a submission and phase I trial. A developer of gene therapies for severe genetic and orphan diseases, bluebird bio (www.bluebirdbio.com, Cambridge, MA), acquired Precision Genome Engineering (Pregenen) on June 30 in a deal that could have the buyer shelling out as much as $139.9 million for the company and its debt. The deal gives bluebird access to Pregenen’s gene-editing and cell signaling technologies, which the companies said could have a broad range of potential therapeutic applications in gene therapy as well as cancer immunotherapies. Pregenen’s homing endonucleases (HEs), also called meganucleases, enable ‘‘multiplex’’ gene editing by targeting multiple genomic sequences for modification using a single gene delivery vector. HEs are designed to promote the editing or replacement of defective genes through the body’s natural cellular DNA repair mechanisms by employing an integrated binding and cleavage mechanism to target DNA sequences greater than 20 bp in length. According to bluebird and Pregenen, HEs offer the potential for improved efficacy by unlocking multiple mechanisms of action within gene- and cell-based therapies. Pregenen’s MegaTALs combine the natural DNA-cleaving processes of HEs with the DNA-binding region of transcription activator-like (TAL) effectors in a single-chain fusion enzyme. The companies say that the protein fusion architecture of the MegaTALs enables the generation of highly specific and compact nucleases designed to be compatible with all current viral and nonviral cell delivery methods. Bluebird issued 408,667 shares of its common stock at the deal’s closing to former shareholders of privately held Pregenen, and agreed to pay or assume about $4.9 million of current liabilities of Pregenen and its shareholders. The Pregenen shareholders are also eligible for up to an additional $15 million cash tied to achieving preclinical milestones, as well as $20.1 million cash for meeting clinical milestones and $99.9 million cash contingent on commercial milestones regarding product candidates identified using Pregenen’s technology. ‘‘While we remain focused on driving our core programs forward, this acquisition represents a significant investment in our stated strategy to integrate emerging technologies that can enhance our ability to develop innovative and potentially transformative gene therapy and cancer immunotherapy products for patients,’’ Nick Leschly, bluebird’s president and CEO, said in a statement (bluebird bio, 2014a). Initial positive clinical data from its HGB-205 clinical study were released by bluebird bio (www.bluebirdbio.com, Cambridge, MA) on June 14 at the 19th Annual Congress of the European Hematology Association in Milan, Italy. The initial results showed that the first two patients with betathalassemia major and the Beta E/Beta 0 genotype achieved transfusion independence within 2 weeks of an autologous transplant with the company’s lentiviral gene therapy product candidate LentiGlobin BB305. At 4.5 months following autologous transplant, the first patient had a total hemoglobin of 10.1 g/dl, of which 6.6 g/dl was therapeutic betaAT87Q-globin. At 2 months posttransplant,
GENE THERAPY BRIEFS
the second patient had a total hemoglobin of 11.6 g/dl, of which 4.2 g/dl was betaAT87Q-globin. Patients 1 and 2 received their last blood transfusion on days 10 and 12, respectively, posttransplant. Both remain blood transfusion independent, according to bluebird. ‘‘We are encouraged by the early and high-level production of corrected betaAT87Q-globin and the rapid onset of transfusion independence in these initial subjects, as well as the absence of any gene therapy-related adverse events,’’ David Davidson, MD, bluebird bio’s chief medical officer, said in a statement. ‘‘We are gratified that the improvements we introduced into the BB305 lentiviral vector design and manufacturing process appear to have translated into clinical results that we believe support the potential for our LentiGlobin BB305 gene therapy to transform the lives of patients with beta-thalassemia major’’ (bluebird bio, 2014b). No drug product-related adverse events were reported, and the integration site analysis performed on the first patient at the 3-month time point showed polyclonal reconstitution, bluebird reported. Vector copy number in the drug product for subjects 1 and 2 was 1.5 and 2.1, respectively— multiple times higher than the drug product vector copy numbers reported in the earlier LG001 study, where the copy numbers were 0.6 for a third patient and 0.3 for a fourth. The company bluebird reported updated results from LG001, focused on the earlier lentiviral candidate HPV569. The third patient remains blood transfusion independent 72 months after being transplanted with HPV569. Patients 3 and 4 produced 2.7 and 0.4 g/dl of therapeutic betaA-T87Qglobin posttransplant, respectively. He added that bluebird will provide additional data from HGB-205 and its ongoing multicenter Northstar Study later this year.
681 References
Bluebird bio (2014a). bluebird bio acquires Precision Genome Engineering (Pregenen). Available at http://investor.bluebirdbio .com/phoenix.zhtml?c = 251820&p = irol-newsArticle&ID = 1943834&highlight = (accessed July 11, 2014). Bluebird bio (2014b). bluebird bio reports rapid transfusion independence in beta-thalassemia major patients treated with its LentiGlobin product candidate. Available at http://investor .bluebirdbio.com/phoenix.zhtml?c = 251820&p = irol-newsArticle &ID = 1939867&highlight = (accessed July 11, 2014). Cardium Therapeutics (2014). Cardium announces positive interim phase 3 clinical data showing significant efficacy of Generx angiogenic gene therapy for myocardial ischemia due to coronary artery disease at the 2014 BIO International Convention. Available at http://phx.corporate-ir.net/phoenix.zhtml?c = 77949 &p = irol-newsArticle&ID = 1942146&highlight = (accessed July 11, 2014). Dimension Therapeutics (2014). Dimension Therapeutics and Bayer HealthCare enter collaboration to develop novel gene therapy for hemophilia A. Available at http://dimensiontx .com/pdfs/Dimension%20-%20Bayer%20Release%206.20 .14.pdf (accessed July 11, 2014). Gaffney, A. (2014). FDA wants sponsors of biotech products to assess product’s impact on environment. Available at www .raps.org/regulatory-focus/news/2014/06/19566/EnvironmentalAssessment-for-Biotechnology-Products/ (accessed July 30, 2014). U.S. Food and Drug Administration (2014). Draft guidance for industry: determining the need for and content of environmental assessments for gene therapies, vectored vaccines, and related recombinant viral or microbial products. Available at www.fda.gov/downloads/BiologicsBloodVaccines/Guidance ComplianceRegulatoryInformation/Guidances/Cellularand GeneTherapy/UCM402063.pdf (accessed July 11, 2014).
—Alex Philippidis
Briefs
Gene Therapy Briefs
The U.S. Food and Drug Administration (FDA) has issued a draft guidance spelling out when sponsors of investigational new drug (IND) applications, and applicants for a biologics license application (BLA) or a supplement to a BLA, will be required to file an environmental assessment (EA) for gene therapies, vectored vaccines, and related recombinant viral or microbial products (GTVVs). INDs are ordinarily categorically excluded from the requirement to submit an EA absent extraordinary circumstances: ‘‘FDA believes that, in most cases, agency action on an IND for a clinical study using a GTVV will not significantly affect the quality of the environment because, in brief, these clinical trials are closely monitored and are limited to a designated study group’’ (U.S. Food and Drug Administration, 2014). Extraordinary circumstances for GTVVs are those that the FDA finds may significantly affect environmental quality based on the degree to which environmental effects are likely to be highly controversial; are highly uncertain or involve unique or unknown risks; may adversely affect an endangered or threatened species or its habitat; or threaten to violate federal, state, or local environment protection laws. A categorical exclusion from EA requirements is also allowed for BLAs involving substances that occur naturally in the environment when the FDA determines that its action does not significantly alter the concentration or distribution of the substance, its metabolites, or degradation products in the environment (Gaffney, 2014). According to the draft guidance, most GTVVs are considered to be substances that do not occur naturally because they include functional protein-coding sequences from a genus that differs from the organism that is expressing the sequences—unlike GTVVs that include functional protein-coding sequences from one or more species within a single genus. ‘‘Applications requesting agency action for GTVVs that are engineered to express one or more proteins from a different genus should include an EA,’’ the draft guidance concluded (U.S. Food and Drug Administration, 2014). The FDA added that it generally considers GTVVs that differ from a wild-type substance only in attenuating point mutations or deletions to be substances that occur naturally in the environment. Such mutations can occur as natural variants during replication/propagation and can remain exempt if the changes were introduced to reduce virulence, or to restrict the ability of the product to replicate in humans. GTVVs killed or inactivated through a specific manufacturing step designed to eliminate their ability to replicate are generally considered to be naturally occurring substances, and thus EA-exempt. Such GTTVs were not viable and have degraded into substances that occur naturally in the environment, the FDA stated. Also exempt from EA requirements, according
to the FDA, are GTVVs that consist of genetically modified human cells, since they have stringent nutritional requirements for survival and replication and are therefore not viable in the environment, causing them to degrade into naturally occurring substances. The draft guidance also contains recommendations on information that should be included in an EA and what sponsors can expect once an EA is filed. When finalized, the draft will supplement ‘‘Guidance for Industry: Environmental Assessment of Human Drug and Biologics Applications,’’ finalized in July 1998 (63 FR 40127), and supersede its recommendations for GTVVs in assessing toxicity to environmental organisms. Generx [Ad5FGF-4], an angiogenic gene therapy product candidate being developed by Cardium Therapeutics (www .cardiumtx.com; San Diego, CA) for patients with myocardial ischemia caused by coronary artery disease, reported positive phase III interim results on June 24. Cardium said Ad5FGF-4 met the primary endpoint of the ASPIRE clinical study, namely, improvement in blood flow compared with a control group. At 8 weeks, Ad5FGF-4 treatment resulted in a 24% improvement in reversible perfusion defect size (RPDS) as determined by singlephoton emission computed tomography—a result Cardium said was consistent with RPDS improvement previously reported in the 52-patient Ad5FGF-4 AGENT phase II trial, where 88% of patients were men. ‘‘This represents another important step forward in the development of an innovative biology-based microvascular gene therapy tool for the interventional cardiologist designed to broaden the cycle of care for a large number of patients worldwide with myocardial ischemia,’’ said Timothy Henry, MD, FACC, chief of cardiology at the Cedars-Sinai Heart Institute, in a company statement (Cardium Therapeutics, 2014). Cardium added that the RPDS improvements reported by patients in the ASPIRE and AGENT trials were similar to either bypass surgery or angioplasty involving the right coronary artery, the left anterior descending artery, and the left circumflex artery. ASPIRE is a 100-patient randomized, multicenter study conducted at medical centers in the Russian Federation. Following ASPIRE’s successful completion, Cardium will seek marketing and sales authorization in the federation, and is expected to seek similar approvals elsewhere in the Commonwealth of Independent States. Cardium also plans to pursue FDA approval and seek a ‘‘breakthrough therapy’’ designation, as well as discuss the harmonization of the U.S. and international clinical study protocols. Ad5FGF-4 alferminogene tadenovec uses an adenovirus serotype 5 delivery vector that is replication-deficient and
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nonintegrating and drives short-term transient expression of the fibroblast growth factor-4 (FGF-4) transgene. Ad5FGF-4 is designed to stimulate the body’s natural healing response to ischemic coronary artery disease by promoting microvascular angiogenesis and arteriogenesis, and enhancing blood flow. Cardium Therapeutics is a drug developer whose holding company is publicly traded Taxus Cardium Pharmaceuticals Group. Christopher Reinhard, Taxus Cardium’s CEO and Cardium Therapeutics’s cofounder, presented the results from ASPIRE at the Biotechnology Industry Organization 2014 International Convention in San Diego. Bayer HealthCare (www.healthcare.bayer.com; Leverkusen, Germany) will use the adeno-associated virus (AAV) technology of Dimension Therapeutics (www.dimensiontx.com; Cambridge, MA) under a collaboration by the companies to develop and commercialize a new gene therapy for hemophilia A. The deal could net Dimension up to $252 million. The AAV vector technology is designed to allow for systemic intravenous administration of the clotting factor gene in vivo. The technology has been shown in preclinical studies to target the liver, resulting in long-lasting expression of the FVIII protein at therapeutic levels. Dimension’s vectors apply the NAV technology platform of co-owner ReGenX Biosciences (http://regenxbio.com; Washington, DC). NAV includes novel AAV vectors such as rAAV7, rAAV8, rAAV9, and rAAVrh10. The company says that NAV provides further advantages over traditional AAV vectors, including greater efficiency for delivering genes in vivo, faster onset of gene expression, high tissue selectivity, and high-titer manufacture. The technology was discovered in the lab of ReGenX’s scientific founder James M. Wilson, MD, PhD, director of the gene therapy program at the University of Pennsylvania. Dr. Wilson also chairs Dimension’s Scientific and Technical Advisory Board, and is the editor-in-chief of Human Gene Therapy. In October, Dimension entered into an exclusive license and collaboration with ReGenX that gave Dimension preferred access to NAV vector technology and rights in ReGenX product programs in multiple rare disease indications. ‘‘We are proud to partner with Bayer, a leader in the treatment of hemophilia A, to develop a therapy with the potential to significantly change the treatment landscape,’’ Thomas R. Beck, MD, Dimension’s CEO, said in a statement (Dimension Therapeutics, 2014). Dimension will receive $20 million upfront from Bayer, and is eligible for up to $232 million in payments tied to development and commercialization milestones. Dimension will oversee all preclinical development activities and the phase I/IIa clinical trial, with funding from Bayer. Depending on results of the phase I/IIa trial, Bayer will advance the gene therapy to a phase III trial, make all regulatory submissions, and hold worldwide rights to commercialize the potential treatment for hemophilia A. Dimension is also eligible for tiered royalties based on product sales. Separately, Dimension said that it closed on a $30 million financing, with new investor OrbiMed joining existing investor Fidelity Biosciences in the round. Fidelity—whose partners include Beck and Dimension Chairman Ben Auspitz—joined ReGenX in launching the company last year, focusing on developing gene therapies for rare diseases. Dimension con-
GENE THERAPY BRIEFS
tinues to advance a wholly owned hemophilia B program toward clinical development. The program has progressed past candidate selection toward IND-enabling work in advance of a submission and phase I trial. A developer of gene therapies for severe genetic and orphan diseases, bluebird bio (www.bluebirdbio.com, Cambridge, MA), acquired Precision Genome Engineering (Pregenen) on June 30 in a deal that could have the buyer shelling out as much as $139.9 million for the company and its debt. The deal gives bluebird access to Pregenen’s gene-editing and cell signaling technologies, which the companies said could have a broad range of potential therapeutic applications in gene therapy as well as cancer immunotherapies. Pregenen’s homing endonucleases (HEs), also called meganucleases, enable ‘‘multiplex’’ gene editing by targeting multiple genomic sequences for modification using a single gene delivery vector. HEs are designed to promote the editing or replacement of defective genes through the body’s natural cellular DNA repair mechanisms by employing an integrated binding and cleavage mechanism to target DNA sequences greater than 20 bp in length. According to bluebird and Pregenen, HEs offer the potential for improved efficacy by unlocking multiple mechanisms of action within gene- and cell-based therapies. Pregenen’s MegaTALs combine the natural DNA-cleaving processes of HEs with the DNA-binding region of transcription activator-like (TAL) effectors in a single-chain fusion enzyme. The companies say that the protein fusion architecture of the MegaTALs enables the generation of highly specific and compact nucleases designed to be compatible with all current viral and nonviral cell delivery methods. Bluebird issued 408,667 shares of its common stock at the deal’s closing to former shareholders of privately held Pregenen, and agreed to pay or assume about $4.9 million of current liabilities of Pregenen and its shareholders. The Pregenen shareholders are also eligible for up to an additional $15 million cash tied to achieving preclinical milestones, as well as $20.1 million cash for meeting clinical milestones and $99.9 million cash contingent on commercial milestones regarding product candidates identified using Pregenen’s technology. ‘‘While we remain focused on driving our core programs forward, this acquisition represents a significant investment in our stated strategy to integrate emerging technologies that can enhance our ability to develop innovative and potentially transformative gene therapy and cancer immunotherapy products for patients,’’ Nick Leschly, bluebird’s president and CEO, said in a statement (bluebird bio, 2014a). Initial positive clinical data from its HGB-205 clinical study were released by bluebird bio (www.bluebirdbio.com, Cambridge, MA) on June 14 at the 19th Annual Congress of the European Hematology Association in Milan, Italy. The initial results showed that the first two patients with betathalassemia major and the Beta E/Beta 0 genotype achieved transfusion independence within 2 weeks of an autologous transplant with the company’s lentiviral gene therapy product candidate LentiGlobin BB305. At 4.5 months following autologous transplant, the first patient had a total hemoglobin of 10.1 g/dl, of which 6.6 g/dl was therapeutic betaAT87Q-globin. At 2 months posttransplant,
GENE THERAPY BRIEFS
the second patient had a total hemoglobin of 11.6 g/dl, of which 4.2 g/dl was betaAT87Q-globin. Patients 1 and 2 received their last blood transfusion on days 10 and 12, respectively, posttransplant. Both remain blood transfusion independent, according to bluebird. ‘‘We are encouraged by the early and high-level production of corrected betaAT87Q-globin and the rapid onset of transfusion independence in these initial subjects, as well as the absence of any gene therapy-related adverse events,’’ David Davidson, MD, bluebird bio’s chief medical officer, said in a statement. ‘‘We are gratified that the improvements we introduced into the BB305 lentiviral vector design and manufacturing process appear to have translated into clinical results that we believe support the potential for our LentiGlobin BB305 gene therapy to transform the lives of patients with beta-thalassemia major’’ (bluebird bio, 2014b). No drug product-related adverse events were reported, and the integration site analysis performed on the first patient at the 3-month time point showed polyclonal reconstitution, bluebird reported. Vector copy number in the drug product for subjects 1 and 2 was 1.5 and 2.1, respectively— multiple times higher than the drug product vector copy numbers reported in the earlier LG001 study, where the copy numbers were 0.6 for a third patient and 0.3 for a fourth. The company bluebird reported updated results from LG001, focused on the earlier lentiviral candidate HPV569. The third patient remains blood transfusion independent 72 months after being transplanted with HPV569. Patients 3 and 4 produced 2.7 and 0.4 g/dl of therapeutic betaA-T87Qglobin posttransplant, respectively. He added that bluebird will provide additional data from HGB-205 and its ongoing multicenter Northstar Study later this year.
681 References
Bluebird bio (2014a). bluebird bio acquires Precision Genome Engineering (Pregenen). Available at http://investor.bluebirdbio .com/phoenix.zhtml?c = 251820&p = irol-newsArticle&ID = 1943834&highlight = (accessed July 11, 2014). Bluebird bio (2014b). bluebird bio reports rapid transfusion independence in beta-thalassemia major patients treated with its LentiGlobin product candidate. Available at http://investor .bluebirdbio.com/phoenix.zhtml?c = 251820&p = irol-newsArticle &ID = 1939867&highlight = (accessed July 11, 2014). Cardium Therapeutics (2014). Cardium announces positive interim phase 3 clinical data showing significant efficacy of Generx angiogenic gene therapy for myocardial ischemia due to coronary artery disease at the 2014 BIO International Convention. Available at http://phx.corporate-ir.net/phoenix.zhtml?c = 77949 &p = irol-newsArticle&ID = 1942146&highlight = (accessed July 11, 2014). Dimension Therapeutics (2014). Dimension Therapeutics and Bayer HealthCare enter collaboration to develop novel gene therapy for hemophilia A. Available at http://dimensiontx .com/pdfs/Dimension%20-%20Bayer%20Release%206.20 .14.pdf (accessed July 11, 2014). Gaffney, A. (2014). FDA wants sponsors of biotech products to assess product’s impact on environment. Available at www .raps.org/regulatory-focus/news/2014/06/19566/EnvironmentalAssessment-for-Biotechnology-Products/ (accessed July 30, 2014). U.S. Food and Drug Administration (2014). Draft guidance for industry: determining the need for and content of environmental assessments for gene therapies, vectored vaccines, and related recombinant viral or microbial products. Available at www.fda.gov/downloads/BiologicsBloodVaccines/Guidance ComplianceRegulatoryInformation/Guidances/Cellularand GeneTherapy/UCM402063.pdf (accessed July 11, 2014).
—Alex Philippidis
