This document provides an overview of current and emerging antibody treatments for multiple sclerosis (MS). It discusses approved therapies like natalizumab, alemtuzumab, and daclizumab. Natalizumab works by inhibiting lymphocyte binding to endothelial cells. Alemtuzumab depletes CD52+ lymphocytes. Daclizumab antagonizes CD25-mediated T cell activation. Emerging therapies discussed include ofatumumab, ustekinumab, and secukinumab which target CD20, IL-12/IL-23, and IL-17A respectively. The document also reviews the mechanisms of action, efficacy data, safety issues like PML risk, and ongoing clinical trials of these antibody treatments for MS.
This document provides an overview of current antibody treatments for multiple sclerosis. It discusses several approved treatments including natalizumab, daclizumab, alemtuzumab, their mechanisms of action in treating MS, and their efficacy and side effects based on clinical trial results. Key side effects discussed include progressive multifocal leukoencephalopathy (PML) with natalizumab, skin reactions and hepatic events with daclizumab, and infusion reactions, infections, and secondary autoimmunities with alemtuzumab.
Rituximab therapy resulted in remission in nearly half of patients with difficult-to-treat steroid-resistant nephrotic syndrome and a 95% reduction in relapse frequency in patients with steroid-dependent nephrotic syndrome. Minimal side effects were observed. Rituximab effectively depleted B-cells and showed promise as an alternative treatment for difficult cases of nephrotic syndrome. Longer-term studies are still needed to assess long-term outcomes and safety.
Rituximab as Induction Immunosuppression in Compatible Kidney Transplantation...Wisit Cheungpasitporn
Rituximab as Induction Therapy After Renal Transplantation: A Randomized, Double-Blind, Placebo-Controlled Study of Efficacy and Safety. This study evaluated the efficacy and safety of rituximab (RTX) as induction therapy in renal transplant patients. The study randomized 280 patients to receive either a single dose of RTX or placebo before transplantation. The primary outcome was biopsy-proven acute rejection within 6 months. The results showed no difference in rejection rates between the overall RTX and placebo groups. However, among high-immunological risk patients, RTX showed a trend toward lower rejection rates compared to placebo. Patient and graft survival did not differ between groups after
Rituximab is a chimeric monoclonal antibody directed against the CD20 antigen found on B cells. It works through several mechanisms to induce B cell depletion. It has been used successfully to treat various B cell-mediated diseases with variable levels of response. These include non-Hodgkin's lymphoma, autoimmune diseases such as rheumatoid arthritis, vasculitis, lupus nephritis, and kidney diseases such as membranous nephropathy. It has also been used prior to transplantation to reduce antibody levels and aid transplantation in sensitized patients.
Three key factors determine the fate of clinical trials for lupus: patients, interventions, and endpoints. Early lupus trials faced challenges including patient heterogeneity, active versus inactive disease definitions, and background treatments obscuring treatment effects. Rituximab and abatacept failed phase 3 trials potentially due to easy-to-fail endpoints and aggressive background medications. Using more sensitive endpoints like BILAG A flares versus milder definitions may have shown benefits. Later trials like BLISS incorporated lessons learned to successfully demonstrate drug efficacy using refined trial designs. Ongoing late-stage trials continue evolving approaches.
Asco 2006 Update Genitourinary Cancer Selected Abstractsfondas vakalis
The document summarizes several studies on targeted therapies for kidney cancer presented at the 2006 ASCO conference. Key findings include:
- Sunitinib and temsirolimus were shown to be superior to interferon for metastatic kidney cancer in phase 3 trials, with longer progression-free and overall survival.
- The TARGET trial found sorafenib increased progression-free survival compared to placebo in advanced RCC and improved overall survival after patients on placebo crossed over.
- A global phase 3 trial found temsirolimus alone or with interferon improved overall survival over interferon in poor-risk metastatic RCC patients.
The document summarizes information about HIV, its life cycle, approved antiretroviral drugs, adverse effects of antiretrovirals, lipodystrophy, drug interactions, and guidelines for initiating antiretroviral therapy in special populations. It provides details on the classes of antiretrovirals including nucleoside and non-nucleoside reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, CCR5 antagonists. It discusses the rationale for combination antiretroviral therapy and boosted protease inhibitors.
This document provides an overview of current antibody treatments for multiple sclerosis. It discusses several approved treatments including natalizumab, daclizumab, alemtuzumab, their mechanisms of action in treating MS, and their efficacy and side effects based on clinical trial results. Key side effects discussed include progressive multifocal leukoencephalopathy (PML) with natalizumab, skin reactions and hepatic events with daclizumab, and infusion reactions, infections, and secondary autoimmunities with alemtuzumab.
Rituximab therapy resulted in remission in nearly half of patients with difficult-to-treat steroid-resistant nephrotic syndrome and a 95% reduction in relapse frequency in patients with steroid-dependent nephrotic syndrome. Minimal side effects were observed. Rituximab effectively depleted B-cells and showed promise as an alternative treatment for difficult cases of nephrotic syndrome. Longer-term studies are still needed to assess long-term outcomes and safety.
Rituximab as Induction Immunosuppression in Compatible Kidney Transplantation...Wisit Cheungpasitporn
Rituximab as Induction Therapy After Renal Transplantation: A Randomized, Double-Blind, Placebo-Controlled Study of Efficacy and Safety. This study evaluated the efficacy and safety of rituximab (RTX) as induction therapy in renal transplant patients. The study randomized 280 patients to receive either a single dose of RTX or placebo before transplantation. The primary outcome was biopsy-proven acute rejection within 6 months. The results showed no difference in rejection rates between the overall RTX and placebo groups. However, among high-immunological risk patients, RTX showed a trend toward lower rejection rates compared to placebo. Patient and graft survival did not differ between groups after
Rituximab is a chimeric monoclonal antibody directed against the CD20 antigen found on B cells. It works through several mechanisms to induce B cell depletion. It has been used successfully to treat various B cell-mediated diseases with variable levels of response. These include non-Hodgkin's lymphoma, autoimmune diseases such as rheumatoid arthritis, vasculitis, lupus nephritis, and kidney diseases such as membranous nephropathy. It has also been used prior to transplantation to reduce antibody levels and aid transplantation in sensitized patients.
Three key factors determine the fate of clinical trials for lupus: patients, interventions, and endpoints. Early lupus trials faced challenges including patient heterogeneity, active versus inactive disease definitions, and background treatments obscuring treatment effects. Rituximab and abatacept failed phase 3 trials potentially due to easy-to-fail endpoints and aggressive background medications. Using more sensitive endpoints like BILAG A flares versus milder definitions may have shown benefits. Later trials like BLISS incorporated lessons learned to successfully demonstrate drug efficacy using refined trial designs. Ongoing late-stage trials continue evolving approaches.
Asco 2006 Update Genitourinary Cancer Selected Abstractsfondas vakalis
The document summarizes several studies on targeted therapies for kidney cancer presented at the 2006 ASCO conference. Key findings include:
- Sunitinib and temsirolimus were shown to be superior to interferon for metastatic kidney cancer in phase 3 trials, with longer progression-free and overall survival.
- The TARGET trial found sorafenib increased progression-free survival compared to placebo in advanced RCC and improved overall survival after patients on placebo crossed over.
- A global phase 3 trial found temsirolimus alone or with interferon improved overall survival over interferon in poor-risk metastatic RCC patients.
The document summarizes information about HIV, its life cycle, approved antiretroviral drugs, adverse effects of antiretrovirals, lipodystrophy, drug interactions, and guidelines for initiating antiretroviral therapy in special populations. It provides details on the classes of antiretrovirals including nucleoside and non-nucleoside reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, CCR5 antagonists. It discusses the rationale for combination antiretroviral therapy and boosted protease inhibitors.
Recent advances in targeted therapy for metastatic lung cancerAlok Gupta
This document discusses recent advances in targeted therapy for metastatic lung cancer. It summarizes key findings from several clinical trials evaluating third-generation EGFR TKIs like osimertinib for patients with EGFR mutation-positive NSCLC. The document highlights that osimertinib provides significantly longer progression-free survival compared to earlier generation EGFR TKIs, with a median PFS of 18.9 months versus 10.2 months. Osimertinib also demonstrated a higher objective response rate and longer duration of response. Benefits were consistent across patient subgroups.
300 patients with diffuse large B-cell lymphoma (DLBCL) were treated. 200 were cured with RCHOP chemotherapy, while 100 relapsed or were refractory. Of these, 50 were eligible for stem cell transplant while 50 were ineligible. Immunotherapies including checkpoint inhibitors, CAR T-cell therapies, vaccines, and cytokines are being studied in clinical trials for relapsed/refractory DLBCL and other lymphomas with promising response rates seen. Adaptive cell therapies aim to expand tumor-specific T cells in vivo above a threshold needed for cure.
This document summarizes cellular therapy approaches for multiple myeloma, including:
1) Allogeneic stem cell transplantation can exploit the graft-versus-myeloma effect but is associated with transplant-related mortality; reduced intensity conditioning regimens may improve outcomes.
2) Vaccine strategies targeting antigens like MAGE and idiotype have shown safety and immune responses in clinical trials but limited clinical responses so far.
3) Adoptive transfer of chimeric antigen receptor (CAR) T cells and natural killer (NK) cells show pre-clinical activity against myeloma and are being tested in early clinical trials.
4) Ex-vivo expanded cord blood NK cells are being tested in a clinical
Genetic and epigenetic biomarkers for therapeutic monitoring in neurological ...Pranav Sopory
Seminar held on Genetic and epigenetic biomarkers for therapeutic monitoring in neurological disorders.
Multiple Sclerosis, Alzheimer's Disease and Parkinson's Disease.
Biomarkers and epigenetic explained. New epigenetic drug targets.
This document discusses immunoglobulin G (IgG) replacement therapy. It covers the structure and function of antibodies, mechanisms of IgG replacement therapy, routes of administration, catabolism, pharmacokinetics, indications, and available products. Specific topics include intravenous IgG (IVIg) replacement therapy, subcutaneous IgG (SCIg) replacement therapy, a comparison of IVIg and SCIg, switching between routes, and immunoglobulin products available in King Chulalongkorn Memorial Hospital. Guidelines for IgG replacement therapy in primary immunodeficiency diseases and criteria for approving its use in severe dermatomyositis are also presented.
This document discusses various topics related to immunosuppressive drugs used in renal transplantation. It begins by reviewing mTOR inhibitors used in combination with calcineurin inhibitors, noting their synergistic effect. It then discusses a study finding lower rates of discontinuation and better graft function with mTORi-CNI compared to MMF/MPA-CNI. Finally, it briefly touches on induction immunosuppression methods, tolerance without immunosuppression, and withdrawal of steroids and calcineurin inhibitors.
This document summarizes key issues in HIV psychiatry, including:
1. Common psychiatric issues associated with HIV like adjustment, depression, and neurocognitive deficits.
2. Guidelines for treating depression, psychosis, and other mental illnesses in HIV patients.
3. The persistence of HIV-associated neurocognitive disorders even in patients on antiretroviral therapy.
4. The concept of HIV compartmentalization in the central nervous system and challenges in treating neuroAIDS.
5. Recommendations for first-line psychiatric medications based on liver metabolism and drug-drug interactions with antiretrovirals.
This document provides an overview of multiple sclerosis (MS) models and the challenges of translating findings from animal models to clinical applications. It discusses key aspects of MS like pathogenesis, clinical courses, and neurodegeneration. Common MS models like experimental autoimmune encephalomyelitis (EAE) are described along with their limitations in mimicking the human disease. Issues like preclinical failure to translate findings and limitations of experimental design that can contribute to clinical trial failures are reviewed. Guidelines for improving experimental design and reporting are also mentioned.
Changing Landscape of Treatment for Multiple Myelomaspa718
1) Treatment for multiple myeloma has improved significantly over time, with median overall survival increasing from 30 months in 1971-1996 to 45 months in 1996-2006.
2) Newer proteasome inhibitors like carfilzomib have shown effectiveness in heavily pre-treated multiple myeloma patients, with overall response rates of 15-24% and median durations of response around 7-8 months. Dose escalation studies indicate carfilzomib is generally well-tolerated.
3) Other novel agents in clinical trials for relapsed/refractory multiple myeloma include second-generation proteasome inhibitors (e.g. oprozomib), immunomodulatory drugs (e
A Randomized, Multicenter, Phase 3 Study Comparing Carfilzomib, Lenalidomide,...spa718
This phase 3 clinical trial will compare the progression-free survival of relapsed multiple myeloma patients receiving carfilzomib, lenalidomide, and dexamethasone (CRd) versus lenalidomide and dexamethasone (Rd) alone. Approximately 700 patients will be randomized 1:1 to receive CRd for 12 cycles then CRd without carfilzomib, or Rd alone. The primary endpoint is progression-free survival, with secondary endpoints including overall survival, response rates, safety, and time to progression or next treatment.
Pembrolizumab was compared to ipilimumab for the treatment of advanced melanoma. In the first interim analysis, 6-month progression-free survival was higher for patients receiving pembrolizumab every 2 or 3 weeks compared to ipilimumab. Median progression-free survival was also longer for both pembrolizumab regimens versus ipilimumab. Response rates were significantly higher for pembrolizumab compared to ipilimumab. Fewer grade 3-5 adverse events occurred in patients receiving pembrolizumab. In the second interim analysis, 1-year overall survival estimates were higher for both pembrolizumab regimens compared to ipilimumab. P
1) Advances in pre-transplant optimization include using rituximab for CD20+ ALL, TKIs for Ph+ ALL to improve outcomes, and blinatumomab for MRD+ ALL.
2) For AML, using FLT3 inhibitors in FLT3 mutated AML and optimizing conditioning regimens can improve CR rates and reduce MRD.
3) Post-transplant strategies to prevent relapse include maintenance therapies like TKIs, azacitidine, FLT3 inhibitors, and preemptive or prophylactic donor lymphocyte infusions.
The document summarizes a clinical trial comparing the treatments erlotinib and gefitinib for non-small cell lung cancer. It found that erlotinib improved overall survival compared to standard chemotherapy, with a median survival of 6.7 months for erlotinib versus 4.7 months for chemotherapy. Erlotinib also prolonged progression-free survival compared to chemotherapy. The study provides support for using erlotinib or gefitinib as treatments for non-small cell lung cancer.
EFV has a low resistance barrier and its toxicity has been underestimated due to a high prevalence of slow metabolizers in South Africa. Dolutegravir is an attractive alternative to EFV for first-line ART due to its high resistance barrier, which means fewer switches to second-line treatment. Lopinavir/ritonavir may not be the best choice for second-line ART; atazanavir/ritonavir or darunavir/ritonavir are better tolerated but require pharmacokinetic studies of adjusted doses with rifampicin. Tenofovir alafenamide has fewer toxic effects than tenofovir disoproxil fumarate and similar efficacy
Induction therapy is used to prevent or delay acute rejection in kidney transplant recipients. Common induction agents include antithymocyte globulin (Thymoglobulin), basiliximab, alemtuzumab, and corticosteroids. Induction agents are either monoclonal antibodies like daclizumab and basiliximab, or polyclonal antibodies like Thymoglobulin. Depleting agents like Thymoglobulin and alemtuzumab cause T-cell depletion, while non-depleting agents do not. High-risk patients may benefit more from depleting induction to improve graft survival. However, depleting agents also carry higher risks of infections and side effects. Current guidelines recommend IL-2 receptor antagonists like basil
This document summarizes a debate on the role of autologous stem cell transplant (ASCT) in the treatment of multiple myeloma in the era of novel agents. It presents results from several randomized controlled trials comparing ASCT plus standard therapy to standard therapy alone. While some trials showed a progression-free survival benefit to ASCT, most did not show an overall survival benefit. Additionally, novel agent combinations like daratumumab-lenalidomide-dexamethasone have shown high rates of minimal residual disease negative responses without ASCT. Therefore, the presenter concludes that ASCT is not always needed, particularly not upfront, given the potent induction regimens now available and lack of clear overall survival improvement with AS
Membranous nephropathy is a common cause of nephrotic syndrome in adults. It has variable natural history, with about 1/3 of patients achieving spontaneous remission, 1/3 having persistent proteinuria but stable renal function, and 1/3 progressing to end-stage renal disease over 5-10 years. Several factors predict poorer prognosis, including older age, nephrotic syndrome, lower serum albumin and higher proteinuria levels. Studies show immunosuppressive therapy may alter the natural history for patients at high risk of progression, but risks of treatment must be weighed against the likelihood of spontaneous remission.
Recent advances in targeted therapy for metastatic lung cancerAlok Gupta
This document discusses recent advances in targeted therapy for metastatic lung cancer. It summarizes key findings from several clinical trials evaluating third-generation EGFR TKIs like osimertinib for patients with EGFR mutation-positive NSCLC. The document highlights that osimertinib provides significantly longer progression-free survival compared to earlier generation EGFR TKIs, with a median PFS of 18.9 months versus 10.2 months. Osimertinib also demonstrated a higher objective response rate and longer duration of response. Benefits were consistent across patient subgroups.
300 patients with diffuse large B-cell lymphoma (DLBCL) were treated. 200 were cured with RCHOP chemotherapy, while 100 relapsed or were refractory. Of these, 50 were eligible for stem cell transplant while 50 were ineligible. Immunotherapies including checkpoint inhibitors, CAR T-cell therapies, vaccines, and cytokines are being studied in clinical trials for relapsed/refractory DLBCL and other lymphomas with promising response rates seen. Adaptive cell therapies aim to expand tumor-specific T cells in vivo above a threshold needed for cure.
This document summarizes cellular therapy approaches for multiple myeloma, including:
1) Allogeneic stem cell transplantation can exploit the graft-versus-myeloma effect but is associated with transplant-related mortality; reduced intensity conditioning regimens may improve outcomes.
2) Vaccine strategies targeting antigens like MAGE and idiotype have shown safety and immune responses in clinical trials but limited clinical responses so far.
3) Adoptive transfer of chimeric antigen receptor (CAR) T cells and natural killer (NK) cells show pre-clinical activity against myeloma and are being tested in early clinical trials.
4) Ex-vivo expanded cord blood NK cells are being tested in a clinical
Genetic and epigenetic biomarkers for therapeutic monitoring in neurological ...Pranav Sopory
Seminar held on Genetic and epigenetic biomarkers for therapeutic monitoring in neurological disorders.
Multiple Sclerosis, Alzheimer's Disease and Parkinson's Disease.
Biomarkers and epigenetic explained. New epigenetic drug targets.
This document discusses immunoglobulin G (IgG) replacement therapy. It covers the structure and function of antibodies, mechanisms of IgG replacement therapy, routes of administration, catabolism, pharmacokinetics, indications, and available products. Specific topics include intravenous IgG (IVIg) replacement therapy, subcutaneous IgG (SCIg) replacement therapy, a comparison of IVIg and SCIg, switching between routes, and immunoglobulin products available in King Chulalongkorn Memorial Hospital. Guidelines for IgG replacement therapy in primary immunodeficiency diseases and criteria for approving its use in severe dermatomyositis are also presented.
This document discusses various topics related to immunosuppressive drugs used in renal transplantation. It begins by reviewing mTOR inhibitors used in combination with calcineurin inhibitors, noting their synergistic effect. It then discusses a study finding lower rates of discontinuation and better graft function with mTORi-CNI compared to MMF/MPA-CNI. Finally, it briefly touches on induction immunosuppression methods, tolerance without immunosuppression, and withdrawal of steroids and calcineurin inhibitors.
This document summarizes key issues in HIV psychiatry, including:
1. Common psychiatric issues associated with HIV like adjustment, depression, and neurocognitive deficits.
2. Guidelines for treating depression, psychosis, and other mental illnesses in HIV patients.
3. The persistence of HIV-associated neurocognitive disorders even in patients on antiretroviral therapy.
4. The concept of HIV compartmentalization in the central nervous system and challenges in treating neuroAIDS.
5. Recommendations for first-line psychiatric medications based on liver metabolism and drug-drug interactions with antiretrovirals.
This document provides an overview of multiple sclerosis (MS) models and the challenges of translating findings from animal models to clinical applications. It discusses key aspects of MS like pathogenesis, clinical courses, and neurodegeneration. Common MS models like experimental autoimmune encephalomyelitis (EAE) are described along with their limitations in mimicking the human disease. Issues like preclinical failure to translate findings and limitations of experimental design that can contribute to clinical trial failures are reviewed. Guidelines for improving experimental design and reporting are also mentioned.
Changing Landscape of Treatment for Multiple Myelomaspa718
1) Treatment for multiple myeloma has improved significantly over time, with median overall survival increasing from 30 months in 1971-1996 to 45 months in 1996-2006.
2) Newer proteasome inhibitors like carfilzomib have shown effectiveness in heavily pre-treated multiple myeloma patients, with overall response rates of 15-24% and median durations of response around 7-8 months. Dose escalation studies indicate carfilzomib is generally well-tolerated.
3) Other novel agents in clinical trials for relapsed/refractory multiple myeloma include second-generation proteasome inhibitors (e.g. oprozomib), immunomodulatory drugs (e
A Randomized, Multicenter, Phase 3 Study Comparing Carfilzomib, Lenalidomide,...spa718
This phase 3 clinical trial will compare the progression-free survival of relapsed multiple myeloma patients receiving carfilzomib, lenalidomide, and dexamethasone (CRd) versus lenalidomide and dexamethasone (Rd) alone. Approximately 700 patients will be randomized 1:1 to receive CRd for 12 cycles then CRd without carfilzomib, or Rd alone. The primary endpoint is progression-free survival, with secondary endpoints including overall survival, response rates, safety, and time to progression or next treatment.
Pembrolizumab was compared to ipilimumab for the treatment of advanced melanoma. In the first interim analysis, 6-month progression-free survival was higher for patients receiving pembrolizumab every 2 or 3 weeks compared to ipilimumab. Median progression-free survival was also longer for both pembrolizumab regimens versus ipilimumab. Response rates were significantly higher for pembrolizumab compared to ipilimumab. Fewer grade 3-5 adverse events occurred in patients receiving pembrolizumab. In the second interim analysis, 1-year overall survival estimates were higher for both pembrolizumab regimens compared to ipilimumab. P
1) Advances in pre-transplant optimization include using rituximab for CD20+ ALL, TKIs for Ph+ ALL to improve outcomes, and blinatumomab for MRD+ ALL.
2) For AML, using FLT3 inhibitors in FLT3 mutated AML and optimizing conditioning regimens can improve CR rates and reduce MRD.
3) Post-transplant strategies to prevent relapse include maintenance therapies like TKIs, azacitidine, FLT3 inhibitors, and preemptive or prophylactic donor lymphocyte infusions.
The document summarizes a clinical trial comparing the treatments erlotinib and gefitinib for non-small cell lung cancer. It found that erlotinib improved overall survival compared to standard chemotherapy, with a median survival of 6.7 months for erlotinib versus 4.7 months for chemotherapy. Erlotinib also prolonged progression-free survival compared to chemotherapy. The study provides support for using erlotinib or gefitinib as treatments for non-small cell lung cancer.
EFV has a low resistance barrier and its toxicity has been underestimated due to a high prevalence of slow metabolizers in South Africa. Dolutegravir is an attractive alternative to EFV for first-line ART due to its high resistance barrier, which means fewer switches to second-line treatment. Lopinavir/ritonavir may not be the best choice for second-line ART; atazanavir/ritonavir or darunavir/ritonavir are better tolerated but require pharmacokinetic studies of adjusted doses with rifampicin. Tenofovir alafenamide has fewer toxic effects than tenofovir disoproxil fumarate and similar efficacy
Induction therapy is used to prevent or delay acute rejection in kidney transplant recipients. Common induction agents include antithymocyte globulin (Thymoglobulin), basiliximab, alemtuzumab, and corticosteroids. Induction agents are either monoclonal antibodies like daclizumab and basiliximab, or polyclonal antibodies like Thymoglobulin. Depleting agents like Thymoglobulin and alemtuzumab cause T-cell depletion, while non-depleting agents do not. High-risk patients may benefit more from depleting induction to improve graft survival. However, depleting agents also carry higher risks of infections and side effects. Current guidelines recommend IL-2 receptor antagonists like basil
This document summarizes a debate on the role of autologous stem cell transplant (ASCT) in the treatment of multiple myeloma in the era of novel agents. It presents results from several randomized controlled trials comparing ASCT plus standard therapy to standard therapy alone. While some trials showed a progression-free survival benefit to ASCT, most did not show an overall survival benefit. Additionally, novel agent combinations like daratumumab-lenalidomide-dexamethasone have shown high rates of minimal residual disease negative responses without ASCT. Therefore, the presenter concludes that ASCT is not always needed, particularly not upfront, given the potent induction regimens now available and lack of clear overall survival improvement with AS
Membranous nephropathy is a common cause of nephrotic syndrome in adults. It has variable natural history, with about 1/3 of patients achieving spontaneous remission, 1/3 having persistent proteinuria but stable renal function, and 1/3 progressing to end-stage renal disease over 5-10 years. Several factors predict poorer prognosis, including older age, nephrotic syndrome, lower serum albumin and higher proteinuria levels. Studies show immunosuppressive therapy may alter the natural history for patients at high risk of progression, but risks of treatment must be weighed against the likelihood of spontaneous remission.
Precision medicine is a rapidly growing field of medicine that proposes individually customized diagnostics and therapeutics based upon molecular and genetic profile of individual patients. The main goal of precision medicine is to minimize harmful side effects and maximize benefits. In particular, hematological malignancies were seen as the most direct candidates of the most promising applications of precision medicine. However, Precision medicine approaches face multiple challenges. Despite these challenges and limitations, continuous effort is carried out to use these molecular findings as disease biomarkers and targets for therapeutic intervention. In the last decade the hemato-oncology witnessed a major revolution in the understanding of the molecular pathogenesis of hematological malignancies. While the therapeutic research for hematologic malignancies is continuously expanding, some medicines have been approved in hematological malignancies patients’ therapeutic algorithm and many are still under investigation.
1. Sipuleucel-T (Provenge) is an autologous cellular immunotherapy for asymptomatic metastatic prostate cancer that works by activating antigen-presenting cells and T-cells against prostatic acid phosphatase.
2. Clinical trials showed Provenge improved overall survival in metastatic castration-resistant prostate cancer patients.
3. Manufacturing and delivering Provenge presents logistical challenges due to its personalized nature that Dendreon aims to address through an advanced planning system and partnerships.
Sipuleucel-T (Provenge) is an autologous cellular immunotherapy for asymptomatic metastatic prostate cancer. It consists of autologous dendritic cells activated ex vivo with a recombinant fusion protein and infused back to the patient to stimulate an immune response against prostate cancer cells. Clinical trials demonstrated a significant survival benefit for patients treated with Sipuleucel-T compared to placebo. Dendreon is preparing for the commercial launch of Provenge in the US and EU, which will require a major manufacturing and logistics effort to process and deliver the personalized immunotherapy to thousands of patients.
Kidney transplantation is the most effective therapy for end-stage renal disease. It involves transplanting a kidney from a living or deceased donor. Immunosuppressive medications are used to prevent rejection and include corticosteroids, calcineurin inhibitors like cyclosporine and tacrolimus, mTOR inhibitors like sirolimus, and antimetabolites. Common post-transplant complications include infection from viruses like CMV and BK virus, acute rejection, chronic allograft dysfunction, and malignancy. Long-term management requires monitoring for these complications and adjusting immunosuppression.
Hyper IgM Syndrome is characterized by immunodeficiency with elevated serum IgM and low or absent other immunoglobulins due to a defect in class switching recombination. The most common form is X-linked Hyper IgM Syndrome caused by mutations in the CD40 ligand gene, affecting approximately 1 in 1,000,000 males. Clinical manifestations include recurrent respiratory and gastrointestinal infections. Treatment involves hematopoietic stem cell transplantation which is curative but has better outcomes when performed at a younger age before organ damage develops.
Dasatinib is an effective first-line treatment for chronic myeloid leukemia (CML) based on results from the DASISION trial. The trial showed that dasatinib induced higher and faster rates of complete cytogenetic response and major molecular response compared to imatinib. At 5 years of follow-up, dasatinib maintained superior rates of molecular responses including deeper responses below 0.1% BCR-ABL1. Dasatinib therefore provides improved long-term outcomes for patients with newly diagnosed CML compared to standard imatinib treatment.
Monoclonal antibodies (MAbs), guided by molecular studies and personalised medicine are changing the face of clinical medicine. They hold the promise of controlling diseases and improving survival whilst reducing the side effects of some ‘traditional’ therapies. MAbs are being used in conditions familiar to intensivists such as asthma, invasive candidiasis, RSV infection, reversal of novel anticoagulants and clostridium difficile infection as well as in those less commonly seen by intensivists such as multiple sclerosis, migraine, rheumatoid arthritis and numerous malignancies. Side effects of MAb treatment pose particular challenges for intensivists and range from cytokine release syndrome to autoimmune states (such as colitis, endocrinopathies, skin reactions), pneumonitis, thromboemboli, and infections. Pharmcokinetic interactions of MAbs with other drugs remain poorly studied and may be immune dependent, cytokine dependent or target dependent. Our traditional approach of triaging patients for ICU, based on organ failures and ‘prognosis of underlying disease’ is going to be challenged by MAbs with their disease modifying properties and unique side effects.
Immunological Checkpoints and Cancer Immunotherapyimgcommcall
Immunological checkpoints and cancer immunotherapy were reviewed. Immune checkpoint inhibitors like anti-CTLA-4 and anti-PD-1/PD-L1 antibodies can activate the immune system against cancer by blocking inhibitory signals to T cells. Clinical trials show these drugs produce durable responses in various cancers like melanoma, lung cancer, and Merkel cell carcinoma. Combining different immunotherapies or with other treatments may help more patients by overcoming resistance. Ongoing research aims to better understand combination approaches and biomarkers of response.
In this presentation, I discuss a new standard of treatment in cancers which is immunotherapy. I also discuss the few cancers for which it has been approved.
Advances in immunotherapy, including checkpoint inhibitors targeting CTLA-4 and PD-1, have significantly improved outcomes for patients with metastatic melanoma. Combination immunotherapy with nivolumab and ipilimumab produces response rates over 60%, compared to around 40% for nivolumab alone and 11% for ipilimumab alone. Many patients receiving the combination immunotherapy continue to respond even after stopping treatment, achieving a state of treatment-free survival. While combination immunotherapy is more toxic than single-agent treatments, the toxicities are often manageable. Ongoing research continues to explore optimizing combination immunotherapy regimens to improve outcomes while reducing toxicity.
This document provides information on multiple sclerosis (MS), including its epidemiology, pathogenesis, clinical presentations, diagnosis, and treatment options. It summarizes that MS is the most common autoimmune demyelinating disease of the central nervous system characterized by inflammation and demyelination in the brain and spinal cord. Current first-line treatments for relapsing-remitting MS include interferon beta, glatiramer acetate, fingolimod, fumarate, teriflunomide, natalizumab, mitoxantrone, and alemtuzumab, which aim to reduce relapse rates and progression of disability.
Building Bridges Between Discovery, Preclinical, And Clinical Research 2008tsornasse
The document discusses several case studies highlighting the importance of bidirectional information flow between clinical, preclinical, and discovery research:
1) A study of rituximab immunotherapy in lymphoma patients found that allowing longer B cell recovery time before vaccination improved responses, informed by preclinical studies.
2) Development of an anti-IgVH monoclonal antibody for lymphoma was guided by preclinical toxicology in monkeys to explore depletion of target B cells.
3) Gene expression analysis of pediatric IBD patient biopsies generated hypotheses tested with discovery research and preclinical models.
4) Increased IP-10 levels correlated with clinical response in UC patients treated with anti-CD3 visilizumab, informing the mechanism of
This document discusses approaches to angiogenesis and predictive biomarkers for anti-angiogenic therapies. It summarizes that:
1) Angiogenesis is driven by VEGF and its receptors, and agents targeting this pathway like bevacizumab have shown efficacy in some cancers;
2) No predictive biomarker for anti-angiogenic response has been validated, but candidates include HER2 positivity in breast cancer and multi-omics approaches to identify VEGF-driven tumors;
3) Future progress may require more selective patient populations that are likely to respond to anti-angiogenic therapies based on their tumor and host biology.
This document summarizes various drugs used to treat multiple sclerosis (MS). It discusses disease-modifying therapies for relapsing-remitting MS including interferon beta, glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod, and natalizumab. It also covers mitoxantrone for secondary progressive MS and ocrelizumab and alemtuzumab for primary progressive MS. Potential side effects of each treatment are provided. New investigational immunotherapies for MS like stem cells, DNA vaccines and nanoparticles are also mentioned.
This document summarizes a presentation by Professor David Baker on targeting B and plasma cells in central nervous system inflammatory diseases. It discusses B cell lineages and differentiation, antibodies involved in diseases like multiple sclerosis and neuromyelitis optica, and potential therapeutic targets including CD20, CD38, IL-6 receptor and CD19 expressing B cells and plasma cells. Slides provide details on B cell and plasma cell biology, locations in lymphoid and CNS tissues, their role in disease pathogenesis and current and emerging therapies.
Revised B cell covid vaccine review paperBartsMSBlog
1) Anti-CD20 monoclonal antibodies used to treat MS and other diseases cause prolonged depletion of B cells, including memory B cells important for vaccine responses. This puts individuals at higher risk for severe COVID-19 and poor antibody response to SARS-CoV-2 infection and vaccines.
2) Vaccination prior to starting anti-CD20 treatment or delaying subsequent doses to allow for B cell repopulation may optimize protective antibody responses against COVID-19. Most individuals require 12 months after treatment to reach sufficient B cell recovery levels.
3) While continuous CD20 depletion inhibits vaccine responses, memory B cell depletion is prolonged after treatment stops, supporting potential temporary treatment breaks for vaccination to boost immunity.
This document summarizes a presentation on selective B cell depletion therapies for managing highly active relapsing multiple sclerosis (MS). The presentation discusses:
- Drugs available that selectively deplete B cells including rituximab, ocrelizumab, and ofatumumab.
- Benefits of B cell depletion therapies like avoiding hospital visits during COVID-19, minimal monitoring requirements, and long-term efficacy from short-term treatment.
- Ocrelizumab as the preferred treatment based on its safety profile and 2020 sales of $4.6 billion.
- Professor David Baker presented on targeting CNS plasma cells in multiple sclerosis. He discussed B cell and plasma cell biology, the role of oligoclonal bands and autoantibodies in MS pathology, and evidence that antibodies are involved in MS disease mechanisms.
- Baker described current disease-modifying therapies that target B cells and plasma cells, but noted many may not effectively reach and deplete cells in the central nervous system. Effective treatment of MS may require targeting plasma cells and their niches directly within the CNS.
1. Professor David Baker presented on whether ocrelizumab and cladribine should be treated like alemtuzumab in terms of COVID-19 risk.
2. Alemtuzumab causes long-term CD4 and CD8 T cell depletion and is associated with an increased risk of lung infections. Cladribine and ocrelizumab do not cause similar long-term lymphopenia.
3. Cladribine maintains T cell levels within normal ranges and has minimal monitoring requirements compared to alemtuzumab which requires frequent monitoring and hospital visits due to risks of cytokine release syndrome.
This document describes the development of a cell-based assay to detect neutralizing antibodies against the drug alemtuzumab, which is used to treat multiple sclerosis. Researchers generated a stable CHO cell line expressing human CD52 and used it to detect anti-alemtuzumab antibodies in serum from an MS patient treated with alemtuzumab. The assay involves measuring inhibition of alemtuzumab-Alexa 488 binding to the CHO-CD52 cells by antibodies in patient serum. This assay provides a quantitative method for routine screening of serum from patients treated with alemtuzumab to detect neutralizing antibodies.
- CD20 B cell therapies like ocrelizumab work in multiple sclerosis through several mechanisms including direct inhibition of T cells, increasing regulatory T cells, blocking antigen presentation, and directly inhibiting B cells. While MS is considered a T cell-mediated disease, B cells can induce the proliferation and activation of pathogenic T cells. CD20 therapies may work by depleting this pathogenic B cell population. However, the mechanisms are not fully understood as CD20 therapies do not fully deplete long-lived plasma cells in the central nervous system.
This document summarizes a presentation given by Professor David Baker on B cell therapy for multiple sclerosis. It discusses B cell subsets, the role of B cells in the pathogenesis of MS, response to different therapies as a key experiment to understand biology, and repopulation characteristics of immune cells after treatment. It also provides diagrams on immune cell differentiation and repopulation, the two compartment model of treating inflammatory lesions in MS, phenotypes seen in active MS lesions, and types of monoclonal antibodies used as treatments.
The document provides guidelines for reporting animal research studies in a transparent manner. It outlines the ARRIVE guidelines, which include 10 essential items that should be reported in research papers involving animal subjects. The guidelines aim to improve reproducibility, transparency and quality of reporting. They include reporting the study's objectives and design, the animals used, experimental procedures, and the statistical analysis to allow rigorous assessment of the study. Adhering to these guidelines can help improve communication of research findings.
This document provides guidance on reading and understanding medical research papers. It discusses the key elements of clinical trial papers and science papers, and emphasizes the importance of reading papers to gain knowledge and the ability to critically evaluate research. It also reviews guidelines for reporting clinical trials and animal studies, and provides tips on analyzing data and interpreting various types of charts, graphs, and statistics commonly found in medical research papers.
This study evaluated the efficacy and safety of tabalumab in treating relapsing-remitting multiple sclerosis (RRMS). 210 patients with RRMS were randomized to receive either tabalumab (4, 12, 40, or 120 mg every 4 weeks or 4 or 120 mg every 12 weeks) or a placebo. The primary outcome was the number of new or enlarging MRI lesions over 24 weeks. Treatment with tabalumab did not significantly reduce MRI lesions compared to placebo. Adverse events were more common with tabalumab but were generally mild. The study found that tabalumab was not effective for reducing disease activity in RRMS.
This document discusses the history and biology of medical cannabis in the UK. It provides key dates in the UK regarding cannabis cultivation, medical use, and legislation. It then covers the biology of the endocannabinoid system and cannabinoid receptors. The remainder discusses evidence for using cannabis to treat MS symptoms like spasticity through its effects on the endocannabinoid system and inhibitory neurotransmission. It also discusses the use of Sativex and different policies around medical and recreational cannabis internationally.
The European Medicines Agency announced that Medday Pharmaceuticals withdrew its application for marketing authorization of Qizenday, a medicine containing biotin intended to treat progressive multiple sclerosis. After evaluating the company's submission and responses to questions, the Committee for Medicinal Products for Human Use had concerns about the robustness of effectiveness data, uncertainties regarding safety, and the need for more information on how the body processes biotin. At the time of withdrawal, the Committee's provisional opinion was that the benefits of Qizenday did not outweigh its risks for treating progressive multiple sclerosis. The company withdrew the application based on this opinion. Patients currently taking Qizenday in clinical trials or compassionate use programs
Cases of progressive multifocal leukoencephalopathy (PML), a rare brain disease caused by the JC virus, have been reported in patients treated with the drug cladribine. PML diagnosis occurred months to years after cladribine treatment and was associated with prolonged lymphopenia in several cases. Healthcare professionals are advised to consider PML in patients with new neurological symptoms who have been treated with cladribine. Patients who develop suspected PML should discontinue cladribine treatment. Manufacturers are updating drug information materials to include this safety risk.
Cases of progressive multifocal leukoencephalopathy (PML), a rare brain disease caused by the JC virus, have been reported in patients treated with the drug cladribine. PML diagnosis occurred months to years after cladribine treatment and was associated with prolonged lymphopenia in several cases. Healthcare professionals are advised to consider PML in patients with new neurological symptoms who have been treated with cladribine. Patients who develop suspected PML should discontinue cladribine treatment. Manufacturers are updating drug information materials to include this safety risk.
This document summarizes a debate about whether B cells or T cells are the key pathogenic cell in multiple sclerosis (MS). It provides evidence from MS therapies, animal models, and human data that memory B cells may drive MS pathology. Studies show that effective MS treatments like alemtuzumab, rituximab, and ocrelizumab strongly deplete memory B cells and reduce relapse rates. Memory B cell levels are also higher in the cerebrospinal fluid of patients during MS relapses. While T cells outnumber B cells in MS lesions, B cells may have an important role in antigen presentation and driving inflammation. Genetic studies also link MS risk genes to B cell functions. Overall, the document argues that
This document summarizes a debate between David Baker (for) and Heinz Weindl (against) the proposition that "The Key Pathogenic Cell in MS is a B cell and is Independent of Antigen-Presentation to T cells." Baker argues that B cells, not T cells, are the key pathogenic cells in MS. He notes that treatments targeting B cells like ocrelizumab are effective, while T cell-targeted treatments have failed. He also argues that animal models showing T cell dependence are suboptimal. Weindl counters some of Baker's evidence and interpretations. The document provides details on B cell subsets and their roles, effects of MS treatments on memory B cells, and evidence from pathology.
This document summarizes a debate between David Baker-For and Heinz Weindl-Against on whether B cells or T cells are the key pathogenic cell in multiple sclerosis (MS). It provides evidence from animal models, response to various MS therapies, and B cell and T cell biology to argue that memory B cells, not T cells, are the primary driver of MS pathology. Graphics show that treatments which reduce memory B cells in the blood correlate with decreased relapse rates and lesions in MS patients. The document concludes that while T cells may facilitate the disease, memory B cells are the main culprit in destroying myelin in MS.
This document provides the schedule for the Scientific Programme of a conference on Wednesday, October 25th, 2017. It includes 10 teaching courses held in different halls from 8:30-10:00, 10:30-12:00, and 12:30-14:00 on various topics related to multiple sclerosis (MS) research and treatment. There are also several parallel sessions, young scientific investigator sessions, nurses' sessions, and hot topic sessions scheduled throughout the day focused on specific areas of MS science.
Prof mouse pint of neuroscience part iiBartsMSBlog
This document discusses the importance of hand function in assessing treatment outcomes for multiple sclerosis (MS). It notes that current clinical trials and regulatory outcomes primarily focus on mobility scales that are dominated by lower limb function, excluding people who use wheelchairs. It argues that assessing hand function could have led to different outcomes in past trials and enabled treatments years ago. The document advocates increasing awareness of hand function for people with MS, neurologists, and regulators. It promotes developing new patient-reported outcome measures that better capture elements of hand function that are important to people living with MS.
Does Over-Masturbation Contribute to Chronic Prostatitis.pptxwalterHu5
In some case, your chronic prostatitis may be related to over-masturbation. Generally, natural medicine Diuretic and Anti-inflammatory Pill can help mee get a cure.
Basavarajeeyam is an important text for ayurvedic physician belonging to andhra pradehs. It is a popular compendium in various parts of our country as well as in andhra pradesh. The content of the text was presented in sanskrit and telugu language (Bilingual). One of the most famous book in ayurvedic pharmaceutics and therapeutics. This book contains 25 chapters called as prakaranas. Many rasaoushadis were explained, pioneer of dhatu druti, nadi pareeksha, mutra pareeksha etc. Belongs to the period of 15-16 century. New diseases like upadamsha, phiranga rogas are explained.
Osteoporosis - Definition , Evaluation and Management .pdfJim Jacob Roy
Osteoporosis is an increasing cause of morbidity among the elderly.
In this document , a brief outline of osteoporosis is given , including the risk factors of osteoporosis fractures , the indications for testing bone mineral density and the management of osteoporosis
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
Here is the updated list of Top Best Ayurvedic medicine for Gas and Indigestion and those are Gas-O-Go Syp for Dyspepsia | Lavizyme Syrup for Acidity | Yumzyme Hepatoprotective Capsules etc
Adhd Medication Shortage Uk - trinexpharmacy.comreignlana06
The UK is currently facing a Adhd Medication Shortage Uk, which has left many patients and their families grappling with uncertainty and frustration. ADHD, or Attention Deficit Hyperactivity Disorder, is a chronic condition that requires consistent medication to manage effectively. This shortage has highlighted the critical role these medications play in the daily lives of those affected by ADHD. Contact : +1 (747) 209 – 3649 E-mail : sales@trinexpharmacy.com
Cell Therapy Expansion and Challenges in Autoimmune DiseaseHealth Advances
There is increasing confidence that cell therapies will soon play a role in the treatment of autoimmune disorders, but the extent of this impact remains to be seen. Early readouts on autologous CAR-Ts in lupus are encouraging, but manufacturing and cost limitations are likely to restrict access to highly refractory patients. Allogeneic CAR-Ts have the potential to broaden access to earlier lines of treatment due to their inherent cost benefits, however they will need to demonstrate comparable or improved efficacy to established modalities.
In addition to infrastructure and capacity constraints, CAR-Ts face a very different risk-benefit dynamic in autoimmune compared to oncology, highlighting the need for tolerable therapies with low adverse event risk. CAR-NK and Treg-based therapies are also being developed in certain autoimmune disorders and may demonstrate favorable safety profiles. Several novel non-cell therapies such as bispecific antibodies, nanobodies, and RNAi drugs, may also offer future alternative competitive solutions with variable value propositions.
Widespread adoption of cell therapies will not only require strong efficacy and safety data, but also adapted pricing and access strategies. At oncology-based price points, CAR-Ts are unlikely to achieve broad market access in autoimmune disorders, with eligible patient populations that are potentially orders of magnitude greater than the number of currently addressable cancer patients. Developers have made strides towards reducing cell therapy COGS while improving manufacturing efficiency, but payors will inevitably restrict access until more sustainable pricing is achieved.
Despite these headwinds, industry leaders and investors remain confident that cell therapies are poised to address significant unmet need in patients suffering from autoimmune disorders. However, the extent of this impact on the treatment landscape remains to be seen, as the industry rapidly approaches an inflection point.
Integrating Ayurveda into Parkinson’s Management: A Holistic ApproachAyurveda ForAll
Explore the benefits of combining Ayurveda with conventional Parkinson's treatments. Learn how a holistic approach can manage symptoms, enhance well-being, and balance body energies. Discover the steps to safely integrate Ayurvedic practices into your Parkinson’s care plan, including expert guidance on diet, herbal remedies, and lifestyle modifications.
Muktapishti is a traditional Ayurvedic preparation made from Shoditha Mukta (Purified Pearl), is believed to help regulate thyroid function and reduce symptoms of hyperthyroidism due to its cooling and balancing properties. Clinical evidence on its efficacy remains limited, necessitating further research to validate its therapeutic benefits.
Role of Mukta Pishti in the Management of Hyperthyroidism
Pegs m abs in rx ms
1. Overview on the Current Antibody
Treatments for Multiple Sclerosis
Gavin Giovannoni
2. Disclosures
Over the last 15 years I have received personal compensation for participating in
advisory boards in relation to clinical trial design, trial steering committees, and
data and safety monitoring committees from: Abbvie, Bayer-Schering Healthcare,
Biogen, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW
Pharma, Ironwood, MSD, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Synthon
BV, Teva, UCB Pharma and Vertex Pharmaceuticals
3. Background
1. Commonest non-disabling disease to affect young adults
2. Reduces life expectancy by ~8-10 years
3. Major socio-economic impact
4. Incidence of 6-9/100,000. Prevalence 125-250/100,000, latitudinal gradient
5. Average age of onset 31 years (majority of cases between 18-50)
6. Females:Males = 2-3:1 (increasing sex ratio)
7. Complex disease: genes, environment (sunlight/vD, EBV and smoking)
8. Presumed autoimmune
- No autoantigens identified
9. Pathologically: inflammatory demyelination with variable degrees of neuroaxonal loss and gliosis
6. Agent Target Proposed MOA Phase
Natalizumab α4 subunit of α41 and α47 integrins Inhibition of lymphocyte binding to endothelial receptors,
preventing entry into the CNS (59)
Approved
Alemtuzumab CD52 on lymphocyte and monocyte cell
surfaces
Depletion of CD52+ cells Approved
Daclizumab CD25 on activated T-lymphocytes Antagonizes CD25-mediated signalling blocking T-cell
activation and expansion; expands regulatory CD56bright NK
cells
Phase 3
Ocrelizumab CD20 Depletes CD20+ B cells Phase 3
Ofatumumab CD20 Inhibits early-stage B lymphocyte activation Phase 2
Ustekinumab P40 subunit of IL-12 and IL-23 Disrupts IL-12– and IL-23–mediated signalling which would
otherwise elicit inflammatory and immune responses
Phase 2
Tabalumab (LY2127399) BAFF Counteracts dysregulated BAFF expression which may
contribute to MS via effects on abnormal B lymphocyte
activation, proliferation, survival, and Ig secretion
Phase 2
Secukinumab IL-17A Inhibition of the release of pro-inflammatory cytokines and
chemokines.
Phase 2
GNbAC1 Envelope protein of MS-associated
retrovirus
Blocks upstream pathophysiology of MS Phase 2
Vatelizumab VLA-2 Interferes with collagen-binding in areas of inflammation Phase 2
Opicinumab Anti-Lingo-1 Binding of the Fab (fragment antibody-binding) region of
the antibody to LINGO-1, and the resulting complex
formation, blocks epitopes in the LINGO-1 IgG domain that
function in oligodendrocyte differentiation
Phase 2
mAbsinMS
7. Two compartment model
T
Te
B
APC T
Tc
Tc
Tc
Tc
B
Treg
BBB CNS
Bi
Te
Te
Bi
Te
Te
B
Treg Treg
Systemic
immune
compartment
APC, antigen presenting cells; B, B lymphocytes; BBB, blood-brain barrier; Bi, inflammatory B cells; CNS, central nervous system; Tc, T lymphocytes;
Te, encephalitogenic T cells; Treg, regulatory T cells. Figure is reproduced with permission from Wiendl H, Kieseier B. Nat Rev Neurol. 2013;9:125-6
1. Wiendl H, Kieseier B. Nat Rev Neurol. 2013;9:125-6
Intrathecal
immune
compartment
15. Effect of plasma exchange in accelerating natalizumab
clearance and restoring leukocyte function
Khatri et al. Neurology 2009;72:402–409
16. Wenning et al. N Engl J Med. 2009;361:1075-80.
Immune reconstitution inflammatory syndrome (IRIS)
Rx: IV methylprednisolone 1g daily x 5
days, followed by tapered dose of oral
steroids.
Prophylaxis: I recommend prophylactic
corticosteroids if high burden of
disease and/or posterior fossa
involvement.
Clifford DB, et al. Lancet Neurol. 2010;9:438–446.
18. Alemtuzumab: a humanized monoclonal antibody
approved for treatment of patients with active RRMS
• A humanized monoclonal antibody that selectively targets CD52, a protein abundant on
the surface of B and T lymphocytes1
• Novel dosing regimen: administered 12 mg/day via intravenous (IV) infusions on 5
consecutive days at baseline and on 3 consecutive days 12 months later2,3
• Approved for adult patients with relapsing-remitting MS (RRMS) with active disease
defined by clinical or imaging features4
• First approved - EU in 20135*
1. Hu Y et al. Immunology 2009;128:260-70; 2. Cohen JA et al. Lancet 2012;380:1819-28; 3. Coles AJ et al. Lancet 2012;380:1829-39; 4. Lemtrada (alemtuzumab)
Peru Summary of Product Characteristics, 2014; 5. Lemtrada (alemtuzumab) EU Summary of Product Characteristics, September 2013.
19. 1. Weber MS et al. Results Probl Cell Differ 2010;51:115-26; 2. Hu Y et al. Immunology 2009;128;260-70; 3.Turner MJ et al. J Neuroimmunol 2013;261:29-36; 4.
Cox AL et al. Eur J Immunol 2005;35:3332-42; 5. Fox EJ. Exp Rev Neurother 2010;10:1789-97.
Alemtuzumab: mechanism of action
1. Selection
• Animal studies indicate that innate immune
cells that express lower levels of CD52 are
minimally or transiently impacted by
alemtuzumab treatment2
2. Depletion
Decreases MS inflammation
• Alemtuzumab selectively depletes
circulating T and B cells2,3
• Many lymphocytes remain present in
lymphoid organs after treatment2,3
3. Repopulation
Reduces MS disease activity
• Lymphocyte progenitor cells are presumably
unaffected by alemtuzumab2,4,5
• A distinctive pattern of T- and B-cell
repopulation begins within weeks, potentially
changing the balance of the immune
system2,4,5
BT
CD52
B
CD52
T
T cell
precursor
Pre/Pro
B cell
B
CD52
T CD52
Monocytes
Macrophages
Neutrophils
Lymphocyte
precursor
Targets T and B cells thought to
mediate MS inflammation1
Lymphocyte
precursor
Lymphocyte
precursor
Stem cell
20. T- and B-cell Pharmacodynamics
• Alemtuzumab depleted circulating lymphocytes in SPMS patients treated between
1994–1997 (N=29)
– CD4 and CD8 counts were 30-40% of pretreatment values 18 months later1
– B cells repopulated more rapidly, with counts reaching 179% of pretreatment
values at 18 months
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
Pre Post
(Day 2)
3 6 9 12 15 18
Months after Alemtuzumab (20 mg × 5)
Tcells
(×109/L)
0.0
0.1
0.2
0.3
0.4
0.5
Bcells
(×109/L)
B cells
CD4+ T cells
CD8+ T cells
Coles AJ et al. Lancet 1999;354:1691-5.
21. CARE-MS I: Alemtuzumab Pharmacokinetics
Unique PK/PD profile of alemtuzumab allows for 2 short treatment courses
– Alemtuzumab is administered on 5 consecutive days at Month 0 and on another 3 days 12 months later
– Serum concentrations are low or undetectable within 1 month after dosing
Lycke J et al. EFNS 2012.
Alemtuzumab administration
1500
4000
4500
2500
3500
500
0
2000
3000
1000
Day 0
Concentration(ng/mL)
Day 5 Day 10 Day 15 Day 20 Day 25 Month 1
First treatment course
Time
1500
4000
4500
2500
3500
500
0
2000
3000
1000
0 1 3 6 9 12 2415 18 21
Concentration(ng/mL)
13
Months
22. CARE-MS II3,4
CARE-MS Extension: NEDA Through Year 5
Patients Treated With Alemtuzumab 12 mg in Core Studies
The proportion of alemtuzumab-treated patients with no evidence of disease activity
remained stable through Year 5
No evidence of disease activity: absence of clinical disease activity (relapse and 6-month sustained accumulation of disability) and MRI activity (new Gd-enhancing lesions,
and new/enlarging T2 hyperintense lesions).
1. Compston DA et al. AAN 2015; Platform S4.007; 2. Arnold D et al. ECTRIMS 2015; 3. Havrdova E et al. AAN 2015; Poster P7.276; 4. Traboulsee A et al. ECTRIMS 2015.
P=0.0001
(↑61.2%)
P<0.0001
(↑82.6%)
ProportionofPatients,%(95%CI)
SC IFNB-1a 44 μg
Alemtuzumab 12 mg
SC IFNB-1a 44 μg
Alemtuzumab 12 mg
ProportionofPatients,%(95%CI)
CARE-MS I1,2
P=0.0053
(↑32.2%)
P<0.0001
(↑44.5%)
174 369 169 354No. of
patients
326 324 187 414 171 402 361 336319 325No. of
patients
301 311
24. MS treatments mostly rely on direct targeting of proinflammatory cells
B, B cell; BBB, blood–brain barrier; CNS, central nervous system; HCAR2, hydroxycarboxylic acid receptor 2; MoA, mechanism of action; nrf 2, nuclear factor (erythroid-derived 2)-like
2; S1P1, sphingosine-1-phosphate receptor 1; T, T cell; Th, T-helper cell.
Adapted from: Loleit V, et al. Curr Pharm Biotechnol. 2014;15:276–96; Scannevin R, et al. J Pharmacol Exp Ther. 2012;341:274–84; Chen H, et al. J Clin Invest. 2014;124:2188–92.
Alemtuzumab
CD52
Lysis of mature
B and T cells
Proposed MoA: Anti-migratory
Fingolimod
Natalizumab
Lymph node
BBB
CNS
S1P1
B
T
α4-integrin
Proposed MoA: Pleiotropic effects
Limits pyrimidine
availability for
rapid cell division
Teriflunomid
e
IFNs
Activation of 100+
IFN-response genes
Activation of 700+ nrf 2
responsive genes and HC-AR2
Glatiramer acetate
Modulation of Th1:Th2 balance
Dimethyl fumarate
Proposed MoA: Targeted cell lysis
Periphery
Proposed MoA: Reduced proliferation
CD20
Ocrelizumab CladribineIL2 modulator
expands CD56-bright NK cells
Daclizumab (anti-CD25)
25. Daclizumab blocks IL-2 binding to high-affinity IL-2 receptors on activated T cells
Amaravadi L, et al. Poster presentation at AAN 2015;P1.149; Bielekova B. Neurotherapeutics. 2013;10:55–67; Pfender N, Martin R. Exp Neurol. 2014;262:44–51.
• IL-2 signalling induces expansion and
differentiation of activated T cells
• Daclizumab binds the α chain (CD25)
and blocks IL-2 association with the high-
affinity IL-2 receptor
• IL-2 signalling induces expansion and
activation of CD56bright NK cells
• Daclizumab does not prevent
IL-2 signalling through the intermediate-
affinity IL-2 receptor
Intermediate-affinity IL-2 receptorHigh-affinity IL-2 receptor
CD4+
Tact
cell
CD56bright
β γ β γIL
-2 IL
-2α
26. Mode of action of daclizumab
Adapted from: Amaravadi L, et al. Poster presentation at AAN 2015;P1.149; Zinbryta® (daclizumab) SmPC. July 2016.
IL-2
Daclizumab blocks high-affinity IL-2 receptor signalling, resulting in higher levels
of IL-2 available for signalling through intermediate-affinity IL-2 receptor
IL-2 intermediate-affinity (βγ) receptor
IL-2 high-affinity (βαγ) receptor
Daclizumab
Activation
CD4+
CD4+
Tact
cell
CD4+
Tact
cell
CD56bright
27. Effects of IL-2 pathway modulation include selective antagonism of activated T-
cell responses and expansion of immunoregulatory CD56bright NK cells
Adapted and elaborated from: Amaravadi L, et al. Poster presentation at AAN 2015;P1.149; Zinbryta® (daclizumab) SmPC. July 2016.
Activation
CD4+
CD4+
Tact
cell
CD4+
Tact
cell
CD56bright CD56bright
CD56bright
CD56brightCD56bright
CD56bright
IL-2
IL-2 intermediate-affinity (βγ) receptor
IL-2 high-affinity (βαγ) receptor
Daclizumab
28. Daclizumab induces a sustained increase in serum IL-2 concentrations
*Difference first observed; P<0.0001. IQR, interquartile range.
Amaravadi L, et al. Poster presentation at AAN 2015;P1.149; Zinbryta® (daclizumab) SmPC. July 2016.
0 4 8 16 24 40 48 52
Time (weeks)
0
2
4
6
8
10
Median(±IQR)IL-2(pg/mL)
Daclizumab 150mg (n=129)
Placebo (n=38)
*
29. CD25 blockade prevented IL-2 binding
but resulted in a moderate reduction in T-cell numbers
NK, natural killer.
Statistically significant differences (P<0.05) between baseline, combination therapy, and monotherapy time points are indicated by horizontal bidirectional arrows (↔) in the graphs.
Bielekova B, et al. Arch Neurol. 2009;66:483–89.
CD8+ T cellsCD4+ T cells
0
600
800
200
400
Mo-3
Mo-1
Mo2.5
Mo4.5
Mo6.5–8.6
Mo10.5
Mo12.5–14.5
Absolutenumberofcellsperulofblood
IFN-β IFN-β
+dacliz daclizumab
0
2000
2500
500
Mo-3
Mo-1
Mo2.5
Mo4.5
Mo6.5–8.6
Mo10.5
Mo12.5–14.5
Absolutenumberofcellsperulofblood
IFN-β IFN-β
+dacliz daclizumab
1500
1000
CD56bright NK cells
0
200
250
50
Mo-3
Mo-1
Mo2.5
Mo4.5
Mo6.5–8.6
Mo10.5
Mo12.5–14.5
Absolutenumberofcellsperulofblood
IFN-β IFN-β
+dacliz daclizumab
1500
100
30. During daclizumab treatment, mean cell counts for the major
immune subsets remained within normal ranges
LLN, lower limit of normal.
*P<0.05 vs placebo; **P<0.01 vs placebo.
Elaborated from: Gold R, et al. Lancet. 2013;381:2167–75; Zinbryta® (daclizumab) SmPC. July 2016.
Total lymphocytes CD4+ cells CD8+ cells
1000
750
500
250
0
Baseline Week 24 Week 52
Mean(±SD)CD4+(cells/mm3)
800
600
400
200
0
Baseline Week 24 Week 52
Mean(±SD)CD8+(cells/mm3)
+3.9
%
-
4.4%
**
+2.8
%
-
7.0%
**
+4.8
%
-
1.3%*
+1.9
%
-
3.6%*
+4.1
%
-
4.7%
**
+3.1
%
-
9.1%
**
Daclizumab 150 mg (n=184) Placebo (n=179)
Total lymphocyte, T- and B-cell counts decreased on average
by ≤10% from baseline during the first year of treatment
2000
1500
1000
500
0
Baseline Week 24 Week 52
Mean(±SD)
totallymphocytes(cells/mm3)
LLN
31. Primary endpoint: Annualised relapse rate
CI, confidence interval.
1. Gold R, et al. Lancet. 2013;381:2167–75; 2. Zinbryta® (daclizumab) SmPC. July 2016; 3. Kappos L, et al. N Engl J Med. 2015;373:1418–28.
Placebo
(n=196)
Daclizumab
150 mg
(n=201)
Daclizumab
300 mg
(n=203)
54%
relative
reduction
P<0.0001
50%
relative
reduction
P=0.00015
At Week 521,2 Up to Week 1442,3
IM IFN beta-1a
(n=922)
Daclizumab
150 mg
(n=919)
45%
relative
reduction
P<0.0001
SELECT: vs placebo DECIDE: vs IFN beta-1a
The 300 mg dose did not provide additional
benefit over the licensed 150 mg dose
Annualisedrelapserate(95%
CI)
Annualisedrelapserate(95%
CI)
32. 24-week confirmed disability progression
*Post-hoc analysis. †Tertiary endpoint. ‡Secondary endpoint. HR, hazard ratio.
1. Zinbryta® (daclizumab) SmPC. July 2016; 2. Biogen, data on file; 3. Kappos L, et al. N Engl J Med. 2015;373:1418–28.
No. at risk
SELECT: vs placebo1,2 DECIDE: vs IFN beta-1a1,3
196
201
192
198
183
190
171
185
167
184
114
132
0 12 24 36 48 60 72 84 96 108 120 132 144
27% relative risk reduction
HR=0.73 (95% CI: 0.55–0.98)
P=0.03
922
919
878
897
829
863
790
817
743
796
704
755
669
722
647
688
624
662
462
502
362
361
254
266
134
131
Daclizumab (n=201)
Placebo (n=196)
Time on study (weeks) No. at risk
13%
18%
0 12 24 36 48 52
20
10
0
25
15
5
76% relative risk reduction
HR=0.24 (95% CI: 0.09–0.63)
P=0.0037
2.6%
11%
Up to Week 52* Up to Week 144†
No. at risk
Time on study (weeks) No. at risk
Patientswithconfirmed
disabilityprogression
(%)
20
15
10
5
0
25
• 12-week confirmed disability progression: 57% relative risk reduction vs placebo† (HR=0.43, 95% CI: 0.21-0.88; P=0.021);
16% relative risk reduction vs IFN beta-1a‡ (HR=0.84, 95% CI: 0.66-1.07; P=0.16)1
33. NEDA, no evidence of disease activity; OR, odds ratio.
*Post-hoc analyses. NEDA was defined as: no clinical relapses, no onset of 12-week confirmed disability progression, no new/newly enlarging T2 hyperintense lesions vs the start of the period and no Gd+ lesions
(at Week 24 for baseline–Week 24 and at Week 96 for Weeks 24–96). NEDA status was considered missing for patients with missing assessments but whose available outcomes satisfied NEDA criteria.
Giovannoni G, et al. Poster presentation at ECTRIMS 2016;P664.
Patients achieving no evidence of disease activity
DECIDE: vs IFN beta-1a
PatientsachievingNEDA
(%)
OR: 2.96
P<0.0001
IM IFN beta-1a
Daclizumab
n=347/77
6
n=173/77
3
n=367/88
4
n=282/86
4
EDSS
Brain
MRI
✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓
0 12 24 36 48 60 72 84 96-144
OR: 1.51
P<0.0001
34. Hepatic injury
*Only patients treated with daclizumab 150 mg in development programme studies are shown; patients exposed to daclizumab 300 mg dose in SELECT and/or SELECTION not represented. Duration was defined as length of
time in days from the last ALT or AST measurement ≤1× ULN until return of both ALT and AST to ≤1.5× ULN.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal.
1. Giovannoni G, et al. Mult Scler Rel Dis. 2016;9:36–46; 2. Kappos L, et al. N Engl J Med. 2015;373:1418–28. 3. Zinbryta® (daclizumab) SmPC. July 2016; 4. Fam S, et al. Poster presentation at EAN 2016;P31134.
• Elevation of transaminases in daclizumab-treated patients occurred throughout treatment1,4
• Most elevations were asymptomatic and resolved spontaneously3,4
• In DECIDE median (25th–75th percentiles) duration of ALT or AST elevation >5× ULN
was 87.0 (50.0–128.0) days in daclizumab group vs 100.0 (75.5–136.5) in IM IFN beta-1a4
INTEGRATED SAFETY
ANALYSIS1*
DECIDE
(2–3 y; vs IFN beta-1a)1–3
Daclizumab 150 mg
(n=1943)
IM IFN beta-1a
(n=922)
Daclizumab 150 mg
(n=919)
Hepatic events, % 15 14 16
Serious hepatic events, % <1 <1 1
ALT or AST, %
≥3× ULN 9 9 10
>5× ULN 6 3 6
Discontinuation due to hepatic events, % 5 4 5
35. Skin reactions
*Only patients treated with daclizumab 150 mg in development programme studies are shown; patients exposed to daclizumab 300 mg dose in SELECT and/or SELECTION not represented.
1. Giovannoni G, et al. Mult Scler Rel Dis. 2016;9:36–46; 2. Zinbryta® (daclizumab) SmPC. July 2016; 3. Kappos L, et al. N Engl J Med. 2015;373:1418–28; 4. Krueger JG, et al. Adv Ther. 2016;33:1231–45.
INTEGRATED
SAFETY
ANALYSIS1,2*
DECIDE
(2-3 y, vs IFN beta-1a)1–3
Daclizumab 150 mg
n=1943
IM IFN beta-1a
n=922
Daclizumab 150 mg
n=919
Skin reactions, % 32 19 37
Serious skin reactions, % 2 <1 2
Discontinuation due to skin reactions, % 4 1 5
• In DECIDE, incidence of events assessed as related to treatment by investigators was
7% in IM IFN beta-1a and 15% in daclizumab groups4
• In daclizumab studies the most common skin reactions were rash, dermatitis and eczema1–4
• In DECIDE, the majority (94%) of events associated with daclizumab were mild or moderate in severity2,4
• In DECIDE, serious skin reactions in ≥2 patients included dermatitis (n=3) and angioedema (n=2)4
36. Infections
*Only patients treated with daclizumab 150 mg in development programme studies are shown; patients exposed to daclizumab 300 mg dose in SELECT and/or SELECTION not represented.
1. Giovannoni G, et al. Mult Scler Rel Dis. 2016;9:36–46; 2. Kappos L, et al. N Engl J Med. 2015;373:1418–28. 3. Zinbryta® (daclizumab) SmPC. July 2016.
INTEGRATED
SAFETY ANALYSIS1*
DECIDE
(2–3 y, vs IFN beta-1a)1–3
Daclizumab 150 mg
n=1943
IM IFN beta-1a
n=922
Daclizumab 150 mg
n=919
Infections, % 58 57 65
Serious infections, % 4 2 4
• The most common infections were upper respiratory tract infections and viral infections3
• In daclizumab studies there has been no evidence of an increased risk of opportunistic infections typically seen in
immunocompromised patients1,2
• In DECIDE, median duration of infection was similar in daclizumab and IM IFN beta-1a groups3
• Majority of patients with infections continued on treatment (discontinuation due to infections <1%)3
37. Lymphopaenia
Zinbryta® (daclizumab) SmPC. July 2016.
• In controlled studies, incidence of total lymphocyte count <800/mm3 in daclizumab group was similar to
that in placebo (SELECT: 5% versus 4%) and IM IFN beta (DECIDE: 8% versus 9%) groups
• When observed during daclizumab clinical studies, lymphopenia was mostly mild to moderate
(≥500/mm3)
• Sustained severe lymphopenia (<500/mm3) was not observed in clinical studies with daclizumab
• As a precaution, monitoring of complete blood count is recommended every 3 months
39. pro-B
pre-B
Stem cell
Plasma cell
(long lived)
Mature naive
B cell
Activated
B cell
Lymph follicle
with germinal center
Plasmablast Memory
B cell
Follicle-like
aggregates
Bystander
activation
Plasma cell
(long lived)
OCB
CNS Educated B cells CSF
Dendritic
Cell
T cell
B cells and the brain
Plasmablast
Bone Marrow Central Nervous SystemSecondary Lymphoid TissuesCNS, central nervous system; CSF, cerebrospinal fluid; OCB, oligoclonal band.
40. Antigen presentation1,2
Autoantibody production4
1. Crawford A, et al. J Immunol 2006;176(6):3498–506. 2. Bar-Or A, et al. Ann Neurol 2010;67(4):452–61. 3. Lisak RP, et al. J Neuroimmunol 2012;246(1-2):85–95. 4. Weber MS, et al. Biochim Biophys Acta
2011;1812(2):239–45. 5. Serafini B, et al. Brain Pathol 2004;14(2):164–74.
6. Magliozzi R, et al. Ann Neurol 2010;68(4):477–93.
Ectopic lymphoid
follicle-like aggregates5,6
Cytokine production2,3
B cells play key functional roles in MS
41. B cells express different surface markers throughout development
BAFF = B cell activating factor; BCMA = B cell maturation antigen; TACI = transmembrane activator and calcium-modulator and cytophilin ligand interactor
Image adapted from Krumbholz M, et al. Nat Rev Neurol 2012;8(11):613–23.
1. Stashenko P, et al. J Immunol 1980;125:1678–85; 2. Loken MR, et al. Blood 1987;70:1316–24; 3. Tedder TF, Engel P. Immunol Today 1994;15:450–4;
4. Martin F, Chan AC. Annu Rev Immunol 2006;24:467–96.
CD20
CD19
CD52
CD138
a4-INTEGRIN
BAFF-R
BCMA
TACI
B cell reconstitution
preserved1-3
Long-term memory
preserved1,2,4
42. OCR Selectively Targets Mature B Cells While Sparing Other Immune Cells
Cytotoxic T cells
T helper cellsNatural Killer cells
CD19 B cells
43. Reduction in ARR compared with IFN β-1a
Primary endpoint
ITT
*Adjusted ARR calculated by negative binomial regression and adjusted for baseline EDSS score (<4.0 vs ≥4.0), and geographic region
(US vs ROW).
ARR, annualized relapse rate; EDSS, Expanded Disability Status Scale; ROW, rest of the world.
46%
ARR reduction vs
IFN β-1a
p<0.0001
OPERA I OPERA II
47%
ARR reduction
vs IFN β-1a
p<0.0001
44. Risk reduction: 40%
HR (95% CI): 0.60 (0.45, 0.81); p=0.0006
Risk reduction: 40%
HR (95% CI): 0.60 (0.43, 0.84); p=0.0025
Time to CDP for ≥12 weeks Time to CDP for ≥24 weeks
ITT
CDP, confirmed disability progression; CI, confidence interval; HR, hazard ratio; IFN, interferon; OCR, ocrelizumab
15.2
9.8
12.0
7.6
Reduction in pre-specified pooled analysis of confirmed
disability progression (CDP) at 12 and 24 weeks
45. Substantial reduction in total new and/or enlarging T2
hyperintense lesions compared with IFN β-1a
45
OPERA I OPERA II
ITT
*Adjusted by baseline T2 lesion count, baseline EDSS (<4.0 vs ≥4.0) and geographical region (US vs ROW).
EDSS, Expanded Disability Status Scale; IFN, interferon; MRI, magnetic resonance imaging; ROW, rest of the world.
41%
p=0.0002
94%
p<0.0001
98%
p<0.0001
61%
p<0.0001
96%
p<0.0001
97%
p<0.0001
46. 46
ITT (EDSS ≥ 2.0)
*Compared using the Cochran–Mantel–Haenszel test stratified by geographic region (US vs ROW) and baseline EDSS score (<4.0 vs. ≥4.0).
NEDA Percentage Change in Brain Volume
from Baseline to Week 9674%
NEDA improvement
vs IFN β-1a
p<0.0001
NEDA is defined as: no protocol-defined relapses, no CDP events, no
new or enlarging T2 lesions, and no Gd-enhancing T1 lesions
Week
Higher proportion of patients with No Evidence of Disease Activity
(NEDA) compared with IFN β-1a
OPERA I
47. n (%)
IFN β-1a
44 μg
(n=826)
Ocrelizumab
600 mg
(n=825)
Total number of patients with ≥1 AE 688 (83.3) 687 (83.3)
Total number of patients with ≥1 AE occurring at relative frequency ≥5% 539 (65.3) 544 (65.9)
Injury, Poisoning and Procedural Complications
Infusion-related reaction
General Disorders and Administration-site Conditions
Influenza-like illness
Injection-site erythema
Fatigue
Injection-site reaction
Infections and Infestations
Upper respiratory tract infection
Nasopharyngitis
Urinary tract infection
Sinusitis
Bronchitis
Nervous System Disorders
Headache
Psychiatric Disorders
Depression
Insomnia
Musculoskeletal and Connective Tissue Disorders
Back pain
Arthralgia
80 (9.7)
177 (21.4)
127 (15.4)
64 (7.7)
45 (5.4)
87 (10.5)
84 (10.2)
100 (12.1)
45 (5.4)
29 (3.5)
124 (15.0)
54 (6.5)
38 (4.6)
37 (4.5)
51 (6.2)
283 (34.3)
38 (4.6)
1 (0.1)
64 (7.8)
2 (0.2)
125 (15.2)
122 (14.8)
96 (11.6)
46 (5.6)
42 (5.1)
93 (11.3)
64 (7.8)
46 (5.6)
53 (6.4)
46 (5.6)
Adverse events
47
Table includes only AEs occurring in ≥5% of patients in at least one treatment group.
AE, adverse event; IFN, interferon.
48. Serious adverse events
• During OPERA I and OPERA II three deaths occurred
– IFN β-1a 44 μg arm: completed suicide, mechanical ileus
– Ocrelizumab 600 mg arm: completed suicide
n (%)
IFN β-1a
44 μg
(n=826)
Ocrelizumab
600 mg
(n=825)
Overall patients with ≥1 SAE 72 (8.7) 57 (6.9)
Infections and infestations 24 (2.9) 11 (1.3)
Nervous system disorders 11 (1.3) 8 (1.0)
Injury, poisoning, and procedural complications 10 (1.2) 6 (0.7)
IFN, interferon; SAE, serious adverse event.
49. 1.4
0.5
1.5
0.5
1.7
0.95.1
1.3
0.1
Most common AE associated with ocrelizumab was infusion-related reactions (IRR)
Mostly mild to moderate in severity*,†
49
*Numbers in columns represent the proportion of patients experiencing a grade of IRR
†Grading per Common Terminology Criteria (CTCAE): Grade 1 Mild; asymptomatic or mild symptoms; Grade 2 Moderate; minimal, local or noninvasive intervention indicated; Grade 3 Severe or medically significant but not immediately life-
threatening; Grade 4 Life-threatening consequences; urgent intervention indicated; Grade 5 Death related to adverse event.
Note: All received 100 mg i.v. methylprednisolone.
IRR, infusion-related reaction.
Ocrelizumab
600 mg
IFN β-1a
44 μg
Grade 1 Grade 2 Grade 3 Grade 4
Dose 1 Dose 2 Dose 3 Dose 4Dose 1 Dose 2 Dose 3 Dose 4
1.0
0.1 3.6
1.1
6.0
1.8
10.8
2.6
0.4
7.4
1.8
0.4
18.3
7.4
1.7
0.1
The incidence of withdrawal due to IRRs was low in the ocrelizumab arm
– 1.3% (11 patients) withdrew from ocrelizumab treatment due to an IRR during the first infusion
Infusion 1 Infusion 2Infusion 1 Infusion 2
50. ORATORIO PPMS
50
Confidential — For internal use only. Do not
copy, distribute or use without prior written
consent
Placebo
n=244
Ocrelizumab
600 mg
n=488
Age, yr, mean (SD) 44.4 (8.3) 44.7 (7.9)
Female, n (%) 124 (50.8) 237 (48.6)
Time since symptom onset, yr, mean (SD) 6.1 (3.6) 6.7 (4.0)
Time since diagnosis, yr, mean (SD) 2.8 (3.3) 2.9 (3.2)
MS disease modifying treatment naive, n (%) 214 (87.7) 433 (88.7)
EDSS, mean (SD) 4.7 (1.2) 4.7 (1.2)
MRI findings
Gd– lesions, n (%)
Number of Gd+ T1 lesions, mean (SD)
T2 lesion volume, cm3, mean (SD)
Normalised brain volume, cm3, mean (SD)
183 (75.3%)
0.6 (1.6)
10.9 (13.0)
11.0 (0.9)
351 (72.5%)
1.2 (5.1)
12.7 (15.1)
12.8 (0.7)
EDSS, Expanded Disability Status Scale; Gd, gadolnium; MRI, magnetic resonance imaging; SD, standard deviation; yr, year.
51. Reduction in confirmed disability progression for ≥12 Weeks
Primary Endpoint
24%
reduction in risk of CDP
HR (95% CI): 0.76 (0.59, 0.98); p=0.0321
Time to CDP for ≥12 weeks
Analysis based on ITT population; p-value based on log-rank test stratified by geographic region and age
Patients with initial disability progression who discontinued treatment early with no confirmatory EDSS assessment were considered as having confirmed disability progression
52. Reduction in confirmed disability progression for ≥24 weeks
25%
reduction in risk of CDP
HR (95% CI): 0.75 (0.58, 0.98); p=0.0365
Time to CDP for ≥24 weeks
Analysis based on ITT population; p-value based on log-rank test stratified by geographic region and age
Patients with initial disability progression who discontinued treatment early with no confirmatory EDSS assessment were considered as having confirmed disability progression
53. * Week 120 during the Double-Blind Treatment Period (ranked ANCOVA, MMRM)
10%
change in 25-foot walk
vs. placebo
p=0.404
Reduction in rate of decline in walking speed
57. Premyelinating oligodendrocytes
in chronic MS lesions1
Negative regulators of OPC differentiation have been
identified2,3
Investigating LINGO-1 as a target for remyelination
and neuroprotection/neuroreparation
OPC=oligodendrocyte precursor cells; NCAM=neural cell adhesion molecule;
PSA=polysialic acid; RNAi=ribonucleic acid interference.
1. Chang A et al. N Engl J Med. 2002;346:165-173; 2. Adapted from Rudick RA et al. Expert Opin Biol Ther. 2008;8:1561-1570;
3. Mi S et al. Ann Neurol. 2009;65:304-315; 4. Mi S et al. Nat Neurosci. 2005;8:745-751; 5. Cadavid D et al. Presented at AAN; Philadelphia, USA; 2014:P2.262.
In vivo effects of anti-LINGO-1 in rat optic nerve
crush model5
Reduced neurodegeneration and increased
axonal outgrowth (arrows) vs control
Control RNAiLINGO-1 RNAi
In vitro effects of LINGO-1 blockade4
Mature
oligodendrocyte
OPCs
Differentiation
LINGO-1,
PSA-NCAM, Notch
Anti-LINGO-1
treatment
Proximal Distal
Control
treatment
Fluorescein isothiocyanate-conjugated cholera
toxin B–labeled axons after optic nerve crush
and vehicle injection
58. Anti-LINGO-1 results in remyelination in animal models of CNS demyelination2
LPC=lysophosphatidylcholine/lysolecithin; mAb=monoclonal antibody.
Adapted from 1. Mi S et al. Nature Neurosci. 2004;7:221-228; 2. Mi S et al. Ann Neurol. 2009;65:304-315.
1 µm
Control mAb Anti-LINGO-1
1 µm
Cuprizone
LPC
Demyelinated axons
*Remyelinated axons
EAE
59. New phase 2 study designs: Acute optic neuritis
to assess neuroprotection and remyelination
1. Cadavid D et al. Presented at AAN; Philadelphia, USA; 2014:P2.262
2. Cadavid D et al. Presented at AAN; Washington, USA; 2015:P7.202.
RENEW1,2
Anti-LINGO-1
(multi-centre)
Anti-LINGO-1 (100 mg/kg IV Q4W x 6)
Placebo (IV Q4W x 6)
Participants with first
episode of unilateral AON
(n=82)
Randomised within 4
weeks of symptom onset
Dosing period
20 weeks
Assessments at
24 and 32 weeks
3–5 days’
IV steroids
End of study
follow-up
32 weeks
Primary outcome: VEP
60. RENEW primary outcome: Anti-LINGO-1 and recovery of full-field VEP latency in AON
*Adjusted mean change in optic nerve conduction latency of the affected eye compared with the unaffected fellow eye at baseline, Week 24 (ANCOVA), Week 32 (MMRM). ANCOVA=analysis of covariance;
ITT=intent-to-treat; MMRM=mixed-effect model repeated measure; PP=per-protocol.
Adapted from 1. Cadavid D et al. Presented at AAN; Washington, USA; 2015:P008; 2. Cadavid D et al. Presented at AAN; Washington, USA; 2015:P7.202.
Placebo 100 mg/kg anti-LINGO-1
25
20
15
10
5
0
PP ITT
22.24
14.69
20.83
17.34
Week 24
34%
Latency
recovery
P=0.05
17%
Latency
recovery
P=0.33
Adjustedmean
changein
Full-fieldVEP
latency*(ms)
n=36 n=33 n=41 n=41
PP=Subjects who completed the study, did not miss >1 dose of treatment
and did not receive MS modifying therapy
ITT=All randomised subjects who received ≥1 dose of study treatment
PP ITT
22.35
13.22
21.15
15.08
Week 32
41%
Latency
recovery
P=0.01
29%
Latency
recovery
P=0.07
n=36 n=33 n=41 n=41
61. SD-OCT values at baselinea
Affected eye n=77 Fellow eye n=80 Difference n=77b
RGCL/IPL thickness, μm 64.8 (7.3) 69.5 (5.6) -4.76 (5.5)
aValues are mean (SD); bSD-OCT was not available in the affected eye for 3 participants (missing data were not imputed).
Mean GCL/IPL thickness at each visit in the affected eye in the ITT population up to Week 32
No difference observed in RENEW secondary OCT efficacy endpoints at W32
RGCL=retinal ganglion cell layer; SD=standard deviation.
1. Cadavid D et al. Presented at ACTRIMS-ECTRIMS; Boston, USA; 2014:P731; 2. Cadavid D et al. Presented at AAN; Washington, USA; 2015:P7.202.
62. Revolutionised the treatment of MS
Targeted therapies
Better outcomes
Complex biology
New insights
Anti-trafficking - rebound/IRIS
Challenging dogmas
T-cell vs. B-cells
CD56-bright NK cells
Secondary autoimmunity
Better outcomes, but more risk
Increased monitoring requirement, e.g. lymphopaenia, LFTs, etc.
De-risking strategies, e.g. JCV-testing
Anti-drug antibodies
Conclusion - mAbs