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BioPharmAnalyses is a news platform including databases
for the tracking and the strategic monitoring in the Biopharmaceutical area.
We can give you a concise overview of hot topics
(agreements, fundraisings, clinical studies, mergers...). 
We are also conducting relevant strategic reports
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INNOVATIVE BIOTHERAPIES
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contents
April 2019, 26th

FEATURE STORY
●  A safe and potent anti-CD19 CAR T cell therapy
GENE THERAPY
 ● Chimeric antigen receptor T cell persistence and memory cell formation
DISRUPTIVE TECHNOLOGIES 
● Hemophilia A : Restoration of FVIII expression by targeted gene insertion in the FVIII
CLINICAL TRIALS - DATA
● AveXis data reinforce effectiveness of Zolgensma® in treating SMA Type 1
● Lentiviral gene therapy in infants with SCID-X1
INDUSTRIAL LANDSCAPE & AGREEMENTS
● Novasep and Theravectys enter into a new license agreement for GMP manufacturing of lentiviral vectors
● Eli Lilly invests in Avidity Biosciences as part of new collaboration
● Gracell Bio announces fast, cost-effective CAR-T manufacturing technology
● Kite announces plans for new facility to expand cell therapy production capabilities
MISCELLANEOUS
● Medicare proposes raising CAR-T pay, but reimbursement solution years away
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FEATURE STORY
A safe and potent anti-CD19 CAR T cell therapy
Anti-CD19 chimeric antigen receptor (CAR) T cell therapies can cause severe cytokine-release syndrome (CRS) and neurotoxicity, impeding their therapeutic application. Chinese and American researchers have generated a new anti-CD19 CAR molecule (CD19-BBz(86)) derived from the CD19-BBz prototype bearing co-stimulatory 4-1BB and CD3ζ domains. Researchers found that CD19-BBz(86) CAR T cells produced lower levels of cytokines, expressed higher levels of antiapoptotic molecules and proliferated more slowly than the prototype CD19-BBz CAR T cells, although they retained potent cytolytic activity. They performed a phase 1 trial of CD19-BBz(86) CAR T cell therapy in patients with B cell lymphoma. Complete remission occurred in 6 of 11 patients (54.5%) who each received a dose of 200 to 400 millions of CD19 CD19-BBz(86) CAR T cells. Notably, no neurological toxicity or CRS (greater than grade 1) occurred in any of the 25 patients treated. No significant elevation in serum cytokine levels after CAR T cell infusion was detected in the patients treated, including in those who achieved complete remission. CD19-BBz(86) CAR T cells persistently proliferated and differentiated into memory cells in vivo.
The results appeared in April 22nd online issue of Nat Med. 
Related Informations/Publications
-Curr Oncol Rep. 2019 Mar 27;21(5):38. Chimeric Antigen Receptor-Engineered T Cell Therapy in Lymphoma. Strati P et al. The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 429, Houston, TX, 77030, USA.
Results/Comments: Multicenter trials evaluating three CAR T cell products targeting CD19 have shown that they are highly effective and induce durable remissions in a substantial proportion of patients with relapsed or refractory aggressive B cell non-Hodgkin lymphoma (NHL). The most common toxicities were cytokine release syndrome and neurotoxicity. Two anti-CD19 CAR T cell products were approved by the FDA for the treatment of patients with relapsed or refractory aggressive B cell NHL. Link: Abstract
-Nat Rev Clin Oncol. 2019 Mar 5. Mechanisms of resistance to CAR T cell therapy. Shah NN et al. National Institutes of Health, Bethesda, MD, USA Link: Abstract  
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GENE THERAPY
Chimeric antigen receptor T cell persistence and memory cell formation
It is now becoming clear that less differentiated naive and memory T cells are superior to effector T cells in the transfer of immunity for adoptive cell therapy. This review outlines the challenges faced by CAR T cell therapy in the generation of persistence and memory for CAR T cells, and summarise recent strategies to improve CAR T cell persistence, with a focus on memory cell formation. The relevance of enhancing persistence in more differentiated effector T cells is also covered, because genetic and pharmacological interventions may prolong effector T cell activity and lifespan, thereby improving anti-cancer activity. In particular, it may be possible to enforce epigenetic changes in differentiated T cells to enhance memory CAR T cell formation. Optimising the generation of self-renewing T cell populations (e.g. memory cells), whilst maintaining differentiated effector T cells through epigenome modification, will help overcome barriers to T cell expansion and survival, thereby improving clinical outcomes in CAR T cell therapy.
The review appeared in April 22nd online issue of Immunol Cell Biol.  
Related Informations / Publications
-Int J Mol Sci. 2019 Apr 17;20(8). CAR-T with License to Kill Solid Tumors in Search of a Winning Strategy. Sacchetti B et al. University Roma Tre, 00146 Rome, Italy
Results/Comments: General experience with checkpoint inhibitors and CAR-T cell immunotherapy has identified a series of variables, weaknesses and strengths, influencing the clinical outcome of the oncologic illness. These aspects will be shortly outlined with the intent of identifying the still "missing strategy" to combat epithelial cancers.
 Link: Abstract - Full Text
 -J Clin Invest. 2019 Apr 15;130. Improving CAR T cell immunotherapy-mediated remissions for pediatric leukemia. Barrett DM. University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
Results/Comments : The role of transplantation as consolidative therapy is unclear in this nonrandomized data, but clearly warrants further study
Link: Abstract
-Transfus Med Rev. 2019 Feb 14. Risks and Benefits of Chimeric Antigen Receptor T-Cell (CAR-T) Therapy in Cancer: A Systematic Review and Meta-Analysis. Grigor EJM et al. The Ottawa Hospital, Ottawa, Ontario, Canada Results/Comments : There was a strong signal for efficacy of CAR-T cell therapy in patients with CD19+ hematologic malignancies and no overall signal in solid tumor trials published to date. These results will help inform patients, physicians, and other stakeholders of the benefits and risks associated with CAR-T cell therapy. Link: Abstract - Full Text
-Dis Markers. 2019 Feb 11;2019:3425291. Efficiency of CAR-T Therapy for Treatment of Solid Tumor in Clinical Trials: A Meta-Analysis. Hou B et al. The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China Results/Comments : Although CAR-T cell therapy did not have satisfactory responses in solid tumors, researchers were still holding an optimistic attitude towards its future efficacy with more modifications of its structure
Link: Abstract - Full Text
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DISRUPTIVE TECHNOLOGIes
Hemophilia A : Restoration of FVIII expression by targeted gene insertion in the FVIII
Target-specific genome editing, using engineered nucleases zinc finger nuclease (ZFN), transcription activator-like effector nuclease (TALEN), and type II clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9), is considered a promising approach to correct disease-causing mutations in various human diseases. In particular, hemophilia A can be considered an ideal target for gene modification via engineered nucleases because it is a monogenic disease caused by a mutation in coagulation factor VIII (FVIII), and a mild restoration of FVIII levels in plasma can prevent disease symptoms in patients with severe hemophilia A. In a recent study, Korean researchers describe a universal genome correction strategy to restore FVIII expression in induced pluripotent stem cells (iPSCs) derived from a patient with hemophilia A by the human elongation factor 1 alpha (EF1α)-mediated normal FVIII gene expression in the FVIII locus of the patient.
The results appeared in April 17th online issue of Exp Mol Med. 
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Related Informations / Publications
-Ther Adv Hematol. 2018 Aug 27;9(9):273-293. Gene therapy for hemophilia: what does the future hold? Doshi BS et al. Children's Hospital of Philadelphia, Philadelphia, PA, USA
Link: Abstract
-Stem Cell Reports. 2018 Dec 11;11(6):1391-1406. Patient-Specific iPSC-Derived Endothelial Cells Provide Long-Term Phenotypic Correction of Hemophilia A. Olgasi C et al. Università del Piemonte Orientale "A. Avogadro", 28100 Novara, Italy.
Link: Abstract - Full Text 
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CLINICAL TRIALS - DATA
AveXis data reinforce effectiveness of Zolgensma® in treating SMA Type 1
AveXis, a Novartis company, announced on April 16th that interim data from its Phase 3 STR1VE trial of Zolgensma® (onasemnogene abeparvovec-xioi; AVXS-101) in spinal muscular atrophy (SMA) Type 1 showed prolonged event-free survival, an early and rapid increase in CHOP-INTEND scores and significant milestone achievement compared to untreated natural history, consistent with data from the pivotal Phase 1 START trial. First-in-human biodistribution individual case study data from STR1VE showed Zolgensma successfully transduced intended targets in the central nervous system (CNS) and provided widespread SMN expression comparable to tissue from unaffected individual. Additional data presented showed 95 percent of patients screened across the Zolgensma clinical development program and Managed Access Program were not excluded from treatment due to elevated AAV9 antibody titers greater than 1:50. These data were presented at the 2019 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference in Orlando, Florida. STR1VE is an ongoing, open-label, single-arm, single-dose, multi-center trial designed to evaluate the efficacy and safety of a one-time intravenous infusion of Zolgensma in patients with SMA Type 1 who are less than six months of age at the time of gene therapy. The study was designed to enroll the broadest possible population of SMA Type 1 patients with one or two copies of the SMN2 backup gene and who have bi-allelic SMN1 gene deletion or point mutations. These criteria are well-matched to the patient population that was enrolled in the pivotal Phase 1 START trial while potentially providing treatment to some of the rarer subpopulations on an exploratory basis. STR1VE is projected to complete in 2020. For further information
Related Informations / Publications
-APR 2019 : AveXis expands world-leading gene therapy manufacturing capacity with purchase of advanced biologics therapy manufacturing campus in Longmont, Colorado
Results/Comments : The facility is to become the largest of four state-of-the-art sites involved in manufacturing of AveXis gene therapies for pipeline of rare genetic diseases including spinal muscular atrophy. Link: Press Release
-J Neurosurg Spine. 2019 Apr 19:1-5. Lumbar laminotomy for the intrathecal administration of nusinersen for spinal muscular atrophy: technical note and outcomes. Ko D et al. Neurological Surgery, Oregon Health & Science University, Portland, Oregon, USA
Results/Comments : For patients with SMA and posterior fusion from prior scoliosis treatment, lumbar laminotomy is an effective method for creating thecal access for the administration of nusinersen (Spinraza, Biogen). Link: Abstract
-Adv Ther. 2019 Mar 16. Survival, Motor Function, and Motor Milestones: Comparison of AVXS-101 Relative to Nusinersen for the Treatment of Infants with Spinal Muscular Atrophy Type 1.Dabbous O et al. AveXis, Inc., Bannockburn, IL, USA
Results/Comments: This indirect comparison (AVXS-101-CL-101 vs. ENDEAR) among symptomatic SMA type 1 infants suggests that AVXS-101 may have an efficacy advantage relative to nusinersen for overall survival, independence from permanent assisted ventilation, motor function, and motor milestones. Link: Abstract
-DEC 2018 : Novartis announces FDA filing acceptance and Priority Review of AVXS-101, a one-time treatment designed to address the genetic root cause of SMA Type 1. Link: Press Release  
Lentiviral gene therapy in infants with SCID-X1
Allogeneic hematopoietic stem-cell transplantation for X-linked severe combined immunodeficiency (SCID-X1) often fails to reconstitute immunity associated with T cells, B cells, and natural killer (NK) cells when matched sibling donors are unavailable unless high-dose chemotherapy is given. In previous studies, autologous gene therapy with γ-retroviral vectors failed to reconstitute B-cell and NK-cell immunity and was complicated by vector-related leukemia. Researchers have a dual-center, phase 1–2 safety and efficacy study of a lentiviral vector to transfer IL2RG complementary DNA to bone marrow stem cells after low-exposure, targeted busulfan conditioning in eight infants with newly diagnosed SCID-X1. Eight infants with SCID-X1 were followed for a median of 16.4 months. Bone marrow harvest, busulfan conditioning, and cell infusion had no unexpected side effects. In seven infants, the numbers of CD3+, CD4+, and naive CD4+ T cells and NK cells normalized by 3 to 4 months after infusion and were accompanied by vector marking in T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors. St. Jude licensed the therapy to Mustang Bio last August. The Massachusetts-based biotech paid 1MUS$ upfront along with a provision for a 0.1MUS annual fee starting in 2019. The deal also laid out 13.5MUS$ in milestone payments to the nonprofit hospital, as well as mid-single digit royalty payments should the therapy ever be sold.
The results appeared in April 18th online issue of New Engl J Med. 
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Related Informations / Publications
-Nat Commun. 2019 Apr 9;10(1):1634. Gene correction for SCID-X1 in long-term hematopoietic stem cells. Pavel-Dinu M et al. Stanford University, Stanford, CA, 94305, USA
Results/Comments: The study provides specificity, toxicity and efficacy data supportive of clinical development of genome editing to treat SCID-Xl. Link: Abstract - Full Text
-AUG 2018 : Mustang Bio and St. Jude Children’s Research Hospital Enter into Exclusive Worldwide License Agreement for a Ground-Breaking, Clinical-Stage Lentiviral Gene Therapy with Curative Potential for X-linked Severe Combined Immunodeficiency
For further information
-Mol Ther Methods Clin Dev. 2018 Mar 10;9:257-269. Preclinical Development of a Lentiviral Vector for Gene Therapy of X-Linked Severe Combined Immunodeficiency. Poletti V et al. Genethon, Evry, France
Results/Comments: The study enables a phase I/II clinical trial aimed at restoring both T and B cell immunity in SCID-X1 children upon non-myeloablative conditioning.
Link: Abstract - Full Text 
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INDUSTRIAL LANDSCAPE
& AGREEMENTS
Novasep and Theravectys enter into a new license agreement for GMP manufacturing of lentiviral vectors
Novasep, a leading supplier of services and technologies for the life sciences industry, and Theravectys , a discovery & clinical development biotech company, announced on April 16th the signing of a license agreement allowing Novasep to use Institut Pasteur’s DNA Flap Technology to produce GMP-grade lentiviral vectors for clinical use in all therapeutic applications including gene therapy, cell therapy, immunotherapy and vaccination, for any customer, worldwide. Financial terms were not disclosed.
Theravectys holds a license from the Institut Pasteur, covering the production of lentiviral vectors and their use for vaccination applications. The DNA Flap technology is derived from the genome of a lentivirus and consists of a DNA sequence, including the cPPT and CTS cis-active sequences, that actively enables the import of any gene into a cell nucleus. Lentiviral vectors are thus employed to deliver genes of therapeutic interest to non-replicating cells, hence their efficacy in gene therapy and in T-cell engineering (CAR-T).
For further infomation 
Related Informations / Publications
-OCT 2018 : Novasep opens €27m new Viral Vector Commercial Production Facility
Link: Press Release
 -Best Pract Res Clin Haematol. 2018 Jun;31(2):126-134. GMP CAR-T cell production. Gee AP. cGMP Facilities, Center for Cell & Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA
Results/Comments: This article reviews the issues that must be addressed in order to achieve this goal. It includes the manufacturing infrastructure, the regulatory environment, practical aspects of production, and the costs involved. Link: Abstract  
Eli Lilly invests in Avidity Biosciences as part of new collaboration
Eli Lilly and Avidity Biosciences announced on April 22nd a global licensing and research collaboration focused on the discovery, development and commercialization of potential new medicines in immunology and other selected indications. The companies will utilize Avidity’s technology platform to progress new therapeutic approaches toward clinical development and commercialization. Avidity’s platform seeks to combine the tissue selectivity of monoclonal antibodies and the precision of oligonucleotide-based therapeutics to potentially overcome barriers to the delivery of oligonucleotides and target genetic drivers of disease. Under the terms of the agreement, Avidity will receive an upfront payment of $20 million, as well as an investment of $15 million. Avidity is also eligible to receive up to approximately $405 million per target for development, regulatory and commercialization milestones, as well as tiered royalties ranging from the mid-single to low-double digits on product sales.
For further information 
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Related Informations / Publications
-MAR 2019: Lilly and ImmuNext Announce Licensing and Research Collaboration
Link : Press Release
 -N Engl J Med. 2019 Jan 3;380(1):57-70. Treating Disease at the RNA Level with Oligonucleotides. Levin A. Avidity Biosciences, La Jolla, CA, USA. Link: Interview
-OCT 2018: Eli Lilly puts up $100M in RNAi deal with Dicerna. Link : Press Release
 -JAN 2017: Avidity Biosciences Raises $16 Million in Series B Financing to Advance Antibody-siRNA Conjugate Platform. Link : Press Release  
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Gracell Bio announces fast, cost-effective CAR-T manufacturing technology
Gracell Biotechnologies, a Suzhou immune cell gene therapy company, announced a new technology, FasT CAR-T, that shortens the manufacturing time of CAR-T treatments from two weeks to one day. FasT CAR-T also lowers manufacturing costs to a fraction of previous CAR-T therapies, said Gracell, while showing higher potency of CD19-directed FasT CAR-T in B-Cell acute lymphoblastic leukemia (B-ALL) (20-40 times) and non-Hodgkin Lymphoma (NHL), both in vitro and in vivo. A first-in-human clinical study of CD19-F-CAR-T is underway. Gracell said early clinical results show the therapy is safe and significantly more potent than conventionally manufactured CAR-T agents for treating B-ALL. Gracell released the data of CD19-F-CAR-T during a presentation at the Global CAR-T Cell Therapy Development Shanghai Forum, held April 16-17, 2019. According to Gracell, FasT CAR-T requires only one day for manufacturing (plus 7 days for releasing tests per regulatory requirement), while C-CAR-T manufacturing takes about two weeks plus 7 days for testing. That means FasT CAR-T reduces vein-to-vein time by an average of 12 days, which is critical for patients with rapidly progressing disease. In addition, CD19-F-CAR-T has demonstrated superior expansion capability, with a younger and less exhausted phenotype, according to the Company. For further information, ChinaBio Today  
Related Informations / Publications
-FEB 2019: Gracell Biotechnologies Completes $85 Million Series B for Immune Cell Gene Therapies Results/Comments : The financing was led by Temasek with Lilly Asia Ventures, Kington Capital, King Star Capital and Chengdu Miaoji also participating in the round. This new funding will enable Gracell to enter clinical trials with several of its next generation immune cell gene therapy drug candidates. Link: PRNewswire  
Kite announces plans for new facility to expand cell therapy production capabilities
Kite, a Gilead company, announced on April 24th plans for a new facility in Frederick County, Maryland, which will produce innovative cell therapies for people with cancer. The 20-acre site will significantly expand Kite’s ability to manufacture a variety of chimeric antigen receptor T (CAR T) therapies, including Yescarta® (axicabtagene ciloleucel), Kite’s first commercially available CAR T cancer therapy, and investigational T cell receptor (TCR) cell therapies being evaluated in solid tumors.
For further information 
Related Informations / Publications
-Clin J Oncol Nurs. 2019 Apr 1;23(2):6-12. CAR T-Cell Therapy: Update on the State of the Science. Lamprecht M et al. Dana-Farber/Boston Children's Cancer and Blood Disorders Center, USA
Results/Comments: Tisagenlecleucel (Kymriah®) and axicabtagene ciloleucel (Yescarta®) received approval in 2017 for the treatment of B-cell precursor acute lymphoblastic leukemia in pediatric and young adult patients, and relapsed or refractory diffuse large B-cell lymphoma after two or more lines of systemic therapy in adult patients, respectively. Additional indications have since been approved, and new agents are in development.
Link: Abstract
-DEC 2018: Gilead and Agenus Enter Into Collaboration to Develop Immuno-Oncology Therapies. Link : Press Release
-DEC 2018: Kite Announces Two-Year Data for Yescarta® (Axicabtagene Ciloleucel) in Patients With Refractory Large B-Cell Lymphoma. Link : Press Release  
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miscellaneous
Medicare proposes raising CAR-T pay, but reimbursement solution years away
The US CMS (Centers for Medicare and Medicaid Services) proposed on April 23rd increasing Medicare reimbursement to hospitals that treat lymphoma patients with CAR-T therapies in order to address concerns that underpayment is limiting patient access. Under the proposal, hospitals would receive nearly $56,000 more per patient treated with Novartis' Kymriah® and Gilead Sciences' Yescarta® beginning Oct. 1. The increase would come from a change to a CMS mechanism allowing Medicare to increase payments for the reimbursement category of bone marrow and stem cell transplants, which CAR-T treatments now fall under. CMS Administrator Seema Verma said developing a separate reimbursement category for CAR-T could take three years. Resolving Medicare payment could be crucial for Novartis and Gilead to expand sales as rival experimental therapies requiring simpler medical procedures advance through the clinic.
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Related Informations / Publications
-Chin Clin Oncol. 2018 Apr;7(2):21. de Lima Lopes G et al. University of Miami, Miami, Florida, USA Results / Comments : As CAR T cells expand the boundaries of immunotherapy with extraordinary results, the need for a lower price in combination for more availability of CAR T cells will grow until some of these fundamental issues are addressed. Link : Abstract - Full Text   
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