Industry update: the latest developments in the field of therapeutic delivery, February 2021
2021; Future Science Ltd; Volume: 12; Issue: 6 Linguagem: Inglês
10.4155/tde-2021-0031
ISSN2041-6008
Autores Tópico(s)Cell death mechanisms and regulation
ResumoTherapeutic DeliveryVol. 12, No. 6 Industry NewsFree AccessIndustry update: the latest developments in the field of therapeutic delivery, February 2021Peter TimminsPeter Timmins *Author for correspondence: Tel.: +44 1484 473 102; E-mail Address: p.timmins@hud.ac.ukhttps://orcid.org/0000-0002-5840-0678Department of Pharmacy, University of Huddersfield, Queensgate, Huddersfield HD1 3DH, UKPublished Online:9 May 2021https://doi.org/10.4155/tde-2021-0031AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: antibody–drug conjugatecell therapiesclinical trialsCOVID-19drug deliverygene therapymergers and acquisitionsproduct approvalsrare diseasestargeted therapeuticsBusiness newsAcquisitions, mergers, licensingJazz Pharmaceuticals & GW PharmaceuticalsJazz Pharmaceuticals (Dublin, Ireland) and GW Pharmaceuticals (London, UK) have announced that they have entered into an agreement under which Jazz will acquire GW, with closure of the $7.2 billion deal expected in the second quarter of this year. The approved cannabidiol oral solution product Epidiolex®/Epidyolex® developed and commercialized by GW will add a rare childhood diseases medicine to an existing neuroscience franchise (sleep disorders) established at Jazz. The cannabidiol oral solution is approved in the USA for the treatment of seizures in Lennox-Gastaut syndrome (LGS), Dravet syndrome and tuberous sclerosis complex in children 1 year of age and older and is approved in the EU for use in conjunction with clobazam to manage seizures in LGS and Dravet syndrome in patients 2 years of age and older. The Jazz neuroscience pipeline may be further extended with this acquisition through other cannabinoid candidates in development at GW, including among others, Sativex® (Δ-9-tetrahydrocannibiol/cannabidiol) oromucosal spray solution for spasticity associated with multiple sclerosis in adults, the cannabidiol homologue GWP42006 for autism spectrum disorder, plus GWP42003 with potential in schizophrenia and in neonatal hypoxic-ischemic encephalopathy [1,2].Imcyse & PfizerNovel specific immunotherapies are the focus of a license agreement and research collaboration between Imcyse (Liège, Belgium) and Pfizer (NY, USA). Under the agreement, evolved out of an existing research collaboration initiated in 2017, the two companies will discover and develop drug candidates based on Imcyse Imotrope™ technology intended as therapeutic agents in the treatment of rheumatoid arthritis [3]. Imotrope technology produces specifically modified peptides, typically involving the incorporation a short additional chain of amino acids that includes cysteine at each end of that amino acid sequence, and flanking the antigenic determinant or epitope of an antigen. These modified epitopes can effectively and potently induce generation of cytolytic CD4 T-cells, which target and eliminate antigen-presenting cells and autoantigen-specific lymphocytes. Through this effect, the disease-associated immune cells involved in inflammation and tissue damage are specifically addressed while the remainder of the immune system is spared, leaving it to function normally. Most current approaches for autoimmune diseases like rheumatoid arthritis suppress the immune system more broadly, impairing desirable, normal immune defense mechanisms [4]. The initial work under the agreement will involve the two companies in the development of existing lead candidates and further optimization of potential candidate molecules. Once candidates are identified, Pfizer will assume responsibility for clinical development and commercialization and Imcyse will benefit from milestone payments and royalties on top of the initial cash payments and equity purchase defined under the agreement.Horizon Therapeutics & Viela BioViela Bio (MD, USA) has been acquired by Horizon Therapeutics (Dublin, Ireland), extending the development pipeline and rare diseases therapy portfolio of the Irish company. The B-cell depleting monoclonal antibody inebilizumab-cdon (Uplizna®) developed by Viela Bio is a key asset acquired through the deal. It is already approved by the US FDA for the treatment of a rare autoimmune disease of adults who are antiaquaporin-4 (APQ4) antibody positive, neuromyelitis optica spectrum disorder, which involves damage to the optic nerve, spinal cord and brain stem leading to blindness and paralysis. Uplinza is also in late-stage trials in myasthenia gravis and in a group of disorders defined as IgG4-related disease, which manifest as tumor-like swellings and fibrosis of affected organs. Additionally, it is in mid-stage trials for kidney transplant desensitization. Three other early- to mid-stage trial Viela Bio assets for therapy of a number of autoimmune and inflammatory disease also come to Horizon as a consequence of this deal [5].Tmunity Therapeutics & University of PennsylvaniaDescribing itself as having an ambition to 'uncancer the world' by advancing the best T-cell medicines for the treatment of solid tumors, Tmunity Therapeutics (PA, USA) has announced a deal with the Perelman School of Medicine at the University of Pennsylvania that will build on existing arrangements and allow its continued access to innovations emanating from the university's Center for Cellular Immunotherapies and expands it rights to cell manufacturing and platform technologies developed there [6]. Tmunity has already licensed four clinical stage assets created at the university and the expanded collaboration gives Tmunity an exclusive license to a further clinical stage asset, a mesothelin chimeric antigen receptor (CAR) T-cell product. The authors from the Perelman School of Medicine have published research on the potential for mesothelin CAR T-cell therapy in the treatment of metastatic pancreatic cancer [7].AbbVie & Caribou BiosciencesAlthough it walked away from a CRISPR genome-editing technology in returning rights to a portfolio of gene edited ocular medicines to Editas Medicine (MA, USA) when it acquired Allergan last year [8], AbbVie (IL, USA) has not given up on the technology. They have announced a licensing and collaboration agreement with Caribou Bioscience for research and development of CAR-T cell therapeutics employing Caribou's expertise in CRISPR genome-editing capabilities. The Caribou approach allows the creation of allogenic CAR-T cell therapies that can withstand the rejection of the administered therapeutic engineered cells by the host immune system and provide for 'off the shelf' availability of CAR-T cell products. AbbVie gains exclusive rights to Caribou's Cas 12a CRISPR hybrid RNA-DNA genome editing and cell therapy technologies to develop two new oncology therapies to be directed at specific targets identified by AbbVie, with an option to expand to two further therapies. Through the deal Caribou will focus on preclinical research, development and manufacturing to support the collaboration programmes, while AbbVie will contribute all clinical development, commercialization and manufacturing activities. Caribou will receive upfront cash and equity investment along with agreed future milestone payments and royalties [9].Tonix Pharmaceuticals & InsermThe French National Institute of Health and Medical Research (Inserm) has licensed its technology for oxytocin-based therapeutics for the treatment of a rare genetic childhood eating disorder to Tonix Pharmaceuticals (NJ, USA). The agreement allows Tonix to further develop its existing patented intranasal potentiated oxytocin formulation for an additional indication. The company is already investigating the benefit of intranasal oxytocin in the treatment of migraine. Administered by the nasal route, oxytocin can bind to receptors on neurons of the trigeminal ganglia, thus modulating transmission of pain signals. Nasal oxytocin may also block calcitonin gene-related peptide release, which is implicated in migraine attacks. A clinical program for the use of intranasal oxytocin to treat insulin resistance is also being advanced. The Inserm license enables Tonix to pursue therapy of Prager-Willi syndrome, a rare genetic disorder that manifests as failure to thrive in infants but then as uncontrollable appetite in childhood into adulthood resulting in severe obesity and complications with risk of significant mortality. The syndrome is accompanied by physical mental and behavioral problems and currently there are no approved treatments [10].Merck & Pandion TherapeuticsMerck (NJ, USA), known as MSD outside the USA and Canada, and Pandion Therapeutics (MA, USA) have announced a definitive agreement under which Merck will acquire Pandion and its pipeline of development products for the treatment of autoimmune diseases such as ulcerative colitis (UC). The lead candidate in the Pandion pipeline, PT101, is an engineered IL-2 modification, which is fused to a protein backbone to create a compound that can selectively activate and expand regulatory T cells, potentially allowing the regain of control of the patient's immune system and preventing it inappropriately targeting of the patients own cells. PT101 has already gone through a Phase I trial demonstrating its safety and tolerability. The Pandion pipeline also includes other compounds discovered using its TALON (Therapeutic Autoimmune reguLatOry proteiN) drug design and discovery platform, including PD-1 agonists, which could similarly modulate the immune system in a specific way to help manage certain autoimmune diseases. The deal is expected to complete in the first half of the year [11].Bristol Myers Squibb & The Rockefeller UniversityA novel complementary monoclonal antibody (mAb) pair that can neutralize the SARS-CoV-2 virus and therefore may be a possible treatment or prevention therapy for COVID-19 is the subject of a newly announced license agreement between the discovering partner, The Rockefeller University (NY USA), and the in-licensing partner, Bristol Myers Squibb (NJ, USA). Each of the antibodies in the combination blocks the virus spike protein in an individual way with high affinity, offering good activity against several known virus variants and they have been engineered using proprietary technology to provide for a long circulation half-life. The mAb combination is already in Phase I trials with Rockefeller (already supported by Bristol Myers Squibb), exploring intravenous and subcutaneous dosing with a view to the partnership moving quickly to registrational trials. Despite the roll out of vaccines, effort in making effective treatments available for patients who still contract the disease remains important. As a low dose, subcutaneous product, this mAb combination would offer convenience of treatment administration and as such it may offer availability and affordability opportunities in countries and communities where healthcare resources are constrained [12].CollaborationsGlaxoSmithKline & CureVacCureVac (Tübingen, Germany/MA, USA), established for over 20 years in the field of mRNA technology, and global healthcare player GlaxoSmithKline (GSK, London, UK) have announced a further collaboration, building on an existing relationship, to jointly develop new mRNA vaccines against SARS-CoV-2, which offer not just a monovalent approach, as in currently available mRNA vaccines, but have potential for a multivalent approach. This would be advantageous in dealing with multiple circulating variants of the virus and allow healthcare providers to keep ahead of the evolving disease, not just offering protection to previously unvaccinated individuals but giving opportunity to provide booster vaccinations to those previously vaccinated and where immunity has reduced with time. Development work is starting immediately with an ambition to provide the new vaccine in 2022, dependent upon gaining regulatory approval. Under the agreement, GSK will also support the manufacture of CureVac's first-generation COVID-19 vaccine, which is in Phase IIb/III clinical studies, using its Belgian operations to provide up to 100 million doses of vaccine in 2021 [13].GlaxoSmithKline & Vir BiotechnologyIn another expansion of an existing deal in virology, GSK and Vir Biotechnology (CA, USA) have agreed to collaborate on the development of mAb candidates for the prevention or treatment of influenza A including Vir's VIR-2482, which is designed to function as a 'universal' preventative treatment. This candidate has been demonstrated as being active against all strains that have emerged since the 1918 'Spanish' flu epidemic and overcomes perceived shortcomings in current vaccines for flu in that it offers very broad strain coverage and as an antibody does not require the treated subject to be able to mount an immune response to combat the infection. A single treatment has the potential to offer protection across the entire annual flu season due to the designed-in long half-life of the mAb. This new collaboration builds on an existing collaboration around therapeutics for coronavirus infections, including SARS-CoV-2. Two Vir mAbs (VIR-7831 and VIR-7832) against SARS-CoV-2 are in clinical trial with a VIR-7831 monotherapy Phase III trial due to read out during early 2021. Its activity is based on it binding to an epitope shared by SARS-CoV-2 and the coronavirus that causes SARS, SARS-CoV-1, suggesting possibility of low potential for development of resistance [14].Bristol Myers Squibb & Molecular TemplatesTexas, USA-based Molecular Templates has announced that it has entered into a research collaboration with Bristol Myers Squibb for the discovery and development of engineered toxin body (ETB) targeted therapeutics for the treatment of cancer [15]. ETBs are a novel therapeutic approach that can force receptor internalization, deliver a therapeutic payload and directly kill targeted cells through action on ribosomes. They are based on an antibody domain fused to a genetically engineered Shiga-like Toxin A subunit, which is a bacterially derived protein that inactivates ribosomes, so shutting own protein synthesis in the cell and so causing cell death; it also can induce its own entry into a cell. The antibody domain component of the ETB provides for the targeting to tumor cells [16]. Bristol Myers Squibb has selected a first target and Molecular Templates will conduct discovery activities to produce appropriate ETBs against the target. An option for Bristol Myers Squibb to take an exclusive worldwide license to develop and commercialize ETBs directed to each selected target is included in the deal, and on exercising the option would give the company sole responsibility for that activity for the licensed ETBs [15].Eli Lilly & Rigel PharmaceuticalsA collaboration to develop small-molecule receptor-interacting serine/threonine-protein kinase 1 (RIPK1) inhibitors for indications that include autoimmune and inflammatory diseases has been announced by Eli Lilly (IN, USA) and Rigel Pharmaceuticals (CA, USA). RIPK1 is implicated in a number of inflammatory processes including cytokine production and a form of cell death that leads to cellular rupture with the consequent discharge of cellular contents that can trigger an immune response and inflammation. Rigel's lead RIPK1 candidate R552 is the primary focus of the codevelopment and commercialization collaboration, but Lilly will also lead clinical development of CNS-penetrating RIPK1 inhibitors, which may offer a new approach in neurodegenerative diseases. R552 has demonstrated activity in animal models of inflammatory disease of skin and joints and has already completed Phase I trials, with Phase II studies set to start during 2021. A lead CNS-penetrating RIPK1 inhibitor is in ongoing preclinical studies. The deal aligns with Lilly's stated strategy in immunology to advance agents with actions at novel targets with potential to lead to best-in-class medicines [17].i2O Therapeutics & SanofiSpecialists in enabling the oral delivery of therapies normally limited to injectable administration such as biologics, i2O Therapeutics (MA, USA) have announced a research collaboration with Sanofi (Paris, France) to investigate the potential for oral delivery of Sanofi's Nanobody®-based medicines. Nanobodies are proprietary therapeutic proteins based on single variable domains of camelid immunoglobulin and are being explored as treatment across several areas such as oncology (including immuno-oncology), inflammatory disease, hematology and rare diseases [18]. The oral drug-delivery technology from i2O employs an ionic liquid vehicle based on choline and geranic acid that helps mucus penetration and opens epithelial cell tight junctions to allow passage of large molecules such as proteins that would normally not be significantly absorbed increasing the oral bioavailability manyfold. Prevention of protein degradation through exposure to gastric enzymes and gastric acid may be contributed also by the vehicle but protection by enteric coating of ionic – liquid-enabled solid dosage forms has also been studied [19,20]. i2O Therapeutics gained seed funding in April 2020, said investment being led by Sanofi Ventures, the corporate venture capital arm of Sanofi, along with JDRFT1D Fund [18].Cytovia Therapeutics & CellectisCytovia Therapeutics (MA, USA) and Cellectis (NY, USA) have announced a collaboration to apply Cellectis TALEN® (transcription activator-like effector nuclease) gene-editing technology develop novel induced pluripotent stem cell (iPSC) natural killer (NK) and CAR-NK cells as potential therapeutic agents in the treatment of solid tumours. TALEN is built on highly specific DNA-binding proteins known as transcription activator-like effectors (TALEs). By fusing the DNA cutting domain of a nuclease to selected TALE domains, a fusion protein which can act as 'DNA scissors' for gene-editing applications is created. Targeted by virtue of the TALE domain, genome modifications such as sequence insertion, deletion, repair and replacement can be achieved. Cellectis will provide custom TALEN constructs to Cytovia who will apply it to NK cells to modify them to address multiple gene targets in cancer [21,22].Sirion Biotech & SanofiGene therapy treatments based on improved adeno-associated virus (AAV) capsid vectors are the subject of a collaboration between Sirion Biotech (Munich, Germany) and Sanofi. AAV vectors are already established as an approach in gene therapy but Sirion has been working to develop new and modified virus capsids with improved tissue selectivity that can enhance specificity and enable a higher delivery efficiency in gene therapy. Sirion's expertise in AAV vector development, along with technology from Professor Dirk Grimm of Heidelberg University Hospital (Heidelberg, Germany) and combined with Sanofi's capabilities in virus-based vaccine and viral vector manufacturing will offer new opportunities for providing more effective gene therapies [23].Other business newsNovo Nordisk to expand production facilities for oral semaglutide tabletsTo support anticipated growth in demand for its oral peptide delivery-enabled formulation of GLP-1 agonist semaglutide (Rybelsus® tablets), Novo Nordisk (Bagsværd, Denmark) has announced plans to invest DKK 500 million to expand tablet-manufacturing facilities at its Måløv, Denmark site [24]. Novo announced the acquisition of Emisphere Technologies, provider of the Eligen® SNAC peptide bioavailability-enhancing technology used in oral semaglutide (and hence ownership of that technology) in November 2020 [25].Evox Therapeutics completes financing to support advancement of exosome therapeuticsEvox Therapeutics (Oxford, UK) has completed a financing round raising £69.2 million that will enable the company to continue the development of its DeliverEX™ exosome therapeutics technology [26], including advancing several assets targeting rare diseases into the clinic. The company asserts that exosome-based drugs might overcome some of the current possible limitations of protein, antibody and oligonucleotide therapeutics by providing for more effective delivery of drug payloads to cells and tissues compared alternative existing drug delivery technologies [27].Jaguar Gene Therapy launches to undertake development of therapies for severe genetic diseasesA new gene therapy company, Jaguar Gene Therapy (IL, USA) has emerged that is intending to focus on advancing a portfolio of AAV vector-based therapeutics (using AAV9) for genetic diseases with unmet need including galactosemia, autism spectrum disorder with a genetic cause, Type 1 diabetes and a subset Bardet-Biedl syndrome (a rare neurometabolic condition marked by progressive vision loss, severe obesity, kidney disorders and learning disorders). The company already has identified lead assets for each of these programs. Members of the former management team at AveXis, now acquired and transformed into Novartis Gene Therapies, occupy the leadership roles at Jaguar and investment and access to key academic expertise to support Jaguar is being provided by Deerfield Management (NY, USA) [28].Orna Therapeutics receives financing to develop a new class of circular RNA therapiesOrna Therapeutics (MA, USA) has gained $80 million of financing to enable it to progress its innovative circular RNA (oRNA) therapeutics to an IND-enabling stage. Based on research out of the Massachusetts Institute of Technology (MIT) and inspired by RNA enzymes and RNA viruses, Orna's unique technology may overcome limitations of current linear mRNA therapeutics, particularly for long coding RNA, with potential in oncology, autoimmune and genetic diseases [29]. Unlike linear RNA therapies, oRNA does not require cap and tail chemistry or modified nucleotides to impart stability and deal with innate immune responses, have better resistance to degradation, can offer superior protein expression through extended translation duration and can have simpler and more cost-effective manufacturing. Orna is incorporating its oRNA agents in lipid nanoparticle formulations for delivery, along similar lines to the drug-delivery approaches currently utilized for linear mRNA. The potential to deliver CARs directly to immune cells, avoiding some of the manipulation required of current ex vivo approaches (e.g., CAR-T cell therapies) and effectively create an in situ CAR therapy approach [30,31].Product approvals & other regulatory newsOzanimod capsules (Zeposia®, Bristol Myers Squibb)Ozanimod (Zeposia®, Bristol Myers Squibb) is a sphingosine 1-phosphate receptor modulator which reduces the migration of lymphocytes from lymph nodes, lowering their numbers in the peripheral circulation. It has potential therefore in the treatment of autoimmune diseases marked by significant inflammatory responses. It was approved by the US FDA and the European Commission in early 2020 for the treatment of relapsing forms of multiple sclerosis. The company has now announced that its filing for the use of ozanimod for the treatment of UC has been accepted by the FDA with Priority Review, and the drug is already under review for this condition by the EMA. It is believed the effectiveness seen in clinical trials of ozanimod as an induction and maintenance therapy in moderately to severely active UC may be due to the drug being able to reduce the migration of lymphocytes into inflamed intestinal mucosa [32].Tepotinib tablets (Tepmetko®, EMD Serono)The US FDA has approved a once-daily oral targeted therapy treatment for patients with metastatic non-small-cell lung cancer (NSCLC) of a particular genetic subset, those having exon 14 skipping alterations in the MET gene (METex14 alterations). The medicine is tepotinib (Tepmetko®) from EMD Serono (MA, USA), the US and Canada operation of Merck KGaA (Darmstadt, Germany). The approval given, completed under the FDA Real-Tie Oncology Review pilot program, is an accelerated approval based on overall response rate and duration of response in a Phase II monotherapy trial. The FDA had previously granted tepotinib Breakthrough Therapy Status, which can speed regulatory review and also granted it Orphan Drug Designation. Clinical trial subjects in the study on which the approval was based were a very focused group of patients for the targeted therapy and were identified for inclusion through having advanced or metastatic disease and with METex14 alterations, EGFR wild-type and anaplastic lymphoma kinase-negative status. As this is an accelerated approval based on strong results in a mid-phase trial, continued approval will require verification in additional trials. Tepotinib is currently also under review by the EMA and a number of other regulatory authorities around the world [33].Umralisib tablets (Ukoniq™, TG Therapeutics)TG Therapeutics (NY, USA) has announced that the US FDA has approved its dual kinase inhibitor umralisib (Ukoniq™) for the treatment of adult patients with specific forms of relapsed or refractory of non-Hodgkin lymphoma. These are patients with marginal zone lymphoma (a group of indolent mature B-cell non-Hodgkin lymphomas) who have had one prior anti-CD-20-based therapy and patients with relapsed or refractory follicular lymphoma (FL, an indolent non-Hodgkin lymphoma arising from B-lymphocytes) who have previously been treated with at least three lines of systemic therapy. Umralisib is the first oral inhibitor of both phosphoinositide 3 kinase (PI3K) delta and casein kinase 1 (CK1) epsilon. PI3K-delta, expressed by normal cells and also malignant cells, is involved in cell proliferation and survival, intracellular trafficking and immunity, whereas CK1-epsilom, a regulator of oncoprotein translation, is implicated in lymphoid cancers. The regulatory approval is an accelerated approval based on overall response rate seen in a Phase II trial and the continued approval is subject to confirmatory trials. The US FDA also granted Breakthrough Therapy Designation for the treatment of marginal zone lymphoma and Orphan Drug Designation for the treatment of FL [34].Peginterferon β-1a injection (Plegridy®, Biogen)As an alternative to the established subcutaneous (SC) route of administration, regulatory approval for intramuscular (IM) administration of peginterferon β-1a (Plegridy®) has been received from the US FDA by Biogen (MA, USA). The potential for significantly reduced injection site reactions (more than halved in the IM group compared with the SC group in clinical studies) is the claimed benefit of IM dosing in the use of peginterferon β-1a injection in the treatment of relapsing forms of multiple sclerosis. Bioequivalence of dosing by the two routes was confirmed in studies undertaken as part of the development work supporting the regulatory filing. The alternate dosing regimen was approved by the European Commission at the end of 2020 [35].Evinacumab injection (Evkeeza™, Regeneron)An advance in the treatment of an ultra-rare genetic form of high blood cholesterol has been announced by Regeneron Pharmaceuticals (NY, USA) with the approval of its angiopoietin-like 3 (ANGPTL3) blocker evinacumab-dgnb (Evkeeza™). ANGPTL3 plays a key role in lipid metabolism. Patients with homozygous familial hypercholesterolemia (HoFH) have extremely high levels of low-density lipoprotein cholesterol (LDL-C) with consequent risk of premature atherosclerotic disease and associated cardiac risk, with possibility of events while they are teenagers. Added to existing lipid-lowering therapy, evinacumab given as a once-monthly intravenous infusion, reduced LDL-C by nearly half at the 24-week point in trials and also was effective in reducing other disease markers such as apolipoprotein B, non-high-density lipoprotein cholesterol and total cholesterol levels. The mechanism of action of evinacumab is novel and it is effective across the different forms of HoFH, including those patients with almost no LDL receptor activity, a group of patients for which some existing therapies for HoFH are not suitable given their mode of action involving LDL receptors [36].Lisocabtagene maraleucel infusion (Breyanzi®, Bristol Myers Squibb)Bristol Myers Squibb has announced that its CD19-directed CAR-T-cell therapy lisocabtagene maraleucel ('liso-cel', Breyanzi®) has been approved by the US FDA for the treatment of adult patients with relapsed or refractory large B-cell lymphoma (the most common form of non-Hodgkin lymphoma), following two or more prior lines of treatment. This includes diffuse large B-cell lymphoma (including that arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma and grade 3B FL, but it is not approved for the treatment of patients with primary CNS lymphoma. Lisocabtagene maraleucel is described as having a defined composition (1:1 CAR-positive variable T cells of the CD component) and having a 4-1BB costimulatory domain, the defined composition reducing variability of the dose of the CD8 and CD4 components and the 4-1BB signaling enhancing the cell therapy's expansion and persistence [37]. The company has announced that it will manufacture the product at its cellular immunotherapy manufacturing facility in Bothell, WA, USA, but has further announced that it will construct a new state-of-the-art cell therapy manufacturing facility at its Devens, MA, USA site where it already has activities around biologics medicines (including immune-oncology products) including process development, clinical supply manufacturing and commercialized product manufacturing [38].Pilocarpine ophthalmic solution (Allergan)Pilocarpine ophthalmic solution across a range of concentrations up to 4% has been used to treat ocular hypertension and some forms of glaucoma although has been largely replaced by topical prostaglandin analogs, topical β blockers or topical carbonic anhydrase inhibitors, and is reserved for therapy where all of these initial lines of interventi
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