Jan 20, 2020: The European Commission (EC) approved Novartis Mayzent® (siponimod) for the treatment of adult patients with secondary progressive multiple sclerosis (SPMS) with active disease evidenced by relapses or imaging features of the inflammatory activity.
Although every patient’s MS journey is unique, up to 80% of the relapsing remitting MS (RRMS) patients will eventually transition to SPMS. According to the European marketing authorization, Mayzent (sphingosine 1-phosphate receptor) that selectively binds to S1P1 and S1P5 receptors and is the first and only indicated oral treatment proven in SPMS patients with vigorous disease based on the randomized clinical trial of a broad range of SPMS patients.
The EC’s approval is based on figures from the EXPAND study, a randomized, double-blind, placebo-controlled trial, comparing the efficiency and safety of Mayzent versus placebo in the broad range of the SPMS patients (EDSS score 3·0–6·5 at baseline).
Grow incorporated a subgroup of the patients with dynamic sickness (n=779), characterized as patients with backslides in the two years past to the examination or potentially nearness of Gd-improving T1 sores at gauge.
The gauge attributes were comparative aside from indications of action contrasted with the general populace. In the subgroup of Mayzent-treated patients with dynamic sickness, results appeared:
The danger of multi month and half year affirmed handicap movement (CDP) was altogether decreased by 31% contrasted with fake treatment and by 37% contrasted with fake treatment, respectively.
Noteworthy ideal results in other pertinent proportions of MS malady movement, including annualized backslide rate (ARR – affirmed backslides), MRI sickness action and cerebrum volume misfortune (mind shrinkage).
Results in the general populace indicated that Mayzent altogether decreased the danger of three-month CDP (essential endpoint; 21% decrease versus fake treatment, p=0.013) and definitively deferred the danger of half year CDP (26% versus fake treatment, p=0.0058)
Chimeric antigen receptor T cells (also known as CAR T cells) are T-cells that have been genetically engineered in order to produce an artificial T-cells receptor for use in immunotherapy.
Chimeric antigen receptors (CARs, also known as chimeric immunoreceptors, chimeric T cell receptors or artificial T cell receptors) are the receptor proteins that have been engineered to give T-cells the new capability to target a specific protein. The receptors are called chimeric because they combine both antigen-binding and T-cell activating functions into a single receptor.
CAR-T cell therapy uses T cells engineered with CARs for the cancer therapy. The premise of CAR-T immunotherapy is to alter T cells to recognize cancer cells in order to more efficiently target and destroy them. Scientists harvest T cells from people, genetically modify them, then infuse the resulting CAR-T cells into patients to attack their tumors. CAR-T cells can be either derived from the T cells in a patient’s own blood (autologous) or derived from T cells of another healthy donor (allogenic). Once isolated from a person, these T cells are genetically engineered in order to express a specific CAR, which programs them to target an antigen that is present on the surface of tumors. For safety, CAR-T cells are engineered to be specific to an antigen expressed on a tumor that is not expressed on the healthy cells.
After the infusion of CAR-T cells into a patient, they act as a “living drug” against cancer cells. As they come in contact with their targeted antigen on a cell, CAR-T cells bind to it and become activated, then proceed to proliferate and becomec cytotoxic. CAR-T cells destroy cells through numerous mechanisms, including extensive stimulated cell proliferation, increasing the degree to which they are toxic to other living cells (cytotoxicity) and by causing the improved secretion of factors that can affect other cells such as cytokines, interleukins and growth factors.
For the production of CAR-T cells the first step is the isolation of T cells from human blood. CAR-T cells may be manufactured either from the patient’s own blood (autologous treatment), or from the blood of a healthy donor(allogeneic treatment). The manufacturing process is the same in both cases; only the initial blood donor is different.
First, leukocytes are isolated using blood cell separator in a process known as leukocyte apheresis. Peripheral blood mononuclear cells (PBMC) are separated and then collected. The products of leukocyte apheresis are then transferred to the cell-processing center. In the cell processing center, specific T cells are stimulated so that they will aggressively proliferate and expand to large numbers. In order to driven their expansion, T cells are typically treated with the cytokine interleukin-2(IL-2) and anti- CD3 antibodies.
The expanded T cells are then purified and transduced with a gene encoding the engineered CAR via a retroviral vector, typically either an integrating gammaretrovirus (RV) or a lentiviral (LV) vector. These vectors are very safe in present times due to a partial deletion of the U3 region. The new gene editing tool CRISPR/Cas9 has recently been used as an alternative of retroviral vectors to integrate the CAR gene into specific sites in the genome.
The patient undergoes lymphodepletion chemotherapy earlier to the
introduction of the engineered CAR-T cells. The depletion of number of
circulating leukocytes in the patient upregulates the number of cytokines that
are produced and reduces the competition for resources, which helps to promote
the extension of the engineered CAR-T cells.
CAR-T Cell therapy is developed using the patient’s own T-Cells which are part of the body immune system and play a central role in fighting certain types of cancers . A patient’s T cells are extracted and reprogrammed outside of the body to recognize and fight cancer cells and other cells expressing a particular antigen.
The first two FDA-approved CAR-T therapies both target CD19 antigen and found on many types of B-cell cancers. Tisagenlecleucel (Kymriah) is approved in order to treat relapsed/refractory B-cell precursor acute lymphoblastic leukemia (ALL), while axicabtagene ciloleucel (Yescarta) is approved in order to treat relapsed/refractory diffuse large B-cell lymphoma (DLBCL).
As of March 2019, there were approximately 364 ongoing clinical trials occurring globally involving CAR-T cells. The majority of those trials target blood cancers: CAR-T therapies account for above half of all trials for hematological malignancies. CD19 continues to be the most popular antigen target, followed by BCMA (generally expressed in multiple myeloma).
In 2016, studies began in order to explore the viability of other antigens, such as CD20.Trials for the solid tumors are less dominated by CAR-T, with about half of the cell therapy-based trials involving other platforms such as NK cells. Even though the initial clinical remission rates after CAR-T cell therapy in all the patients are as high as 90%, long term survival rates are much lower.
The cause is normally the emergence of leukemia cells that do not express CD19 and so avoid recognition by the CD19–CAR T cells, a phenomenon known as antigen escape.
Preclinical studies developing the CAR-T cells with double targeting of CD19 plus CD22 or CD19 plus CD20 have been demonstrated promise, and trials studying bispecific targeting to the circumvent CD19 down-regulation are ongoing.
How CAR-T Therapy Work 1.Leukapheresis A patients white cells,including T cells are extracted through a specialized blood filtration process known as Leukapheresis, then T -cells are cryopreserved and send to manufacturing unit for reprogramming.
2.Reprogrammed cells T cells are genetically encoded to recognize cancer cells by using viral vector (inactive virus)and other cells expressing a specific antigen.
3.Expansion Newly formed Car -T cells undergo expansion.
4.Quality checking Strict quality check occurs before release and shipment of the CAR-T cells back to patient.
5.Lymphodepleting Chemotherapy Lymphodepleting Chemotherapy is given to patient in order to reduce the level of WBCs and help the body accept the Reprogrammed cells
7. Cell Death Now CAR-T cell present in patient body have the potential to recognize the patient’s cancer cells and other cells expressing a specific antigen and attach to them,which may be start with direct cell death.
Kymriah (tisagenlecleucel, formerly CTL019) was the first CAR-T cell therapy approved by the US FDA. Kymria uses 4-1BB costimulatory domain, which is critical for full activation of the therapy, enhancement of the cellular expansion and durable persistence of the cancer-fighting cells.
The approved indications for the treatment of pediatric and young adult patients up to 25 years with B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post-transplant or in the second or later relapse; and for the treatment of adult patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) after two or more lines of the systemic therapy. Route of administration: intravenous infusion. Reasons to delay Kymriah treatment Kymriah treatment should only be delayed, if the patient has any of the following conditions: Unresolved serious adverse reactions (particularly pulmonary reactions, cardiac reactions or hypotension) from the preceding chemotherapies. vigorous uncontrolled infection. Active graft-versus-host disease (GVHD). considerable clinical worsening of leukemia burden or lymphoma following lymphodepleting chemotherapy.
Limitation
of Use:
KYMRIAH is not indicated for the treatment of patients with primary central
nervous system lymphoma. Pregnancy, Lactation, Females and Males of Reproductive Potential(No data are accessible of
KYMRIAH use for the pregnant or
lactating women)
Adverse effects:
KYMRIAH have adverse effect such as Cytokine
release syndrome and neurological toxicities and allergic rections
.
Cytokine Release Syndrome (CRS) includes fatal or
life-threatening reactions, occurs in
patients receiving KYMRIAH. Patients with active infection or inflammatory
disorders must not administer KYMRIAH.
Treat severe or life-threatening CRS with the tocilizumab, or tocilizumab and
corticosteroids.
Neurological toxicities, which may be severe or
life-threatening and can occur following treatment with KYMRIAH.
Allergic reactions may also
occur with KYMRIAH like serious hypersensitivity reactions, including
anaphylaxis, may be due to dimethyl sulfoxide or dextran 40 in KYMRIAH.
Monitoring
after Kymriah infusion: Kymriah may cause side effects that might be severe, life-threatening or
fatal. As a result, patients should be monitored daily for the first
10 days following the infusion for signs and symptoms of the potential
cytokine release syndrome, neurological events and other toxicities.
Drug Interactions : HIV and lenti-virus used to make KYMRIAH have limited, short spans of the identical genetic material (RNA). consequently, some commercial HIV nucleic acid tests (NATs) may yield false positive results in the patients who have received KYMRIAH.
Jan 20,2020: AstraZeneca’s Imfinzi (durvalumab) and tremelimumab, an anti-CTLA4 antibody and potential new medicine,both have been granted Orphan Drug Designation (ODD) in US for the treatment of hepatocellular carcinoma (HCC), the most common type of the liver cancer.
The U.S. FDA grants ODD to medicines proposed for the treatment, diagnosis or prevention of rare diseases or disorders that affect less than 200,000 people in the US. Liver cancer is the third leading cause of cancer death worldwide for the patients with unresectable or advanced disease, only 13% are living five years after diagnosis.
The Phase III HIMALAYA trial is testing Imfinzi and the combination of Imfinzi plus tremelimumab in the patients with unresectable, advanced HCC who have not been treated with previous systemic therapy and are not suitable for locoregional therapy (treatment localised to the liver).
CAR-T cells are genetically engineered in order to express chimeric antigen receptors specially directed toward antigens on a patient’s tumour cells and then infused into the patient where they attack and kill the cancer cells.
Adoptive transfer of the T cells expressing CARs is a promising anti-cancer therapeutic because CAR-modified T cells can be engineered to target nearly any tumour-associated antigen.
GFRvIII is being targeted by the O’Rourke Laboratory in the treatment of glioblastoma. This approach has great potential in order to improve patient-specific cancer therapy in a profound way.
Early CAR-T cell research has focused on the blood cancer, first approved treatments use CARs that target the antigen CD19, present in B-cell-derived cancers such as acute lymphoblastic leukaemia (ALL) and diffuse large B-cell lymphoma (DLBCL).
Also, there are efforts in progress to engineer CARs targeting many other blood cancer antigens, including CD30 in refractory Hodgkin’s lymphoma; CD33, CD123, and FLT3 in acute myeloid leukaemia (AML); and BCMA in multiple myeloma. Solid tumours have been presented a more difficult target.
Identification of good antigens proved challenging: such antigens must be extremely expressed on the majority of cancer cells, but mostly absent on normal tissues. CAR-T cells are also not trafficked powerfully into the centre of solid tumour masses, and the hostile tumour microenvironment suppresses T cell activity.
Above diagram represents the process of chimeric antigen
receptor T-cell therapy (CAR), this is a method of immunotherapy, which is a
growing practice in the treatment of cancer.
The final product should be a production of equipped T-cells that can recognize and fight the infected cancer cells of the body. 1. T-cells (labelled as ’t’) are removed from the patient’s blood.
2. Then in a lab setting the gene that encodes for specific antigen receptors are incorporated into the T-cells.
3. Thus producing the CAR receptors (labelled as ‘c’) on the surface of cells.
4. The recently modified T-cells are then further harvested and grown in the lab. 5. After a certain time period, the engineered T-cells are then infused back into the patient.
Safety concerns: CAR-T cells are unquestionably a major breakthrough in the cancer treatment. However, there are serious side effects from CAR-T cells being introduced into the body, including cytokine release syndrome and neurological toxicity.
Because it is a comparatively new treatment, there is very little data about the long-term effects of CAR-T cell therapy. There are still concerns about long-term patient survival, as well as pregnancy complications in the female patients treated with CAR-T cells.
The most widespread issue behind treatment with CAR-T cells is cytokine release syndrome (CRS), a condition in which immune system is activated and releases an increased number of the inflammatory cytokines.
The clinical manifestation of this syndrome resembles sepsis with high fever, fatigue, myalgia, nausea, capillary leakages, tachycardia and other cardiac dysfunction, liver failure, and kidney impairment.
This syndrome occur in almost all patients treated with CAR-T cell therapy and in fact, the presence of CRS is a diagnostic marker that indicates the CAR-T cells are working as intended in order to kill the cancer cells.
Neurological toxicity is frequently associated with CAR-T cell treatment. Clinical manifestations include delirium, the one-sided loss of the ability to speak coherently while still having the ability to interpret language (expressive aphasia), lowered alertness (obtundation), and seizures.
During some clinical trials deaths caused by the neurotoxicity, the main cause of death from neurotoxicity is cerebral edema. Anaphylaxis is an expected side effect, as the CAR is made with the foreign monoclonal antibody and as a result, incites an immune response.
There is also the unlikely possibility that engineered CAR-T cells will themselves become transformed into cancerous cells during insertional mutagenesis, due to viral vector inserting the CAR gene into a tumour suppressor or oncogene in the host T cell’s genome.
Chimeric antigen receptors combine numerous facets of normal T cell activation into a single protein.
They link an extracellular antigen recognition domain to an intracellular signalling domain, which can activate the T cell when an antigen is bound.
Chimeric antigen receptors (CARs) are self-possessed of four regions:
Antigen recognition domain
Extracellular hinge region
Transmembrane domain, and
Intracellular T-cell signaling domain.
Antigen recognition domain: The antigen recognition domain is showing outside the cell, in the ectodomain portion of the receptor. It interacts with the potential target molecules and is responsible for targeting the CAR-T cell to any cell expressing a matching molecule.
The antigen recognition domain is typically derived from the variable regions of a monoclonal antibody linked collectively as a single-chain variable fragment (scFv). An scFv is the chimeric protein made up of the light (VL) and heavy (VH) chains of the immunoglobins, connected with a short linker peptide.
These VL and VH regions are selected in advance for their binding capability to the target antigen (such as CD19). The linker between the two chains consists of the hydrophilic residues with elongated glycine and serine in it for flexibility as well as stretches of glutamate and lysine for added solubility.
In addition to the scFvs, non‐antibody‐based approaches have also been used in order to direct CAR specificity, usually taking advantage of ligand/receptor pairs that normally bind to each other. Cytokines, instinctive immune receptors, TNF receptors, growth factors, and structural proteins have all been successfully used as the CAR antigen recognition domains.
Hinge region(Spacer) :The hinge, also known as spacer, is a small structural domain that sits between the antigen recognition region and the cell’s outer membrane. An ideal hinge enhances the elasticity of the scFv receptor head, reducing the spatial constraints between CAR and its target antigen.
This promotes the antigen binding and synapse formation between the CAR-T cells and target cells. Hinge sequences are often based on the membrane-proximal regions from other immune molecules that includes IgG, CD8, and CD28.
Transmembrane domain:The transmembrane domain is a structural constituent, consist of a hydrophobic alpha helix that spans the cell membrane.
It anchors the CAR to the plasma membrane, bridging the extracellular hinge and also antigen recognition domains with the intracellular signaling region.This domain is necessary for the stability of the receptor as a whole.
In general, the transmembrane domain from the most membrane-proximal constituent of the endodomain is used, but different transmembrane domains effect in different receptor stability.
The CD28 transmembrane domain is known in order to result in a highly expressed, stable receptor.Use of CD3-zeta transmembrane domain is not recommended, as it can result in incorporation of the artificial TCR into the native TCR.
Intracellular T-cell signaling domain: The intracellular T-cell signaling domain lies in the receptor’s endodomain, within the cell.After an antigen is bound to the exterior antigen recognition domain, CAR receptors group together and transmit an activation signal.
Then the internal cytoplasmic end of the receptor continues signaling inside the T cell. Normal T cell activation relies on the phosphorylation of the immunoreceptor tyrosine-based activation motifs (ITAMs) present in the cytoplasmic domain of CD3-zeta.
In order to mimic this process, CD3-zeta’s cytoplasmic domain is commonly used as the main CAR endodomain component. Other ITAM-containing domains have also been tried, but are not as efficient.
T cells also require co-stimulatory molecules in addition to CD3 signaling to persist after activation. For this cause, the endodomains of the CAR receptors normally include one or more chimeric domains from co-stimulatory proteins.
Signaling domains from a wide range of co-stimulatory molecules have been successfully tested and include CD28, CD27, CD134 (OX40), and CD137 (4‐1BB).
Jan 20, 2020:Heroic-Faith Medical Science expects its AI-powered respiratory monitor in order to receive US FDA clearance this year, according to Taiwan-based startup.
Heroic-Faith said the AI-powered nonstop respiratory monitor can perform the breathing sounds auscultation precisely, using Taiwan’s cutting-edge noise-cancelling technology, but also count breathing rate and identify the so-called adventitious sounds caused by the airway obstruction, spasm, and increased secretion, credit to the advanced AI algorithm.
Medical personnel can listen to the breathing sounds broadcasting from the device or through Bluetooth earphones in real-time, and meanwhile, visually monitor the sound spectrogram from the screen.
The alert system additional assists clinicians in early detection of respiratory compromises, according to the company.
The National Medical Products Administration (NMPA) ( Chinese name translation in English “State Drug Administration” or China Food and Drug Administration CFDA) and the Ethical Committee must approve a clinical trial application prior to the sponsor initiating a clinical trial.
First EC approves the application and NMPA’s approval depends on it. China Follows the centralized process for ethical review of the clinical trial application.
The ethical review process has three layers: national EC, provincial ECs, and institutional level ECs.
China’s National Health Commission (NHC) is responsible for managing ECs nationwide by establishing the National Committee of Medical Ethics Experts which develop policies for ethical review.
Please see the below tables for a comprehensive view of the drug approval process. The drugs are characterized into 5 Categorize as per New regulation by CFDA on Mar-2016. Credit: https://www.sfdachina.com/info/202-1.htm
In 1989, first CAR-T cells were developed by Gideon Gross and Zelig Eshhar at Weizmann Institute, Israel.
The complexity of the engineered CAR receptors has evolved over time, and depending on their composition, they are referred to as first, second , third, or fourth generation CARs.
Since the conventional cornerstones of cancer treatment (surgery, chemotherapy, and radiation therapy) manifest more and more limitations against multiple human malignancies, the novel immunotherapy is growing excitement with stutter steps, particularly the CAR-T therapy.
Hailstones as “a living drug”, CAR-T is an admirable example of the application of basic research to the clinic.
Representative CARs
The first fusion receptors
CAR stands for chimeric antigen receptor or artificial T cell receptor, which is engineered abundantly and endowing an immune effector cell (T cell) with an uninformed specificity via a monoclonal antibody.
The original CAR-T or the first-generation CAR consists of the intracellular domain from the CD3 ζ- chain and the primary transmitter of signals from the endogenous TCRs, which showed success in pre-clinical trials and entered in Phase I clinical trials in ovarian cancer, neuroblastoma and various types of leukaemia and lymphoma.
Even though the anti-tumor activity was limited due to insufficient activation, determination and homing to the cancer tissue, some significant effects certainly existed in patients with B-cell lymphoma treated with α-CD20-CD3 ζ CAR-modified T cells and also some neuroblastoma treated with ScFv-CD3 ζ CAR-Ts.
This is the most common form of CARs in order to fuse single-chain variable fragments (scFv) derived from monoclonal antibodies to CD3 ζ transmembrane and endo domain.
To augment the antitumor efficiency of 1st-generation CARs, the 2nd-generation CARs were designed to combine the intracellular signaling domains from various co stimulatory protein receptors (e.g., CD28, 41BB, ICOS) that are incorporated in the cytoplasmic tail of the CAR to enhance the signaling.
For instance, the CD19-targeted CARs incorporated with CD28 or 4-1BB signaling domains manifested outstanding complete remission rates in patients with refractory B-cell malignancies.
consequently, the CD28-based CARs showed a brisk proliferative response and boost effector functions. Meanwhile, the 4-1BB-based CARs manifested a other progressive T cell accumulation.
The three generations of CARs
As the expectation of more antitumor efficiency, the 3rd-generation of CARs combined with multiple signaling domains (e.g., CD3 ζ-CD28-41BB, CD3 ζ-CD28-OX40) to acquire additional enhanced activation signals, proliferation, production of cytokines and effective function.
For instance, the α-CD19-CD3 ζ-4-1BB CAR-Ts for chronic lymphocyte leukemia illustrates complete remission to infiltrate and lyse cancer tissue. Even better, a portion of CAR-Ts functioned as a memory phenotype for preventing the tumor relapses.
Despite the significant therapeutic effect, the emerging unmanageable activity accompanied with more antitumor efficacy caused life-threatening lysis activity as the most critical adverse effect or toxicity including clinically significant release of pro-inflammatory cytokines, pulmonary toxicity, multi-organ failure, and ultimate death.
The 4th generation CAR
The previous CAR strategies are extremely specific and useful in redirecting T cells targeting malevolent cancer cells. However, the major limitation on solid tumors with a tremendous phenotypic heterogeneity and relapse due to antigen-negative cancer cells is the huge confront to trigger a novel CAR strategy.
The 4th-generation CAR-T is designed to shape the tumor environment by the inducible release of the transgenic immune modifiers, such as IL-12, which augments T-cell activation, attracts and activates native immune cells in order to eliminate antigen-negative cancer cells in the targeted lesion.
Control mechanisms: Adding a synthetic control mechanism to engineered T cells allows doctors to precisely control the persistence or activity of the T cells in the patient’s body, with the goal of reducing toxic side effects.
The major control techniques that trigger T cell death or limit T cell activation, and often regulate the T cells via a separate drug that can be introduced or withdrawn as needed.
Suicide genes: Heritably modified T cells are engineered in order to include one or more genes that can induce apoptosis when activated by an extracellular molecule.
Herpes simplex virus thymidine kinase (HSV-TK) and inducible caspase 9 (iCasp9) are two types of suicide genes that have been incorporated into CAR-T cells.
ON-switch: In this system, CAR-T cells can only function in the existence of both tumor antigen and a benign exogenous molecule. To achieve this, the CAR-T cell’s engineered chimeric antigen receptor is rip into two separate proteins that must come together to function.
The first receptor protein usually contains the extracellular antigen binding domain, while the second protein contains the downstream signaling elements and co-stimulatory molecules (such as CD3ζ and 4-1BB).
In the presence of an exogenous molecule (such as a rapamycin analog), the binding and signaling proteins dimerize collectively, allowing the CAR-T cells to attack the tumor.
Small molecule drug conjugates adaptor technology
SMDCs (small molecule drug conjugates) platform in immuno-oncology is an experimental approach that makes feasible the engineering of a single universal CAR T cell, which binds with extraordinarily high resemblance to a benign molecule designated as fluorescein isothiocyanate (FITC).
Also these cells are used to treat various cancer types when co-administered with bispecific SMDC adaptor molecules. These unique bispecific adaptors are constructed with a FITC molecule and a tumor-homing molecule to accurately bridge the universal CAR T cell with the cancer cells, which causes localized T cell activation.
Anti-tumor activity in mice is induced only when both the universal CAR T cells and the correct antigen-specific adaptor molecules are present. By adjusting the administered adaptor molecule dosing, anti-tumor activity and toxicity can be controlled.
Treatment of antigenically varied tumors can be achieved by administration of a mixture of the desired antigen-specific adaptors. There are several challenges of current CAR T cell therapies, such as:
the inability to control the rate of cytokine release and tumor lysis
the absence of an off switch that would terminate cytotoxic activity when tumor abolition is complete
Jan 16, 2020: WuXi Biologics and Bayer jointly announced an acquisition agreement that WuXi Biologics Germany GmbH will take over the operations of one of Bayer’s final drug product manufacturing plants in Leverkusen, Germany, and purchase the related equipment, in combination with a long-term lease contract for the building.
Based on the manufacturing agreement to be negotiated, the plant would be operated by the WuXi Biologics and serve as a back-up site for final product manufacturing of Kovaltry™, an antihemophilic factor (recombinant).
The transaction is expected to be concluded in the coming months subject to the satisfaction of the customary closing conditions. Financial details were not disclosed. https://www.wuxibiologics.com/wuxi-biologics-bayer-enter-acquisition-agreement-drug-product-plant-germany/
Jan. 16, 2020: TG Therapeutics, Inc. announced that the Company has been initiating a rolling submission of a New Drug Application (NDA) to the U.S. FDA requesting accelerated approval of umbralisib, oral, once-daily, dual inhibitor of PI3K-delta and CK1-epsilon, as a treatment for the patients with previously treated marginal zone lymphoma (MZL) and follicular lymphoma (FL).
The Company has received guidance from the FDA that the submission of a single NDA for both the MZL and FL indications is acceptable. Umbralisib has earlier been granted both orphan drug designation and breakthrough therapy designation by the FDA for MZL.
The Company expects to complete the NDA rolling submission with the first half of 2020.The UNITY- NHL trial is the multicenter, open-label Phase 2b trial.
The Marginal Zone Lymphoma (MZL) cohort was designed in order to evaluate the safety and efficacy of single agent umbralisib, in the patients with MZL who have received at least one prior anti-CD20 regimen.
The primary endpoint is overall response rate (ORR) as determined by the central Independent Review Committee (IRC) assessment.
The Follicular Lymphoma (FL) cohort was designed in order to evaluate the safety and efficacy of single agent umbralisib in the patients with FL who have received at least two prior lines of the therapy, including an anti-CD20 regimen and an alkylating agent.
Jan. 16, 2020: Arena Pharmaceuticals, Inc. announced that the U.S. FDA granted Fast Track designation for APD418, a β3-adrenergic receptor (AdrR) antagonist and cardiac myotrope, in development for the treatment of decompensated heart failure (DHF). Around 10 million DHF patient hospital visits expected in the US by 2025 and few viable treatment options.
APD418 has the prospective to make a significant impact for these patients.APD418 is a β3-adrenergic receptor (AdrR) antagonist and cardiac myotrope for the decompensated heart failure (DHF).
