Pipeline

INDICATION:

Spinal muscular atrophy (SMA) is a rare genetic neurodegenerative disorder characterized by the loss of motor neurons, atrophy of the voluntary muscles of the limbs and trunk, and progressive muscle weakness that is often fatal and typically diagnosed in young children. The underlying pathology of SMA is caused by insufficient production of the SMN (survival of motor neuron) protein, essential for the survival of motor neurons, and is encoded by two genes, SMN1 and SMN2. In the US, SMA affects approximately 1 in 11,000 births, and about 1 in every 50 Americans is a genetic carrier.

RATIONALE:

Taldefgrobep is an investigational, muscle-targeted recombinant protein with the potential to enhance muscle mass and strength in people living with SMA when used in combination with other approved treatments. Taldefgrobep targets myostatin, a natural protein that limits skeletal muscle growth, through two mechanisms: lowering myostatin directly and blocking key downstream signaling mechanisms. Myostatin inhibition is a potential therapeutic strategy for children and adults with a range of neuromuscular conditions for whom active myostatin can limit the skeletal muscle growth needed to achieve developmental and functional milestones.

INDICATION:

Obesity is a disease of excess and/or abnormal deposits of adipose tissue and a current global public health crisis. By 2030, it is expected that nearly one billion people will be living with obesity, including 50% of the adult and 25% of the adolescent US population. The primary driver of obesity-related morbidity and mortality is metabolically active visceral adipose tissues and associated deposits in and around organs such as the heart, liver, kidneys, and muscle.

RATIONALE:

Taldefgrobep is an investigational fusion protein with the potential to induce physical and metabolic changes that are highly relevant to individuals living with overweight and obesity. Taldefgrobep targets myostatin, a natural protein that limits skeletal muscle growth. Taldefgrobep’s binding of myostatin prevents activin receptor signaling, resulting in muscle hypertrophy. Current anti-obesity therapies achieve weight loss through the reduction in both fat mass and lean muscle mass. Taldefgrobep offers a potential novel approach to addressing the primary pathology of obesity. Through its unique mechanism of action, taldefgrobep may be able to meaningfully reduce total body and visceral adipose tissue volumes and improve insulin sensitivity, while increasing lean muscle mass.

INDICATION:

Epilepsy affects approximately 3.5 million Americans and more than 50 million people worldwide; approximately 1/3 are refractory to available anti-seizure medications (ASMs). After starting an ASM, 80% of patients will experience burdensome adverse events, which can include somnolence, dizziness, cognitive dysfunction, and mood disturbances. Epilepsy can also be lethal; each year, more than one in 1,000 people with epilepsy die from SUDEP (sudden, unexpected death of someone with epilepsy).

RATIONALE:

BHV-7000 is a potent, selective activator of Kv7.2/7.3 potassium channels, a clinically validated target to regulate the hyperexcitable state in epilepsy. BHV-7000 is structurally and pharmacologically distinct from other potassium channel activators and demonstrates minimal GABA_A receptor activation, potentially providing better tolerability compared to other ASMs. BHV-7000 was potent in the maximal electroshock (MES) preclinical epilepsy model without adverse neurobehavioral or motor effects and was well-tolerated in a Phase 1 SAD/MAD clinical study without the central nervous system (CNS) adverse events typical of anti-seizure medications. A Phase 1 EEG biomarker study confirmed evidence of target engagement in the CNS.

INDICATION:

Epilepsy affects approximately 3.5 million Americans and more than 50 million people worldwide; approximately 1/3 are refractory to available anti-seizure medications (ASMs). After starting an ASM, 80% of patients will experience burdensome adverse events, which can include somnolence, dizziness, cognitive dysfunction, and mood disturbances. Epilepsy can also be lethal; each year, more than one in 1,000 people with epilepsy die from SUDEP (sudden, unexpected death of someone with epilepsy).

RATIONALE:

BHV-7000 is a potent, selective activator of Kv7.2/7.3 potassium channels, a clinically validated target to regulate the hyperexcitable state in epilepsy. BHV-7000 is structurally and pharmacologically distinct from other potassium channel activators and demonstrates minimal GABA_A receptor activation, potentially providing better tolerability compared to other ASMs. BHV-7000 was potent in the maximal electroshock (MES) preclinical epilepsy model without adverse neurobehavioral or motor effects and was well-tolerated in a Phase 1 SAD/MAD clinical study without the central nervous system (CNS) adverse events typical of anti-seizure medications. A Phase 1 EEG biomarker study confirmed evidence of target engagement in the CNS.

INDICATION:

Bipolar disorder affects 11 million adults in the US and requires lifelong treatment. Approximately 50% of patients with bipolar disorder are medication nonadherent, with discontinuations most commonly due to poor tolerability. In the last 20 years, no new mood stabilizer has been approved for the treatment of bipolar disorder, with the only new agents being antipsychotics.

RATIONALE:

BHV-7000 is a potent, selective activator of Kv7.2/7.3 potassium channels, a compelling target for bipolar disorder based on human genetics, molecular and cellular profiling, and preclinical models as well as mechanistic overlap with existing bipolar treatments. BHV-7000 has the potential for best-in category tolerability and safety with no expected long-term metabolic adverse events, titration, or laboratory monitoring. The novel mechanism of BHV-7000 also has potential for antidepressant effects without the risk of mood switching.

INDICATION:

Major depressive disorder (MDD) is a highly prevalent disorder with significant disease burden and unmet need. Approximately 21 million adults (8.3%) in the US have had at least one depressive episode, and there are over 1 million suicides per year globally and rising. Significant morbidity and mortality are attributable to MDD worldwide due to its chronic, recurrent nature, as well as its impact on mood, cognition, behavior, and suicidality. Currently available treatments for MDD often fail patients, and are limited by adverse events and inadequate efficacy, leaving more than 1/3 of patients resistant to antidepressant drug treatment.

RATIONALE:

BHV-7000 is a potent, selective activator of Kv7.2/7.3 potassium channels. Kv7 activation normalizes the pathological hyperexcitability that contributes to depression and has demonstrated efficacy in multiple preclinical models. Clinical proof-of-concept studies with Kv7 activators have demonstrated antidepressant activity and provide strong clinical support for Kv7 activation as a novel treatment for depression and anhedonia.

INDICATION:

Migraine & Pain Disorders

RATIONALE:

BHV-2100 is a first-in class, orally administered, highly selective, potent, small molecule TRPM3 antagonist that is being developed for the treatment for migraine and other pain disorders. TRPM3 is a novel druggable calcium channel in the transient receptor potential (TRP) channel family. TRPM3 is expressed in the trigeminovascular system, where it drives neurogenic inflammation and sensitization/activation of nociceptors, and TRPM3 antagonism normalizes nociceptor function. TRPM3 gene mutations/variants are associated with migraine risk and pain sensitivity in humans. TRPM3 regulates activity of other TRP channels (TRPV1 and TRPA1); and preliminary clinical data supports therapeutic benefit of inhibiting these TRP channels in migraine. BHV-2100 offers a novel, non-addictive treatment approach to migraine and pain and has demonstrated potent pain reversal in preclinical models and favorable safety, tolerability, and pharmacokinetic properties in Phase 1 clinical studies.

INDICATION:

Prevention of Amyloid Therapy Induced ARIA

RATIONALE:

ARIA represent a spectrum of imaging abnormalities seen on brain MRI in individuals living with Alzheimer’s Disease (AD) who are initiating amyloid-modifying therapies. Emerging data demonstrate the role of a mixed inflammatory response in the progression of ARIA, including complement activation as well as glial cell and peripheral T cell infiltration. This immune response contributes to a loss of vascular integrity and subsequent leakage of proteinaceous fluid (ARIA-E) or blood (ARIA-H) into the peri-arterial space and brain parenchyma resulting in the changes seen on MRI. ARIA are among the most common adverse events complicating the use of anti-amyloid monoclonal antibodies for the treatment of people living with early AD. These events generally occur early after the initiation of anti-amyloid therapy (within the first 3 months). Among the major risk factors for ARIA is APOE-ε4 carrier status. Homozygotes have a meaningfully higher rate of ARIA (~40%) compared to heterozygotes (~15-20%) and those who are non-carriers (~10-15%). While most ARIA events are asymptomatic, serious radiographic and life-threatening cases can occur. Notably, the long-term health consequences of asymptomatic ARIA are not well understood. Anti-inflammatory medications including corticosteroids have demonstrated benefit in the treatment of ARIA events. BHV-8000, as a brain-penetrant selective TYK2/JAK1 inhibitor, has the potential to disrupt the mixed inflammatory response driving ARIA and may represent a novel and promising approach to the prevention of these events in individuals living with AD who are undergoing anti-amyloid therapy.

INDICATION:

Parkinson’s Disease

RATIONALE:

Parkinson’s Disease (PD) is a progressive, neurodegenerative disorder that is characterized by worsening tremor, muscle rigidity, and slow, imprecise movements along with a range of non-motor symptoms such as impaired sleep and cognition. Strong evidence now exists that neuroinflammation is a critical driver of neurodegeneration in PD. Abnormal genetic variants in the TYK2/JAK1 pathway have been found to be associated with disease expression. Epidemiologic data also support an autoimmune component to PD and indicate the ability to mitigate that risk by targeting pathways associated with TKY2/JAK1 function. Further, abnormal immune activation including the presence of activated microglia, T-cell infiltration into the central nervous system, and elevated levels of a range of pro-inflammatory cytokines, has been consistently found in PD patients; findings that have been prevented or reversed via modulation of the JAK/STAT pathway in an animal PD model. BHV-8000 represents a novel and promising therapeutic approach for targeting symptoms and disease progression in this debilitating, neurodegenerative disease.

INDICATION:

Alzheimer’s Disease

RATIONALE:

Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder that is characterized by cognitive and functional decline. AD represents the most common neurodegenerative disease worldwide, accounting for approximately two-thirds of all cases of dementia and affecting up to 20% of individuals older than 80 years. Strong evidence now exists that chronic inflammation, including persistent activation of the central innate and the peripheral adaptive immune systems, play an important role in the development of AD, progression of its pathognomonic biological changes, and stereotypical clinical manifestations. Epidemiologic data demonstrate an increased incidence in AD among individuals living with autoimmune disease and the potential for risk mitigation with the chronic use of anti-inflammatory medications. Abnormal genetic variants in the TYK2/JAK1 pathway have been found to be associated with Alzheimer’s disease expression. Further, evidence of a hyperactive and destructive immune response that includes microglial activation, reactive astrocytosis, and the infiltration of peripheral effector T-cells into the brain, along with a resulting storm of inciting cytokines, has been consistently found in the tissues of AD patients; findings that have been prevented or reversed via modulation of the JAK/STAT pathway in an AD preclinical models. BHV-8000 represents a novel and promising therapeutic approach for targeting symptoms and disease progression in this debilitating, neurodegenerative disease.

INDICATION:

Multiple Sclerosis

RATIONALE:

Multiple Sclerosis (MS) is an immune-mediated inflammatory disease in which over-active immune cells and microglia drive chronic neuroinflammation resulting in neuronal injury, death, gliosis, and demyelination of axons in the central nervous system. Genetic evidence supports TYK2 as a pathogenic driver of MS, and nonclinical data suggest that the JAK/STAT pathway regulates differentiation and function of Th1 and Th17 cells which are responsible for development of inflammation and demyelination in animal models of MS. Clinical literature supports the presence of abnormal immune activation in MS, and targeting these pathways has demonstrated benefit in MS. Blocking TYK2/JAK1 signaling with a highly potent, selective, brain-penetrant agent has the potential to slow disease progression through modulation of pathogenic microglial cells, which drive cognitive and physical disabilities in MS, and inhibiting Th1 and Th17 lymphocytes which drive MS neuroinflammation and myelitis. CNS targeting of immune cells with BHV-8000 may enable a promising therapeutic approach for addressing disability progression, cognitive impairment, and reduced quality of life in both relapsing and progressive forms of MS.

INDICATION:

Common Disease (Graves’, RA)

RATIONALE:

Molecular Degraders of Extracellular Proteins (“MoDE™”) are bispecific molecules that target pathologic circulating proteins and direct them to the liver (or other organ systems) for degradation by the endosomal/lysosomal pathway. Hepatic asialoglycoprotein receptor (ASGPR) ligand degraders able to recognize all potentially pathogenic isoforms of IgG represent a novel, competitive platform with a differentiated profile relative to FcRN inhibitors. Specifically, high circulating levels of antibodies (monoclonal or polyclonal gammopathy) drive conditions such as myasthenia gravis, rheumatoid arthritis, systemic lupus erythematosus, pemphigus vulgaris, and many other diseases. It is hypothesized that rapid and sustained lowering of pathogenic antibody titers in blood will significantly reduce disease symptoms. In preclinical models, BHV-1300 demonstrated 75-80% reduction of IgG levels two days after a single dose and over 90% IgG lowering after three doses, in contrast to FcRn inhibitors which show 60-80% lowering in 7-21 days after initiation of dosing. Subcutaneously administered BHV-1300 achieved deep lowering of targeted IgG, with reductions > 60% in the lowest subcutaneous dose tested in the ongoing multiple ascending dose (MAD) study. Therapeutic pan-IgG depletion using Biohaven’s proprietary MoDE™ platform technology is expected to have significant potential benefit for multiple diseases.

INDICATION:

Rare Disease (Myasthenia Gravis)

RATIONALE:

Molecular Degraders of Extracellular Proteins (“MoDE™”) are bispecific molecules that target pathologic circulating proteins and direct them to the liver (or other organ systems) for degradation by the endosomal/lysosomal pathway. Hepatic asialoglycoprotein receptor (ASGPR) ligand degraders able to recognize all potentially pathogenic isoforms of IgG represent a novel, competitive platform with a differentiated profile relative to FcRN inhibitors. Specifically, high circulating levels of antibodies (monoclonal or polyclonal gammopathy) drive conditions such as myasthenia gravis, rheumatoid arthritis, systemic lupus erythematosus, pemphigus vulgaris, and many other diseases. It is hypothesized that rapid and sustained lowering of pathogenic antibody titers in blood will significantly reduce disease symptoms. BHV-1310 demonstrates 90% IgG depletion with a single dose. Therapeutic pan-IgG depletion using Biohaven’s proprietary MoDE™ platform technology is expected to have significant potential benefit for multiple diseases.

INDICATION:

IgA Nephropathy

RATIONALE:

IgA nephropathy (“IgAN”) is the most common primary glomerulonephritis that can progress to renal failure and is characterized by immune-complex deposits in the renal mesangium comprised of IgA1 bound to IgG. Patients are managed with the aim of controlling blood pressure and maintaining renal function. We are leveraging our MoDE™ platform to develop novel bispecific molecules for the treatment of IgA nephropathy (“IgAN”) that remove potentially disease-causing Gd-IgA, with preservation of normal IgA potentially permits disease remission without incurring an infection risk in patients and prevent harmful kidney deposits. We have taken a published rodent format IgG antibody that recognizes Gd-IgA and converted it into a partially-humanized, liver-targeted degrader MoDE™ using Multimodal Antibody Therapy Enhancer (“MATE™”) conjugation that potently binds Gd-IgA and causes its endocytosis in human liver cells. BHV-1400 represents a novel and promising therapeutic approach for progressive, debilitating renal disease.

INDICATION:

Peripartum Cardiomyopathy

RATIONALE:

Cardiac beta-1 adrenergic receptors (β1AR), when activated, increase heart rate, contractility, and cardiac output. There is a high prevalence of agonistic autoantibodies that activate cardiac β1AR in multiple cardiomyopathies, which lead to dilation of the heart and heart failure. The presence of β1AR autoantibodies correlates with a poor prognosis, and removing or neutralizing β1AR autoantibodies has shown potential therapeutic benefits. BHV-1600 is a bifunctional MoDE designed to selectively degrade pathogenic β1AR autoantibodies and should augment the limited efficacy of beta-blockers, providing a novel approach to treating multiple cardiomyopathies.