FDA Approves Ukoniq (umbralisib) for Marginal Zone Lymphoma and Follicular Lymphoma

TG Therapeutics, Inc,   announced the U.S. Food and Drug Administration (FDA) approval of  Ukoniq (umbralisib), for the treatment of adult patients with relapsed or refractory marginal zone lymphoma (MZL) who have received at least one prior anti-CD20 based regimen and adult patients with relapsed or refractory follicular lymphoma (FL) who have received at least three prior lines of systemic therapy.


Ukoniq is the first and only, oral, once daily, inhibitor of phosphoinositide 3 kinase (PI3K) delta and casein kinase 1 (CK1) epsilon. Accelerated approval was granted for these indications based on overall response rate (ORR) data from the Phase 2 UNITY-NHL Trial (NCT02793583). Continued approval for these indications may be contingent upon verification and description of clinical benefit in a confirmatory trial. This application was granted priority review for the MZL indication. In addition, Ukoniq was granted Breakthrough Therapy Designation (BTD) for the treatment of MZL and orphan drug designation (ODD) for the treatment of MZL and FL.
Michael S. Weiss, Executive Chairman and Chief Executive Officer of TG Therapeutics stated, “Today’s approval of Ukoniq marks a historic day for our Company with this being our first approval and we are extremely pleased to be able to bring our novel inhibitor of PI3K-delta and CK1-epsilon to patients with relapsed/refractory MZL and FL. We have built a commercial team with significant experience who will immediately start to engage our customers to educate them on Ukoniq and how to access the product for patients in need and expect to make Ukoniq available to US distributors in the next few days.” Mr. Weiss continued, “We want to thank the patients, physicians, nurses and clinical coordinators for their support and participation in our clinical trials, and the FDA for their collaboration throughout this process. We remain dedicated to patients with B-cell diseases and our mission of developing treatment options for those in need.”
“Despite treatment advances, MZL and FL remain incurable diseases with limited treatment options for patients who relapse after prior therapy and no defined standard of care. With the approval of umbralisib we now have a targeted, oral, once-daily option, offering a needed treatment alternative for patients,” stated Dr. Nathan Fowler, Professor of Medicine at The University of Texas MD Anderson Cancer Center and the Study Chair of the UNITY-NHL MZL &FL cohorts.
“The approval of umbralisib for the treatment of relapsed/refractory marginal zone lymphoma and follicular lymphoma offers patients a new treatment option, and new hope in the fight against these diseases,” stated Meghan Gutierrez, Chief Executive Officer of the Lymphoma Research Foundation.
The safety of Ukoniq monotherapy was based on a pooled population from the 221 adults with MZL and FL in three single arm, open label trials and one open label extension trial. Patients received Ukoniq 800 mg orally once daily. Serious adverse reactions occurred in 18% of patients who received Ukoniq. Serious adverse reactions that occurred in ≥2% of patients were diarrhea-colitis (4%), pneumonia (3%), sepsis (2%), and urinary tract infection (2%). The most common adverse reactions (>15%), including laboratory abnormalities, were increased creatinine (79%), diarrhea-colitis (58%, 2%), fatigue (41%), nausea (38%), neutropenia (33%), ALT increase (33%), AST increase (32%), musculoskeletal pain (27%), anemia (27%), thrombocytopenia (26%), upper respiratory tract infection (21%), vomiting (21%), abdominal pain (19%), decreased appetite (19%), and rash (18%).

EFFICACY & SAFETY DATA IN RELAPSED/REFRACTORY MZL AND FL

The efficacy of Ukoniq monotherapy was evaluated in two single-arm cohorts, within the Phase 2 UNITY-NHL clinical trial, in 69 patients with MZL who received at least 1 prior therapy, including an anti-CD20 regimen, and in 117 patients with FL who received at least 2 prior systemic therapies, including an anti-CD20 monoclonal antibody and an alkylating agent. The UNITY-NHL Phase 2 trial is an open-label, multi-center, multi-cohort study with patients receiving Ukoniq 800 mg once daily. The primary endpoint was independent review committee (IRC) assessed overall response rate (ORR) according to the Revised International Working Group Criteria.

https://en.wikipedia.org/wiki/Umbralisib

FDA Approves Xpovio (selinexor) for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma

In continuation of my update on Selinexor

Karyopharm Therapeutics Inc. an oncology-focused pharmaceutical company, announced that the U.S. Food and Drug Administration (FDA) has approved oral Xpovio (selinexor), a nuclear export inhibitor, in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM) who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. The ongoing, randomized Phase 3 BOSTON study evaluating selinexor in combination with Velcade® (bortezomib) and low-dose dexamethasone will serve as the confirmatory trial. The FDA’s Accelerated Approval Program was developed to allow for expedited approval of drugs that treat serious conditions and that fill an unmet medical need.  

Karyopharm expects Xpovio to become commercially available in the U.S. on or before July 10, 2019.  A Marketing Authorization Application for selinexor is also currently under review by the European Medicines Agency.

“With today’s accelerated approval of Xpovio by the FDA, patients with heavily pretreated multiple myeloma will now have a new therapeutic option to treat their disease,” said Sharon Shacham, PhD, MBA, Founder, President and Chief Scientific Officer of Karyopharm. “Discovering, developing and securing FDA approval for XPOVIO with its novel mechanism of action over the past decade required the dedication of many people, including the patients, caregivers and physicians involved in our clinical trials, along with the many employees at Karyopharm.  We are tremendously grateful for everyone’s contributions to this important milestone, and we look forward to the next stage in our pursuit of improving the lives of patients with cancer.”

“The 25.3% response rate seen in the subgroup of 83 patients in the pivotal Phase 2b STORM study that served as the basis for Xpovio's accelerated approval is clinically meaningful and a validated surrogate marker for clinical benefit in our patients with advanced refractory disease,” said Sundar Jagannath, MD, Director of the Multiple Myeloma Program, Professor of Medicine (Hematology and Medical Oncology) at Tisch Cancer Institute at Mount Sinai School of Medicine, and principal investigator of the STORM study.

“Despite recent advances in the treatment of multiple myeloma, almost all our patients will develop disease that is resistant to the five most commonly used anti-myeloma drugs we currently have available, and the prognosis for this patient population is particularly poor.  The accelerated approval of oral Xpovio marks an important advance in the treatment paradigm for patients with relapsed refractory multiple myeloma, and in my view, is an important addition to our therapeutic armamentarium,” said Dr. Paul Richardson, MD, Clinical Program Leader and Director of Clinical Research, Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute.

Michael G. Kauffman, MD, PhD, Chief Executive Officer of Karyopharm, commented, “Having worked on novel drugs in myeloma beginning with Velcade in the year 2000, I have been thrilled to see such exciting progress overall in the field where there are substantial increases in patients’ duration and quality of life.  The accelerated approval of oral Xpovio targeting XPO1 represents the first approval against a new target in myeloma since 2015, and we look forward to advancing the further clinical development of Xpovio.”

https://pubchem.ncbi.nlm.nih.gov/compound/Selinexor

Karyopharm Announces FDA Extension of Review Period for Selinexor New Drug Application

  

Karyopharm Therapeutics Inc. (Nasdaq: KPTI), a clinical-stage pharmaceutical company,  announced that the U.S. Food and Drug Administration (FDA) has extended the Prescription Drug User Fee Act (PDUFA) action date for the New Drug Application (NDA) for selinexor. The NDA, which is currently under Priority Review by the FDA, is seeking accelerated approval for selinexor in combination with dexamethasone for the treatment of patients with relapsed refractory multiple myeloma who have received at least three prior therapies and whose disease is refractory to at least one proteasome inhibitor (PI), one immunomodulatory agent (IMiD), and one anti-CD38 monoclonal antibody. The previously disclosed April 6, 2019 PDUFA date has been extended by three months to July 6, 2019.

On February 26, 2019, the FDA'sOncologic Drugs Advisory Committee (ODAC) met to discuss the selinexor NDA and voted 8 to 5 recommending that the FDA wait for the results from Karyopharm's randomized, open-label, Phase 3 BOSTON study evaluating selinexor in patients with relapsed or refractory multiple myeloma, before making a final decision regarding approval.  Although the FDA considers the recommendation of this panel, the final decision regarding the approval of the product is made by the FDA solely, and the recommendations by the panel are non-binding.

Following the ODAC meeting, at the FDA's request,  Karyopharm submitted additional, existing clinical information as an amendment to the NDA, which allowed the FDA to extend the PDUFA action date by three months. "We look forward to the continued collaboration with FDA in trying to meet the needs of patients with relapsed refractory multiple myeloma," said Sharon Shacham, PhD, MBA, Founder, President and Chief Scientific Officer of Karyopharm.

About Selinexor

Selinexor is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. Selinexor functions by binding with and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. In 2018, Karyopharm reported positive data from the Phase 2b STORM study evaluating selinexor in combination with low-dose dexamethasone in patients with triple class refractory multiple myeloma who have been previously exposed to all five of the most commonly prescribed anti-myeloma therapies currently available. Selinexor has been granted Orphan Drug Designation in multiple myeloma and Fast Track designation for the patient population evaluated in the STORM study. Karyopharm's New Drug Application (NDA) has been accepted for filing and granted Priority Review by the FDA, and oral selinexor is currently under review by the FDA as a possible new treatment for patients with triple class refractory multiple myeloma. The Company has also submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) with a request for conditional approval and was granted accelerated assessment. Selinexor is also being studied in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In 2018, Karyopharm reported positive top-line results from the Phase 2b SADAL study evaluating selinexor in patients with relapsed or refractory DLBCL after at least two prior multi-agent therapies and who are ineligible for transplantation, including high dose chemotherapy with stem cell rescue. Selinexor has received Fast Track designation from the FDA for the patient population evaluated in the SADAL study.  Selinexor is also being evaluated in several other mid-and later-phase clinical trials across multiple cancer indications, including in multiple myeloma in a pivotal, randomized Phase 3 study in combination with Velcade® (bortezomib) and low-dose dexamethasone (BOSTON), as a potential backbone therapy in combination with approved therapies (STOMP), in liposarcoma (SEAL), and an investigator-sponsored study in endometrial cancer (SIENDO), among others. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with approved therapies in a variety of tumor types to further inform Karyopharm's clinical development priorities for selinexor. Additional clinical trial information for selinexor is available at www.clinicaltrials.gov.

https://pubchem.ncbi.nlm.nih.gov/compound/Selinexor#section=2D-Structure

Karyopharm Announces FDA Extension of Review Period for Selinexor New Drug Application

DECT trial shows combination of epirubicin and trastuzumab improves outcomes in breast cancer patients

In continuation of my update on epirubicin 

The study entitled "A phase II neoadjuvant sequential regimen of docetaxel followed by high-dose epirubicin in combination with cyclophosphamide administered concurrently with trastuzumab. The DECT trial" has recently appeared in the Journal of Cell Physiology, an international, per-reviewed journal focused on cancer-related issues. The authors belong to a multidisciplinary Italian-American team with a long and productive history of collaboration with Prof. Antonio Giordano, Director of the Sbarro Institute for Cancer Research of Philadelphia, Temple University Pennsylvania, USA and the Department of Medicine Surgery and Neuroscience at University of Siena.

 epirubicin

"The use of trastuzumab, a monoclonal antibody targeting the HER2 receptor, has dramatically improved the prognosis of the subgroup of breast cancer patients whose tumors overexpress this specific receptor. One of the greatest challenges in these patients has been combining trastuzumab with extremely effective drugs such as anthracyclines at the cost of an acceptable toxicity. Initial evidence seemed to discourage this approach due to the high-rate of cardiotoxicity, i.e., 27%, reported in the pivotal phase III trial of metastatic breast cancer from Slamon and colleagues. Subsequent studies have partly downsized these results. Yet, several doubts have remained concerning the combined use of these drugs. The DECT trial was design to further address this key question. We also used the data from this randomized trial to interpret treatment efficacy in light of hormonal and metabolic determinants, including the expression of estrogen and progesterone receptors and body mass index," says Prof. Antonio Giordano.

"We enrolled 45 HER2-positive breast cancer patients with locally advanced or operable HER2-positive disease to test the efficacy and toxicity of epirubicin combined with trastuzumab. We observed an exceptionally high rate of responses, particularly in the subgroup of patients with inflammatory disease, and no relevant toxicity, including cardiotoxicity. In addition, some specific disease-and patient-related features were associated with better outcomes. More specifically, the highest chances of optimal response were associated with the lack of hormone receptors and higher BMI," says Dr. Maddalena Barba, researcher at the Regina Elena National Cancer Institute of Rome.

"Although current guidelines discourage from the concurrent use of trastuzumab and anthracyclines in HER2-positive breast cancer, we challenged once more the available evidence by administering a less cardiotoxic anthracycline, i.e., epirubicin at a high dose. The results obtained were remarkable in terms of efficacy and absolutely encouraging in terms of toxicity. In addition, our finding on BMI may deserve further investigation in future studies of HER2-positive breast cancer. The goal we pursue is to define the HER2-positive patient profile which better matches with the highest efficacy at the price of an absolutely acceptable toxicity, including cardiotoxicity," clarifies and concludes Prof. Giordano, a renowned expert in breast cancer.

Lilly, Merck expand oncology clinical trial collaboration

Eli Lilly and Company (NYSE: LLY) and Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced the extension of an existing collaboration to evaluate the safety and efficacy of the combination of Lilly's ALIMTA® (pemetrexed for injection) and Merck's KEYTRUDA® (pembrolizumab) in a pivotal Phase III study in first-line nonsquamous non-small cell lung cancer (NSCLC). The study will be sponsored by Merck and will be open to patients with NSCLC in the first-line setting, regardless of PD-L1 status. Financial details of the collaboration were not disclosed.

The expansion of this oncology clinical trial collaboration comes following the release of encouraging data from a Phase I study, presented earlier this year at the 16th World Congress on Lung Cancer, which evaluated pemetrexed, carboplatin and pembrolizumab in first-line nonsquamous NSCLC.

Pemetrexed is a leading therapeutic option used in combination with platinum-based therapies in this setting, making it an ideal candidate for combination studies with immunotherapy treatments. Pembrolizumab is a humanized monoclonal antibody that works by increasing the ability of the body's immune system to help detect and fight tumor cells. Pembrolizumab blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes, which may affect both tumor cells and healthy cells – and is currently approved as a single-agent therapy for certain types of NSCLC.

Lilly, Merck expand oncology clinical trial collaboration

FDA Approves Kadcyla for Late-Stage Breast Cancer

We know that, Trastuzumab emtansine  in the United States, ado-trastuzumab emtansine, trade name Kadcyla) is anantibody-drug conjugate consisting of the monoclonal antibody trastuzumab (Herceptin) linked to the cytotoxic agentmertansine (DM1). Trastuzumab alone stops growth of cancer cells by binding to the HER2/neu receptor, whereas mertansine enters cells and destroys them by binding to tubulin. Because the monoclonal antibody targets HER2, and HER2 is only over-expressed in cancer cells, the conjugate delivers the toxin specifically to tumor cells.

In the EMILIA clinical trial of women with advanced HER2 positive breast cancer who were already resistant to trastuzumab alone, it improved survival by 5.8 months compared to the combination of lapatinib and capecitabine. Based on that trial, the U.S. Food and Drug Administration (FDA) approved marketing on February 22, 2013.

Trastuzumab emtansine was developed by Genentech. The planned cost is expected to be $9,800 a month, or $94,000 for a typical course of treatment..

Now....

FDA Approves Kadcyla for Late-Stage Breast Cancer

Smart drug improves survival in older patients with acute myeloid leukemia

Gemtuzumab ozogamicin (marketed by Wyeth as Mylotarg) is a drug-linked monoclonal antibody that was used to treat acute myelogenous leukemia from 2000-2010. It was withdrawn from market in June 2010 when a clinical trial showed the drug increased patient death and added no benefit over conventional cancer therapies.

Gemtuzumab is a monoclonal antibody to CD33 linked to a cytotoxic agent from the class of calicheamicins. CD33 is expressed in most leukemic blast cells but also in normal hematopoietic cells, the intensity diminishing with maturation of stem cells. In the United States, it was approved under an accelerated-approval process by the FDA in 2000 for use in patients over the age of 60 with relapsed acute myelogenous leukemia (AML); or those who are not considered candidates for standard chemotherapy.

Within the first year after approval, the FDA required a black box warning be added to Gemtuzumab packaging. The drug was noted to increase the risk of veno-occlusive disease in the absence of bone marrow transplantation. Later the onset of VOD was shown to occur at increased frequency in Gemtuzumab patients even following bone marrow transplantation. The drug was discussed in a 2008 JAMA article, which criticized the inadequacy of postmarketing surveillance of biologic agents. 

Common side effects of administration included shivering, fever, nausea and vomiting. Serious side effects included severe myelosuppression (suppressed activity of bone marrow, which is involved in formation of various blood cells [found in 98% of patients]), disorder of the respiratory system, tumor lysis syndrome, Type III hypersensitivity, venous occlusion, and death. 

Now researchers from a major phase III Cancer Research UK-funded trial led by Cardiff University, have come out with an interesting conclusion that is, adding GO to treatment could improve the effectiveness of chemotherapy without excessively increasing side effects, providing a potential lifeline for older AML patients who are often too frail to tolerate more intensive chemotherapy regimes.....

New targeted therapy for advanced prostate cancer shows anti-tumour activity in phase I clinical trials

Researchers lead by Prof. Daniel Petrylakwill reports that,  a new drug that specifically targets a protein found on the surface of prostate cancer cells has performed well in a phase I clinical trial, and a phase II trial has started. The drug reduced levels of circulating tumour cells (CTC) and levels of prostate specific antigen (PSA), a marker for tumour activity, in patients who had already failed previous chemotherapy and hormone treatments.

The drug is made up of a monoclonal antibody, which targets a protein called prostate specific membrane antigen (PSMA), linked to a cancer cell-killing drug called monomethyl auristatin E (MMAE see structure), which disrupts tubulins, the tiny molecules inside a cell that are essential for cell division. The PSMA antibody drug conjugate (PSMA ADC) binds to the PSMA on the surface of the prostate cancer cell and is absorbed into the cell where the MMAE is released, causing cell cycle arrest and cell death.

Prof.Daniel Petrylak, who was Professor of Medicine at Columbia University Medical Center (USA) when the phase I trial started and who is now Director of the Prostate Cancer Program/Genitourinary Cancer Program and co-director of the Signal Transduction Program at Yale University Medical Centre (USA), said: "By conjugating the antibody with a chemotherapeutic agent, we hoped that this would lead to more targeted therapy, which would have fewer toxic side-effects and would be more effective against the cancer."

Prof Petrylak and his colleagues from other US cancer centres recruited 50 patients to the phase I clinical trial. The patients had the most advanced form of prostate cancer, which had spread to the bone and other organs; they had failed hormone therapy and had received up to two previous chemotherapies. The researchers treated them with doses of PSMA ADC at levels ranging from 0.4 to 2.8 mg/kg, by intravenous infusion, over a period of three weeks per cycle, and for up to four treatment cycles.

The researchers detected antitumour activity among the patients who were treated at the higher doses. About half of the patients who received doses of 1.8 mg/kg or more showed either a 50% or more reduction in PSA levels, or a fall in CTC in the blood to less than five cells per 7.5 ml of blood, or both.

The drug was generally well tolerated by patients, although levels of white blood cells were significantly reduced (neutropenia) at the highest dose of 2.8 mg/kg and one patient died. The researchers say the cause of the death is unclear.

Prof Petrylak said: "These results show that PSMA ADC has anti-tumour activity in patients who have failed up to two prior chemotherapies and hormone therapy. We have initiated a phase II trial of up to 75 patients in which the recommended dose will be 2.5 mg/kg. This new trial will evaluate responses in PSA and CTC; it will evaluate control of metastases in bone, internal organs and lymph nodes; and it will look at the effect on pain. Safety also will be assessed.

"The fact that this new targeted therapy is active against the most advanced forms of prostate cancer is encouraging, as few or no therapeutic options are available at present."

 More...

New targeted therapy for advanced prostate cancer shows anti-tumour activity in phase I clinical trials

Experimental cholesterol drug, REGN727 (PCSK9 inhibitor) results called ‘game changing

In continuation on my update on drug discovery in the class of  Monoclonal antibodies

Researchers have known for some time that when the protein PCSK9, (below structure) which stands for proprotein convertase subtilisin/kexin 9, binds to LDL receptors on the liver, it compromises the organ’s ability to filter the bad cholesterol from the blood.

Too much LDL cholesterol circulating in the blood can lead to the thickening of artery walls, making them less flexible and therefore impairing their function and increasing the risk of heart disease.

In a phase one clinical trial, which is designed to determine if a drug is safe, researchers found that using a monoclonal antibody (lab-produced protein) called REGN727, was not only safe, but effectively blocked PCSK9 and therefore signficantly reduced bad cholesterol in healthy patients as well as those also taking the popular cholesterol-lowering drug Lipitor.

“Wars for PCSK9 are far bigger than the statin wars,” said Dr. Evan A Stein, lead author of the study and researcher at the Metabolic and Atherosclerosis Research Center in Cincinnati, Ohio. “This is a hot research area and everybody is so close together.”

The REGN727 study included three trial arms. Two arms used 72 healthy volunteers who were either injected with a single dose of the drug in increasing amounts to test for side effects, which is the purpose of a phase one clinical trial.  A third arm included 21 people with a family history of high cholesterol, and 30 people with nonfamilial high cholesterol. All of those subjects were also receiving treatment with the statin Lipitor.

A control group of subjects with nonfamilial high cholesterol was treated only with a special diet.  None of the subjects who received REGN727 discontinued the study because of adverse effects, and the subjects who received REGN727 had a striking reduction of 60 to 65%  in LDL cholesterol, according to Stein.

A PCSK9 inhibitor, Stein said, differs from statins “because it’s unlike any other drug. With statins you get toxicity – with these drugs we don’t see any side effects with the antibody.”

In an accompanying editorial, authors Dr. Stephen G. Young, and Loren G. Fong, Ph.D. write: “At this point, the status of PCSK9 therapeutics appears to be full speed ahead. Soon, we can expect more human trials in which investigators will dissect the properties of different PCSK9 antibodies and assess the effect of these agents.”

However, without long-term safety data and evidence that PCSK9 inhibitors truly help prevent heart disease, Young and Fong caution that it will remain unclear how important this class of drugs will be.

The cost of this drug will also play a role in determining which patients might use it, Fong and Young say.  But they also note that “patients who cannot tolerate statins could benefit greatly.”

Researchers also claim that,  the study methodology was thorough because it included people with high cholesterol as well as people with genetic familial high cholesterol, which is proven to be a result of impaired PCSK9 genetic function.

Researchers have known for some time that when the protein PCSK9, which stands for proprotein convertase subtilisin/kexin 9, binds to LDL receptors on the liver, it compromises the organ’s ability to filter the bad cholesterol from the blood.

Researchers conclude that, In three phase 1 trials, a monoclonal antibody to PCSK9 significantly reduced LDL cholesterol levels in healthy volunteers and in subjects with familial or nonfamilial hypercholesterolemia.

Ref : http://www.nejm.org/doi/full/10.1056/NEJMoa1105803

New drug to tackle body fat problems

Leptin regulates energy homeostasis, fertility, and the immune system, making it an important drug target. However, due to a complete lack of structural data for the obesity receptor (ObR), leptin's mechanism of receptor activation remains poorly understood. Researchers have crystallized the Fab fragment of a leptin-blocking monoclonal antibody (9F8), both in its uncomplexed state and bound to the leptin-binding domain (LBD) of human ObR. They describe the structure of the LBD-9F8 Fab complex and the conformational changes in 9F8 associated with LBD binding. A molecular model of the putative leptin-LBD complex reveals that 9F8 Fab blocks leptin binding through only a small (10%) overlap in their binding sites, and that leptin binding is likely to involve an induced fit mechanism. This crystal structure of the leptin-binding domain of the obesity receptor will facilitate the design of therapeutics to modulate leptin signaling.

Ref : http://www.shef.ac.uk/mediacentre/2012/drug-tackles-fat-problems.html

New drug to tackle body fat problems

Experimental Cholesterol Drug Could Be 'Game Changing'

 Initially, I was reluctant about  "Monoclonal antibody therapy". Recently  there is surge of interest in " human monoclonal antibodies". 

History behind this surge : The idea of a "magic bullet" was first proposed by Paul Ehrlich, who, at the beginning of the 20th century, postulated that, if a compound could be made that selectively targeted against a disease-causing organism, then a toxin for that organism could be delivered along with the agent of selectivity. He and Élie Metchnikoff received the 1908 Nobel Prize for Physiology or Medicine for this work, which led to an effective syphilis treatment by 1910....

Experimental Cholesterol Drug Could Be 'Game Changing': Experimental Cholesterol Drug Could Be 'Game Changing' [St.Joseph News-Press (Mo)] From St. Joseph News-Press (MO) (March 22, 2012) (CNN) -- A new, experimental cholesterol-fighting drug is creating quite a buzz among researchers and other...

Gout drug success for Novartis

Canakinumab (trade name Ilaris, previously ACZ885) is a human monoclonal antibody targeted at interleukin-1 beta. It has no cross-reactivity with other members of the interleukin-1 family, including interleukin-1 alpha.

We know that, Canakinumab was approved for the treatment of cryopyrin-associated periodic syndromes (CAPS) by the US FDA on June 2009 and by the European Medicines Agency in October 2009. CAPS is a spectrum of autoinflammatory syndromes including familial cold autoinflammatory syndrome, Muckle–Wells syndrome, and neonatal-onset multisystem inflammatory disease.

Canakinumab was being developed by Novartis for the treatment of rheumatoid arthritis but this trial has been discontinued. Canakinumab is also in phase I clinical trials as a possible treatment for chronic obstructive pulmonary disease.

Gout drug success for Novartis

Combination of Lapatinib and Trastuzumab a better treatment for breast cancer....

Lapatinib or lapatinib ditosylate is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer. Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer. On March 13, 2007, FDA approved lapatinib in combination therapy for breast cancer patients already using capecitabine.

Recently, researchers from Duke University Medical Center. Dr. Kimberly Blackwell have found more interesting results when they did try the combination of Trastuzumab (monoclonal antibody). As per the claim by the researchers, Lapatinib plus trastuzumab are significantly better than lapatinib alone in extending the lives of breast cancer patients whose tumors are HER2-positive.

Blackwell says, the combination targeted therapy gave patients more than a four-month survival advantage over those who took lapatinib alone. She says the findings may be the first step toward a chemotherapy-free future. This is the first time that a pair of targeted therapies has been shown to be superior to any intervention that paired a targeted therapy with a hormonal or chemotherapy based approach, she said. The interesting claim by the researchers trastuzumab binds to and blocks part of the HER2 growth factor that appears on the surface of some breast cancer cells while lapatinib binds to a second growth factor, EGFR, and part of HER2 that sits below the cell surface. It's sort of a double whammy, disabling the HER2 protein in two places instead of one......

Ref : http://www.dukehealth.org/health_library/news/targeted_therapy_prolongs_life_in_patients_with_her2_positive_breast_cancer

Methotrexate & Ocrelizumab combination a new hope for RA patients....

In recent days, I have seen many researchers are trying the combination of existing drugs in combination with a monoclonal antibodies for many diseases like cancer, rheumatoid arthritis and are successful too. As synthetic chemist I was interested in knowing about these monoclonal antibodies and found some interesting info, which I am sharing herewith...

About monoclonal antibodies :

monoclonal antibodies (mAb or moAb) are monospecific antibodies that are identical because they are produced by one type of immune cell that are all clones of a single parent cell. Given almost any substance, it is possible to create monoclonal antibodies that specifically bind to that substance; they can then serve to detect or purify that substance. This has become an important tool in biochemistry, molecular biology and medicine. When used as medications, the non-proprietary drug name ends in -mab.

The invention is generally accredited to Georges Köhler, César Milstein, and Niels Kaj Jerne in 1975; who shared the Nobel Prize in Physiology or Medicine in 1984 for the discovery. The key idea was to use a line of myeloma cells that had lost their ability to secrete antibodies, come up with a technique to fuse these cells with healthy antibody-producing B-cells, and be able to select for the successfully fused cells. In 1988 Greg Winter (Nat Rev Cancer 2001;1:118-129) and his team pioneered the techniques to humanize monoclonal antibodies, removing the reactions that many monoclonal antibodies caused in some patients. Interestingly, many monoclinical antibodies have been tried for rheumatoid arthritis, chrohn's disease and as anticancer agents.

Many monoclonal antibodies like infliximab, etanercept and adalimumab were tried for the rheumatoid arthritis now its interseting to note that Genentech and Biogen Idec reported positive outcome from ocrelizumab ( humanized anti-CD20) -MTX (Methotrexate - see the structure : this drug is a part of DMARD treatment meant for RA patients) combination study in RA. The results are significant because they are the first data from a large Phase III trial to show that a humanized antibody targeted at B-cells improves the signs and symptoms of rheumatoid arthritis. Hope patients suffering from RA and those are not responding will breathe a sigh of relief in the days to come...

Ref : http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=12487

Stelara approved by the FDA for treating psoriasis

We know that Stelara (Ustekinumab), is a human monoclonal antibody that binds to the shared p40 protein subunit of human IL-12 and IL-23 with high affinity and specificity, thereby preventing interaction with their surface IL-12Rβ1 receptor. Hope this approval provides an alternative treatment for people with plaque psoriasis, which can cause significant physical discomfort from pain and itching and result in poor self-image for people who are self-conscious about their appearance...

Stelara approved by the FDA for treating psoriasis

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Simponi the first biologic therapy to be approved for rheumatologic diseases !

We did know about the three 3 TNF inhinitors (namely-Infliximab, Etanercept and Adalimumab), the last still to be approved by US.

Like Infliximab and Etanercept, Adalimumab binds to TNFα preventing it from activating TNF receptors; adalimumab was constructed from a fully human monoclonal antibody, while infliximab is a mouse-human chimeric antibody and etanercept is a TNF receptor-IgG fusion protein. TNFα inactivation has proven to be important in down regulating the inflammatory reactions associated with autoimmune diseases. As of 2008 adalimumab has been approved by the FDA for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, moderate to severe chronic psoriasis and juvenile idiopathic arthritis.

Humira (brand name is an abbreviation of "Human Monoclonal Antibody in Rheumatoid Arthritis") is marketed in both preloaded 0.8 ml syringes and also in preloaded pen devices (called Humira Pen), both injected subcutaneously, typically by the patient at home. It cannot be administered orally, because the digestive system would destroy the drug. But its now the turn of Golimumab, a new fully human monoclonal antibody. Being a fully human MAb directed against TNF, Golimumab resembles Adalimumab (Humira, Abbott), which was the first such product to reach the market. Now the Canadian government has approved Golimumab along with ‘methotrexate’ for the treatment of three forms of Rheumatiod arthritis (Rheumatoid Arthritis, Ankylosing Spondylitis & Psoriatic Arthritis) and more over making this treatment the first biologic therapy to be approved.

With this approval in Canada, Simponi (Golimumb), in combination with methotrexate (MTX), is indicated for reducing the signs and symptoms in adult patients with moderately to severely active RA; reducing signs and symptoms in adult patients with moderately to severely active PsA, alone or in combination with MTX; and reducing signs and symptoms in adult patients with active AS who have had an inadequate response to conventional therapies. More...