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Multiple Sclerosis Dimethyl and monomethyl fumarates Nrf2 inhibitors MS is an autoimmune disease characterized by the demyelination of axons in the central nervous system. For most patients, the initial course of the disease is characterized by discreet relapses with episodic and transient neurological impairment and near complete recovery as endogenous remyelination is sufficient to repair most of the damaged axons. Over time, however, patients experience reduced recovery following relapses leading to an accumulation of neurological impairment and concomitant disability, either due to failure of remyelination, increase in the intensity of immune attack, or other factors. A small subset of patients present with progressive decrease in neurological function without discreet relapses or evidence of improvement. Nonetheless, even patients initially presenting with relapses will eventually convert to a progressive form of the disease. Current treatments focus on modulating the immune system to prevent the immunological flares mainly associated with relapses, while several new drugs are being developed to enhance remyelination. Attempts to treat progressive MS have been unsuccessful to date. NDA Biogen Idec (BG-12/dimethyl fumarate) BID with superior efficacy Mechanism poorly understood, but decreases levels of circulating lymphocytes Xenoport (monomethyl fumarate prodrug/XP23829) 49% reduction in annualized relapse rate - modest side effect profile allows for combination with injectables or other agents - however, BID or TID dosing Non-specific immunomodulator ... Teva/Active Biotech (laquinimod) numerous potential mechanisms of action with unclear primary effect Considered safe low efficacy, 21% reduction in annualized relapserate - relatively safe, and once a day QD with lower efficacy May be used first line and compete with interferons and Copaxone Disease Modifying Treatments Anti-LINGO-1 Antibody • Merck Serono (IFN beta:Fc) Remyelination Inhaled Interferon Beta Biogen Idec (BIIB-033) •* Lingo and Nogo Given the relative convenience of once weekly injectable interferon, a daily inhaled formulation may not offer a large enough advantage for patients. Demyelination In MS patients, it is believed that interactions between cell surface signaling molecules including Nogo and Lingo-1inhibit remyelination efforts. Antibodies that block either Lingo-1 or Nogo-A may therefore enhance or accelerate remyelination of the effected neurons. Preventing MS progression and disability ("Disease modifying therapy"). Although the cause of MS is unknown, inflammation, demyelination, and axon degeneration are the major pathologic mechanisms that cause the clinical manifestations of MS. Following the resolution of active inflammation, most axons remain intact, but unable to conduct neural signaling after their myelin sheaths are destroyed (conduction block) producing clinical symptoms. Remyelination is thought to be responsible for the resolution of clinical symptoms during a remission. The specific role of remyelination during progressive disease is less well understood. Caused by Inflammation Anti-NOGO-A Antibody GSK (GSK-1223249) Controlled porcine whipworm Coronado Biosciences (CNDO-201, Trichuris suis Ova) colonization Potentially less than QD Forces the immune system react to non-infectious porcine whipworm altering the cytokine milieu. Th2 responses are favored, though the significance in MS is not yet clear. Oral or non- M Novartis (fingolimod/Gilenya) injectable Receptors (RPC-1063) .. •• Merck KGAA/Ono Pharma (ONO-4641) Gilenya and other sphingosine-1-phosphate modulators •• Actellion (ponesimod/ACT-128800) Prevent lymphocytes from leaving lymph nodes, thus decreasing their migration in the blood, and entry to nervous system S1P-1 and S1P-3 receptors are expressed by cardiac tissue, potentially accounting for cardiac toxicity (off label use) Mycophenolate mofetil/CellCept G up to 55% reduction in annualized relapse rate •• Novartis (BAF-312/siponimod) (off label use) azathiopine/Imuran G recently associated with unexplained deaths, FDA revised and strengthened first dose observation requirements in response Purine Synthesis Inhibitor Abbott (ABT-413) FDA recommends 6-24hr ongoing cardiac monitoring after first time dose of Gilenya, a major hassle factor for physicians, though Novartis is allowed to reimburse the physicians for the time (off label use) cladribine/Leustatin G • Abbott (ABT-363) appears to be primarily reserved for JCV positive patients who cannot take Tysabri (off label use) Novartis (mycophenolic acid/Myfortic) M Mitsubishi Tanabe (MT-1303) With Oral Tysabri follow-ons (VLA4 antagonists) significant safety Cytoxic Chemotherapy Topoisomerase II Inhibitor •• Elan (ELND-002) Induce immunosuppression by destroying and depleting immune cells to prevent or reduce MS pathology (generic) mitoxantrone/Novantrone G concerns •• GSK (firategrast) Prevents immune cells from crossing the blood brain barrier, by blocking alpha4/beta lintegrin required for adhesion to blood brain barrier. Tysabri is a VLA4 antagonist. No oral agents in this class have yet been approved. JCV cases may limit adoption, though uptake in JCV negative patients can be expected. Significant safety risks and limited evidence of benefit Used cautiously, and rarely first line. Currently compete with IV infusions (Tysabri). Typically reserved for patients with rapidly progressive disease or patients that failed multiple previous agents Low potency chemotherapy agent Disease Modifying Treatments (off label use) cyclophosphamide/Cytoxan G Alkylating Agent Pyrimidine inhibitor. Depletes immune cells. Accentia (high-dose cyclophosphamide) .. Immunomodulation - Closely related to chemotherapy agents Currently used off label NDA Sanofi (teriflunomide) Modest efficacy, 31% reduction in annualized relapse rate Significant rate of immunosuppression (49%) at all doses, and liver enzyme abnormalities at high doses Preventing MS progression and/or relapses ("Disease modifying therapy"). Cosmetic issues (hair loss), and pregnancy category X, a problem for most recently diagnosed female MS patients who tend to be in their 20s. Autoreactive immune cells are thought to attack either the myelin basic protein or other myelin proteins, leading to selective destruction of oligodendrocytes, the myelin producing cells during an inflammatory exacerbation. - Chronically limiting the activity of the immune system decreases associated disease pathology. Novartis (fingolimod/Gilenya) •.. • Merck KGAA/Peptimune (plovamer) Sphingosine-1- Phosphate Modulator QW Copaxone and follow-ons (random and short peptides) Relapsing-Remitting MS Progressive Forms of MS ... Teva (high concentration Copaxone) Ocrelizumab ... 3x week dosing Unclear mechanism Anti-CD20 30% reduction in annualized relapse rate Relapsing-Remitting MS is characterized by discrete exacerbations followed by complete or partial restoration of function. The rate of these exacerbations is considered the most objective endpoint for clinical studies by the FDA. M Teva (glatiramer acetate/Copaxone) early registration studies showed a modest benefit against placebo, though Copaxone was since found superior in studies against Betaseron, and Rebif (No Relapses) Targeted Elan/Biogen Idec (natalizumab/Tysabri) ... VLA4 Antagonist Most remitting-relapsing MS patients (>80%) eventually progress to the secondary progressive from of multiple sclerosis. In this form, accumulation of disability is continuous, lacking discreet exacerbations followed by improvements. In addition, 15% of all MS patients receive an initial diagnosis of primary progressive MS, which progresses more rapidly, and also lacks relapses. In the absence of relapse rate, the agency must rely on MRI endpoints, and progression to disability. Only one drug has ever been formally approved for a progressive form of MS and it is not widely used due to its adverse safety profile. QD Copaxone is the most prescribed MS treatment (can enter end of 2015) Momenta (generic copaxone) Drugs on these branches compete based on: - safety of chronic administration - dosing convenience (long-acting injectables or once a day orals) .• Biogen Idec (PEG-Avonex) Microparticle Immunomodulator Innate Immunotherapeutics (MIS-416) .. Allozyne (AZ-01). QM Low dose Immune modulation via cross-linked bacteria derived ligands for Nod2 and TLR9. - efficacy comparable or superior to interferon beta interferons AB Sciences (masitinib) ... Considered less potent by physicians, but more convenient. Very low rate of neutralizing antibodies (2-5% of patients develop antibodies) Dirty TKI-Targets Mast Cells M Biogen Idec (Avonex) QW Interferon Beta Potentiates inhibitory cytokine signaling 25-40% reduction in annualized relapse rate Subcutaneous - up to 60% reduction in MRI lesion burden injections M Merck KGaA (Rebif) reduction in MRI lesion size High dose interferons neutralizing antibodies are thought to be at least partially responsible for treatment failure M Bayer (Betaseron) 3x week dosing Considered more potent by physicians, but less convenient. High rate of neutralizing antibodies (25- 34% of patients develop antibodies) M Novartis (Avonex) ..• Nuron Biotech (low immunogenicity Extavia) Anti-CD25 Antibody prevents IL-2R signaling, inhibiting T cell expansion ... Abbott/Biogen Idec (daclizumab) QM - showed 54% reduction in ARR 57% reduction in progression of disability, the most seen in MS studies potential efficacy biomarker: levels of NK cells Anti-CD52 Antibody Injectables Potential Cure - depletes circulating T cells that are thought to be responsible for MS pathology Based on current theory, eliminating or reprogramming the offending clone of autoreactive lymphocytes could prove curative extremely effective at both slowing down progression of disability, and reducing the annualized relapse rate significant toxicity: 22.5% of patients treated with Lemtrada develop a new autoimmune disease (some severe) within 12-18 months of treatment T-cell directed requires only 2 infusions one month apart repeated annually Ablative: Selective destroys one line of immune cells, requires less frequent dosing, but will result in long-term immune suppression Q6M Anti-CD20 - depleted pro-B cells and mature B cells ocrelizumab showed an 80% reduction in ARR in phase 2, but also caused one death due to brain swelling B-cell directed Analogous T Cell Vaccine agents in this class do have a black box warning about the potential of PML, just like Tysabri Opexa (tovaxin/Tcelna) .. Attempt to vaccinate the patient against his or her own myelin reactive T cells Tysabri and follow-ons (VLA4 agonists) QM Sequestoring: IV Infusions Prevents immune cells from crossing the blood brain barrier, by blocking alpha4/beta 1 integrin required for adhesion to blood brain barrier Prevents the immune cells from •• Antisense Therapeutics (ATL-1102) 67% reduction in annualized relapse rate, most of any approved agents entering the brain reserved for patients who fail interferons and copaxone due to cases of fatal multifocal leukoencephalopathy related to JC virus infection • Sanofi/Glenmark (vatelizumab) however, JC virus antibody test is commonplace now, and the use has been increasing in JCV negative patients, with Gilenya gaining traction in JCV positive patients • Morphosys (MOR-103) Anti-GM-CSF - limits the activity of neutrophils, eosenophils, basophils, monocytes . BMS (abatacept/Orencia) CTLA-4/B7 Inhibition Inhibitory: Prevent the activation and/or - prevents antigen presenting cells from stimulating T cells upon antigen presentation expansion of immune cells •• Eli Lilly (LY2127399) Anti-BAFF Scavenge and remove the B cell activating factor Multiple Sclerosis Dimethyl and monomethyl fumarates Nrf2 inhibitors MS is an autoimmune disease characterized by the demyelination of axons in the central nervous system. For most patients, the initial course of the disease is characterized by discreet relapses with episodic and transient neurological impairment and near complete recovery as endogenous remyelination is sufficient to repair most of the damaged axons. Over time, however, patients experience reduced recovery following relapses leading to an accumulation of neurological impairment and concomitant disability, either due to failure of remyelination, increase in the intensity of immune attack, or other factors. A small subset of patients present with progressive decrease in neurological function without discreet relapses or evidence of improvement. Nonetheless, even patients initially presenting with relapses will eventually convert to a progressive form of the disease. Current treatments focus on modulating the immune system to prevent the immunological flares mainly associated with relapses, while several new drugs are being developed to enhance remyelination. Attempts to treat progressive MS have been unsuccessful to date. NDA Biogen Idec (BG-12/dimethyl fumarate) BID with superior efficacy Mechanism poorly understood, but decreases levels of circulating lymphocytes Xenoport (monomethyl fumarate prodrug/XP23829) 49% reduction in annualized relapse rate - modest side effect profile allows for combination with injectables or other agents - however, BID or TID dosing Non-specific immunomodulator ... Teva/Active Biotech (laquinimod) numerous potential mechanisms of action with unclear primary effect Considered safe low efficacy, 21% reduction in annualized relapserate - relatively safe, and once a day QD with lower efficacy May be used first line and compete with interferons and Copaxone Disease Modifying Treatments Anti-LINGO-1 Antibody • Merck Serono (IFN beta:Fc) Remyelination Inhaled Interferon Beta Biogen Idec (BIIB-033) •* Lingo and Nogo Given the relative convenience of once weekly injectable interferon, a daily inhaled formulation may not offer a large enough advantage for patients. Demyelination In MS patients, it is believed that interactions between cell surface signaling molecules including Nogo and Lingo-1inhibit remyelination efforts. Antibodies that block either Lingo-1 or Nogo-A may therefore enhance or accelerate remyelination of the effected neurons. Preventing MS progression and disability ("Disease modifying therapy"). Although the cause of MS is unknown, inflammation, demyelination, and axon degeneration are the major pathologic mechanisms that cause the clinical manifestations of MS. Following the resolution of active inflammation, most axons remain intact, but unable to conduct neural signaling after their myelin sheaths are destroyed (conduction block) producing clinical symptoms. Remyelination is thought to be responsible for the resolution of clinical symptoms during a remission. The specific role of remyelination during progressive disease is less well understood. Caused by Inflammation Anti-NOGO-A Antibody GSK (GSK-1223249) Controlled porcine whipworm Coronado Biosciences (CNDO-201, Trichuris suis Ova) colonization Potentially less than QD Forces the immune system react to non-infectious porcine whipworm altering the cytokine milieu. Th2 responses are favored, though the significance in MS is not yet clear. Oral or non- M Novartis (fingolimod/Gilenya) injectable Receptors (RPC-1063) .. •• Merck KGAA/Ono Pharma (ONO-4641) Gilenya and other sphingosine-1-phosphate modulators •• Actellion (ponesimod/ACT-128800) Prevent lymphocytes from leaving lymph nodes, thus decreasing their migration in the blood, and entry to nervous system S1P-1 and S1P-3 receptors are expressed by cardiac tissue, potentially accounting for cardiac toxicity (off label use) Mycophenolate mofetil/CellCept G up to 55% reduction in annualized relapse rate •• Novartis (BAF-312/siponimod) (off label use) azathiopine/Imuran G recently associated with unexplained deaths, FDA revised and strengthened first dose observation requirements in response Purine Synthesis Inhibitor Abbott (ABT-413) FDA recommends 6-24hr ongoing cardiac monitoring after first time dose of Gilenya, a major hassle factor for physicians, though Novartis is allowed to reimburse the physicians for the time (off label use) cladribine/Leustatin G • Abbott (ABT-363) appears to be primarily reserved for JCV positive patients who cannot take Tysabri (off label use) Novartis (mycophenolic acid/Myfortic) M Mitsubishi Tanabe (MT-1303) With Oral Tysabri follow-ons (VLA4 antagonists) significant safety Cytoxic Chemotherapy Topoisomerase II Inhibitor •• Elan (ELND-002) Induce immunosuppression by destroying and depleting immune cells to prevent or reduce MS pathology (generic) mitoxantrone/Novantrone G concerns •• GSK (firategrast) Prevents immune cells from crossing the blood brain barrier, by blocking alpha4/beta lintegrin required for adhesion to blood brain barrier. Tysabri is a VLA4 antagonist. No oral agents in this class have yet been approved. JCV cases may limit adoption, though uptake in JCV negative patients can be expected. Significant safety risks and limited evidence of benefit Used cautiously, and rarely first line. Currently compete with IV infusions (Tysabri). Typically reserved for patients with rapidly progressive disease or patients that failed multiple previous agents Low potency chemotherapy agent Disease Modifying Treatments (off label use) cyclophosphamide/Cytoxan G Alkylating Agent Pyrimidine inhibitor. Depletes immune cells. Accentia (high-dose cyclophosphamide) .. Immunomodulation - Closely related to chemotherapy agents Currently used off label NDA Sanofi (teriflunomide) Modest efficacy, 31% reduction in annualized relapse rate Significant rate of immunosuppression (49%) at all doses, and liver enzyme abnormalities at high doses Preventing MS progression and/or relapses ("Disease modifying therapy"). Cosmetic issues (hair loss), and pregnancy category X, a problem for most recently diagnosed female MS patients who tend to be in their 20s. Autoreactive immune cells are thought to attack either the myelin basic protein or other myelin proteins, leading to selective destruction of oligodendrocytes, the myelin producing cells during an inflammatory exacerbation. - Chronically limiting the activity of the immune system decreases associated disease pathology. Novartis (fingolimod/Gilenya) •.. • Merck KGAA/Peptimune (plovamer) Sphingosine-1- Phosphate Modulator QW Copaxone and follow-ons (random and short peptides) Relapsing-Remitting MS Progressive Forms of MS ... Teva (high concentration Copaxone) Ocrelizumab ... 3x week dosing Unclear mechanism Anti-CD20 30% reduction in annualized relapse rate Relapsing-Remitting MS is characterized by discrete exacerbations followed by complete or partial restoration of function. The rate of these exacerbations is considered the most objective endpoint for clinical studies by the FDA. M Teva (glatiramer acetate/Copaxone) early registration studies showed a modest benefit against placebo, though Copaxone was since found superior in studies against Betaseron, and Rebif (No Relapses) Targeted Elan/Biogen Idec (natalizumab/Tysabri) ... VLA4 Antagonist Most remitting-relapsing MS patients (>80%) eventually progress to the secondary progressive from of multiple sclerosis. In this form, accumulation of disability is continuous, lacking discreet exacerbations followed by improvements. In addition, 15% of all MS patients receive an initial diagnosis of primary progressive MS, which progresses more rapidly, and also lacks relapses. In the absence of relapse rate, the agency must rely on MRI endpoints, and progression to disability. Only one drug has ever been formally approved for a progressive form of MS and it is not widely used due to its adverse safety profile. QD Copaxone is the most prescribed MS treatment (can enter end of 2015) Momenta (generic copaxone) Drugs on these branches compete based on: - safety of chronic administration - dosing convenience (long-acting injectables or once a day orals) .• Biogen Idec (PEG-Avonex) Microparticle Immunomodulator Innate Immunotherapeutics (MIS-416) .. Allozyne (AZ-01). QM Low dose Immune modulation via cross-linked bacteria derived ligands for Nod2 and TLR9. - efficacy comparable or superior to interferon beta interferons AB Sciences (masitinib) ... Considered less potent by physicians, but more convenient. Very low rate of neutralizing antibodies (2-5% of patients develop antibodies) Dirty TKI-Targets Mast Cells M Biogen Idec (Avonex) QW Interferon Beta Potentiates inhibitory cytokine signaling 25-40% reduction in annualized relapse rate Subcutaneous - up to 60% reduction in MRI lesion burden injections M Merck KGaA (Rebif) reduction in MRI lesion size High dose interferons neutralizing antibodies are thought to be at least partially responsible for treatment failure M Bayer (Betaseron) 3x week dosing Considered more potent by physicians, but less convenient. High rate of neutralizing antibodies (25- 34% of patients develop antibodies) M Novartis (Avonex) ..• Nuron Biotech (low immunogenicity Extavia) Anti-CD25 Antibody prevents IL-2R signaling, inhibiting T cell expansion ... Abbott/Biogen Idec (daclizumab) QM - showed 54% reduction in ARR 57% reduction in progression of disability, the most seen in MS studies potential efficacy biomarker: levels of NK cells Anti-CD52 Antibody Injectables Potential Cure - depletes circulating T cells that are thought to be responsible for MS pathology Based on current theory, eliminating or reprogramming the offending clone of autoreactive lymphocytes could prove curative extremely effective at both slowing down progression of disability, and reducing the annualized relapse rate significant toxicity: 22.5% of patients treated with Lemtrada develop a new autoimmune disease (some severe) within 12-18 months of treatment T-cell directed requires only 2 infusions one month apart repeated annually Ablative: Selective destroys one line of immune cells, requires less frequent dosing, but will result in long-term immune suppression Q6M Anti-CD20 - depleted pro-B cells and mature B cells ocrelizumab showed an 80% reduction in ARR in phase 2, but also caused one death due to brain swelling B-cell directed Analogous T Cell Vaccine agents in this class do have a black box warning about the potential of PML, just like Tysabri Opexa (tovaxin/Tcelna) .. Attempt to vaccinate the patient against his or her own myelin reactive T cells Tysabri and follow-ons (VLA4 agonists) QM Sequestoring: IV Infusions Prevents immune cells from crossing the blood brain barrier, by blocking alpha4/beta 1 integrin required for adhesion to blood brain barrier Prevents the immune cells from •• Antisense Therapeutics (ATL-1102) 67% reduction in annualized relapse rate, most of any approved agents entering the brain reserved for patients who fail interferons and copaxone due to cases of fatal multifocal leukoencephalopathy related to JC virus infection • Sanofi/Glenmark (vatelizumab) however, JC virus antibody test is commonplace now, and the use has been increasing in JCV negative patients, with Gilenya gaining traction in JCV positive patients • Morphosys (MOR-103) Anti-GM-CSF - limits the activity of neutrophils, eosenophils, basophils, monocytes . BMS (abatacept/Orencia) CTLA-4/B7 Inhibition Inhibitory: Prevent the activation and/or - prevents antigen presenting cells from stimulating T cells upon antigen presentation expansion of immune cells •• Eli Lilly (LY2127399) Anti-BAFF Scavenge and remove the B cell activating factor