−Removed: We are a global clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of life-changing therapies for people with debilitating neurological and neuropsychiatric diseases, including rare disorders.
−Removed: Our experienced management team brings with it a track record of delivering new drug approvals for products for diseases such as migraine, depression, bipolar and schizophrenia.
−Removed: We are advancing a pipeline of therapies for diseases with little or no treatment options, leveraging our proven drug development capabilities and proprietary platforms, including Kv7 ion channel modulation for epilepsy and neuronal hyperexcitability, glutamate modulation for Obsessive-Compulsive Disorder (“OCD”) and Spinocerebellar Ataxia ("SCA"), myostatin inhibition for neuromuscular diseases, and brain-penetrant Tyrosine Kinase 2/Janus Kinase 1 ("TYK2/JAK1") inhibition for immune-mediated brain disorders.
−Removed: Our portfolio of early- and late-stage product candidates also includes discovery research programs focused on TRPM3 channel activation for neuropathic pain, CD-38 antibody recruiting, bispecific molecules for multiple myeloma, antibody drug conjugates ("ADCs"), and extracellular target degrader platform technology ("MoDE") with potential application in neurological disorders, cancer, and autoimmune diseases.
−Removed: We are advancing our broad and diverse pipeline, across early and late stage development, including three Phase 3 clinical programs.
−Removed: We have built a highly experienced team of senior leaders and neuroscience drug developers who combine a nimble, results-driven biotech mindset with capabilities in drug discovery and development.
−Removed: In addition, we have several preclinical assets in our early discovery program, targeting indications in neuroscience and immunology.
+Added: Biohaven is a biopharmaceutical company focused on the discovery, development, and commercialization of life-changing treatments in key therapeutic areas, including immunology, neuroscience, and oncology.
+Added: We are advancing our innovative portfolio of therapeutics, leveraging our proven drug development experience and multiple proprietary drug development platforms.
+Added: Our extensive clinical and preclinical programs include Kv7 ion channel modulation for epilepsy and mood disorders;
+Added: extracellular protein degradation for immunological diseases;
+Added: Transient Receptor Potential Melastatin 3 ("TRPM3") antagonism for migraine and neuropathic pain;
+Added: Tyrosine Kinase 2/Janus Kinase 1 ("TYK2/JAK1") inhibition for neuroinflammatory disorders;
+Added: glutamate modulation for obsessive-compulsive disorder (“OCD”) and spinocerebellar ataxia ("SCA");
+Added: myostatin inhibition for neuromuscular and metabolic diseases, including spinal muscular atrophy ("SMA") and obesity;
+Added: and antibody recruiting, bispecific molecules and antibody drug conjugates ("ADCs") for cancer.
Separation from Biohaven Pharmaceutical Holding Company Ltd.
−Removed: On May 9, 2022, the Board of Directors of Biohaven Pharmaceutical Holding Company Ltd.
−Removed: (the “Former Parent”) approved and directed Former Parent’s management to effect the spin-off of the Kv7 ion channel activators, glutamate modulation and myostatin inhibition platforms, preclinical product candidates, and certain corporate infrastructure then owned by Former Parent, or collectively the “Biohaven Business”.
−Removed: On October 3, 2022, the Former Parent completed the distribution (the “Distribution”) to holders of its common shares of all of the outstanding common shares of Biohaven Ltd.
+Added: On October 3, 2022, Biohaven Pharmaceutical Holding Company Ltd.
+Added: (the “Former Parent”) completed the distribution (the “Distribution”) to holders of its common shares of all of the outstanding common shares of Biohaven Ltd.
and the spin-off of Biohaven Ltd.
from the Former Parent (the “Spin-Off”) described in Biohaven’s Information Statement attached as Exhibit 99.1 to Biohaven’s Registration Statement on Form 10, as amended (Reg.
−Removed: 001-41477), which was declared effective by the Securities and Exchange Commission ("SEC") on September 22, 2022 (the “Form 10”).
−Removed: Each holder of Former Parent common shares received one common share of Biohaven for every two of the Former Parent common shares held of record as of the close of business on September 26, 2022.
−Removed: To implement the Spin-Off, the Former Parent transferred the related license agreements, intellectual property and the Former Parent’s corporate infrastructure, including certain non-commercial employee agreements, share-based awards and other corporate agreements to Biohaven Ltd.
Collectively, we refer to the Distribution and Spin-Off throughout this Annual Report on Form 10-K as the "Separation." As a result of the Separation, Biohaven Ltd.
−Removed: is an independent, publicly traded company, effective as of October 3, 2022, and commenced regular way trading under the symbol “BHVN”’ on the New York Stock Exchange ("NYSE") on October 4, 2022.
−Removed: Where we describe historical business activities in this report, we do so as if Former Parent’s activities related to such assets and liabilities had been performed by the Company.
+Added: became an independent, publicly traded company as of October 3, 2022, and commenced regular way trading under the symbol “BHVN”’ on the New York Stock Exchange (the "NYSE") on October 4, 2022.
+Added: Where we describe historical business activities in this report, we do so as if the Former Parent’s activities related to such assets and liabilities had been performed by the Company.
Product Candidates
−Removed: The following table summarizes some of our key clinical programs in addition to upcoming clinical development milestones for our product candidates.
−Removed: We hold the worldwide rights to all of our product candidates.
−Removed: Kv7 Platform Acquisition
−Removed: In February 2022, we announced that we entered into a definitive agreement with Channel Biosciences, LLC, a subsidiary of Knopp Biosciences, LLC, to acquire a drug discovery platform targeting Kv7 ion channels, adding the latest advances in ion channel modulation to our growing neuroscience portfolio.
−Removed: BHV-7000 (formerly known as KB-3061), the lead asset from the Kv7 platform is an activator of Kv7.2/Kv7.3, a key ion channel involved in neuronal signaling and in regulating the hyperexcitable state in epilepsy.
−Removed: In the second quarter of 2022, our Clinical Trial Application for BHV-7000 was approved by Health Canada, and we subsequently began phase 1 clinical development, including a SAD/MAD study.
−Removed: The Company is evaluating and has not yet finalized potential future clinical trial designs, including trial size, and primary and secondary endpoints and expects to initiate an EEG study in the first half of 2023 and expects to initiate phase 2/3 studies in focal epilepsy patients and bipolar disorder patients in the second half of 2023.
−Removed: Kv7’s Role in Epilepsy and Other Central Nervous System Disorders
−Removed: Because of their fundamental role in health and their aberrant role in disease, ion channels in cell membranes represent a broad and important class of drug targets.
−Removed: Sodium channels and potassium channels form the ionic basis of the action potential in electrically charged cells throughout the body (see figures below).
−Removed: The Kv7 protein in particular forms a channel that exquisitely regulates the flow of charged potassium ions (K+) across cell membranes, repolarizing nerve cells and resetting them for normal action potential firing.
−Removed: Kv7 channels include a family of channel subtypes, designated as Kv7.1 through Kv7.5, and they are formed by tetramers of identical or compatible subunits.
−Removed: Some of these channel subtypes localize in nerve cells (neurons) while others can be found in cardiac muscle, smooth muscle, and other tissue types.
−Removed: The Kv7 subunits, Kv7.2 and Kv7.3, are widely expressed in the brain, notably in the cortex and hippocampus, and together they form Kv7.2/7.3 heteromeric channels that produce the M-current ( I KM ), a critical regulator of neuronal excitability (see figures below).
−Removed: Kv7.2/7.3 channels normally perform a natural “braking” function by regulating the electrical excitability and hyperexcitability of brain cells.
−Removed: Dysfunction of these channels, due to genetic mutations or other factors, increases seizure risk, while augmenting the ‘open’ activity of these channels has been demonstrated to reduce
−Removed: neuronal hyperexcitability and seizure frequency in electrophysiology laboratories, in animal models, and, most importantly, in patients.
−Removed: White, Role of Potassium Channel Ions in Epilepsy, Medscape.org
−Removed: We are synthesizing novel Kv7.2/7.3 activators that improve on the selectivity, potency, and other characteristics of ezogabine (Potiga in the U.S.
−Removed: and Trobalt (retigabine) in Europe), a drug approved in 2011 for the treatment of refractory epilepsy and voluntarily withdrawn from the market in 2017 because of poor tolerability and structure-related toxicities that limited its use, and ezogabine-like compounds while averting its negative attributes, including off-target activity at a different brain ion channel, gamma-aminobutyric acid (“GABA”) A receptor (“GABA A -R”).
−Removed: Using a structure-based approach, supplemented by in silico modeling, we have identified structural features of our molecules critical to Kv7 activation.
−Removed: We have applied these analyses to the generation of proprietary chemical leads structurally distinct from known Kv7 activators, including ezogabine and flupirtine, the only other approved Kv7 modulator, approved in Europe for the treatment of acute pain.
−Removed: Our team has synthesized a large library of Kv7-activating molecules and are advancing them according to stringent criteria requiring improvements over ezogabine, including chemical stability, synthetic tractability, the avoidance of structural motifs associated with the generation of reactive metabolites and other unwanted, off-target activity, including GABA A -R activation.
−Removed: Epilepsy is the initial disease we are targeting with activators from our Kv7 platform.
−Removed: Epilepsy affects approximately 3.5 million Americans, or more than 1.2% of adults and 0.6% of children in the U.S., and more than 50 million patients worldwide, according to the World Health Organization (“WHO”).
−Removed: It is the fourth most common neurological disorder, and many patients struggle to achieve freedom from seizures, with more than one third of patients requiring two or more medications to manage their epilepsy.
−Removed: While the use of anti-seizure medications is often accompanied by dose-limiting side effects, our clinical candidate BHV-7000 is specifically designed to target subtypes of Kv7 potassium channels without engagement of GABA A receptors.
−Removed: The lack of GABA A -R activity potentially gives BHV-7000 a wide therapeutic window and is expected to result in an improved side effect profile, limiting the somnolence and fatigue often seen in patients receiving anti-seizure medications.
−Removed: This preclinical profile is supported by preliminary safety data from our Phase 1 SAD/MAD trial of BHV-7000 in healthy volunteers, which showed a favorable CNS tolerability profile.
−Removed: By adding BHV-7000 to our pipeline, we aim to bring this potassium channel modulator as a potential solution to patients with epilepsy who remain uncontrolled on their current regimens.
−Removed: BHV-7000 is a Kv7.2/7.3 channel activator from a novel, bicyclic imidazole class with significant in vivo anticonvulsant activity and a wide therapeutic index.
−Removed: In the most widely used and positively-predictive preclinical model of epilepsy, the maximal electroshock (“MES”) model, data for BHV-7000 and ezogabine were collected in independent experiments (see figures below), measuring the activity of both compounds in preventing seizures (ED50) and recording the neurologic deficit five minutes prior to the MES test to calculate the tolerability index (“TI”).
−Removed: The neurologic deficit is a behavioral index ranging from normal activity (score of 0) to a loss of righting reflex (score of 3).
−Removed: As shown below, BHV-7000 was demonstrated to have an ED50 = 0.5 mg/kg with almost no impact on behavior producing a TI > 40x.
−Removed: In contrast, ezogabine was 40x less potent (ED50 = 20 mg/kg) in the MES model with a narrow TI < 3x.
−Removed: The narrow preclinical TI for ezogabine is consistent with the clinical experience with the drug where side effects such as somnolence and dizziness limited its use at doses that prevented seizures in patients.
−Removed: KCNQ2 Epileptic Encephalopathy
−Removed: KCNQ2 epileptic encephalopathy (“KCNQ2-EE”) is a rare pediatric epileptic encephalopathy first described in 2012 resulting from dominant-negative mutations in the KCNQ2 gene.
−Removed: Epileptic encephalopathies (“EE”) comprise a group of epilepsy syndromes in which onset of recurrent and medically refractory seizures are associated with cognitive and broader developmental delay or regression.
−Removed: Early infantile epileptic encephalopathy, also called Ohtahara syndrome, and early myoclonic encephalopathy are the earliest-presenting of these age-dependent syndromes, clinically defined by onset within the first three months after birth.
−Removed: Although only recently described, heterozygous de novo variants in KCNQ2 are a highly validated cause of early onset epileptic encephalopathy, and KCNQ2-EE has emerged as a well-defined clinical entity with a characteristic neonatal presentation, including hypotonia, treatment-resistant tonic seizures, a profoundly abnormal interictal electroencephalogram (“EEG”) with prominent burst-suppression, and most often with moderate-to-profound global developmental delay, resulting from a defined subset of missense variants in the gene.
−Removed: KCNQ2-EE is thus both a seizure disorder and a developmental disorder caused by pathogenic, dominant-negative KCNQ2 mutations.
−Removed: Identification of genetic etiologies has created the opportunity to treat not just the symptoms of KCNQ2-EE, including seizures, but also the underlying causes, including attenuating or reversing the effects of the dominant-negative variants responsible for KCNQ2-EE.
−Removed: Developmental delay is an intractable feature of KCNQ2-EE even though seizure frequency tends to diminish after infancy and EEG organization tends to improve.
−Removed: Importantly, limited clinical evidence, including a case series of four infants with KCNQ2-EE, suggests that pharmacological augmentation of reduced Kv7.2 channel current with ezogabine reduces seizures and may improve developmental milestone attainment.
−Removed: Severe pathogenic KCNQ2 mutations disrupt the function of the KCNQ2 gene product, Kv7.2, a voltage-gated potassium channel subunit which, in addition to being a critical regulator of neuronal excitability, plays a fundamental role in early brain development.
−Removed: Kv7.2 polypeptides are co-assembled in either homotetrameric channels, or, in combination with Kv7.3 subunits, to form heterotetrameric channels.
−Removed: Both subunit configurations contribute to IKM.
−Removed: Significant reduction of Kv7.2/7.2 activity or Kv7.2/7.3 activity with loss of 50% of more of current density through these channels abrogate these functions, leading to neuronal hyperexcitability and impaired brain development.
−Removed: In addition to its activity in the MES model, we explored the ability of BHV-7000 to reverse the reduced current density associated with KCNQ2-EE and support its use as potential treatment for the disease.
−Removed: Most encephalopathy-associated pathogenic KCNQ2 variants identified to date disrupt channel function in any of four distinct “hot spots” of the protein, including the S4 voltage sensor, the ion channel pore, and the proximal and distal regions of the C-terminal domain (see figure below).
−Removed: Millichap, Neurol Genet (2016)
−Removed: To determine the effects of BHV-7000 on the function of Kv7.2 and Kv7.2/7.3 channels poisoned by dominant-negative KCNQ2 mutations, four highly recurrent human missense variants representative of the “hot spot” domains were introduced into KCNQ2 cDNA by site-directed mutagenesis.
−Removed: Using lipid-mediated transfection, plasmids including the pathogenic variants were co-expressed with wild-type (“wt”) KCNQ2 subunits or wt KCNQ2 and wt KCNQ3 subunits in Chinese hamster ovary cells.
−Removed: The figure below shows the effects of BHV-7000 on current density of wt/wt Kv7.2 channels and those formed by 1:1 coexpression of wt KCNQ2 genes with either of two KCNQ2 pore domain variants (T274M, A294V), a C-terminal variant (R581L), or a voltage-sensing variant (R210H).
−Removed: In the control condition, all pathogenic variants produced a marked reduction in current density to below wt/wt levels.
−Removed: BHV-7000 at 0.3µM restored current density in mutated pore and C-terminal channels to or beyond wt control current density (**<0.01).
−Removed: Similarly, application of BHV-7000 at 1 µM restores function to mutated channels expressing the R210H KCNQ2 S4 voltage sensor domain pathogenic variant in the heterotetrameric (wt/R210H) configuration, to above wt/wt levels of activation.
−Removed: BHV-7000 has been granted Rare Pediatric Disease Designation by the U.S.
−Removed: Food and Drug Administration ("FDA") for the treatment of KCNQ2-EE.
−Removed: Neuropathic Pain
−Removed: Neuropathic pain, as defined by the International Association for the Study of Pain, is pain caused by a lesion or disease of the somatosensory nervous system and includes a collection of heterogeneous conditions that are often chronic and debilitating and for which long term therapy is difficult.
−Removed: In the United States, over 30 million adults are estimated to be living with neuropathic pain.
−Removed: Pharmacological treatments for neuropathic pain vary according to patient needs, although recommendations such as the WHO analgesic ladder, United States Centers for Disease Control (“CDC”), and FDA guidelines are in use.
−Removed: Initial or first line treatment for neuropathic pain includes non-opioid analgesics, in particular, antidepressants, anticonvulsants, steroids, and anxiolytics.
−Removed: Second line treatment of persistent, severe pain
−Removed: may require escalation to opiates, often less potent ones at first, followed by more potent opiates for intense refractory pain.
−Removed: Thus, an urgent need exists for effective, non-addictive pain therapies.
−Removed: Flupirtine, a non-selective Kv7 activator, was previously approved in several European countries and indicated for the treatment of pain.
−Removed: However, the European Medicines Agency recommended withdrawal of its marketing authorization in 2018 because of the risk of serious liver injury.
−Removed: Selective Kv7 potassium channel activators represent a new approach in the development of non-opioid therapeutic options for neuropathic pain.
−Removed: In addition to leveraging reduced abuse and addiction risk potential of potassium channel activators, our Kv7 potassium channel platform addresses the complexities of channel subtype physiology through targeted pharmacology to overcome the limitations inherent in unbiased Kv7 activators and is intended to deliver a well-tolerated, highly effective, non-opioid treatment for neuropathic pain.
−Removed: Our Kv7 program research was supported in part with funding from the National Institutes of Health (“NIH”) to advance the development of novel Kv7 non-opioid therapies for the treatment of chronic pain.
−Removed: The NIH funding is by the NIH Helping to End Addiction Long-term Initiative (“NIH HEAL Initiative”), which aims to improve treatments for chronic pain, curb the rates of opioid use disorder and overdose, and achieve long-term recovery from opioid addiction.The goal of our Kv7 program is to discover a small-molecule activator of the Kv7.2/7.3 voltage-gated potassium channel to treat neuropathic pain.
−Removed: Similar to our epilepsy program, we are targeting compounds with these characteristics:
−Removed: • Biased for Kv7.2/3 activation vs.
−Removed: Kv7.4 activation to minimize potential adverse smooth muscle effects
−Removed: • Selective against GABA A receptors to minimize potential tolerability issues
−Removed: • Selective against Kv7.1/KCNE1 (IKs) and hERG (IKr) to minimize cardiac side-effects
−Removed: • Potent and effective across animal models of neuropathic pain
−Removed: A fundamental program hypothesis is that creating Kv7.2/3 activators with minimal activation of Kv7.4 and GABA A receptors will greatly improve the tolerability profile of a successful candidate compound.
−Removed: Ezogabine has known effects on the GABA system, both directly as a GABA A positive allosteric modulator, and indirectly by affecting GABA synthesis or metabolism, a pharmacology consistent with the dose-related increases in somnolence and dizziness reported in ezogabine clinical trials.
−Removed: Our program is directed to reducing this potential source of poor tolerability by selecting compounds with no or minimal activity for the GABA A receptor.
−Removed: Axonal excitability and neurotransmitter release are altered in neuropathic pain due to sodium channel plasticity, increased voltage-gated calcium channels in the spinal cord, and diminished potassium channel activity in dorsal root ganglion (“DRG”) neurons.
−Removed: These changes in ion channel number, distribution, and function are common to many neuropathic pain subtypes.
−Removed: The functional density of Kv7.2/3 channels is a key variable governing sensory DRG control of intrinsic excitability.
−Removed: There are some reports that demonstrate downregulation of Kv7 potassium channel mRNA, protein and function in experimental neuropathic pain models.
−Removed: Using human induced pluripotent stem cell (“iPSC”)-derived DRG sensory neurons, we have assessed the physiological activity of these neurons by modulating Kv7 channels across three electrophysiologic parameters:
−Removed: resting membrane potential (Vm), rheobase = the current required to stimulate an action potential (“AP”), and the number of APs elicited by a suprathreshold stimulus (3x rheobase).
−Removed: We are currently evaluating the activity of various compounds from our proprietary series of selective Kv7.2/7.3 activators in multiple preclinical models of neuropathic pain.
−Removed: Mood disorders
−Removed: Approximately 1 in 5 adults in the U.S.
−Removed: are living with neuropsychiatric illnesses that are, in turn, associated with inadequate treatment, poor quality of life, disability, and considerable direct and indirect costs.
−Removed: There is significant unmet need for novel and effective therapeutic options that are not limited by long latency periods to clinical effects, low response rates, and significant risks and side effects.
−Removed: Increasing evidence from animal models and clinical trials now suggests that Kv7.2/7.3 targeting drugs offer the potential to treat a spectrum of these neuropsychiatric diseases including, but not limited to, mood disorders such as major depressive disorder, bipolar disorder and anxiety.
−Removed: Bipolar disorder is the initial mood disorder that we intend to target with activators from our Kv7 platform.
−Removed: Bipolar disorder affects approximately 7-11 million Americans, with an estimated 4.4% of US adults having bipolar disorder over their lifetime.
−Removed: Bipolar disorder is associated with significant morbidity, decreased quality of life and economic burden.
−Removed: Treatment guidelines recommend patients receive life-long treatment for bipolar disorder.
−Removed: However, medication adherence is typically very low in this population, due in large part to undesirable side effects that are poorly tolerated by patients.
−Removed: The mainstays of treatment include mood stabilizing agents that are also used as anti-seizure medicines (i.e., valproic acid, lamotrigine, and topiramate).
−Removed: Preclinical and pilot clinical data similarly suggest a potential therapeutic role for Kv7 activation in bipolar disorder, which is expected to result in an improved side effect profile compared to other anti-
−Removed: seizure medications.
−Removed: We plan to advance BHV-7000 as a potential treatment for patients with bipolar disorder and intend to start a clinical trial targeting this indication by the end of 2023.
−Removed: BHV-7010 is being developed as a next generation Kv7.2/7.3 activator with improved selectivity over Kv7.4 and differentiated absorption, distribution, metabolism, and excretion ("ADME") properties that provide flexibility for the treatment of different neurological diseases.
−Removed: The IND is expected to be submitted in the second half of 2023.
−Removed: Agreement with Hangzhou Highlightll Pharmaceutical Co.
−Removed: In March 2023, we entered into an exclusive, worldwide (excluding People’s Republic of China and its territories and possessions) license agreement with Hangzhou Highlightll Pharmaceutical Co.
−Removed: ("Highlightll") (the "Highlightll Agreement"), whereby we obtained the right to research, develop, manufacture and commercialize Highlightll’s brain penetrant dual TYK2/JAK1 inhibitor program.
−Removed: Refer to 15, "Subsequent Events," of the Notes to the Consolidated Financial Statements appearing elsewhere in this Annual Report on Form 10-K for further discussion of the Highlightll Agreement.
−Removed: Dysregulation of the immune system has been implicated in several neurodegenerative and neuroinflammatory disorders including Parkinson's Disease, Multiple Sclerosis, Alzheimer's Disease, Amyotrophic Lateral Sclerosis and Autoimmune Encephalitis.
−Removed: Over-active immune cells and microglia driving chronic neuroinflammation results in release of cytokines with activation of leukocytes and is thought to contribute to neuronal injury, death, gliosis, and demyelination.
−Removed: The tyrosine kinase 2 ("TYK2") and janus jinase 1 ("JAK1") signal transduction pathways mediate highly complementary immune and inflammatory signaling events.
−Removed: Targeted, small-molecule therapies that inhibit TYK2 or JAK kinases have separately demonstrated robust efficacy in autoimmune, dermatologic and gastrointestinal disorders.
−Removed: TYK2 is a validated immune target as evidenced by a recent peripheral program that gained FDA approval, and there are multiple additional peripheral non-CNS programs in clinical development.
−Removed: Brain penetrant inhibitors of TYK2/JAK1 have the potential to bring this validated immune target to brain disorders.
−Removed: There are currently no brain penetrant, selective, dual TYK2/JAK1 inhibitors approved for brain disorders.
−Removed: We expect to advance BHV-8000 (previously TLL-041) into a Phase 1 study in 2023.
−Removed: The Company is evaluating and has not yet finalized potential clinical trial designs, including trial size, and primary and secondary endpoints.
−Removed: The most advanced product candidate from our glutamate receptor antagonist platform is troriluzole (previously referred to as trigriluzole and BHV-4157), which is in two Phase 3 trials in OCD.
−Removed: Other product candidates include BHV-5500, which is an antagonist of the glutamate N-methyl-D-aspartate (“NMDA”) receptor.
+Added: The following table summarizes our programs for our product candidates.
+Added: We hold the worldwide rights to substantially all of our product candidates.
+Added: Glutamate Modulation Platform
+Added: The most advanced product candidate from our glutamate receptor antagonist platform is troriluzole (previously referred to as trigriluzole and BHV-4157), which is currently in two Phase 3 trials in OCD and, for which the Company
+Added: submitted a new drug application (“NDA”) in Spinocerebellar Ataxia Type 3 (“SCA3”) to the U.S.
+Added: FDA and marketing authorisation application ("MAA") to the European Medicines Agency ("EMA").
+Added: Troriluzole is also being evaluated by the Global Coalition for Adaptive Research ("GCAR") as part of Glioblastoma Adaptive Global Innovative Learning Environment - NCT03970447 ("GBM AGILE"), a revolutionary patient-centered, adaptive platform trial for registration that tests multiple therapies for patients with newly-diagnosed and recurrent glioblastoma ("GBM").
+Added: Other product candidates include BHV-5500, which is an antagonist of the glutamate N-methyl-D-aspartate (“NMDA”) receptor and its oral prodrug BHV-5000.
Glutamate is an important neurotransmitter present in over 90% of all brain synapses.
10 unchanged sentences
The figure below depicts the areas of modulation that are affected by our product candidates.
−Removed: (1) As depicted in the glial cell to the right in the figure below, troriluzole increases the activity and expression of the EAATs to increase the clearance of glutamate released from the pre-synaptic neuron.
−Removed: Troriluzole also inhibits presynaptic ion channels that may inhibit the release of glutamate from presynaptic neurons.
−Removed: (2) As depicted in the postsynaptic neuron to the bottom of the figure below, BHV-5500 blocks glutamate signaling that is mediated by post-synaptic NMDA receptors.
−Removed: Modulating glutamate also has the potential to be neuroprotective and increase the release of neurotrophic factors, including brain derived neurotrophic factor (“BDNF”) which are endogenous molecules that help to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses.
Adapted from Glutamate abnormalities in obsessive compulsive disorder:
1 unchanged sentence
Bloch, and K.
+Added: (1) As depicted in the glial cell to the right in the figure, troriluzole increases the activity and expression of the EAATs to increase the clearance of glutamate released from the pre-synaptic neuron.
+Added: Troriluzole also inhibits presynaptic ion channels that may inhibit the release of glutamate from presynaptic neurons.
+Added: (2) As depicted in the postsynaptic neuron to the bottom of the figure, BHV-5500 blocks glutamate signaling that is mediated by post-synaptic NMDA receptors.
+Added: Modulating glutamate also has the potential to be neuroprotective and increase the release of neurotrophic factors, including brain derived neurotrophic factor (“BDNF”) which are endogenous molecules that help to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses.
Glutamate Transporter Modulation
15 unchanged sentences
Romano et al.
−Removed: described results of a second randomized, placebo-controlled trial subjects diagnosed with a hereditary ataxia (including SCAs) randomized to receive 12 months of treatment with either placebo or riluzole (50 mg, twice daily).
+Added: described results of a second randomized, placebo-controlled trial in subjects diagnosed with a hereditary ataxia (including SCAs) randomized to receive 12 months of treatment with either placebo or riluzole (50 mg, twice daily).
60 patients were randomized.
6 unchanged sentences
Once inside the body, the prodrug, troriluzole is cleaved by enzymes in the blood to the parent, riluzole.
−Removed: To mitigate the limitations of riluzole,
−Removed: several classes of prodrugs were designed, synthesized, and evaluated in multiple in vitro stability assays that predict in vivo drug levels.
+Added: To mitigate the limitations of riluzole, several classes of prodrugs were designed, synthesized, and evaluated in multiple in vitro stability assays that predict in vivo drug levels.
Troriluzole is a third generation of prodrug development and the product of six years of intensive chemistry efforts.
11 unchanged sentences
Troriluzole is chemically comprised of riluzole linked via an amide bond to a tripeptide that is a substrate for PepT1 and which contributes to its improved bioavailability.
−Removed: The tripeptide moiety is cleaved by plasma aminopeptidases, releasing riluzole and naturally occurring amino acids, which we believe are readily managed by endogenous metabolic routes.
+Added: The tripeptide moiety is cleaved by plasma aminopeptidases.
We believe that the estate of compounds we acquired, combined with our internally developed intellectual property, will provide a significant protection for our innovations.
−Removed: Troriluzole is stable in fluids from the gastrointestinal tract and expected to have a differentiated profile with regard to any liability for hepatic effects.
+Added: The safety and tolerability of troriluzole has now been demonstrated in approximately 2000 subjects in early- and late-stage clinical studies.
Our Clinical Program for Troriluzole
12 unchanged sentences
The commercial formulation was well-tolerated and provided bioequivalent exposure with the Phase 2/3 formulation.
+Added: Troriluzole for SCA
+Added: Spinocerebellar Ataxias ("SCAs") are a group of ultra-rare, dominantly inherited neurodegenerative disorders predominantly characterized by atrophy of the cerebellum, brainstem, and spinal cord.
+Added: The disease course of SCA is one of relentless progression over years and inevitably leads to clinical deterioration of motor function, gait imbalance with frequent falling, severe speech impairment, swallowing difficulties, and premature death.
+Added: SCAs are thought to be pathogenetically related but disease course and brain region involvement are known to vary between the different genotypes.
+Added: SCA3, also known as Machado-Joseph disease, is the most common genotype, with a prevalence of up to 6,000 in North America and 4,600 in the European Union (“EU”) and Japan, and accounts for approximately 30% to 50% of SCAs worldwide.
+Added: Currently, there are no approved symptomatic or neuroprotective treatments for SCA.
+Added: Based on the results of our Phase 1 trial with troriluzole and two third-party academic trials (Ristori et al 2020, published in Neurology in 2010 and Romano et al 2015, published in The Lancet in 2015) that have shown preliminary efficacy of riluzole in cerebellar ataxias, we advanced troriluzole into development for SCA.
+Added: Initially, we conducted a Phase 2b/3, randomized, double-blind, placebo-controlled, parallel-group study to assess the safety and efficacy of troriluzole over 8 weeks in subjects with SCA (Study BHV4157-201).
+Added: In October 2017, we announced that troriluzole at a dose of 140 mg once daily (“QD”) did not differentiate from placebo on the primary endpoint of the mean change from baseline on the SARA total score after 8 weeks of treatment.
+Added: After eight weeks of treatment, troriluzole treated subjects (n = 64) demonstrated an improvement of –0.81 points [95% CI:
+Added: –1.4 to –0.2] on the SARA versus –1.05 points [95% CI:
+Added: –1.6 to –0.4] improvement in placebo-treated (n = 68), p-value = 0.52.
+Added: In this trial, we observed a favorable safety and tolerability profile of troriluzole, with no drug-related serious adverse events (“SAEs”) and low discontinuation rates due to AEs.
+Added: During open-label treatment over the open-label extension phase, however, troriluzole did show slowing of disease progression in troriluzole-treated subjects in contrast to the measurable decline expected as compared to a matched cohort of untreated patients from the US natural history study (Clinical Research Consortium for Spinocerebellar Ataxias (“CRC-SCA”)).
+Added: Based on our learnings from the proof of concept Study BHV4157-201, including analyses from the open-label extension phase, we advanced troriluzole into a pivotal Phase 3, randomized, double-blind, placebo-controlled, parallel-group study to assess the safety and efficacy of troriluzole over 48 weeks in subjects with SCA (Study BHV4157-206).
+Added: Randomization was stratified by genotype (consisting of these three groupings:
+Added: SCA1 and SCA2;
+Added: and SCA6, SCA7, SCA8, and SCA10) in order to ensure balance within each of these subgroups.
+Added: We enriched this trial with specific SCA genotypes, extended the treatment period of this trial to 48 weeks, implemented the use of a modified SARA scale (“f-SARA”), and increased the dose of troriluzole to 200 mg QD.
+Added: Notably, the f-SARA is a novel, 16-point scale developed in collaboration with FDA and key opinion leaders as the primary outcome measure for this trial;
+Added: the scale was designed to limit subjectivity of the scale and focus on functional aspects of the disease so that significant changes would reflect a clinically meaningful change in function.
+Added: In May 2022, the Company announced top-line results from the Phase 3 clinical trial evaluating the efficacy and safety of its investigational therapy, troriluzole, in adult patients with SCA.
+Added: The primary endpoint, change from baseline to week 48 on the f-SARA, did not reach statistical significance in the overall SCA population as there was less than expected disease progression in the placebo arm over the course of the study.
+Added: In the overall study population (n = 213), the troriluzole and placebo groups each had mean baseline scores of 4.9 on the f-SARA and the two groups showed minimal change at the 48-week endpoint with f-SARA scores of 5.1 and 5.2, respectively (p=0.76).
+Added: Preliminary post hoc analysis of
+Added: efficacy measures by genotype suggested a treatment effect in patients with the SCA3 genotype.
+Added: A risk reduction in falls was also observed in the SCA3 population, as well as across all SCA genotypes .
+Added: Troriluzole was well tolerated with an adverse event profile similar to placebo.
+Added: In May 2023, the Company presented further analysis of Study BHV4157-206 (summarized in the figure below) by prespecified genotype strata that revealed consistent treatment effects of troriluzole in SCA3, the most common genotype worldwide, which represented 41% of study participants.
+Added: In SCA3 subjects, troriluzole 200mg QD demonstrated benefit on the f-SARA compared with placebo at 48 weeks (LS mean treatment difference = -0.56;
+Added: 95% CI = -1.11, -0.01;
+Added: This genotype analysis was post hoc as the All SCA study population (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA 10) was the mITT population for the primary analysis.
+Added: Results for the SCA3 group are based on a model with no covariates with fixed effects for treatment, visit, and visit-by-treatment interaction;
+Added: p-values are descriptive.
+Added: In addition to the beneficial effects observed on the f-SARA, the forest plot below demonstrates a consistent treatment benefit of troriluzole in SCA3 genotype subjects across multiple prespecified primary, secondary, and
+Added: exploratory study outcome measures.
+Added: The SCA3 genotype analysis of the clinician- and patient-rated endpoints in the table represent all of the prespecified endpoints in the study protocol.
+Added: As shown in the figure below, safety data from Study BHV4157-206 showed that troriluzole-treated subjects showed a substantial risk reduction in falls in the All SCA and SCA3 genotype study populations.
+Added: Treatment with troriluzole for 48 weeks reduced the risk of fall events by approximately 53% in subjects in the overall (All SCA) population (p = 0.005), by approximately 54% in subjects in the SCA3 population (p = 0.023), and by approximately 68% in subjects with SCA3 who were ambulatory (i.e., baseline Gait 1 or 2) (p = 0.009).
+Added: This analysis, demonstrating that subjects who were more ambulatory with less severe disease at baseline were more likely to show a benefit from troriluzole, is consistent with the early treatment paradigm for other neurodegenerative diseases.
+Added: Two independent natural history cohorts for SCA, one in the US (CRC-SCA) and one in Europe (EUROSCA), have characterized disease progression in this genetically defined neurodegenerative disorder.
+Added: A Matching Adjusted Indirect Comparison (“MAIC”) was performed to match natural history subjects to subjects in BHV4157-206.
+Added: As demonstrated in the figure below, at years 1, 2, and 3 change from baseline in f-SARA scores was significantly better among troriluzole patients vs the matched natural history referent (combined CRC-SCA and cross-European registry of SCA patients
+Added: (“EUROSCA”) data - all p values ~0.0004).
+Added: These results were consistent for both SCA3 only and All SCA analyses.
+Added: Validation metrics from f-SARA confirm that these changes are clinically relevant and meaningful to patients.
+Added: As seen in the figure below, an additional comparative study was conducted using OLE data from up to 3 years with subjects from BHV4157-201.
+Added: Using a matched control pooled from the same two independent natural history studies (US and European), troriluzole-treated All SCA subjects showed clinically relevant benefit compared to expected progression from the external control at 1 year, 2 years, and 3 years.
+Added: Of note, there was an administrative gap in treatment in BHV4157-201 between the end of the 48-week OLE and the resumption of treatment at the start of the 96-week period.
+Added: This gap was observed to result in a decline in f-SARA scores.
+Added: However, after resumption of treatment patients re-stabilized (did not progress) resulting in the estimation of compelling treatment effects at years 2 and 3.
+Added: Given these findings and the debilitating nature of SCA, in May 2023 we announced that we submitted a New Drug Application ("NDA") to the FDA for troriluzole for the treatment of SCA3.
+Added: In July 2023, the FDA informed us that it would not review the recently submitted NDA application for troriluzole given that the study's primary endpoint was not met and thus, would not permit a substantive review.
+Added: In followup to the regulatory decision on the NDA application, we held followup meetings with the FDA regarding the SCA data.
+Added: We continue to have constructive dialogue with the FDA regarding our SCA development program and potential future data analyses to address regulatory concerns in the previously issued refuse-to-file decision on it's NDA application for SCA3.
+Added: We will provide further updates on the SCA development program as warranted by any continued positive progress from the outcome of future regulatory interactions
+Added: on this topic.
+Added: In October 2023, the European Medicines Agency ("EMA") informed us that our Marketing Authorization Application ("MAA") for troriluzole (Dazluma) in the treatment of SCA has been validated and is now under review by EMA's Committee for Medicinal Products for Human Use ("CHMP").
+Added: We remain committed to working closely with the health authorities to bring troriluzole to people with SCA3, given no therapy is currently approved for this ultra-rare genetic disorder.
Troriluzole for OCD
9 unchanged sentences
A small-scale randomized controlled trial in adults with OCD conducted by a third party showed favorable trends for the use of riluzole in an outpatient setting.
−Removed: Another randomized controlled third-party study demonstrated statistically significant therapeutic effects with the adjunctive use of riluzole as compared to
−Removed: adjunctive placebo in 50 adults with refractory OCD.
+Added: Another randomized controlled third-party study demonstrated statistically significant therapeutic effects with the adjunctive use of riluzole as compared to adjunctive placebo in 50 adults with refractory OCD.
These clinical effects are consistent with findings such as genetic associations of glutamate transporter genes with OCD and increased glutamate concentrations in brain and cerebrospinal fluid of patients with OCD.
5 unchanged sentences
Troriluzole’s safety profile was generally consistent with past clinical trial experience with its active metabolite, riluzole.
−Removed: Treatment emergent adverse events (“TEAE”s) were mostly reported to be mild in intensity.
+Added: Treatment emergent adverse events (“TEAEs”) were mostly reported to be mild in intensity.
TEAEs that occurred in at least 5% of patients in the troriluzole group, and more frequently in the troriluzole group than in the placebo group, were headache, dizziness, fatigue, somnolence, nausea and nasopharyngitis.
Given the strong signal in the Phase 2/3 proof of concept study and after receiving feedback from the FDA in an End of Phase 2 meeting, in December 2020, we initiated enrollment in a Phase 3 program.
−Removed: The Phase 3 program will have an estimated total enrollment of 1,300 participants with a primary endpoint of change from baseline on the Y-BOCS total score at week 4, 8 and 10.
−Removed: The two Phase 3 randomized, double-blind, placebo-controlled trials that make-up our Phase 3 program for OCD are currently ongoing with enrollment expected to be completed in the second half of 2023.
+Added: The Phase 3 program will have an estimated total enrollment of up to 700 participants in each trial with a primary endpoint of change from baseline on the Y-BOCS total score at week 4, 8 and 10.
+Added: The two Phase 3 randomized, double-blind, placebo-controlled trials that make-up our Phase 3 program for OCD are currently ongoing.
+Added: In January 2024, we announced plans to conduct a pre-planned interim analysis ("IA") to evaluate efficacy in the first of our two Phase 3 studies in OCD.
+Added: The IA is planned to be conducted by an independent Data Monitoring Committee, after 350 subjects have had the opportunity to complete the study (representing approximately 70% of subjects in the primary analysis population reach primary endpoint).
+Added: The IA is powered to detect a clinically meaningful difference between troriluzole and placebo on the Y-BOCS primary outcome that is based on the effect size observed in the Phase 2 proof of concept ("POC") study.
+Added: The potential results of the IA include (1) a highly statistically significant evidence of efficacy leading to stopping the study or (2) continuation of the study, with possible sample size re-estimation.
+Added: Last Patient Last Visit and database lock for the IA are anticipated in the first quarter of 2024, with expected IA topline results in the second quarter of 2024.
Troriluzole for Glioblastoma
−Removed: Preclinical and small-scale pilot studies are underway to explore troriluzole’s use in the treatment of a pipeline of other indications such as some cancers whose spread is thought mediated by glutamate transmission, such as melanoma and glioblastoma ("GBM").
+Added: Preclinical and small-scale pilot studies are underway to explore troriluzole’s use in the treatment of a pipeline of other indications such as some cancers whose spread is thought mediated by glutamate transmission, such as melanoma and GBM.
In collaboration with Johns Hopkins University, we explored the potential applicability of troriluzole for GBM.
−Removed: The oncology collaboration Johns Hopkins was based upon the mechanistic rationale that some tumors over express glutamate receptors, the central role that glutamate may have in cancer metabolism and the effect of glutamate on the tumor microenvironment.
−Removed: In December 2021, the Global Coalition for Adaptive Research ("GCAR") selected troriluzole for evaluation in Glioblastoma Adaptive Global Innovative Learning Environment - NCT03970447 ("GBM AGILE").
+Added: The oncology collaboration with Johns Hopkins was based upon the mechanistic rationale that some tumors over express glutamate receptors, the central role that glutamate may have in cancer metabolism and the effect of glutamate on the tumor microenvironment.
+Added: In December 2021, GCAR selected troriluzole for evaluation in GBM AGILE.
GBM AGILE is a revolutionary patient-centered, adaptive platform trial for registration that tests multiple therapies for patients with newly-diagnosed and recurrent GBM, the most fatal form of brain cancer.
17 unchanged sentences
The maximum sample size in Stage 2 is 50 experimental patients in the graduating signature.
−Removed: The primary analysis of a regimen's effect on overall survival (“OS”) uses all patients in both its stages and all control patients in the trial in the graduating signature, suitably adjusted for any possible time trends.
−Removed: Troriluzole for SCA
−Removed: Based on the results of our Phase 1 trial with troriluzole and two third-party academic trials that have shown preliminary efficacy of riluzole in cerebellar ataxias, we advanced troriluzole into a Phase 2/3 clinical trial for SCA.
−Removed: Initially, we had conducted a Phase 2b/3, randomized, double-blind, placebo-controlled, parallel-group study to assess the safety and efficacy of troriluzole over 8 weeks in subjects with SCA.
−Removed: In October 2017, we announced that troriluzole at a dose of 140 mg once daily (“QD”) did not differentiate from placebo on the primary endpoint of the mean change from baseline on the SARA total score after 8 weeks of treatment.
−Removed: After eight weeks of treatment, troriluzole treated subjects (n = 63) demonstrated an improvement of –0.81 points [95% CI:
−Removed: –1.4 to –0.2] on the SARA versus –1.05 points [95% CI:
−Removed: –1.6 to –0.4] improvement in placebo-treated (n = 68), p-value = 0.52.
−Removed: In this trial, we observed a favorable safety and tolerability profile of troriluzole, with no drug-related serious adverse events (“SAEs”) and low discontinuation rates due to AEs.
−Removed: During open-label treatment over the 48-week extension phase, however, troriluzole did show slowing of disease progression in troriluzole-treated subjects in contrast to the measurable decline expected for a cohort of untreated subjects based on the natural history of the disease.
−Removed: Based on our learnings from the Phase 2b/3 study, including analyses from the open-label extension phase, we advanced troriluzole into a Phase 3, randomized, double-blind, placebo-controlled, parallel-group study to assess the safety and efficacy of troriluzole over 48 weeks in subjects with SCA.
−Removed: We enriched this trial with specific SCA genotypes, extended the treatment period of this trial to 48 weeks, implemented the use of a modified SARA scale (“f-SARA”), and increased the dose of troriluzole to 200 mg QD.
−Removed: Notably, the f-SARA is a novel, 16-point scale developed in collaboration with FDA as the primary outcome measure for this trial;
−Removed: the scale was designed to limit subjectivity of the scale and focus on functional aspects of the disease so that significant changes would be considered clinically meaningful.
−Removed: In May 2022, the Company announced top-line results from the Phase 3 clinical trial evaluating the efficacy and safety of its investigational therapy, troriluzole, in adult patients with SCA.
−Removed: The primary endpoint, change from baseline to week 48 on the f-SARA, did not reach statistical significance in the overall SCA population as there was less than expected disease progression over the course of the study.
−Removed: In the overall study population (n = 213), the troriluzole and placebo groups each had mean baseline scores of 4.9 on the f-SARA and the two groups showed minimal change at the 48-week endpoint with f-SARA scores of 5.1 and 5.2, respectively (p=0.76).
−Removed: Troriluzole was well tolerated with an adverse event profile similar to placebo.
−Removed: The frequency of subjects with any TEAE was 80.6% for troriluzole vs.
−Removed: 84.4% for placebo and the frequency of subjects with serious TEAEs was 5.6% for troriluzole vs.
−Removed: 7.3% for placebo.
−Removed: Post-hoc analysis of efficacy measures by genotype suggests a treatment effect in patients with the SCA Type 3 (“SCA3”) genotype, which represents the most common form of SCA and accounted for 41% of the study population.
−Removed: In the SCA3 subgroup, troriluzole showed a numerical treatment benefit on the change in f-SARA score from baseline to week 48 compared to placebo (least squares (“LS”) mean change difference -0.55, nominal p-value = 0.053, 95% CI:
−Removed: -1.12, 0.01).
−Removed: SCA patients treated with troriluzole showed minimal disease progression over the study period.
−Removed: Further, in patients in the SCA3 subgroup who were able to walk without assistance at baseline (i.e., f-SARA Gait Item score = 1), troriluzole demonstrated a greater numerical treatment benefit on the change in f-SARA score from baseline to week 48 compared to placebo (LS mean change difference -0.71, nominal p-value = 0.031, 95% CI:
−Removed: -1.36, -0.07).
−Removed: Across all genotypes, patients who were able to ambulate at baseline (i.e., f-SARA Gait Item score = 1) showed a reduction in the relative risk of falls in troriluzole-treated patients versus placebo.
−Removed: Patient reported falls, as measured by adverse events reveal an approximately 58% reduction of fall risk in the troriluzole group (10% versus 23% AE incidence of falls in the troriluzole and placebo groups, respectively;
−Removed: nominal p=0.043).
−Removed: The risk reduction of falls in the troriluzole group combined with the progression of f-SARA scores in the untreated SCA3 group compared to SCA3 patients on troriluzole demonstrates that SCA3 patients experienced a clinically meaningful improvement in ataxia symptoms on troriluzole treatment.
−Removed: Given these findings and the debilitating nature of SCA, we intend to interact with the FDA and or European Medicines Agency ("EMA") in the first half of 2023.
−Removed: We have not yet decided on the format of such a regulatory interaction but we could seek advice through various formal or informal interactions with regulatory agencies or we could choose to submit an NDA if we believe that is warranted from the results of our ongoing post-hoc analyses.
−Removed: There are currently no FDA-approved medications for the treatment of SCA or any other cerebellar ataxia, and treatment is supportive.
−Removed: In general, multidisciplinary care provides supportive measures and the goal of this treatment is to improve quality of life and survival.
−Removed: Glutamate NMDA Receptor Antagonism and BHV-5500 for Neuropathic Pain
−Removed: An NMDA receptor antagonist is a type of glutamate antagonist that works to inhibit the action of NMDA receptors which may play a role in various diseases that affect the brain.
−Removed: BHV-5500 (lanicemine) was in-licensed from AstraZeneca and is a low-trapping, NMDA receptor antagonist with differentiating pharmacologic properties from other agents in development targeting this receptor.
−Removed: The unique property of low-trapping antagonists is their ability to uncouple from the NMDA receptor more freely than other agents, a property that is thought to contribute to their mitigated risk of dissociative effects as has been observed in the clinic.
−Removed: Lanicemine, binds within the NMDA channel pore and functionally blocks the flow of charged ions through the NMDA receptor complex.
−Removed: Neuropathic pain is a chronic condition caused by dysfunctional or damaged nerves.
−Removed: Neuropathic pain can be a debilitating and common problem affecting approximately 10% of adults in the United States.
−Removed: Despite the availability of multiple approved drugs, including Lyrica, and guidelines for the treatment of neuropathic pain, treatment of this condition remains a major therapeutic challenge.
−Removed: Existing analgesics are often ineffective, can cause serious side effects and have abuse potential that limits widespread use.
−Removed: Increased NMDA receptor activity is known to contribute to central sensitization in neuropathic pain.
−Removed: NMDA receptor antagonists have been shown to reduce hyperalgesia and pain in animal models of neuropathic pain induced by nerve injury and diabetic neuropathy.
−Removed: Clinically used NMDA receptor antagonists, including ketamine and dextromethorphan, can be effective in patients suffering from neuropathic pain syndromes.
−Removed: The clinical use of robust NMDA antagonists, such as ketamine, is limited due to dissociative, psychotomimetic and abuse potential properties.
−Removed: Novel NMDA receptor antagonists, such as BHV-5500, that are not associated with the psychotomimetic effects and abuse potential could lead to better management of neuropathic pain without causing serious side effects.
−Removed: Verdiperstat is a selective, brain-permeable, irreversible myeloperoxidase (“MPO”) enzyme inhibitor that may have potential for the treatment of neurological diseases.
−Removed: MPO generates an array of cytotoxic oxidants and is a key driver of oxidative and inflammatory processes that underlie a broad range of disorders.
−Removed: MPO plays a key role in neurodegenerative, inflammatory, and immune-mediated diseases, including multiple system atrophy (“MSA”), Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, ischemic and hemorrhagic forms of stroke, epilepsy, depression and other neuropsychiatric disorders.
−Removed: Clinical and experimental studies have revealed the detrimental role of MPO.
−Removed: Hence, suppressing MPO may be a novel treatment approach for these disorders.
−Removed: Verdiperstat (formerly named AZD3241) was in-licensed from AstraZeneca in September 2018.
−Removed: Our Clinical Program for Verdiperstat for ALS
−Removed: ALS is a progressive, life-threatening, and rare neuromuscular disease that affects approximately 30,000 people in the United States.
−Removed: The median age of onset is 55 years and average survival is 3-5 years after onset of first symptoms.
−Removed: ALS is characterized by the loss of motor neurons in the brain, brainstem, and spinal cord that leads to progressive muscle weakness and difficulties in speaking, swallowing, and breathing.
−Removed: There are currently limited treatment options and no cure for ALS.
−Removed: MPO may play a role in increasingly recognized ALS disease mechanisms mediated by peripheral myeloid cells, including those that migrate into the brain as well as those that remain in the periphery, suggesting relevance of MPO as a therapeutic target.
−Removed: In September 2019, we announced that verdiperstat was selected to be studied in the pivotal HEALEY ALS Platform Trial, which is being conducted by the Sean M.
−Removed: Healey & AMG Center for ALS at MGH (“Healey Center”) in collaboration with the Northeast ALS Consortium (“NEALS”) clinical trial network.
−Removed: Promising investigational drugs were chosen for the HEALEY ALS Platform Trial through a competitive process, with the Healey Center providing partial financial support to successful applicants.
−Removed: The HEALEY ALS Platform Trial is a Phase 2/3 randomized, double-blind, placebo-controlled clinical trial evaluating the safety and efficacy of investigational products for the treatment of ALS.
−Removed: HEALEY ALS Platform Trial Regimen B is evaluating the safety and efficacy of verdiperstat in approximately 167 adults with ALS.
−Removed: Participants were randomized in a 3-to-1 ratio treated with verdiperstat 600 mg BID or placebo for 24 weeks.
−Removed: The study's primary efficacy endpoint measures the change in disease severity from baseline to week 24 on the ALS Functional Rating Scale-Revised in patients receiving treatment versus placebo.
−Removed: Secondary endpoints include change in respiratory function, muscle strength, and survival.
−Removed: In August 2020, we announced that the first patients were enrolled in the pivotal HEALEY ALS Platform Trial Regimen B.
−Removed: Enrollment in the trial was completed in November 2021.
−Removed: In September 2022, the Company announced that verdiperstat did not statistically differentiate from placebo on the prespecified primary efficacy outcome, disease progression measured by the ALS Functional Rating Scale-Revised and survival, nor the key secondary efficacy measures during the 24-week study period.
−Removed: Analysis of safety data was consistent with the overall profile of verdiperstat from prior clinical trial experience.
−Removed: The study results have been presented at scientific meetings in 2022, including the NEALS Consortium meeting and the International Symposium on ALS/MND.
−Removed: Publication of these study results in an academic medical journal is pending.
−Removed: At this time, we do not have plans to pursue any additional clinical trials evaluating verdiperstat in ALS, and we may evaluate its potential in other disease indications.
+Added: The primary analysis of a regimen's effect on overall survival uses all patients in both its stages and all control patients in the trial in the graduating signature, suitably adjusted for any possible time trends.
+Added: Enrollment in the study is ongoing.
+Added: Myostatin Platform
Taldefgrobep Alfa (BHV-2000)
In February 2022, we announced a worldwide license agreement with BMS for the development and commercialization rights to taldefgrobep alfa (also known as BMS-986089), a novel Phase 3 asset.
−Removed: Myostatin, a negative regulator of muscle growth, is a key member of the Transforming Growth Factor ("TGF") (symbol Beta) family.
−Removed: Taldefgrobep novelty in a field of myostatin inhibitors is based on the mechanism where it binds to myostatin to both lower overall myostatin levels, but also to function as a receptor antagonist to block myostatin signaling in skeletal muscles.
−Removed: Blocking myostatin activity and signaling has shown to improve muscle function and strength in a number of disease models for neuromuscular wasting.
−Removed: Clinical studies have confirmed that taldefgrobep improved lean body mass directly through increase in contractile muscle and loss of adipose tissue as demonstrated in both normal healthy volunteers and in patients with Duchenne muscular dystrophy (“DMD”).
−Removed: The mechanism of improving overall muscle size and function opens the opportunity for taldefgrobep as a monotherapy or combination therapy in a number of muscle-targeted neuromuscular diseases.
−Removed: The addition of taldefgrobep alfa expanded our Neuroinnovation pipeline.
+Added: Myostatin, a negative regulator of muscle growth, is a key member of the Transforming Growth Factor ("TGF-β") superfamily.
+Added: Taldefgrobep's novelty in a field of myostatin inhibitors is based on the mechanism where it binds to myostatin to both lower overall free myostatin levels, but also to function as a receptor antagonist to block myostatin signaling in skeletal muscles.
+Added: Recently generated data has shown that the taldefgrobep alfa-myostatin complex is stable, and blocks myostatin signaling to both myostatin and to a lesser extent to activin A potentially for a protracted period after cessation of dosing.
+Added: Blocking myostatin activity and signaling has shown to improve muscle function and strength in a number of disease models for neuromuscular wasting along with physical and metabolic changes important to individuals living with overweight and obesity.
+Added: Blocking activin contributes to decreased adipose tissue and improved glucose homeostasis.
+Added: Clinical studies have confirmed that taldefgrobep improved lean body mass directly through increase on contractile muscle and loss of adipose tissue as demonstrated in both normal healthy volunteers and in patients with Duchenne muscular dystrophy (“DMD”).
+Added: The mechanism of increasing overall muscle size and reducing adipose tissue volume provide development opportunities in both neuromuscular disease and individuals living with overweight and obesity.
The advanced taldefgrobep alfa anti-myostatin development program offers extensive human safety data, especially in the pediatric population.
−Removed: About Spinal Muscular Atrophy
+Added: Previous Clinical Trials
+Added: Taldefgrobep was previously studied by Bristol Meyers Squibb ("BMS") and Roche in 4 completed clinical studies in healthy volunteers and subjects with DMD.
+Added: An estimated 360 subjects received taldefgrobep;
+Added: 179 healthy subjects and 181 subjects with DMD.
+Added: Completed clinical pharmacology studies in healthy adult subjects included:
+Added: • CN001001 was a randomized, placebo-controlled, Phase 1 study designed to evaluate the safety, tolerability, PK, and PD of single and multiple ascending subcutaneous doses of taldefgrobep (vial) in healthy adults.
+Added: • CN001023 was a randomized, open-label, single dose, parallel-group, Phase 1 study designed to compare the bioavailability of subcutaneous injections in the arm, thigh, and abdomen and to evaluate the safety, tolerability, PK, and immunogenicity of taldefgrobep (pre-filled syringe) in healthy adults.
+Added: Completed clinical studies in subjects with DMD included:
+Added: • CN001006 was a multi-site, randomized, placebo-controlled, double-blind, dose-ranging, Phase 1b/2 study to evaluate the safety, tolerability, and PK of taldefgrobep in ambulatory boys with DMD aged ≥ 5 to < 11 years.
+Added: • CN001016 was a randomized, double-blind, placebo-controlled, Phase 2/3 study to assess the efficacy, safety, and tolerability of 2 doses of taldefgrobep in ambulatory boys with DMD aged ≥ 6 to < 12 years.
+Added: All studies supported the safety and tolerability of taldefgrobep with fixed doses from 35 mg up to 180 mg administered weekly, subcutaneously ("SC").
+Added: The pharmacokinetics and safety data from the Phase 1 studies supported the continued development with doses of 35 mg and 50 mg administered weekly SC.
+Added: In the Phase 3 Clinical Study, CN001016, a futility analysis based on this primary endpoint, conducted after approximately 30% of subjects had completed 48 weeks of study drug treatment, did not show any statistically significant
+Added: treatment differences.
+Added: A summary of the development and outcome from these studies are published (Neurol Ther.
+Added: 2024 Feb;13(1):183-219).
+Added: There are significant differences between a neuromuscular (DMD) and neurodegenerative disease (SMA).
+Added: The differences in residual muscle in SMA along with adjunctive survival of motor neuron (“SMN”) upregulation therapy support the continued development of taldefgrobep alfa in SMA.
+Added: 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.
4 unchanged sentences
Our Clinical Trial for Taldefgrobep Alfa in SMA
−Removed: In July 2022, we commenced enrollment in a Phase 3 clinical trial assessing the efficacy and safety of taldefgrobep alfa in SMA.
+Added: In September 2023, we completed enrollment in a Phase 3 clinical trial assessing the efficacy and safety of taldefgrobep alfa in SMA.
The Phase 3 placebo-controlled, double-blind trial is designed to evaluate the efficacy and safety of taldefgrobep as an adjunctive therapy for participants who are already taking a stable dose of nusinersen or risdiplam or have a history of treatment with onasemnogene abeparvovec-xioi, compared to placebo.
1 unchanged sentence
Scores range from 0-3 on each item, with higher scores indicating higher functioning.
−Removed: The study is neither restricted nor limited to patients based on ambulatory status or classification of SMA.
−Removed: We expect to randomize approximately 180 patients in this randomized, double-blind, placebo-controlled global trial.
+Added: The study is neither restricted nor limited to patients based on ambulatory status or classification of SMA and is designed to randomize approximately 180 patients in this randomized, double-blind, placebo-controlled global trial.
+Added: We expect to report topline data from our Phase 3 study in the second half of 2024.
In February 2023, we received Fast Track designation from the FDA for taldefgrobep alfa for the treatment of SMA.
−Removed: Fast Track designation enables important new drugs to reach patients earlier by facilitating more frequent communications with the FDA and expeditious review of a drug which treats a serious condition and fills an unmet
−Removed: medical need.
−Removed: In December 2022, we received orphan drug designation from the FDA for taldefgrobep in the treatment of SMA.
+Added: Fast Track designation enables important new drugs to reach patients earlier by facilitating more frequent communications with the FDA and expeditious review of a drug which treats a serious condition and fills an unmet medical need.
+Added: In December 2022, we received orphan drug designation from the FDA for taldefgrobep in the treatment of SMA and from the European Commission in July 2023.
Taldefgrobep Alfa’s Role in Spinal Muscular Atrophy
1 unchanged sentence
Data from both an SMA animal model study that shows advantages of combination SMN therapy with taldefgrobep and the extensive clinical data in DMD support the advancement of taldefgrobep into a SMA Phase 3 study.
−Removed: Other indications in muscle wasting diseases will be a fast follow-on for taldefgrobep along with other life-cycle opportunities.
−Removed: Discovery Research
−Removed: The Company has laboratory facilities located in Science Park in New Haven, Connecticut, in Pittsburgh, Pennsylvania, and in Cambridge, Massachusetts supporting our integrated chemistry and discovery research operations.
−Removed: We will continue to augment our discovery efforts through research partnerships, including research agreements such as with KU Leuven and the Fox Chase Chemical Diversity Center Inc..
−Removed: TRPM3 Antagonists
+Added: Other indications in muscle wasting diseases may be a fast follow-on for taldefgrobep along with other life-cycle opportunities.
+Added: Metabolic Disorders
+Added: Obesity is a disease of excess and/or abnormal deposits of adipose tissue and a current global public health crisis.
+Added: 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.
+Added: The primary driver of obesity-related morbidity and mortality is metabolically active visceral adipose tissue and associated deposits of adipose tissue in and around organs such as the heart, liver, kidneys, and muscle.
+Added: Taldefgrobep Alfa’s Role in the Management of Overweight and Obesity
+Added: Preclinical and clinical data have demonstrated the potential for anti-myostatin therapies to produce physical and metabolic changes that are highly relevant to individuals living with overweight and obesity, including reducing total body fat and visceral adiposity, and improving insulin sensitivity and bone mineral density, while increasing lean muscle mass.
+Added: Taldefgrobep’s novel mode of action and unique impact on body composition suggest it could be used as monotherapy or in combination with other anti-obesity medications.
+Added: In October 2023, we announced preclinical data demonstrating the ability of taldefgrobep to significantly reduce fat mass while increasing lean mass in an obese mouse model.
+Added: In a mouse model of diet-induced obesity, untreated mice exhibited an increase in fat mass of 31%, while the mice treated with taldefgrobep demonstrated increases in lean mass of 25% from baseline (p≤.0.001) and lost 11% of their baseline fat (p≤.0.001) compared to vehicle (placebo) treated mice.
+Added: Insulin and leptin levels were consistently lower in mice treated with taldefgrobep compared to the untreated mice.
+Added: There was no difference in food intake over time across the taldefgrobep and untreated mice, counter to what has been observed with incretin mimetics (e.g., semaglutide) which are consistently associated with a reduction in energy intake.
+Added: Our Clinical Trial for Taldefgrobep Alfa in Obesity
+Added: In a Phase 1 MAD study conducted by BMS in normal healthy volunteers, the cohort using the projected therapeutic 45mg dose of taldefgrobep demonstrated a continued improvement in lean mass and a reduction in fat mass during the 29 day dosing period that continued to increase through the observation period at 4 weeks post dosing (see figure below).
+Added: We plan to initiate a Phase 2 clinical trial of taldefgrobep in the management of metabolic disease in the second quarter of 2024.
+Added: The study will evaluate the ability of taldefgrobep to maintain lean mass muscle as an adjunctive to standard of care GLP-1 therapy in adults living with overweight and obesity (see figure below for anticipated trial design).
+Added: Ion Channel Platform
+Added: Kv7 Platform Acquisition
+Added: In February 2022, we announced that we entered into a definitive agreement with Channel Biosciences, LLC, a subsidiary of Knopp Biosciences, LLC, to acquire a drug discovery platform targeting Kv7 ion channels, adding the latest advances in ion channel modulation to our growing neuroscience portfolio.
+Added: Kv7’s Role in Epilepsy, Mood Disorders, and Other Central Nervous System Disorders
+Added: Because of their fundamental role in health and their aberrant role in disease, ion channels in cell membranes represent a broad and important class of drug targets.
+Added: Sodium channels and potassium channels form the ionic basis of the action potential in electrically charged cells throughout the body (see figures below).
+Added: The Kv7 protein in particular forms a channel that exquisitely regulates the flow of charged potassium ions (K+) across cell membranes, repolarizing nerve cells and resetting them for normal action potential firing.
+Added: Kv7 channels include a family of channel subtypes, designated as Kv7.1 through Kv7.5, and they are formed by tetramers of identical or compatible subunits.
+Added: Some of these channel subtypes localize in nerve cells (neurons) while others can be found in cardiac muscle, smooth muscle, and other tissue types.
+Added: The Kv7 subunits, Kv7.2 and Kv7.3, are widely expressed in the brain, notably in the cortex and hippocampus, and together they form Kv7.2/7.3 heteromeric channels that produce the M-current ( I KM ), a critical regulator of neuronal excitability (see figures below).
+Added: Kv7.2/7.3 channels normally perform a natural “braking” function by regulating the electrical excitability and hyperexcitability of brain cells.
+Added: Dysfunction of these channels, due to genetic mutations or other factors, increases seizure risk, while augmenting the ‘open’ activity of these channels has been demonstrated to reduce neuronal hyperexcitability and seizure frequency in electrophysiology laboratories, in animal models, and, most importantly, in patients.
+Added: White, Role of Potassium Channel Ions in Epilepsy, Medscape.org
+Added: We are synthesizing novel Kv7.2/7.3 activators that improve on the selectivity, potency, and other characteristics of ezogabine (Potiga in the U.S.
+Added: and Trobalt (retigabine) in Europe), a drug approved in 2011 for the treatment of refractory epilepsy and voluntarily withdrawn from the market in 2017 because of poor tolerability and structure-related toxicities that limited its clinical use, and ezogabine-like compounds, while averting its negative attributes, including off-target activity at a different brain ion channel, gamma-aminobutyric acid (“GABA”) A receptor (“GABA A -R”).
+Added: Using a structure-based approach, supplemented by in silico modeling, we have identified structural features of our molecules critical to Kv7 activation.
+Added: We have applied these analyses to the generation of proprietary chemical leads structurally distinct from known Kv7 activators, including ezogabine and flupirtine, the only other approved Kv7 modulator, approved in Europe for the treatment of acute pain.
+Added: Our team has synthesized a large library of Kv7-activating molecules and are advancing them according to stringent criteria requiring improvements over ezogabine, including chemical stability, synthetic tractability, the avoidance of structural motifs associated with the generation of reactive metabolites and other unwanted, off-target activity, including GABA A -R activation.
+Added: Epilepsy, Major Depressive Disorder ("MDD"), and Bipolar Disorder are the initial indications we are targeting with activators from our Kv7 platform.
+Added: In addition to their role in treating epilepsy, anti-seizure medications ("ASMs") are often
+Added: used in the management of bipolar disorder and Kv7 activators have recently shown great promise in the the treatment of MDD.
+Added: While the use of ASMs is often accompanied by dose-limiting side effects, our Kv7 activators are specifically designed to target subtypes of Kv7 potassium channels without engagement of GABA A receptors.
+Added: The lack of GABA A -R activity potentially gives activators from our Kv7 platform a wide therapeutic window and is expected to result in an improved side effect profile, limiting the somnolence and fatigue often seen in patients receiving ASMs.
+Added: BHV-7000 (formerly known as KB-3061), the lead asset from the Kv7 platform, is a potent Kv7.2/7.3 ion channel activator from a novel, bicyclic imidazole class that is structurally-distinct from other Kv7 modulators (e.g., ezogabine and related aniline compounds) with significant in vivo anticonvulsant activity and a wide therapeutic index.
+Added: In the most widely used and positively-predictive preclinical model of epilepsy, the maximal electroshock (“MES”) model, data for BHV-7000 and ezogabine were collected in independent experiments (see figures below), measuring the activity of both compounds in preventing seizures (ED50) and recording the neurologic deficit five minutes prior to the MES test to calculate the tolerability index (“TI”).
+Added: The neurologic deficit is a behavioral index ranging from normal activity (score of 0) to a loss of righting reflex (score of 3).
+Added: As shown below, BHV-7000 was demonstrated to have an ED50 = 0.5 mg/kg with almost no impact on behavior producing a TI > 40x.
+Added: In a separate rotarod experiment of preclinical tolerability, BHV-7000 had no impact on rat motor behavior up to 30 mg/kg, the highest dose tested.
+Added: In contrast, ezogabine was 40x less potent (ED50 = 20 mg/kg) in the MES model with a narrow TI < 3x.
+Added: The narrow preclinical TI for ezogabine is consistent with the clinical experience with the drug where side effects such as somnolence and dizziness limited its use at doses that prevented seizures in patients.
+Added: Phase 1 Clinical Development
+Added: In the second quarter of 2022, our Clinical Trial Application for BHV-7000 was approved by Health Canada, and we subsequently began phase 1 clinical development.
+Added: First-in-human single ascending dose ("SAD") and multiple ascending dose ("MAD") studies have now been completed.
+Added: In the SAD and MAD cohorts, 77 subjects received BHV-7000 (N=58) or placebo (N= 19).
+Added: Thirty-nine SAD subjects were randomized to BHV-7000 or placebo and thirty-eight MAD subjects were
+Added: randomized to BHV-7000 or placebo.
+Added: The rates of adverse events ("AEs") by MedDRA System Organ Class across the pooled SAD and MAD cohorts among subjects treated with BHV-7000 and placebo are presented in the tables below.
+Added: Treatment‐emergent adverse events ("TEAEs") Occurring in ≥ 2 Subjects Receiving BHV-7000 in SAD Cohorts
+Added: All AEs reported in the SAD cohorts were mild in severity.
+Added: TEAEs Occurring in ≥ 2 Subjects Receiving BHV-7000 in MAD Cohorts
+Added: All AEs reported in the MAD cohorts were mild in severity, except 1 case of back pain (moderate severity, 40 mg) and 1 case of dizziness (moderate severity, 80 mg).
+Added: a Data are included from a separate study evaluating higher MAD doses.
+Added: b Data are pooled across studies.
+Added: In 2023, we initiated a Phase 1 open-label electroencephalogram ("EEG") study designed to evaluate the effects of BHV-7000 on EEG parameters in healthy adults.
+Added: The study’s objective was to demonstrate BHV-7000 target engagement in the cerebral cortex and to help refine dose selection for Phase 3 trials.
+Added: Study measures included continuous EEG monitoring, time locked pharmacokinetic ("PK") sampling, and changes in EEG spectral power post dose.
+Added: The Phase 1 EEG study was designed to evaluate qualitative changes from baseline in EEG spectral power after administration of single doses of BHV-7000 (10, 25, or 50 mg) to 11 healthy male and female adult volunteers.
+Added: EEG spectral power is a measure derived from quantitative analysis of EEG signals that assesses the amount of rhythmic activity in different frequency bands, including delta [1-3.5 Hz], theta [3.5-7.5 Hz], alpha [7.5-13 Hz], beta [13-30 Hz], and gamma [30-100 Hz].
+Added: Changes in spectral power have been used to evaluate the risk, onset and progression of seizures, assess cognitive and behavioral impairments, and characterize the effects of anti-seizure medications ("ASMs");
+Added: and, they may also have utility in refining dose selection in clinical trials of ASMs.
+Added: Spectral analysis was performed by Epilog (Ghent, Belgium), a global leader in EEG analytics.
+Added: Interim data from the Phase 1 EEG study were presented in December 2023 at the American Epilepsy Society meeting in Orlando, Florida.
+Added: BHV-7000 was well-tolerated at all doses studied, without the typical CNS AEs associated with other ASMs, such as somnolence or cognitive/mood disturbances, and EEG data showed dose-dependent increases in brain spectral power in healthy subjects (Figure 1 below).
+Added: Unlike prior reports where EEG effects of a Kv7.2/7.3 activator showed the greatest power increase in the delta frequency band (Biondi et al.
+Added: 2022), the highest spectral power increases with BHV-7000 were seen in alpha, beta, and gamma frequency bands (Figure 2 below).
+Added: While changes in spectral power were observed across all frequency bands with BHV-7000, the minimal impact on slower frequencies (i.e., delta) is consistent with the low incidence of CNS adverse events, in particular somnolence, seen in the BHV-7000 Phase 1
+Added: SAD/MAD studies.
+Added: EEG delta activity is associated with somnolence, an undesirable CNS adverse event often seen with other ASMs.
+Added: BHV-7000 shows dose-dependent increases in spectral power over all brain regions.
+Added: BHV-7000 effect on spectral power in resting -state EEGs.
+Added: Greatest impact observed on alpha frequency with minimal impact on delta and theta frequencies.
+Added: The preliminary EEG study results confirm the CNS activity of BHV-7000 at projected therapeutic concentrations, dose-dependent and time-dependent changes in EEG spectral power, and are consistent with the quantitative EEG effects observed with other ASMs approved for the treatment of epilepsy.
+Added: Based on the results from the EEG study and the safety profile in SAD/MAD trials, along with PK data from a new once-daily extended-release (“ER”) formulation, Biohaven plans on exploring three oral doses of BHV-7000 (once daily 25 mg ER, once daily 50 mg ER, and once daily 75 mg ER) in the Phase 2/3 clinical trials in epilepsy and mood disorders.
+Added: dosing approach with a Kv7 activator will allow for assessment of distinct target concentrations over a wide range, above and below projected efficacious EC50 drug concentrations (Figure 3), not previously feasible with drugs in this class.
+Added: Predicted PK profile of BHV-7000 ER, mean predicted concentration vs.
+Added: time profiles for 25 mg ER, 50 mg ER and 75 mg ER once-daily dosing at steady state relative to EC20 and EC50 (EC values from preclinical MES models).
+Added: Epilepsy affects approximately 3.5 million Americans, or more than 1.2% of adults and 0.6% of children in the U.S., and more than 50 million patients worldwide, according to the World Health Organization (“WHO”).
+Added: It is the fourth most common neurological disorder, and many patients struggle to achieve freedom from seizures, with more than one third of patients requiring two or more medications to manage their epilepsy.
+Added: While the use of anti-seizure medications is often accompanied by dose-limiting side effects, our clinical candidate BHV-7000 is specifically designed to target subtypes of Kv7 potassium channels without engagement of GABA A receptors.
+Added: The lack of GABA A -R activity potentially gives BHV-7000 a wide therapeutic window and is expected to result in an improved side effect profile, limiting the somnolence and fatigue often seen in patients receiving anti-seizure medications.
+Added: This preclinical profile is supported by safety data from our Phase 1 SAD/MAD trial of BHV-7000 in healthy volunteers, which showed a favorable CNS tolerability profile.
+Added: We aim to bring this potassium channel modulator as a potential solution to patients with epilepsy who remain uncontrolled on their current regimens.
+Added: In January 2024, we completed our End-of-Phase 2 meeting with the FDA to advance to Phase 3 trials and announced that more than 110 global clinical sites have been selected in the first of two focal epilepsy trials, with enrollment commencing in the first quarter of 2024.
+Added: The two pivotal studies evaluating the efficacy of BHV-7000 in refractory focal epilepsy are planned as randomized, double-blind, placebo-controlled, 8- and 12-week trials with a primary endpoint of change from baseline in 28-day average seizure frequency in adults and adolescents with focal epilepsy.
+Added: One of the focal epilepsy studies will evaluate 25 mg and 50 mg doses of BHV-7000 and the second study will evaluate 50 mg and 75 mg doses of BHV-7000 (see figure below).
+Added: In addition to the focal epilepsy program, we anticipate initiating a Phase 2/3 study of BHV-7000 in idiopathic generalized epilepsy ("IGE") in the second quarter of 2024.
+Added: The pivotal study evaluating the efficacy of BHV-7000 with IGE is planned as a randomized, double-blind, placebo-controlled 24-week time-to-event trial with a primary endpoint of time to second generalized seizure in adults and adolescents with IGE (see figure below).
+Added: Mood disorders
+Added: Approximately 1 in 5 adults in the U.S.
+Added: are living with neuropsychiatric illnesses that are associated with inadequate treatment, poor quality of life, disability, and considerable direct and indirect costs.
+Added: There is significant unmet need for
+Added: novel and effective therapeutic options that are not limited by long latency periods to clinical effects, low response rates, and significant risks and side effects.
+Added: Increasing evidence from animal models and clinical trials now suggests that Kv7.2/7.3 targeting drugs offer the potential to treat a spectrum of these neuropsychiatric diseases including, but not limited to, mood disorders such as major depressive disorder, bipolar disorder and anxiety.
+Added: Major Depressive Disorder
+Added: Major depressive disorder is a leading cause of morbidity.
+Added: Prevalence estimates for MDD episodes in the U.S.
+Added: accordingly, there is an urgent need for more effective treatments.
+Added: Within the current armamentarium of treatments nearly one third of patients fail to respond.
+Added: Kv7 activation has emerged as a novel strategy to treat and prevent depressive episodes and holds significant potential as a novel treatment for patients with MDD.
+Added: The therapeutic role for Kv7 activation in MDD is supported by a broad range of epigenetic, mechanistic, preclinical, and clinical evidence.
+Added: Multiple depression models have demonstrated the antidepressant efficacy of enhancing potassium channel activity.
+Added: As preclinical studies demonstrate upregulation of Kv7 channels in mice subject to chronic stress, increasing potassium channel function either through genetic over expression or via potassium channel activation (via ezogabine) reverses depressive and anhedonic behaviors in mice across multiple studies.
+Added: Recent randomized, controlled clinical trials of Kv7 activators demonstrated efficacy in MDD.
+Added: Together, these data, coupled with the favorable clinical safety and tolerability profile exhibited by BHV 7000 to date, provide a compelling rationale for the evaluation of Kv7 activation with BHV-7000 in MDD.
+Added: We plan to initiate a Phase 2 clinical trial with BHV-7000 for the treatment of MDD in the first half of 2024.
+Added: We anticipate the study will be a 6 week, randomized, double-blind, placebo-controlled trial in approximately 300 subjects, with a primary endpoint of measurement on the Montgomery-Asberg Depression Rating Scale ("MADRS").
+Added: See below for expected trial design detail.
+Added: Bipolar disorder
+Added: Bipolar disorder affects approximately 7 to 11 million Americans, with an estimated 4.4% of U.S.
+Added: adults having bipolar disorder over their lifetime.
+Added: Bipolar disorder is associated with significant morbidity, decreased quality of life and economic burden.
+Added: Treatment guidelines recommend patients receive life-long treatment for bipolar disorder.
+Added: However, medication adherence is typically very low in this population, due in large part to undesirable side effects that are poorly tolerated by patients.
+Added: The mainstays of treatment include mood stabilizing agents that are also used as anti-seizure medicines (i.e., valproic acid, lamotrigine, and topiramate).
+Added: Preclinical and pilot clinical data similarly suggest a potential therapeutic role for Kv7 activation in bipolar disorder, which is expected to result in an improved side effect profile compared to other anti-seizure medications.
+Added: We are advancing BHV-7000 as a potential treatment for patients with bipolar disorder and intend to start a Phase 2/3 clinical trial targeting this indication in the first half of 2024.
+Added: We expect the study to be a 3 week, randomized, double-
+Added: blind, placebo-controlled trial in approximately 256 subjects, with a primary endpoint of measurement on the Young Mania Rating Scale ("YMRS").
+Added: See below for expected trial design detail.
+Added: Developmental Epileptic Encephalopathies
+Added: KCNQ2 developmental epileptic encephalopathy (“KCNQ2-DEE”) is a rare pediatric epileptic encephalopathy first described in 2012 resulting from dominant-negative mutations in the KCNQ2 gene.
+Added: Epileptic encephalopathies (“EE”) comprise a group of epilepsy syndromes in which onset of recurrent and medically refractory seizures are associated with cognitive and broader developmental delay or regression.
+Added: Although only recently described, heterozygous de novo variants in KCNQ2 are a highly validated cause of early onset epileptic encephalopathy, and KCNQ2-DEE has emerged as a well-defined clinical entity with a characteristic neonatal presentation, including hypotonia, treatment-resistant tonic seizures, a profoundly abnormal EEG, and most often with moderate-to-profound global developmental delay.
+Added: KCNQ2-DEE is thus both a seizure disorder and a developmental disorder caused by pathogenic KCNQ2 mutations.
+Added: Identification of genetic etiologies has created the opportunity to treat not just the symptoms of KCNQ2-DEE, including seizures, but also the underlying causes, including attenuating or reversing the effects of the disease-causing variants.
+Added: In addition to its activity in the MES model, we explored the ability of BHV-7000 to reverse the reduced current density associated with KCNQ2-DEE and support its use as potential treatment for the disease).
+Added: To determine the effects of BHV-7000 on the function of Kv7.2 and Kv7.2/7.3 channels poisoned by dominant-negative KCNQ2 mutations, four highly recurrent human missense variants known to cause KCNQ2-DEE were evaluated in an in vitro model measuring current density in cells expressing the pathologic proteins.
+Added: The figure below shows the effects of BHV-7000 on current density of wt/wt Kv7.2 channels and those formed by 1:1 coexpression of wt KCNQ2 genes with four disease-causing KCNQ2 variants (T274M, A294V, R581L, R210H).
+Added: In the control condition, all pathogenic variants produced a marked reduction in current density to below wt/wt levels.
+Added: BHV-7000 at either 0.3µM or 1.0 µM restored current density in all mutated channels to or beyond wt control current density (**<0.01).
+Added: BHV-7000 has been granted Rare Pediatric Disease Designation by the U.S.
+Added: Food and Drug Administration ("FDA") for the treatment of KCNQ2-DEE.
+Added: Neuropathic Pain
+Added: Neuropathic pain, as defined by the International Association for the Study of Pain, is pain caused by a lesion or disease of the somatosensory nervous system and includes a collection of heterogeneous conditions that are often chronic and debilitating and for which long term therapy is difficult.
+Added: In the United States, over 30 million adults are estimated to be living with neuropathic pain.
+Added: Pharmacological treatments for neuropathic pain vary according to patient needs, although recommendations such as the WHO analgesic ladder, United States Centers for Disease Control (“CDC”), and FDA guidelines are in use.
+Added: Initial or first line treatment for neuropathic pain includes non-opioid analgesics, in particular, antidepressants, anticonvulsants, steroids, and anxiolytics.
+Added: Second line treatment of persistent, severe pain may require escalation to opiates, often less potent ones at first, followed by more potent opiates for intense refractory pain.
+Added: Thus, an urgent need exists for effective, non-addictive pain therapies.
+Added: Flupirtine, a non-selective Kv7 activator, was previously approved in several European countries and indicated for the treatment of pain.
+Added: However, the European Medicines Agency recommended withdrawal of its marketing authorization in 2018 because of the risk of serious liver injury.
+Added: Selective Kv7 potassium channel activators represent a new approach in the development of non-opioid therapeutic options for neuropathic pain.
+Added: In addition to leveraging the reduced abuse and addiction risk potential of potassium channel activators, our Kv7 potassium channel platform addresses the complexities of channel subtype physiology through targeted pharmacology to overcome the limitations inherent in nonselective Kv7 activators and is intended to deliver a well-tolerated, highly effective, non-opioid treatment for neuropathic pain.
+Added: Our Kv7 program research was supported in part with funding from the National Institutes of Health (“NIH”) to advance the development of novel Kv7 non-opioid therapies for the treatment of chronic pain.
+Added: The NIH funding is by the NIH Helping to End Addiction Long-term Initiative (“NIH HEAL Initiative”), which aims to improve treatments for chronic pain, curb the rates of opioid use disorder and overdose, and achieve long-term recovery from opioid addiction.
+Added: The goal of our Kv7 program is to discover a small-molecule activator of the Kv7.2/7.3 voltage-gated potassium channel to treat neuropathic pain.
+Added: Similar to our epilepsy program, we are targeting compounds with these characteristics:
+Added: • Biased for Kv7.2/3 activation vs.
+Added: Kv7.4 activation to minimize potential adverse smooth muscle effects
+Added: • Selective against GABA A receptors to minimize potential tolerability issues
+Added: • Selective against Kv7.1/KCNE1 (IKs) and hERG (IKr) to minimize cardiac side-effects
+Added: • Potent and effective across animal models of neuropathic pain
+Added: Axonal excitability and neurotransmitter release are altered in neuropathic pain due to sodium channel plasticity, increased voltage-gated calcium channels in the spinal cord, and diminished potassium channel activity in dorsal root ganglion (“DRG”) neurons.
+Added: These changes in ion channel number, distribution, and function are common to many neuropathic pain subtypes.
+Added: The functional density of Kv7.2/3 channels is a key variable governing sensory DRG control of intrinsic excitability.
+Added: al demonstrated downregulation of Kv7 potassium channel mRNA in an experimental nerve injury model and further showed alleviation of neuropathic hyperalgesia with administration of flupirtine.
+Added: Using human induced pluripotent stem cell (“iPSC”)-derived DRG sensory neurons, we have assessed the physiological activity of these neurons by modulating Kv7 channels across three electrophysiologic parameters:
+Added: resting membrane potential (Vm), rheobase = the current required to stimulate an action potential (“AP”), and the number of APs elicited by a suprathreshold stimulus (3x rheobase).
+Added: We are currently evaluating the activity of various compounds from our proprietary series of selective Kv7.2/7.3 activators in multiple preclinical models of neuropathic pain.
+Added: The Company recently initiated a sponsored research agreement with Yale to evaluate the activity of BHV-7000 in an iPSC model of inherited erythromelalgia, a severe rare genetic neuropathy.
+Added: We are currently exploring BHV-7000 as a potential treatment for migraine.
+Added: Kv7.2/7.3 openers have shown significant activity in cortical spreading depression models of migraine.
+Added: TRPM3 Ion Channel Antagonists
KU Leuven Agreement
−Removed: In January 2022, we entered into the KU Leuven Agreement to develop and commercialize TRPM3 antagonists to address the growing proportion of people worldwide living with chronic pain disorders (the "KU Leuven Agreement").
+Added: In January 2022, we entered into an agreement with KU Leuven ("the KU Leuven Agreement") to develop and commercialize TRPM3 antagonists to address the growing proportion of people worldwide living with chronic pain disorders.
The TRPM3 antagonist platform was discovered at the Centre for Drug Design and Discovery and the Laboratory of Ion Channel Research at KU Leuven.
1 unchanged sentence
The portfolio includes the lead candidate, BHV-2100, which we are evaluating in several preclinical pain models and advancing towards the clinic in 2023.
−Removed: We are continuing to support further basic and translational research on the role of TRPM3 in pain and other disorders through our collaboration with Professors Joris Vriens and Thomas Voets, world leaders in TRP biology at KU Leuven.
−Removed: Efforts to target TRP Channels for pain
−Removed: Since the Nobel Prize-winning discovery of the capsaicin receptor TRPV1 in 1997, members of the Transient Receptor Potential (“TRP”) cation channel family have been elusive drug targets for the treatment of pain.
+Added: We are continuing to support further basic and translational research on the role of TRPM3 in pain and other disorders through our collaboration with professors in Transient Receptor Potential ("TRP") biology at KU Leuven.
+Added: Efforts to target TRP Ion Channels for pain
+Added: Since the Nobel Prize-winning discovery of the capsaicin receptor TRPV1 in 1997, members of the TRP cation channel family have been elusive drug targets for the treatment of pain.
Initially, there was much excitement and investment in TRPV1 antagonists due to promising preclinical efficacy and some evidence of clinical pain reduction.
2 unchanged sentences
Though Glenmark’s GRC 17536 showed encouraging results in a subset of diabetic peripheral neuropathic pain subjects in a Phase 2a study, it suffers from poor physiochemical properties and pharmacokinetics like many other TRPA1 antagonists.
−Removed: Due to the challenges with drugging TRPA1, only Eli Lilly’s LY3526318 remains in active clinical development.
TRPM3 is a novel target in the TRP family.
−Removed: Like TRPV1 and TRPA1, preclinical data and human genetic validation support TRPM3’s role in neuropathic pain.
−Removed: Unlike TRPV1 antagonists, TRPM3 antagonists are unlikely to possess significant thermal liabilities, and unlike TRPA1 antagonists, Biohaven’s TRPM3 antagonists have desirable
−Removed: physiochemical properties and good pharmacokinetic profiles.
+Added: Like TRPV1 and TRPA1, preclinical data and human genetic validation support TRPM3’s role in neuropathic pain and migraine.
+Added: Unlike TRPV1 antagonists, TRPM3 antagonists are unlikely to possess significant thermal liabilities, and unlike TRPA1 antagonists, Biohaven’s TRPM3 antagonists have desirable physiochemical properties and good pharmacokinetic profiles.
The figure below illustrates TRPM3 as a differentiated target for the treatment of pain in the TRP family.
Adapted from Efforts to target TRP channels for pain , Kovivisto et al.
−Removed: Transient Receptor Potential Melastatin 3 (“TRPM3”) is a novel druggable target in the TRP cation channel family.
−Removed: TRPM3 is functionally expressed in the human dorsal root ganglion, and several SNPs in TRPM3 are associated with altered pain sensation in response to UVB (see figure below).
+Added: TRPM3 is a novel druggable target in the TRP cation channel family.
+Added: TRPM3 is functionally expressed in the human dorsal root ganglion, and several single nucleotide polymorphisms ("SNPs") in TRPM3 are associated with altered pain sensation in response to ultraviolet B ("UVB") (see figure below).
Additionally, people with TRPM3 gain-of-function mutations experience altered pain sensation (de Sainte Agathe 2020, Dyment 2019, Van Hoeymissen 2020).
−Removed: Knocking out or antagonizing TRPM3 in animal models attenuates the development of various pain states, including those associated with nerve injury, chemotherapy, and diabetic peripheral neuropathy, further indicating that TRPM3 is a promising target for neuropathic pain.
+Added: Knocking out or antagonizing TRPM3 in animal models attenuates the development of various pain states, including those associated with nerve injury, chemotherapy, and diabetic peripheral neuropathy, further indicating that TRPM3 is a promising target
+Added: for neuropathic pain.
Lastly, preclinical evidence suggests that antagonizing TRPM3 may avoid the on-target body temperature effects and TRPV1 antagonist-induced malignant hyperthermia.
Vangeel et al, 2020 Lotsch et al, 2020
−Removed: Our Development of BHV-2100 for the Treatment of Neuropathic Pain
BHV-2100 is an orally-bioavailable small molecule antagonist of TRPM3.
TRPM3 is expressed in the relevant human tissue types for neuropathic pain, and both preclinical models and human genetics implicate TRPM3 in pain signaling.
−Removed: BHV-2100 is our lead orally-bioavailable small molecule TRPM3 antagonist which we are developing as a potential non-opioid treatment for neuropathic pain.
−Removed: We are evaluating the ability of BHV-2100 to reduce pain behaviors across several
−Removed: preclinical models of neuropathic pain, including chemotherapy induced neuropathy, diabetic neuropathy, and nerve injury.
−Removed: We expect to submit an IND application for BHV-2100 with the FDA in the second half of 2023, complementing our efforts with our Kv7 platform.
−Removed: The Company is evaluating and has not yet finalized potential clinical trial designs, including trial size, and primary and secondary endpoints.
+Added: Our Phase 1 Study with BHV-2100
+Added: We have an ongoing Phase 1 study of BHV-2100 in Canada.
+Added: The Phase 1 study is a randomized, double-blind, placebo-controlled, SAD/MAD study in healthy subjects to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of BHV-2100.
+Added: Single ascending dose cohorts are ongoing (including subjects randomized to placebo) with ascending dose levels.
+Added: Each dose cohort will be initiated with sentinel dosing.
+Added: Dose levels for subsequent cohorts are determined based on available PK, PD, safety and tolerability from previous cohort(s).
+Added: Up to approximately 88 subjects are planned to be evaluated.
+Added: Our Development of BHV-2100 for the Treatment of Migraines
+Added: Nearly 40 million people in the U.S.
+Added: suffer from migraine and the World Health Organization classifies migraine as one of the 10 most disabling medical illnesses.
+Added: Migraine is characterized by debilitating attacks lasting four to 72 hours with multiple symptoms, including pulsating headaches of moderate to severe pain intensity that can be associated with nausea or vomiting, and/or sensitivity to sound (phonophobia) and sensitivity to light (photophobia).
+Added: There is a significant unmet need for new treatments as more than 90 percent of migraine sufferers are unable to work or function normally during an attack.
+Added: We expect to initiate a BHV-2100 Phase 2 study in acute migraine in the second half of 2024.
+Added: We are evaluating and have not yet finalized clinical trial design, including trial size, and primary and secondary endpoints for the anticipated clinical trial.
+Added: Our Development of BHV-2100 for the Treatment of Neuropathic Pain
+Added: BHV-2100 is also being developed as a potential non-opioid treatment for neuropathic pain.
+Added: We are evaluating the ability of BHV-2100 to reduce pain behaviors across several preclinical models of neuropathic pain, including chemotherapy induced neuropathy, diabetic neuropathy, and nerve injury.The Company expects to conduct a proof of concept study for neuropathic pain in the second half of 2024.
Additional research on TRPM3-mediated disorders
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In addition to BHV-2100, we are optimizing other lead compounds for TRPM3-mediated disorders of the peripheral and central nervous systems.
+Added: Inflammation and Immunology Platform
+Added: Agreement with Hangzhou Highlightll Pharmaceutical Co.
+Added: In March 2023, we entered into an exclusive, worldwide (excluding People’s Republic of China and its territories and possessions) license agreement with Hangzhou Highlightll Pharmaceutical Co.
+Added: ("Highlightll") (the "Highlightll Agreement"), pursuant to which we obtained the right to research, develop, manufacture and commercialize Highlightll’s brain penetrant dual TYK2/JAK1 inhibitor program.
+Added: Dysregulation of the immune system has been implicated in several neurodegenerative and neuroinflammatory disorders including Parkinson's Disease, Multiple Sclerosis, Alzheimer's Disease, Amyotrophic Lateral Sclerosis and Autoimmune Encephalitis.
+Added: Over-active immune cells and microglia driving chronic neuroinflammation results in release of cytokines with activation of leukocytes and is thought to contribute to neuronal injury, death, gliosis, and demyelination.
+Added: The tyrosine kinase 2 ("TYK2") and Janus kinase 1 ("JAK1") signal transduction pathways mediate highly complementary immune and inflammatory signaling events.
+Added: Targeted, small-molecule therapies that inhibit TYK2 or JAK kinases have separately demonstrated robust efficacy in autoimmune, dermatologic and gastrointestinal disorders.
+Added: TYK2 is a validated immune target as evidenced by a recent peripheral program that gained FDA approval, and there are multiple additional peripheral non-CNS programs in clinical development.
+Added: Brain penetrant inhibitors of TYK2/JAK1 have the potential to bring this validated immune target to brain disorders.
+Added: There are currently no brain penetrant, selective, dual TYK2/JAK1 inhibitors approved for brain disorders.
+Added: In May 2023, we began dosing with BHV-8000 (previously TLL-041), in a phase 1 study in normal healthy volunteers.
+Added: The planned phase 1 study is a randomized, double-blind, placebo-controlled, sequential parallel group, single ascending dose / multiple ascending dose study in healthy subjects to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of BHV-8000 following oral administration.
+Added: In this study, single ascending dose cohorts are planned and ongoing (including subjects randomized to placebo) with up to 6 dose levels.
+Added: Each dose cohort will be initiated with sentinel dosing, e.g., one active and placebo patient will be dosed simultaneously.
+Added: Doses for subsequent cohorts are determined based on available PK, PD, safety and tolerability from previous cohort(s).
+Added: Up to 40 subjects are planned to be evaluated with approximately 30 subjects randomized to receive active drug and approximately 10 subjects randomized to receive placebo in a double-blind fashion.
+Added: In July 2023, we reported that we had successfully dosed three dose cohorts with single ascending doses of BHV-8000 in the ongoing Phase 1 study.
+Added: Based on the preliminary data that are available, BHV-8000 achieved projected therapeutic concentrations and was well tolerated with only mild adverse events reported.
+Added: We anticipate beginning clinical trials with BHV-8000 in the second half of 2024 targeting neuroinflammatory conditions, potentially including Parkinson's disease, Amyloid-Related Imaging Abnormalities ("ARIA") in Alzheimer’s disease, Alzheimer's disease, and multiple sclerosis.
+Added: We are evaluating and have not yet finalized clinical trial designs, including trial size, and primary and secondary endpoints for these anticipated clinical trials.
+Added: MoDE Degraders
Bispecific Molecular Degraders of Extracellular Proteins
Molecular Degraders of Extracellular Proteins (“MoDEs”) 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.
−Removed: Our MoDE platform is being explored for use in a wide range of therapeutic areas, including indications in autoimmune diseases, cancer and infectious disease.
−Removed: We are generally planning for MoDEs to be administered as intravenous or subcutaneous formulations.
−Removed: The Company is evaluating and has not yet finalized potential clinical trial designs, including trial size, and primary and secondary endpoints.
+Added: Our MoDE platform is being explored for use in a wide range of therapeutic areas, including indications in immune-mediated diseases, cancer and other diseases.
+Added: We are planning for MoDEs to be administered as intravenous or subcutaneous formulations.
+Added: We expect to initiate a total of 4 INDs for the degrader program in 2024.
Antibody-based Galactose-deficient IgA (“Gd-IgA”) MoDEs
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Patients with IgAN have increased serum levels of IgA1 with a hinge region containing truncated galactose-deficient O-linked saccharides (“Gd-IgA”) and can present with a range of symptoms, from hematuria or proteinuria to severe hypertension owing to renal damage.
−Removed: The clinical progression varies, with 30–40% of patients reaching end-stage renal disease 20–30
−Removed: years after the first clinical presentation.
−Removed: Currently, no IgAN-specific therapies are available.
−Removed: Patients are managed with the aim of controlling blood pressure and maintaining renal function.
+Added: The clinical progression varies, with 30–40% of patients reaching end-stage renal disease 20–30 years after the first clinical presentation.
+Added: Patients are managed by therapeutic immunosuppression, with the aim of controlling blood pressure and maintaining renal function.
Lai, Nat Rev Dis Primers (2016)
−Removed: 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 or total IgA in patients and prevent harmful kidney deposits.
−Removed: 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.
−Removed: Further work is ongoing to progress this as a potential IgAN treatment.
+Added: 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 and associated immune complexes in patients and thereby prevent harmful kidney deposits.
+Added: We have taken a published rodent format IgG antibody that recognizes Gd-IgA and converted it into a partially-humanized antibody, then subsequently completed the molecule liver-targeted degrader MoDE.
+Added: This compound potently binds Gd-IgA and causes its endocytosis in human liver cells through its ASGPR binding motif.
+Added: Nonclinical development work is ongoing to progress this as a potential IgAN treatment.
+Added: BHV-1400 is a MoDE which is being developed to target Gd-IgA for the treatment of IgA Nephropathy.
+Added: Specific removal of pathogenic Gd-IgA and associated circulating immune complexes with preservation of normal IgA potentially permits disease remission without incurring an infection risk.
+Added: We shared preliminary data demonstrating the chimeric antibody-ASGPR ligand conjugate specifically mediated endocytosis of Gd-IgA, as opposed to normal IgA, in an endocytosis assay with HepG2 cells, and that MoDE degraders successfully internalize and degrade these immune-complexes.
+Added: We expect to initiate Phase 1 studies of BHV-1400 in the second half of 2024.
+Added: We are evaluating and have not yet finalized potential clinical trial designs, including size and primary and secondary endpoints.
Therapeutic pan-IgG depletion
−Removed: Analogous to the depletion of pan-IgA or dg-IgA with molecular degraders, hepatic asialoglycoprotein receptor ("ASGPR") ligand degraders able to recognize all potentially pathogenic isoforms of IgG represent a novel, competitive platform with differentiated profile relative to FcRN inhibitors.
−Removed: FcRN inhibitors such as efgartigimod (Vyvgart) and nipocalimab also deplete IgG.
+Added: Analogous to the depletion of pan-IgA or dg-IgA with molecular degraders, hepatic asialoglycoprotein receptor ("ASGPR") ligand degraders are able to recognize potentially pathogenic isoforms of immunoglobulin ("IgG") and represent a novel, competitive platform with differentiated and improved profile relative to FcRN inhibitors.
+Added: These molecules are specifically designed to spare the IgG3 subclass, to promote better host defense.
+Added: FcRN inhibitors such as efgartigimod (Vyvgart) and nipocalimab also deplete IgG, but are not selective and deplete all IgG subclasses.
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.
−Removed: As this has been shown with FcRN inhibitors for myasthenia gravis (Vyvgard), therapeutic pan-IgG depletion using Biohaven’s proprietary MoDE platform technology is expected to have significant potential benefit for multiple diseases including but not limited to the conditions outlined above.
+Added: As this has been shown with FcRN inhibitors for myasthenia gravis (Vyvgart), therapeutic pan-IgG depletion using Biohaven’s proprietary MoDE platform technology is expected to have significant potential benefit for multiple diseases including but not limited to the conditions outlined above.
Drug candidates utilizing this technology are in nonclinical development, approaching IND.
−Removed: The following graphic shows preclinical data validating this approach.
−Removed: The effect of a single dose of our IgG degrader MoDE, BHV-1300, was evaluated in cynomolgus monkeys.
−Removed: BHV-1300 demonstrated robust reduction of IgG levels, with 75% depletion from baseline.
−Removed: This effect was rapid, occurring by 3 days.
−Removed: For comparison, published data with the standard
−Removed: of care, efgartigimod, are included below, noting that reduction of IgG levels with efgartigimod is 50% and takes 5-7 days to achieve.
−Removed: The Company expects to submit an IND application for BHV-1300 with the FDA in the second half of 2023.
−Removed: MATE Conjugation Technology
−Removed: Antibody Drug Conjugates
−Removed: We are using the MATE conjugation technology to generate site-specific antibody drug conjugates (“ADC”s) from native IgG1 proteins that we believe will show superior stability in comparison with those using current industry-standard cysteine maleimide conjugation.
−Removed: Our expectation is that the enhanced in vivo stability and expected superior physicochemical properties of these ADCs will lead to increased therapeutic indices (more cytotoxic payload reaching cancer cells and less reaching normal tissues).
−Removed: Over 15 site-specific ADCs using the well validated valine-citrulline monomethyl auristatin E ("vcMMAE") payload linker system have been prepared and are undergoing biological testing in comparison with industry standard maleimide conjugated ADCs.
−Removed: MATE Molecule
+Added: BHV-1300 is an IgG1, IgG2 and IgG4 bispecific degrader which we are initially developing for the treatment of rheumatoid arthritis ("RA").
+Added: RA is a chronic autoimmune disease estimated to affect 1 to 2% of the global population.
+Added: RA primarily affects the joints, causing pain, swelling, stiffness, and loss of function.
+Added: We evaluated the effect of single and multiple doses of BHV-1300 in cynomolgus monkeys.
+Added: In September 2023, we reported data from confirmatory studies that showed a 75-80% reduction of IgG levels two days after a single dose and over 90% of IgG lowering after three doses.
+Added: Maximal lowering across FcRn inhibitors is 60-80% within approximately 7 to 21 days after initiation of single or multiple doses, respectively, in cynomolgus.
+Added: In contrast, a single dose of BHV-1300 lowers IgG by approximately 75 to 80% after approximately 2 days, and after three rapid doses to greater than 90% lowering.
+Added: The length of significant exposure to BHV-1300 is approximately one day within the dosage interval compared to continuous exposure required of the FcRn inhibitors.
+Added: Mechanism related liabilities of FcRn inhibitors seen in animals and man, including
+Added: hypoalbuminemia and hypercholeresterolema, are not expected and do not occur with BHV-1300 in cynomolgus.
+Added: See figures below comparing the speed and depth of lowering to FcRn inhibitors.
+Added: In January 2024, we reported preclinical pharmacodynamic single dose data with BHV-1300 which demonstrated the Biohaven IgG degrader technology allows for co-administration with Fc-containing biologics.
+Added: The PK of Humira® was unaltered after being dosed 12 hours after BHV-1300 administration (see figure below).
+Added: * Adapted from BLA 761154, IND 116471, Study no.
+Added: The Phase 1 SAD study examining BHV-1300 in healthy subjects was initiated in the first quarter of 2024 and we expect preliminary results late in the first quarter or early in the second quarter of 2024.
+Added: The FDA indicated that the MAD assessment of BHV-1300 should be performed in a relevant patient population.
+Added: Upon completion of the SAD study, we are planning the MAD portion of the study in a relevant patient population with the possibility of benefit from BHV-1300.
+Added: The Phase 1 study is a randomized, open-label, placebo-controlled, SAD study in healthy subjects to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of BHV-1300.
+Added: Each dose cohort will be initiated with sentinel dosing.
+Added: Dose levels for subsequent cohorts will be determined based on available PK, PD, safety and tolerability from previous cohort(s).
+Added: Up to approximately 32 subjects are planned to be evaluated.
+Added: Phase 2 studies of BHV-1300 are anticipated to initiate in 2024.
+Added: We are evaluating and have not yet finalized potential clinical trial designs, including size and primary and secondary endpoints.
+Added: BHV-1310 is a next generation bispecific IgG degrader with the same specificity as BHV-1300 for IgG1, IgG2 and IgG4 which is initially being developed for the treatment of generalized myasthenia gravis ("gMG") and potentially other acute conditions or conditions with acute exacerbations or flares.
+Added: MG is a chronic autoimmune disorder of the musculoskeletal system that is estimated to affect approximately 36,000 to 60,000 people in the United States.
+Added: Patients with gMG develop antibodies that attack critical signaling receptor proteins at the junction between nerve and muscle cells, inhibiting communication between nerves and muscle and resulting in weakness of the skeletal muscles.
+Added: GMG affects the voluntary muscles of the body, especially those that control the eyes, mouth, throat and limbs.
+Added: In January 2024, we demonstrated optimization of degrader technology with BHV-1310 which allows for deeper reductions in IgG after single dose (see figure below).
+Added: The deep and rapid reductions observed suggest that BHV-1310 could have potential application in acute settings.
+Added: We expect to initiate Phase 1 studies of BHV-1310 in the second half of 2024.
+Added: We are evaluating and have not yet finalized potential clinical trial designs, including size and primary and secondary endpoints.
+Added: BHV-1600 is a selective MoDE designed to remove circulating agonistic antibodies of all isotypes and subclasses directed against myocardial beta-1 adrenergic receptor ("β-1 AR") through hepatic ASGPR binding and hepatocellular degradation.
+Added: This molecule was created using a peptide that mimics the antigenic epitope common to most patients with autoantibodies directed to β-1 AR.
+Added: This peptide is sufficiently similar to the native sequence such that circulating antibodies are efficiently trapped and subsequently removed by hepatic endocytosis through the ASGPR receptor.
+Added: As these agonistic antibodies will be markedly depleted, the rapid cessation of inappropriate agonism of the myocardial β-1 AR receptors should result in rapid reversal of symptoms, as precedented with plasmapheresis.
+Added: We are developing BHV-1600 for the treatment of dilated cardiomyopathy.
+Added: Dilated cardiomyopathy is a condition where the cardiac muscle contracts less effectively, the chambers of the heart are enlarged and thinning of cardiac walls results.
+Added: This can lead to cardiac valvular incompetency, arrhythmias, thrombosis, and heart failure.
+Added: We expect to initiate Phase 1 studies of BHV-1600 in the second half of 2024.
+Added: We are evaluating and have not yet finalized potential clinical trial designs, including size and primary and secondary endpoints.
+Added: Oncology Platform
Antibody Recruiting Molecules
Antibody Recruiting Molecules (“ARMs”) are bispecific molecules that recruit endogenous antibodies to target cancer, virally infected cells, and disease-causing microorganisms for immune-mediated clearance.
−Removed: These molecules are engineered as modular components that are readily interchangeable, giving the platform tremendous flexibility for a variety of indications and therapy areas.
+Added: These molecules are
+Added: engineered as modular components that are readily interchangeable, giving the platform tremendous flexibility for a variety of indications and therapy areas.
By recruiting antibodies to coat the disease cell target, ARMs mark it for removal by the body’s innate antibody-mediated immune mechanisms (antibody dependent cellular cytotoxicity and antibody dependent cellular phagocytosis).
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Our Clinical Trial for BHV-1100 in Newly Diagnosed Multiple Myeloma Patients
−Removed: We have initiated dosing in a Phase 1a/1b trial in newly diagnosed multiple myeloma patients.
+Added: We have initiated dosing in a Phase 1a/1b trial in recovering, post-myeloablative multiple myeloma patients.
Our ARM, BHV-1100, in combination with autologous cytokine induced memory-like (“CIML”) NK cells and immune globulin (“Ig”), is expected to target and kill multiple myeloma cells expressing the cell surface protein CD38.
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This open-label single center Phase 1a/1b study assesses the safety and tolerability as well as exploratory efficacy endpoints in newly diagnosed multiple myeloma patients who have tested positive for minimal residual disease (“MRD+”) in first remission prior to autologous stem cell transplant (“ASCT”).
−Removed: We expect to enroll 30 newly diagnosed multiple
−Removed: myeloma patients.
+Added: We expect to enroll 30 newly diagnosed multiple myeloma patients.
The primary outcome measures are dose limiting toxicities following combination product administration (time frame:
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BHV-1100 Enhances Recruitment of NK Cells and Increases Killing of Multiple Myeloma Cells
−Removed: University of Connecticut License Option
−Removed: In October 2018, we signed an exclusive, worldwide option and license agreement with the University of Connecticut for the development and commercialization rights to UC1MT, a therapeutic antibody targeting extracellular metallothionein ("MT").
−Removed: Under this agreement, we had the option to acquire an exclusive, worldwide license to UC1MT and its underlying patents to develop and commercialize throughout the world in all human indications, which we exercised in September 2022.
−Removed: Extracellular MT has been implicated in the pathogenesis of autoimmune and inflammatory diseases.
−Removed: MTs are a family of low molecular weight, cysteine-rich, metal-binding proteins that have a wide range of functions in cellular homeostasis and immunity.
−Removed: MT has traditionally been considered to be an intracellular protein that can be found in both the cytoplasm and nucleus;
−Removed: however, MT also can be found in extracellular spaces, particularly in disease states involving chronic cellular stress where intracellular MT production is upregulated by inflammatory cytokines, and extracellular MT acts as a danger signal, attracting leukocytes and modulating the immune response.
−Removed: In preclinical studies, UC1MT has been observed to block this extracellular pool of MT and the resulting MT-mediated inflammation and immunomodulation.
−Removed: The Company is evaluating and has not yet finalized potential clinical trial designs, including trial size, and primary and secondary endpoints.
−Removed: Artizan Biosciences Inc License Option
−Removed: In December 2020, we entered into an Option and License Agreement with Artizan Biosciences Inc ("Artizan"), a biotechnology company focused on creating new classes of precision therapies targeting chronic inflammation and immune dysregulation by leveraging the human gut as a drug discovery tool.
−Removed: Pursuant to the agreement, we acquired an option to obtain a royalty-based license from Artizan to manufacture, use and commercialize certain products.
−Removed: Artizan will use the proceeds to continue advancing the preclinical research and development of its lead program for inflammatory bowel disease as well as to explore additional disease targets.
−Removed: In November 2021, we announced a collaborative therapeutic discovery and development program in Parkinson’s disease (“PD”), to exploit recent scientific advances in the understanding of pathogenic roles played by the gut microbiome in PD.
−Removed: In June 2022, we and Artizan executed a non-binding indication of interest (“Artizan Side Letter”) which describes terms under which we and Artizan would amend the 2020 Artizan Agreement to eliminate certain milestone payments required by us in exchange for limiting our option to the selection of the first (ARZC-001) licensed product.
−Removed: In the fourth quarter of 2022, Artizan was unable to secure additional financing to support it's ongoing operations, and, as a result, began reviewing strategic options for the sale of its assets, and secured a small bridge financing to fund operations during the strategic review.
−Removed: In January, Artizan severed substantially all of its employees and halted the PD program.
−Removed: Although Artizan anticipates bringing the inflammatory bowel disease program to the clinic in 2023, its ability to do so will be dependent on its access to adequate funding.
+Added: Antibody Drug Conjugates
+Added: We are using the MATE conjugation technology to generate site-specific antibody drug conjugates (“ADC”s) from native IgG1 proteins and have shown show superior stability in comparison with those using current industry-standard cysteine maleimide and click conjugation methodologies.
+Added: Our expectation is that the enhanced in vivo stability and expected superior physicochemical properties of these ADCs will lead to increased therapeutic indices in patients (more cytotoxic payload reaching cancer cells and less reaching normal tissues, as has been shown in vitro, in mice and cynomolgus).
+Added: Several site-specific ADCs, including BHV-1500, using the well validated valine-citrulline monomethyl auristatin E ("vcMMAE") payload linker system have been prepared and are undergoing biological testing in comparison with industry standard maleimide conjugated ADCs.
+Added: In January 2024, we acquired BHV-1510 through our acquisition of Pyramid Biosciences, Inc.
+Added: BHV-1510 is a next-generation Trophoblast Cell Surface Antigen 2 ("TROP-2") directed ADC employing an optimized next-generation construct with novel linker-payload and enzymatic, site-specific conjugation, targeting TROP2-expressing carcinomas.
+Added: Carcinoma refers to a malignant neoplasm of epithelial origin.
+Added: Carcinomas account for 80 to 90 percent of all cancer cases and several examples have been successfully treated with ADCs.
+Added: Abundant TROP-2 expression has been described for many carcinoma subtypes.
+Added: In preclinical TROP-2 expressing tumor models, BHV-1510 has shown improved antitumor activity versus other TROP-2 directed ADCs, in addition to improved plasma stability, more potent in vitro cytotoxicity, superior bystander effect, and greater immunogenic cell death with the novel TopoIx payload.
+Added: Improved and differentiated safety has been seen in cynomolgus monkey GLP toxicology studies, suggesting a wife therapeutic index.
+Added: BHV-1510 has similar favorable characteristics to our proprietary MATE conjugation technology, which should allow highly stable site-specific conjugation, resulting in a favorable PK, toxicity and manufacturability profile.
+Added: The IND for BHV-1510 was approved by the FDA in January 2024.
+Added: The First-in Human trial evaluating BHV-1510 in patients with advanced solid tumors is expected to start in the second quarter of 2024.
+Added: This trial consists of two parts;
+Added: Phase 1 dose escalation and Phase 2 dose expansion, in patients with advanced incurable cancer that have progressed on or are intolerant to standard therapy.
+Added: The primary objective of Phase 1 is safety, to identify a recommended dose for expansion ("RDE") or maximum tolerated dose.
+Added: Phase 1 dose escalation will be implemented based on a Bayesian optimal interval design, with the lowest dose initiated as a single patient cohort.
+Added: Patients are expected to be dosed in escalating cohorts, with dosing regimens administered intravenously every three weeks.
+Added: The Phase 2 dose expansion part of the study will consist of non-randomized efficacy finding expansion cohorts, defined by specific tumor types that will be treated at the RDE to estimate the anti-tumor activity of BHV-1510.
+Added: Up to approximately 170 subjects are planned to be evaluated.
+Added: BHV-1500 is a next-generation CD30-directed ADC employing a Biohaven proprietary site-specific conjugation (MATE reagent), targeting CD30-expressing tumors such as Hodgkin's and other lymphoma and the MMAE payload.
+Added: Hodgkin's lymphoma, also referred to as Hodgkin's Disease, is a malignant neoplasm of mesothelial origin.
+Added: Approximately 9,000 new Hodgkin's disease cases are diagnosed each year.
+Added: Hodgkin's disease and other CD30-expressing lymphoma are characterized by the uncontrolled growth of malignant lymphocytes or lymphoblasts.
+Added: Adcetris has demonstrated effectiveness in the treatment of Hodgkin's Lymphoma.
+Added: In preclinical CD30 expressing murine tumor models, BHV-1500 has shown improved antitumor activity versus Adcetris (brentuximab vedotin), and substantially improved safety, plasma stability and pharmacokinetics in monkeys.
+Added: We expect to submit an IND for BHV-1500 in 2024.
+Added: Clinical-Stage Milestones
+Added: Our clinical-stage milestones include the following:
The biotechnology and pharmaceutical industries are characterized by rapidly advancing technologies, intense competition and a strong emphasis on proprietary drugs.
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Any product candidates that we successfully develop and commercialize will compete with existing therapies and new therapies that may become available in the future.
−Removed: The key competitive factors affecting the success of all of our product candidates, if approved, are likely to be their safety, efficacy, convenience, price, the level of
−Removed: generic competition and the availability of coverage and reimbursement from government and other third-party payors.
+Added: The key competitive factors affecting the success of all of our product candidates, if approved, are likely to be their safety, efficacy, convenience, price, the level of generic competition and the availability of coverage and reimbursement from government and other third-party payors.
Many of the companies against which we are competing, or against which we may compete in the future, have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals and marketing approved drugs than we do.
Mergers and acquisitions in the pharmaceutical and biotechnology industries may result in even more resources being concentrated among a smaller number of our competitors.
−Removed: Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.
−Removed: These competitors also compete with us in recruiting and retaining qualified scientific and management
−Removed: personnel and establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.
+Added: Smaller or early-stage companies may also prove to be significant
+Added: competitors, particularly through collaborative arrangements with large and established companies.
+Added: These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.
Manufacturing
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We intend to develop and, if approved by the FDA, commercialize our product candidates in the United States, and we may enter into distribution or licensing arrangements for commercialization rights for other regions.
−Removed: With respect to our product candidates, we currently intend to build a neurological specialty sales force to manage commercialization for these product candidates, potentially in combination with a larger pharmaceutical partner, to maximize patient coverage in the United States and to support global expansion.
−Removed: Members of our management team and board of directors have deep experience leading neuroscience research and have been involved in the development and commercialization of drugs such as Abilify, Opdivo and, most recently, Nurtec ODT.
+Added: With respect to our product candidates, we currently intend to build a neurological specialty sales force to manage commercialization for these product candidates, potentially in combination with a larger
+Added: pharmaceutical partner, to maximize patient coverage in the United States and to support global expansion.
+Added: Members of our management team and board of directors have deep experience leading neuroscience research and have been involved in the development and commercialization of drugs such as Abilify, Opdivo and, most recently, Nurtec ODT and Zavzpret.
Our Chief Executive Officer, Vlad Coric, M.D.
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We consider the overall protection of our patents, trademarks, licenses and other intellectual property rights to be of material value and act to protect these rights from infringement.
−Removed: We also rely on trade
−Removed: secrets to protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection.
+Added: We also rely on trade secrets to protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection.
Our success will depend significantly on our ability to obtain and maintain patent and other proprietary protection for commercially important technology, inventions and know-how related to our business, defend and enforce our patents, preserve the confidentiality of our trade secrets and operate without infringing the valid and enforceable patents and other proprietary rights of third parties.
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Patents provide the innovator with the right to exclude others from practicing an invention related to the medicine.
−Removed: Patents may cover, among other things, the active ingredient(s), various uses of a drug product, discovery tools, pharmaceutical formulations, drug delivery mechanisms and processes for (or intermediates useful in) the manufacture of products.
+Added: Patents may cover, among other things, the active ingredient(s),
+Added: various uses of a drug product, discovery tools, pharmaceutical formulations, drug delivery mechanisms and processes for (or intermediates useful in) the manufacture of products.
Protection for individual products extends for varying periods in accordance with the expiration dates of patents in the various countries.
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We have many U.S.
−Removed: and foreign patents and patent applications in our portfolio related to the composition of matter, methods of use, methods of manufacture or formulations of our product candidates which have been filed in major markets throughout the world, including
−Removed: the U.S., Europe, Japan, Korea, China, Hong Kong and Australia.
+Added: and foreign patents and patent applications in our portfolio related to the composition of matter, methods of use, methods of manufacture or formulations of our product candidates which have been filed in major markets throughout the world, including the U.S., Europe, the United Kingdom, Japan, Korea, China, Hong Kong and Australia.
In April 2022, we acquired Channel Biosciences, LLC.
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Patent 10,851,067 (the “‘067 Patent”), issued December 1, 2020, specifically claims BHV-7000 and will expire in March 2039, not including possible patent term extensions.
−Removed: counterparts to the ‘067 patent are pending in Australia, Brazil, Canada, China, European Union, United Kingdom, Hong Kong, Israel, India, Japan, Republic of Korea, Mexico, New Zealand, Singapore and South Africa.
−Removed: If granted, the ex-U.S.
−Removed: patents will expire in March 2039, not including possible patent term extensions in countries where such extensions are available.
+Added: counterparts to the ‘067 patent have been granted in Australia and Mexico, and patent applications to the ‘067 patent are pending in Brazil, Canada, China, European Union, United Kingdom, Hong Kong, Israel, India, Japan, Republic of Korea, New Zealand, Singapore and South Africa.
+Added: patents, and patent applications, if granted, will expire in March 2039, not including possible patent term extensions in countries where such extensions are available.
In addition, U.S.
Patent 9,481,653 (the “‘653 patent”), issued November 1, 2016, claims a class of compounds including BHV-7000 and will expire in September 2035, not including possible patent term extensions.
−Removed: Ex-US counterparts to the ‘653 patent are granted in Belgium, Switzerland, Germany, Denmark, Spain, Finland, France, United Kingdom, Ireland, Iceland, Italy, Netherlands, Norway and Sweden.
+Added: Ex-US counterparts to the ‘653 patent are granted in Belgium, Switzerland, Germany,
+Added: Denmark, Spain, Finland, France, United Kingdom, Ireland, Iceland, Italy, Netherlands, Norway and Sweden.
patents will expire in September 2035, not including possible patent term extensions in countries where such extensions are available.
−Removed: We own a portfolio of patents and patent applications in the U.S.
+Added: In addition, PCT/US23/10295, PCT/US23/63111, PCT/US23/63113 and PCT/US23/63115 directed to various Kv7 activator chemotypes were filed in January and February 2023.
+Added: These applications are pending in the United States Receiving Office of the Patent Cooperation Treaty and all countries were designated for filing.
+Added: The patent applications, if granted, will expire in January/February 2043, not including possible patent term extensions in countries where such extensions are available.
+Added: Other patent application directed to the combination treatment with a Kv7 activator and N-methyl-D-aspartate ("NMDA") receptor antagonist (PCT/US23/73125), a Kv7 activator and glutamate modulator (PCT/US23/73504), and a Kv7 activator and TDP-43 binder (PCT/US23/73491) were filed in August and September 2023.
+Added: These applications are pending in the United States Receiving Office of the Patent Cooperation Treaty and all countries were designated for filing.
+Added: The patent applications, if granted, will expire in August/September 2043, not including possible patent term extensions in countries where such extensions are available.
+Added: We have a portfolio of patents and patent applications in the U.S.
and foreign countries directed to prodrugs of riluzole, including, among others, U.S.
1 unchanged sentence
This patent expires in February 2036, not including possible patent term extensions.
−Removed: Ex-US counterparts to the ‘791 patent have been granted in Albania, Armenia, Austria, Australia, Azerbaijan, Belgium, Bulgaria, Belarus, Canada, Switzerland, China, Cyprus, Czechia, Germany, Denmark, Estonia, Spain, Finland, France, United Kingdom, Greece, Hong Kong, Croatia, Hungary, Ireland, Israel, Italy, Japan, Kyrgyzstan, Kazakhstan, Lithuania, Luxembourg, Latvia, Monaco, North Macedonia, Malta, Mexico, Netherlands, Norway, Philippines, Poland, Portugal, Romania, Serbia, Russia, Sweden, Slovenia, Slovakia, Tajikistan, Turkmenistan, Turkey and South Africa, and patent applications are pending in Brazil, India, Republic of Korea, Macao and Singapore.
+Added: Ex-US counterparts to the ‘791 patent have been granted in Albania, Armenia, Austria, Australia, Azerbaijan, Belgium, Brazil, Bulgaria, Belarus, Canada, Switzerland, China, Cyprus, Czechia, Germany, Denmark, Estonia, Spain, Finland, France, United Kingdom, Greece, Hong Kong, Croatia, Hungary, India, Ireland, Israel, Italy, Japan, Kyrgyzstan, Kazakhstan, Lithuania, Luxembourg, Latvia, Monaco, North Macedonia, Macao, Malta, Mexico, Netherlands, Norway, Philippines, Poland, Portugal, Republic of Korea, Romania, Serbia, Russia, Sweden, Slovenia, Slovakia, Tajikistan, Turkmenistan, Turkey and South Africa, and a patent application is pending in Singapore.
The ex-US patents and patent applications will expire in February 2036, not including possible patent term extensions in countries where such extensions are available.
In addition, the use of these compounds for treating OCD, ALS, SCA, depression, Alzheimer’s Disease and other diseases are described and claimed in these patents and patent applications.
−Removed: We own these patent applications subject to an
−Removed: agreement with ALS Biopharma and FCCDC.
+Added: These patent applications are subject to an agreement with ALS Biopharma and FCCDC.
In addition, we have filed patent applications relating to drug product formulations containing troriluzole and methods of using the formulations to treat various diseases, including, for example, the use of troriluzole with immunotherapies to treat cancer, including among others U.S.
−Removed: Patent 11,400,155, issued August 2, 2022, which expires in May 2037, not including possible patent term extensions.
−Removed: Ex-US counterparts to the ‘155 patent have been granted in Albania, Austria, Australia, Belgium, Bulgaria, Switzerland, China, Cyprus, Czechia, Germany, Denmark, Estonia, Spain, Finland, France, United Kingdom, Greece, Hong Kong, Croatia, Hungary, Ireland, Italy, Republic of Korea, Lithuania, Luxembourg, Latvia, Monaco, North Macedonia, Malta, Netherlands, Norway, Poland, Portugal, Romania, Serbia, Sweden, Slovenia and Slovakia and patent applications are pending in Brazil, Canada, India, Israel, Japan, Mexico, Philippines, Singapore and South Africa.
+Added: 11,400,155, issued August 2, 2022, which expires in May 2037, not including possible patent term extensions.
+Added: Ex-US counterparts to the ‘155 patent have been granted in Albania, Austria, Australia, Belgium, Bulgaria, Switzerland, China, Cyprus, Czechia, Germany, Denmark, Estonia, Spain, Finland, France, United Kingdom, Greece, Hong Kong, Croatia, Hungary, Israel, Ireland, Italy, Japan, Republic of Korea, Lithuania, Luxembourg, Latvia, Mexico, Monaco, North Macedonia, Malta, Netherlands, Norway, Poland, Portugal, Romania, Serbia, Sweden, Slovenia, Slovakia and South Africa and patent applications are pending in Brazil, Canada, India, Philippines and Singapore.
The ex-US patents and patent applications will expire in May 2037, not including possible patent term extensions in countries where such extensions are available.
−Removed: In September 2018, we in-licensed patents from AstraZeneca relating to the composition of matter of verdiperstat, pharmaceutical compositions and various neurological diseases including muscular system atrophy.
−Removed: Patent 7,829,707, issued November 9, 2010, U.S.
−Removed: Patent 8,859,568, issued October 14, 2014, and U.S.
−Removed: Patent 9,580,429, issued February 28, 2017, are directed to compositions of matter of verdiperstat and other compounds, pharmaceutical compositions of verdiperstat and methods of treating diseases.
−Removed: patents expire in December 2025 not including patent term adjustments and extensions.
−Removed: Ex-US counterparts to the U.S.
−Removed: patents have been granted in Australia, Canada, Switzerland, China, Germany, Spain, France, United Kingdom, Hong Kong, India, Italy, Japan, Republic of Korea, Mexico, Russia, Sweden, and Turkey, and a patent application is pending in Brazil.
−Removed: The ex-US patents and patent applications will expire in December 2025, not including possible patent term extensions in countries where such extensions are available.
−Removed: 17/766539, filed April 5, 2022, is directed to novel prodrug forms of verdiperstat.
−Removed: Ex-US counterparts to the ‘539 application have been filed in Australia, Brazil, Canada, China, European Union, United Kingdom, Israel, India, Japan, Republic of Korea, Mexico, New Zealand, Singapore and South Africa.
−Removed: The ex-US patents and patent applications will expire in October 2040, not including possible patent term extensions in countries where such extensions are available.
+Added: In addition, a patent application directed to the use of troriluzole for treating various SCA genotypes was filed in November 2018 (PCT/US18/60232) and national applications are pending in major jurisdictions with patents granted in Japan and Mexico.
+Added: Another patent application directed to the treatment of SCA3 (PCT/US23/67326) was filed in May 2023 and is pending in the United States Receiving Office of the Patent Cooperation Treaty and all countries were designated for filing.
+Added: These patents, if granted, will expire in 2038 through 2043, not including possible patent term extensions in countries where such extensions are available.
+Added: Also, a patent application directed to the use of troriluzole for treating OCD was filed in June 2021 (PCT/US21/38789) and national applications are pending in major jurisdictions.
+Added: These patents, if granted, will expire in 2041, not including possible patent term extensions in countries where such extensions are available.
+Added: Another patent application directed to the treatment of glioblastoma (PCT/US23/69038) was filed June 26, 2023 and is pending in the United States Receiving Office of the Patent Cooperation Treaty and all PCT countries were designated for filing.
MoDEs Platform, ARMs, MATEs
In January 2021, we entered into a worldwide, exclusive license agreement with Yale University for the development and commercialization of a novel Molecular Degrader of Extracellular Protein (MoDEs) platform.
−Removed: The platform pertains to the clearance of disease-causing protein and other biomolecules by
−Removed: targeting them for lysosomal degradation using multi-functional molecules.
+Added: The platform pertains to the clearance of disease-causing protein and other biomolecules by targeting them for lysosomal degradation using multi-functional molecules.
The platform is differentiated from existing approaches in that it does not rely on ubiquitin ligases, and it allows for a broad range of targets to be degraded.
1 unchanged sentence
17/046221, filed October 8, 2020, relates to bifunctional small molecules to target selective degradation of circulating proteins.
−Removed: Ex-US counterparts to the '221 application have been filed in China, European Union and Hong Kong and, if granted, will expire in April 2039, not including possible patent term extensions in countries where such extensions are available.
+Added: Ex-US counterparts to the '221 application have been filed in China, European Union and Hong Kong and, if granted, will expire in April 2039, not including possible patent term extensions in countries where such
+Added: extensions are available.
17/768166, filed April 11, 2022, relates to bifunctional compounds as degraders of autoantibodies.
Ex-US counterparts to the '166 application have been filed in the United Arab Emirates, Australia, Brazil, Canada, China, European Union, Israel, Japan, Republic of Korea, Mexico, Philippines, Saudi Arabia, Singapore, and South Africa and, if granted, will expire in October 2040, not including possible patent term extensions in countries where such extensions are available.
−Removed: 17/046192, filed October 8, 202, relates to bifunctional molecules to degrade circulating proteins.
+Added: 17/046192, filed October 8, 2020 and issued as U.S.
+Added: 11,767,301 on September 26, 2023, relates to bifunctional molecules to degrade circulating proteins.
Ex-US counterparts to the '192 application have been filed in the European Union and Hong Kong, and, if granted, will expire in April 2039, not including possible patent term extensions in countries where such extensions are available.
17/768145, filed April 11, 2022 relates to engineered antibodies as molecular degraders through cellular receptors.
−Removed: Ex-US counterparts to the '145 application have been filed in the , was filed in the United Arab Emirates, Australia, Brazil, Canada, China, countries of the Eurasian Patent Organization, European Union, Israel, India, Japan, Republic of Korea, Mexico, New Zealand, Philippines, Saudi Arabia, South Africa and Singapore and, if granted, will expire in October 2040, not including possible patent term extensions in countries where such extensions are available.
−Removed: PCT/US2022/017319, filed February 22, 2022, which relates to targeted bifunctional degraders, is pending in the United States Receiving Office of the Patent Cooperation Treaty and all countries were designated for filing.
+Added: Ex-US counterparts to the '145 application have been filed in the United Arab Emirates, Australia, Brazil, Canada, China, countries of the Eurasian Patent Organization, European Union, Israel, India, Japan, Republic of Korea, Mexico, New Zealand, Philippines, Saudi Arabia, South Africa and Singapore and, if granted, will expire in October 2040, not including possible patent term extensions in countries where such extensions are available.
+Added: PCT/US2022/017319, which relates to targeted bifunctional degraders, was filed February 22, 2022, and national applications are pending in the United States and major jurisdictions worldwide.
The patent applications, if granted, will expire in February 2042, not including possible patent term extensions in countries where such extensions are available.
−Removed: PCT/US2022/019658, which relates to bifunctional degraders of galactose deficient immunoglobulins, filed March 10, 2022, is pending in the United States Receiving Office of the Patent Cooperation Treaty and all countries were designated for filing.
+Added: PCT/US2022/019658, which relates to bifunctional degraders of galactose deficient immunoglobulins, was filed March 10, 2022, and is pending in the United States and major jurisdictions worldwide.
The patent applications, if granted, will expire in March 2042, not including possible patent term extensions in countries where such extensions are available.
+Added: PCT/US2022/075527 and PCT/US2022/075535, filed August 26, 2022, which relate to difunctional degraders of pathogenic anti-β1ECII (the second extracellular loop of the β1 adrenergic receptor) autoantibodies, are pending in the United States Receiving Office of the Patent Cooperation Treaty and all countries were designated for filing.
We also acquired Kleo Pharmaceuticals, Inc.
in January 2021.
−Removed: This acquisition included Kleo’s proprietary technology platforms which are modular in design and enable rapid generation of novel immunotherapies that can be optimized against
−Removed: specified biological targets and combined with existing cell- or antibody-based therapies.
−Removed: These include Antibody Recruiting Molecules (ARMs) and Monoclonal Antibody Therapy Enhancers (MATEs), which complement the MoDEs technology licensed from Yale.
−Removed: 17/769924, filed November 19, 2020, relates to directed conjugation technologies.
−Removed: Ex-US counterparts to the '924 application have been filed in the United Arab Emirates, Australia, Brazil, Canada, China, countries of the Eurasian Patent Organization, European Union, Israel, India, Japan, Republic of Korea, Mexico, New Zealand, Philippines, Saudi Arabia, South Africa and Singapore and, if granted, will expire in November 2040, not including possible patent term extensions in countries where such extensions are available.
+Added: This acquisition included Kleo’s proprietary technology platforms which are modular in design and enable rapid generation of novel immunotherapies that can be optimized against specified biological targets and combined with existing cell- or antibody-based therapies.
+Added: These include ARMs and MATEs, which complement the MoDEs technology licensed from Yale.
+Added: 17/769924, filed April 18, 2022, relates to directed conjugation technologies.
+Added: Ex-US counterparts to the '924 application have been filed in the United Arab Emirates, Australia, Brazil, Canada, China, countries of the Eurasian Patent
+Added: Organization, European Union, Israel, India, Japan, Republic of Korea, Mexico, New Zealand, Philippines, Saudi Arabia, South Africa and Singapore and, if granted, will expire in November 2040, not including possible patent term extensions in countries where such extensions are available.
17/912563, filed September 19, 2022, relates to technologies for treating COVID infections.
Ex-US counterparts to the '563 application have been filed in the United Arab Emirates, Australia, Brazil, Canada, China, countries of the Eurasian Patent Organization, European Union, Israel, India, Japan, Republic of Korea, Mexico, New Zealand, Philippines, Saudi Arabia, South Africa and Singapore and, if granted, will expire in March 2041, not including possible patent term extensions in countries where such extensions are available.
−Removed: PCT/US2022/015390, filed February 6, 2022, which relates to technologies for preventing or treating infections, is pending in the United States Receiving Office of the Patent Cooperation Treaty and all countries were designated for filing.
+Added: PCT/US2022/015390, which relates to technologies for preventing or treating infections, was filed February 6, 2022 and national applications are pending in the United States and major jurisdictions worldwide.
The patent applications, if granted, will expire in February 2042, not including possible patent term extensions in countries where such extensions are available.
−Removed: PCT/US2022/029533, filed May 17, 2022, which relates to compositions including conjugated therapy enhancers, is pending in the United States Receiving Office of the Patent Cooperation Treaty and all countries were designated for filing.
+Added: PCT/US2022/029533, which relates to compositions including conjugated therapy enhancers, was filed May 17, 2022 and national applications are pending in the United States and major jurisdictions worldwide.
The patent applications, if granted, will expire in May 2042, not including possible patent term extensions in countries where such extensions are available.
−Removed: PCT/US2022/029535, filed May 17, 2022, which relates to agents for directed conjugation techniques and conjugated products, is pending in the United States Receiving Office of the Patent Cooperation Treaty and all countries were designated for filing.
+Added: PCT/US2022/029535, which relates to agents for directed conjugation techniques and conjugated products, was filed May 17, 2022 and national applications are pending in the United States and major jurisdictions worldwide.
The patent applications, if granted, will expire in May 2042, not including possible patent term extensions in countries where such extensions are available.
−Removed: PCT/US2022/030070, filed May 19, 2022, which relates to antibody drug conjugates using MATE technology for delivering cytotoxic agents, is pending in the United States Receiving Office of the Patent Cooperation Treaty and all countries were designated for filing.
+Added: PCT/US2022/030070, which relates to antibody drug conjugates using MATE technology for delivering cytotoxic agents, was filed May 19, 2022 and national applications are pending in the United States and major jurisdictions worldwide.
The patent applications, if granted, will expire in May 2042, not including possible patent term extensions in countries where such extensions are available.
−Removed: We have pending patent applications covering the composition of matter of compounds targeting TDP-43 in neurodegeneration.
−Removed: TDP-43, transactive response
−Removed: (TAR)-DNA protein-43, is a multifunctional nucleic acid-binding protein that is implicated in neurodegeneration.
−Removed: Mutations in the gene that encodes for TDP-43 cause familial and sporadic amyotrophic lateral sclerosis (“ALS”) and frontotemporal dementia (“FTD”).
−Removed: Cytoplasmic TDP-43 aggregates are the neuropathological hallmark of ALS-FTD spectrum disorders.
−Removed: 17/635421, filed February 15, 2022, relates to compounds that target TDP-43.
−Removed: Ex-US counterparts to the '421 application have been filed in Australia, Brazil, Canada, China, countries of the Eurasian Patent Organization, European Union, Israel, India, Japan, Republic of Korea, Mexico, Philippines, South Africa and Singapore and, if granted, will expire in August 2040, not including possible patent term extensions in countries where such extensions are available.
−Removed: PCT/US2022/017116, filed February 20, 2022, which relates to compounds that target TDP-43 for the treatment of ALS and related disorders, is pending in the United States Receiving Office of the Patent Cooperation Treaty and all countries were designated for filing.
−Removed: The patent applications, if granted, will expire in February 2042, not including possible patent term extensions in countries where such extensions are available.
−Removed: IBD and Parkinson’s Disease
−Removed: In December 2020, we entered into an option and license agreement with Artizan Biosciences directed toward the development and commercialization of novel treatments for inflammatory bowel disease (“IBD”) and other gastrointestinal inflammatory disorders, e.g., Crohn’s disease, in the U.S.
−Removed: Under the terms of the agreement, we have the rights to exercise an option on up to three product candidates.
−Removed: In June 2021, we entered into a separate worldwide, exclusive license agreement under the IgA-SEQ patented technology with Artizan to develop and commercialize certain of their compounds for use in Parkinson’s Disease.
−Removed: Patent 9,758,838, issued September 12, 2017, U.S.
−Removed: Patent 10,428,392, issued October 1, 2019, U.S.
−Removed: Patent 10,774,392, issued September 15, 2020, and U.S.
−Removed: Patent 11,299,790, issued April 12, 2022, relate to compositions and methods for identifying secretory antibody microbes.
−Removed: These patents expire in March 2034, not including possible patent term extensions.
−Removed: 15/507357, filed February 28, 2017 and issued as U.S.
−Removed: Patent 10,925,953 on February 23, 2021, relates to compositions and methods for treating an inflammatory disease or disorder.
−Removed: An ex-US counterpart to the '953 application has also been filed in the European Union and will expire in August 2035, not including possible patent term extensions.
−Removed: 17/253333, filed December 17, 2019, relates to compositions and methods for treating inflammatory diseases.
−Removed: Ex-US counterparts to the '333 application have been filed in the United Arab Emirates, Australia, Brazil, Canada, China, European Union, Hong Kong, Israel, Japan, Republic of Korea, Mexico, New Zealand, Russia, South Africa and Singapore and, if granted, will expire in July 2039, not including possible patent term extensions in countries where such extensions are available.
−Removed: US2021/050048, filed September 13, 2021, which relates to small molecule inhibitors of bacterial toxins, is pending the United States Receiving Office of the Patent Cooperation Treaty and all countries were designated for filing.
−Removed: The counterpart application is also pending in Taiwan.
−Removed: The patent applications, if granted, will expire in September 2041, not including possible patent term extensions in countries where such extensions are available.
−Removed: PCT/US2022/012472, filed January 14, 2022, which relates to compositions and methods for treating and preventing diseases or disorders using inter-species interactions, is pending in the United States Receiving Office of the Patent Cooperation Treaty and all countries were designated for filing.
In January 2022, we entered into an exclusive global license and research agreement to develop and commercialize TRPM3 antagonists to address the growing proportion of people worldwide living with chronic pain disorders.
The TRPM3 antagonist platform was discovered at the Centre for Drug Design and Discovery (“CD3”) and the Laboratory of Ion Channel Research (“LICR”) at Katholieke Universiteit Leuven (KU Leuven).
−Removed: PCT/EP2021/082853, filed November 24, 2021, which relates to aryl derivatives for treating TRPM3 mediated disorders, is pending in the European Receiving Office of the Patent Cooperation Treaty and all countries were designated for filing.
−Removed: A counterpart application is also pending in Taiwan.
+Added: PCT/EP2021/082853, which relates to aryl derivatives for treating TRPM3 mediated disorders, was filed November 24, 2021 and national applications are pending in the United Arab Emirates, Australia, Brazil, Canada, China, countries of the Eurasian Patent Organization, European Union, Israel, India, Japan,
+Added: Republic of Korea, Mexico, New Zealand, Philippines, Saudi Arabia, South Africa, Singapore, Taiwan and the U.S.
The patent applications, if granted, will expire in November 2041, not including possible patent term extensions in countries where such extensions are available.
−Removed: PCT/EP2021/082865, filed November 24, 2021, which relates to heterocycle derivatives for treating TRPM3 mediated disorders, is pending in the European Receiving Office of the Patent Cooperation Treaty and all countries were designated for filing.
−Removed: A counterpart application is also pending in Taiwan.
+Added: PCT/EP2021/082865, which relates to heterocycle derivatives for treating TRPM3 mediated disorders, was filed November 24, 2021 and national applications are pending in the United Arab Emirates, Australia, Brazil, Canada, China, Eurasia, European Union, Israel, Japan, Republic of Korea, Mexico, New Zealand, Philippines, Saudi Arabia, Singapore, Taiwan, South Africa and the U.S.
The patent applications, if granted, will expire in November 2041, not including possible patent term extensions in countries where such extensions are available.
−Removed: Patent 9,194,863, issued November 24, 2015, which relates to screening methods for analgesic agents, has also been granted in Belgium, Switzerland, Germany, Denmark, Spain, Finland, France, United Kingdom, Ireland, Israel, Italy, Netherlands and Sweden.
+Added: Patent 9,194,863, issued November 24, 2015, which relates to screening methods for analgesic agents, has also been granted in Belgium, Switzerland, Germany, Denmark, Spain, Finland, France, United Kingdom, Ireland, Italy, Netherlands and Sweden.
The patents, will expire in May 2032, not including possible patent term extensions in countries where such extensions are available.
+Added: In addition, seven PCT applications directed to various TRPM3 antagonist chemotypes were filed in May 2023 (PCT/EP2023/063992, PCT/EP2023/063994, PCT/EP2023/063996, PCT/EP2023/063997, PCT/US2023/067443, PCT/US2023/067446, PCT/US2023/067448).
+Added: The patent applications, if granted, will expire in May 2043, not including possible patent term extensions in countries where such extensions are available.
In December 2021, we entered into a worldwide license agreement with Bristol Myers Squibb for the global development and commercialization rights to taldefgrobep alfa (BHV-2000), a novel, Phase 3-ready anti-myostatin adnectin.
2 unchanged sentences
Patent 8,933,199, issued January 13, 2015, U.S.
−Removed: 8,933,265, issued March 31, 2015, U.S.
+Added: Patent 8,993,265, issued March 31, 2015, U.S.
Patent 9,493,546, issued November 15, 2016, U.S.
Patent 9,662,373, issued May 30, 2017, U.S.
−Removed: Patent 10,245,302, issued April 2, 2019, and U.S.
−Removed: Patent 10,406,212, issued September 10, 2019, are directed to fibronectin based scaffold domain proteins that bind to myostatin.
+Added: Patent 10,245,302, issued April 2, 2019, U.S.
+Added: Patent 10,406,212, issued September 10, 2019, and U.S.
+Added: Patent 11,813,315, issued November 14, 2023, are directed to fibronectin based scaffold domain proteins that bind to myostatin.
patents expire in September 2033, not including possible patent term extensions.
Ex-US counterparts to the U.S.
−Removed: patents have been granted in Argentina, Austria, Australia, Belgium, Bulgaria, Brazil, Canada, Switzerland, Chile, China, Colombia, Czechia, Germany, Denmark, Algeria, Egypt, Spain, Finland, France, United Kingdom, Greece, Hong Kong, Croatia, Hungary, Indonesia, Ireland, Israel, India, Italy, Japan, Republic of Korea, Lithuania, Morocco, Macao, Mexico, Malaysia, Netherlands, Norway, New Zealand, Peru, Philippines, Poland, Portugal, Romania, Serbia, Russia, Sweden, Singapore, Slovenia, Slovakia, Thailand, Tunisia, Turkey, Taiwan, Uruguay, Venezuela, Vietnam and South Africa.
+Added: patents have been granted in Argentina, Austria, Australia, Belgium, Bulgaria, Brazil, Canada, Switzerland, Chile, China, Colombia, Czechia, Germany, Denmark, Algeria, Egypt, Spain, Finland, France, United Kingdom, Greece, Hong Kong, Croatia, Hungary, Indonesia, Ireland, Israel, India, Italy, Japan, Republic of Korea, Lithuania, Morocco, Macao, Mexico, Malaysia, Netherlands, Norway, New Zealand, Peru, Philippines, Poland, Portugal, Romania, Serbia, Russia, Sweden, Singapore, Slovenia, Slovakia,
+Added: Thailand, Tunisia, Turkey, Taiwan, Uruguay, Venezuela, Vietnam and South Africa.
The ex-US patents will expire in September 2033, not including possible patent term extensions in countries where such extensions are available.
16/607688, filed May 3, 2018, relates to stable formulations fibronectin based scaffold domain proteins that bind to myostatin.
−Removed: Ex-US counterparts to the '688 application have been filed in Australia, Canada, China, European Union, Hong Kong, Israel, Japan, Republic of Korea, Mexico, Singapore and Taiwan and, if granted, will expire in May 2038, not including possible patent term extensions in countries where such extensions are available.
+Added: Ex-US counterparts to the '688 application have been granted in Japan and are pending in Australia, Canada, China, European Union, Hong Kong, Israel, Republic of Korea, Mexico, Singapore and Taiwan.
+Added: The ex-US patents and patent applications, if granted, will expire in May 2038, not including possible patent term extensions in countries where such extensions are available.
+Added: In March 2023, we entered into an exclusive, worldwide (excluding People’s Republic of China and its territories and possessions) license agreement with Highlightll pursuant to which we obtained the right to research, develop, manufacture and commercialize Highlightll’s brain penetrant dual TYK2/JAK1 inhibitor program
+Added: Patent RE49834 (the “‘834 Patent”), having an issue date of February 13, 2024, is directed to BHV-8000 and will expire in September 2037, not including possible patent term extensions.
+Added: counterparts to the ‘834 patent have been granted in Australia, European Union, Israel, Japan, Mexico, and New Zealand, and patent applications to the ‘834 patent are pending in Brazil, Canada, Eurasia, India, and Republic of Korea.
+Added: patents and patent applications, if granted, will expire in September 2037, not including possible patent term extensions in countries where such extensions are available.
+Added: In addition, PCT/CN2022/113807, filed August 22, 2022, which relate to methods of treating CNS disorders with dual TYK2/JAK1 inhibitors, is pending in the CNIPA Receiving Office of the Patent Cooperation Treaty and all countries were designated for filing.
+Added: The patent applications, if granted, will expire in August 2042, not including possible patent term extensions in countries where such extensions are available.
Licensing and Other Agreements
1 unchanged sentence
The licensing and other agreements typically include, among other terms and conditions, non-refundable upfront license fees, option fees and option exercise payments, milestone payments and royalties.
−Removed: See Note 11, "Licensing and Other Agreements," to the Consolidated Financial Statements included in this report for additional information regarding our licenses and other agreements.
+Added: See Note 11, "License Agreements," to the Consolidated Financial Statements included in this report for additional information regarding our licenses and other agreements.
Government Regulation
−Removed: In the United States, the FDA regulates drugs under the Federal Food, Drug and Cosmetic Act ("FDCA") and its implementing regulations.
+Added: In the United States, the FDA regulates drugs under the Federal Food, Drug and Cosmetic Act
+Added: ("FDCA") and its implementing regulations.
The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations requires the expenditure of substantial time and financial resources.
Failure to comply with the applicable U.S.
−Removed: requirements at any time during the product development process, approval process or after approval may subject an applicant and/or sponsor to a variety of administrative or judicial sanctions, including imposition of a clinical hold, refusal by the FDA to approve applications, withdrawal of an approval, import/export delays, issuance of warning letters and other types of enforcement letters, product recalls, product seizures, total or partial
−Removed: suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement of profits, or civil or criminal investigations and penalties brought by the FDA and the Department of Justice or other governmental entities.
+Added: requirements at any time during the product development process, approval process or after approval may subject an applicant and/or sponsor to a variety of administrative or judicial sanctions, including imposition of a clinical hold, refusal by the FDA to approve applications, withdrawal of an approval, import/export delays, issuance of warning letters and other types of enforcement letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement of profits, or civil or criminal investigations and penalties brought by the FDA and the Department of Justice or other governmental entities.
The clinical testing, manufacturing, labeling, storage, distribution, record keeping, advertising, promotion, import, export and marketing, among other things, of our product candidates are governed by extensive regulation by governmental authorities in the United States and other countries.
The FDA, under the FDCA, regulates pharmaceutical products in the United States.
−Removed: Key steps required before a drug may be approved for marketing in the United States generally include:
−Removed: • preclinical laboratory tests and animal tests conducted under Good Laboratory Practices ("GLP");
−Removed: • the submission to the FDA of an investigational new drug ("IND") application for human clinical testing, which must become effective before human clinical trials commence;
+Added: The steps required before a drug may be approved for marketing in the United States generally include:
+Added: • nonclinical laboratory tests and animal tests conducted under Good Laboratory Practices ("GLP");
+Added: • the submission to the FDA of an IND application for human clinical testing, which must become effective before human clinical trials commence;
• approval by an independent institutional review board ("IRB"), representing each clinical site before each clinical trial may be initiated;
• adequate and well-controlled human clinical trials to establish the safety and efficacy of the product for each indication and conducted in accordance with Good Clinical Practices ("GCP");
−Removed: • the preparation and submission to the FDA of a New Drug Application ("NDA");
+Added: • the preparation and submission to the FDA of an NDA;
• FDA acceptance, review and approval of the NDA, which might include an Advisory Committee review;
1 unchanged sentence
The testing and approval process requires substantial time, effort and financial resources, and the receipt and timing of any approval is uncertain.
−Removed: The FDA may suspend clinical trials at any time on various grounds, including a finding that the subjects or patients are being exposed to an unacceptable health risk.
−Removed: Preclinical and Human Clinical Trials in Support of an NDA
−Removed: Preclinical studies include laboratory evaluations of the product candidate, as well as in vitro and animal studies to gather information on the safety and activity of the product candidate.
−Removed: The conduct of preclinical trials is subject to federal regulations and requirements including GLP regulations.
−Removed: The results of the preclinical studies, together with manufacturing information and analytical data, among other things, are submitted to the FDA as part of the IND, which must become effective
−Removed: before clinical trials may be commenced.
+Added: The FDA may suspend clinical trials at any time on various
+Added: grounds, including a finding that the subjects or patients are being exposed to an unacceptable health risk.
+Added: Nonclinical and Human Clinical Trials in Support of an NDA
+Added: Nonclinical studies include laboratory evaluations of the product candidate, as well as in vitro and animal studies to gather information on the safety and efficacy of the product candidate.
+Added: The conduct of nonclinical trials is subject to federal regulations and requirements including GLP regulations.
+Added: The results of the nonclinical studies, together with manufacturing information and analytical data, among other things, are submitted to the FDA as part of the IND, which must become effective before clinical trials may be commenced.
The IND will become effective automatically 30 days after receipt by the FDA, unless the FDA raises concerns or questions about the conduct of the trials as outlined in the IND prior to that time.
2 unchanged sentences
Clinical trials involve the administration of the product candidate to human subjects under the supervision of qualified investigators in accordance with GCP requirements.
−Removed: Each clinical trial must be reviewed and approved by an Institutional Review Board ("IRB") at each of the sites at which the trial will be conducted.
+Added: Each clinical trial must be reviewed and approved by an IRB at each of the sites at which the trial will be conducted.
The IRB will consider, among other things, ethical factors, the safety of human subjects and the possible liability of the institution.
8 unchanged sentences
Failure to promptly conduct any required Phase 4 clinical trials could result in enforcement action or withdrawal of approval.
−Removed: A Phase 2/3 trial design, which we have used in our troriluzole development program, is often used in the
−Removed: development of pharmaceutical and biological products.
+Added: A Phase 2/3 trial design, which we have used in our troriluzole development program, is often used in the development of pharmaceutical and biological products.
The trial includes Phase 2 elements, such as an early interim analysis of safety or activity, and Phase 3 elements, such as larger patient populations with less restrictive enrollment criteria.
−Removed: The early interim analysis of clinical or physiologic activity and/or safety allows the study to be stopped, changed or continued before a large number of patients have been enrolled, while still allowing all data from enrolled patients to count in the analysis used to support approval.
+Added: An early interim analysis of clinical or physiologic activity and/or safety allows the study to be stopped, changed or continued before a large number of patients have been enrolled, while still allowing all data from enrolled patients to count in the analysis used to support approval.
Submission and Review of an NDA
−Removed: The results of preclinical studies and clinical trials, together with detailed information on the product's manufacture, composition, quality, controls and proposed labeling, among other things, are submitted to the FDA in the form of an NDA, requesting approval to market the product.
+Added: The results of nonclinical studies and clinical trials, together with detailed information on the product's manufacture, composition, quality, controls and proposed labeling, among other things, are submitted to the FDA in the form of an NDA, requesting approval to market the product.
The application must be accompanied by a significant user fee payment, which typically increases annually, although waivers may be granted in limited cases.
−Removed: The FDA has substantial discretion in the approval process and may refuse to accept an application if they determine that the data are insufficient for approval and require additional preclinical, clinical or other studies.
+Added: The FDA has substantial discretion in the approval process and may refuse to accept an application if they determine that the data are insufficient for approval and require additional nonclinical, clinical or other studies.
Once an NDA has been accepted for filing, which occurs, if at all, 60 days after submission, the FDA sets a user fee goal date that informs the applicant of the specific date by which the FDA intends to complete its review.
−Removed: A standard review is 10 months from the date the application is accepted for filing and a priority review is 6 months from the date the application is accepted for filing.
+Added: A standard review typically takes 10 months from the date that the application is accepted for filing by the FDA and a priority review typically takes 6 months from the date that the application is accepted by the FDA for filing.
The review process can be extended by FDA requests for additional information or clarification.
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The FDA could also require a special warning, known as a boxed warning, to be included in the product label in order to highlight a particular safety risk.
−Removed: The FDA may also convene an advisory committee of external experts to provide input on certain review
−Removed: issues relating to risk, benefit and interpretation of clinical trial data.
+Added: The FDA may also convene an advisory committee of external experts to provide input on certain review issues relating to risk, benefit and interpretation of clinical trial data.
The FDA may delay approval of an NDA if applicable regulatory criteria are not satisfied and/or the FDA requires additional testing or information.
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For example, the FDA may require post-marketing testing, including Phase 4 clinical trials, and surveillance programs to further assess and monitor the product's safety and effectiveness after commercialization.
−Removed: The FDA may also require a REMS, which could involve requirements for, among other things, medication guides, special trainings for prescribers and dispensers, patient registries, and elements to assure safe use.
+Added: The FDA may also require a REMS, which could involve requirements for, among other things, medication
+Added: guides, special trainings for prescribers and dispensers, patient registries, and elements to assure safe use.
In addition, entities involved in the manufacture and distribution of approved drugs are required to register their establishments with the FDA and state agencies, and are subject to periodic unannounced inspections by the FDA and these state agencies for compliance with cGMP requirements.
1 unchanged sentence
Changes to the manufacturing process are strictly regulated and often require prior FDA approval before being implemented.
−Removed: FDA regulations also require investigation and correction of any deviations from cGMP
−Removed: requirements and impose reporting and documentation requirements upon the sponsor and any third-party manufacturers that the sponsor may decide to use.
+Added: FDA regulations also require investigation and correction of any deviations from cGMP requirements and impose reporting and documentation requirements upon the sponsor and any third-party manufacturers that the sponsor may decide to use.
Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality control to maintain cGMP compliance.
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Drugs may be promoted only for the approved indications and in accordance with the provisions of the approved label.
−Removed: The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability, including investigation by federal and state authorities.
+Added: The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-
+Added: label uses may be subject to significant liability, including investigation by federal and state authorities.
Section 505(b)(2) NDAs
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Section 505(b)(2) was enacted as part of the Hatch-Waxman Amendments.
−Removed: A Section 505(b)(2) NDA is an application that contains full reports of investigations of safety and effectiveness, but where at least some of the information required for approval comes from studies
−Removed: not conducted by, or for, the applicant and for which the applicant has not obtained a right of reference or use from the company by or for whom the investigations were conducted.
+Added: A Section 505(b)(2) NDA is an application that contains full reports of investigations of safety and effectiveness, but where at least some of the information required for approval comes from studies not conducted by, or for, the applicant and for which the applicant has not obtained a right of reference or use from the company by or for whom the investigations were conducted.
This type of application permits reliance for such approvals on literature or on an FDA finding of safety, effectiveness or both for an approved drug product.
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A competitor seeking to launch a generic substitute of small molecule drug in the U.S.
−Removed: must file an Abbreviated New Drug Application ("ANDA") with the FDA.
+Added: must file an Abbreviated New Drug Application ("ANDA") with the
In the ANDA, the generic manufacturer needs to demonstrate only “bioequivalence” between the generic substitute and the approved NDA drug.
2 unchanged sentences
The FDA cannot approve an ANDA until after the innovator’s listed patents expire unless there is a successful patent challenge.
−Removed: However, after the innovator has marketed its product for four years, a generic manufacturer may file an ANDA and allege that one or more of the patents listed in the Orange Book
−Removed: under an innovator’s NDA is either invalid or not infringed (a Paragraph IV certification).
+Added: However, after the innovator has marketed its product for four years, a generic manufacturer may file an ANDA and allege that one or more of the patents listed in the Orange Book under an innovator’s NDA is either invalid or not infringed (a Paragraph IV certification).
The innovator then must decide whether to file a patent infringement suit against the generic manufacturer.
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After an innovator has marketed its product for four years, any manufacturer may file an application for approval of a “biosimilar” version of the innovator product.
−Removed: However, although an application for approval of a biosimilar version may be filed four years after approval of the innovator product, qualified innovative biological products will receive 12 years of regulatory exclusivity, meaning that the FDA may not approve a biosimilar version until 12 years after the innovative biological product was first approved by the FDA.
+Added: However, although an application for approval of a biosimilar version may be
+Added: filed four years after approval of the innovator product, qualified innovative biological products will receive 12 years of regulatory exclusivity, meaning that the FDA may not approve a biosimilar version until 12 years after the innovative biological product was first approved by the FDA.
The law also provides a mechanism for innovators to enforce the patents that protect innovative biological products and for biosimilar applicants to challenge the patents.
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European Union
−Removed: A typical route used by innovator companies to obtain marketing authorization of pharmaceutical products in the EU is through the “centralized procedure.” A company seeking to market an innovative pharmaceutical product through the centralized procedure must file a complete set of safety data and efficacy data as part of a Marketing Authorization Application ("MAA") with the EMA.
+Added: A typical route used by innovator companies to obtain marketing authorization of pharmaceutical products in the EU is through the “centralized procedure.” A company seeking to market an innovative pharmaceutical product through the centralized procedure must file a complete set of safety data and efficacy data as part of a MAA with the EMA.
After the EMA evaluates the MAA, it provides a recommendation to the European Commission ("EC") and the EC then approves or denies the MAA.
−Removed: Regulatory approval via the centralized procedure results in a marketing authorization for the innovative pharmaceutical product in each EU member state.
+Added: Regulatory approval via the centralized procedure results in a marketing authorization for the innovative pharmaceutical product
+Added: in each EU member state.
It is also possible for new chemical products to obtain marketing authorization in the EU through a “mutual recognition procedure,” in which an application is made to a single member state, and if the member state approves the pharmaceutical product under a national procedure, then the applicant may submit that approval to the mutual recognition procedure of some or all other member states.
−Removed: After obtaining marketing authorization approval, a company must obtain pricing and reimbursement for the pharmaceutical product, which is typically subject to
−Removed: member state law.
+Added: After obtaining marketing authorization approval, a company must obtain pricing and reimbursement for the pharmaceutical product, which is typically subject to member state law.
In certain EU countries, this process can take place simultaneously while the product is marketed but in other EU countries, this process must be completed before the company can market the new product.
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As in the U.S., patents in Japan may be extended to compensate for the patent term lost during the regulatory review process.
−Removed: In general, Japanese law treats chemically-synthesized and biologically-derived drugs the same with respect to intellectual property and market exclusivity.
+Added: general, Japanese law treats chemically-synthesized and biologically-derived drugs the same with respect to intellectual property and market exclusivity.
To obtain marketing authorization of pharmaceutical products in China, an NDA must be submitted to the National Medical Products Administration ("NMPA") once safety and efficacy has been established in Chinese patients.
−Removed: drugs, this means issuance of an import license.
+Added: For imported drugs, this means issuance of an import license.
The applicant must submit evidence of foreign approval (certificate of pharmaceutical product), unless it is an innovative drug that has never been approved anywhere in the world.
−Removed: In China, medicines of new chemical entities are generally afforded 6 years of data exclusivity for approved indications and dosage.
+Added: In China, medicines of new chemical entities are generally afforded six years of data exclusivity for approved indications and dosage.
Generic copies can receive regulatory approval after data exclusivity and patent expirations.
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The application must contain data in South Korean patients, information regarding safety and efficacy, quality, a good manufacturing practice certificate, and a certificate of pharmaceutical product in an approved country to show that the drug being imported is being sold in the approved country in accordance with the with the relevant rules and regulations in that country.
−Removed: In South Korea, medicines of new chemical entities are generally afforded 6 years of data exclusivity for first approved indications and dosage.
+Added: In South Korea, medicines of new chemical entities are generally afforded six years of data exclusivity for first approved indications and dosage.
Generic copies can receive regulatory approval after data exclusivity and patent expirations.
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Challenges exist that pertain to the coverage and reimbursement status of any products for which regulatory approval is sought.
−Removed: In the United States and foreign markets, sales of any products that receive regulatory approval for commercial sale will depend, in part, on the availability of coverage and the adequacy of reimbursement from third-party payors.
+Added: In the United States and
+Added: foreign markets, sales of any products that receive regulatory approval for commercial sale will depend, in part, on the availability of coverage and the adequacy of reimbursement from third-party payors.
Third-party payors include government authorities, such as Medicare and Medicaid, and private entities, such as managed care organizations, private health insurers and other organizations.
−Removed: The process for determining whether a third-party payor will provide coverage for a product may be separate from the process for setting
−Removed: the reimbursement rate that the payor will pay for the product.
+Added: The process for determining whether a third-party payor will provide coverage for a product may be separate from the process for setting the reimbursement rate that the payor will pay for the product.
The latter is often informed by entities such as the Institute for Clinical and Economic Review ("ICER") which provides a reimbursement rate based on a multifactorial value assessment.
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Adequate third-party reimbursement may not be available to enable us to maintain price levels sufficient to realize an appropriate return on our investment in product development.
−Removed: Third-party payors payors require evidence of value that are supplemental to the regulatory mandates of safety and efficacy in order to support a particular price.
+Added: Third-party payors require evidence of value that are supplemental to the regulatory mandates of safety and efficacy in order to support a particular price.
To obtain coverage and reimbursement for any product that might be approved for sale, there is often a need to conduct expensive pharmacoeconomic studies to demonstrate the medical necessity (based on evidence of disease burden and unmet need) and cost-effectiveness of the therapy.
−Removed: As mentioned, the ICER evidence review mandates such information.These studies will be in addition to the studies required to obtain regulatory approvals.
+Added: As mentioned, the ICER evidence review mandates such information.
+Added: These studies will be in addition to the studies required to obtain regulatory approvals.
If third-party payors do not consider a product to be cost-effective compared to other available therapies, they may not cover the product after approval as a benefit under their plans or, they may deem a subpopulation of eligible patients based on greater unmet need as eligible for reimbursement.
−Removed: Thus, obtaining and maintaining reimbursement status can be time-consuming and costly.But drug developers accept these requirements as a condition of reimbursement, analogous to their acceptance of the level of evidence needed to obtain regulatory approval.
+Added: Thus, obtaining and maintaining
+Added: reimbursement status can be time-consuming and costly.
+Added: However, drug developers accept these requirements as a condition of reimbursement, analogous to their acceptance of the level of evidence needed to obtain regulatory approval.
and foreign governments regularly consider reform measures that affect health care coverage and costs.
For example, the U.S.
−Removed: and particularly state legislatures have implemented cost
−Removed: containment programs that include price controls, restrictions on reimbursement and "first use" of generic products prior to access to branded prescriptions.
+Added: and particularly state legislatures have implemented cost containment programs that include price controls, restrictions on reimbursement and "first use" of generic products prior to access to branded prescriptions.
The Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act ("collectively, the ACA") contains provisions such as increased rebates for products sold to Medicaid programs, extension of Medicaid rebates to Medicaid managed care plans, mandatory discounts for certain Medicare Part D beneficiaries and annual fees based on pharmaceutical companies' share of sales to federal health care programs.
13 unchanged sentences
Physicians, other healthcare providers, and third-party payors will play a primary role in the recommendation and prescription of any product candidates for which we obtain marketing approval.
−Removed: Futur e arrangements wi th healthcare professionals, principal investigators, consultants, customers and third-party payors are and will be subject to various federal, state and foreign fraud and abuse laws and
−Removed: other healthcare laws and regulations.
+Added: Futur e arrangements wi th healthcare professionals, principal investigators, consultants, customers and third-party payors are and will be subject to various federal, state and foreign fraud and abuse laws and other healthcare laws and regulations.
These laws and regulations may impact, among other things, healthcare professionals who participate in our clinical research programs, and our proposed sales, marketing, distribution, and education programs.
4 unchanged sentences
• The federal Health Insurance Portability and Accountability Act of 1996 ("HIPAA") which imposes criminal liability for executing or attempting to execute a scheme to defraud any healthcare benefit program and creates federal criminal laws that prohibit knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false statement in connection with the delivery of or payment for healthcare benefits, items or services;
−Removed: • HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act ("HITECH") enacted as part of the American Recovery and Reinvestment Act of 2009 and its implementing regulations, which imposes certain obligations, including mandatory contractual terms, on entities subject to the law, such as healthcare providers, health plans, and healthcare clearinghouses and their respective business associates to safeguard the privacy, security and transmission of individually identifiable health information from any unauthorized use or disclosures;
−Removed: • The federal transparency requirements under the Physician Payments Sunshine Act, created under the ACA, which requires certain manufacturers of drugs, devices, biologics and medical supplies reimbursed under Medicare, Medicaid, and other programs such as CHIP to report to HHS information related to payments and other transfers of value provided to physicians and
−Removed: teaching hospitals and physician ownership and investment interests;
+Added: • HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act ("HITECH") enacted as part of the American Recovery and Reinvestment Act of 2009 and its implementing regulations, which imposes certain obligations, including mandatory contractual terms, on entities subject to the law, such as healthcare providers, health plans, and healthcare clearinghouses and their respective business associates to safeguard the privacy, security and transmission of individually identifiable
+Added: health information from any unauthorized use or disclosures;
+Added: • The federal transparency requirements under the Physician Payments Sunshine Act, created under the ACA, which requires certain manufacturers of drugs, devices, biologics and medical supplies reimbursed under Medicare, Medicaid, and other programs such as CHIP to report to HHS information related to payments and other transfers of value provided to physicians and teaching hospitals and physician ownership and investment interests;
• Analogous state laws and regulations, such as state anti-kickback and false claims laws, that impose similar restrictions and may apply to items or services reimbursed by non-governmental third-party payors, including private insurers;
7 unchanged sentences
Violations of these laws can subject us to criminal, civil and administrative sanctions including monetary penalties, damages, fines, disgorgement, individual imprisonment, and exclusion from participation in government funded healthcare programs, such as Medicare and Medicaid, additional reporting requirements and oversight if we become subject to a corporate integrity agreement or similar agreement to resolve allegations of non-compliance with these laws, and reputational harm, we may be required to curtail or restructure our operations.
−Removed: Moreover, we expect that there will continue to be federal and state laws and regulations, proposed and implemented, that could impact our future operations and business.
+Added: Moreover, we expect that
+Added: there will continue to be federal and state laws and regulations, proposed and implemented, that could impact our future operations and business.
Healthcare Reform
8 unchanged sentences
• an annual, non-deductible fee on any entity that manufactures or imports certain branded prescription drugs and biologic agents, which is apportioned among these entities according to their market share in certain government healthcare programs;
−Removed: • a new Medicare Part D coverage gap discount program, in which manufacturers must now agree to offer 70% point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D;
−Removed: • new requirements to report certain financial arrangements with physicians and certain others, including reporting “transfers of value” made or distributed to prescribers and other healthcare providers and reporting investment interests;
+Added: • a Medicare Part D coverage gap discount program, in which manufacturers must now agree to offer 70% point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D;
+Added: • requirements to report certain financial arrangements with physicians and certain others, including reporting “transfers of value” made or distributed to prescribers and other healthcare providers and reporting investment interests;
• an increase in the statutory minimum rebates a manufacturer must pay under the Medicaid Drug Rebate Program to 23.1% and 13.0% of the average manufacturer price for branded and generic drugs, respectively;
−Removed: • a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected;
+Added: • a methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected;
• extension of a manufacturer’s Medicaid rebate liability to covered drugs dispensed to individuals who are enrolled in Medicaid managed care organizations;
−Removed: • expansion of eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to certain individuals with income at or below 133% of the federal poverty level, thereby potentially increasing a manufacturer’s Medicaid rebate liability;
+Added: • expansion of eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to certain individuals with
+Added: income at or below 133% of the federal poverty level, thereby potentially increasing a manufacturer’s Medicaid rebate liability;
• expansion of the entities eligible for discounts under the Public Health Service pharmaceutical pricing program;
−Removed: • a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct
−Removed: comparative clinical effectiveness research, along with funding for such research;
+Added: • a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research;
• establishment of the Center for Medicare Innovation at the Centers for Medicare and Medicaid Services ("CMS"), to test innovative payment and service delivery models to lower Medicare and Medicaid spending, potentially including prescription drug spending.
6 unchanged sentences
The Medicare Access and CHIP Reauthorization Act of 2015 also introduced a quality payment program under which certain individual Medicare providers will be subject to certain incentives or penalties based on new program quality standards.
−Removed: Payment adjustments for the Medicare quality payment program were scheduled to begin in 2019.
−Removed: At this time, it is unclear how the introduction of the quality payment program will impact overall physician reimbursement under the Medicare program.
−Removed: Further, there have been several recent Congressional inquiries and proposed federal and state legislation designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for products.
+Added: Further, there have been several Congressional inquiries and proposed federal and state legislation designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for products.
At the federal level, the costs of prescription pharmaceuticals in the United States has also been the subject of considerable discussion.
The previous administration released a "Blueprint" to lower drug prices and reduce out-of-pocket costs of drugs.
−Removed: HHS solicited feedback on some of these measures and, concurrently, implemented others under its existing authority.
+Added: HHS solicited feedback on some
+Added: of these measures and, concurrently, implemented others under its existing authority.
President Biden continues to push for reforms that would address the high cost of drugs.
−Removed: In response to an Executive Order from President Biden, the Secretary of HHS recently
−Removed: issued a comprehensive plan for addressing high drug prices that describes a number of legislative approaches and identifies administrative tools to address the high cost of drugs.
−Removed: And Democrats recently included drug pricing reform provisions reflecting elements of the plan in a broader spending package in late 2021—such as capping Medicare Part D patients’ out-of-pocket costs, establishing penalties for drug prices that increase faster than inflation in Medicare, and authorizing the federal government to negotiate prices on certain select, high-cost drugs under Medicare Parts B and D.
+Added: In response to an Executive Order from President Biden, the Secretary of HHS issued a comprehensive plan for addressing high drug prices that describes a number of legislative approaches and identifies administrative tools to address the high cost of drugs.
+Added: Democrats included drug pricing reform provisions reflecting elements of the plan in a broader spending package in late 2021—such as capping Medicare Part D patients’ out-of-pocket costs, establishing penalties for drug prices that increase faster than inflation in Medicare, and authorizing the federal government to negotiate prices on certain select, high-cost drugs under Medicare Parts B and D.
While a number of these and other proposed measures would require authorization through additional legislation to become effective, Congress has indicated that it will continue to seek new legislative and/or administrative measures to control drug costs.
13 unchanged sentences
Applying NYSE’s listing standards for independence, six of our eight directors are independent.
−Removed: At the management level, we have implemented a cross-functional Sustainability Working Group, which is set to meet on a regular basis and report to the Board of Directors periodically.
−Removed: We also maintain a Chief Talent & Sustainability Officer position to work closely with the working group and coordinate efforts related to the advancement of ESG capabilities across the organization.
+Added: At the management level, we have implemented a cross-functional Sustainability Working Group, which meets on a regular basis and reports to the Board of Directors periodically.
+Added: We also maintain a Chief Talent & Sustainability Officer position who works closely with the working group and coordinate efforts related to the advancement of ESG capabilities across the organization.
Business Ethics
9 unchanged sentences
We monitor resource use, improve efficiency, and at the same time reduce our emissions and waste.
−Removed: In order to reduce the overall impact of our product on the environment, we have taken steps to enhance the sustainability of our manufacturing processes for our drug substances.
+Added: Externally, we strive to reduce the overall impact of our product on the environment by taking steps to enhance the sustainability of our manufacturing processes for our drug substances.
In collaboration with our contract research organization partners, we apply various green chemistry methodologies to our commercial and development
8 unchanged sentences
We foster and encourage a workplace environment that holds possibilities for everyone, with a commitment to respect and acceptance without biases.
−Removed: Development and continuous feedback are priorities for our organization, which was comprised of 202 employees as of January 1, 2023.
+Added: Development and continuous feedback are priorities for our organization, which was comprised of 239 employees as of December 31, 2023.
We believe each person is critical to our success and we invest in our people by supporting continuous training programs and courses.
4 unchanged sentences
We strive to provide an inclusive workplace to foster growth and innovation.
−Removed: Biohaven is committed to gender diversity in the workforce, as evidenced by a workforce that is approximately 60% female and includes a robust group of female leaders in the scientific and associated fields.
+Added: Our efforts to achieve gender diversity in the workforce are evidenced by a workforce that is approximately 57% female and includes a robust group of female leaders in the scientific and associated fields.
Biohaven engages in forward-thinking people policies to allow for our employees to thrive in our workforce.
2 unchanged sentences
Our vacation policy is unlimited and is aimed at giving employees the ability to achieve work/life balance in a way that is bespoke to their circumstances.
−Removed: When the COVID-19 pandemic hit in early 2020, we quickly established both an office-based and field-based response to protect our employees.
−Removed: We first and foremost encouraged all office-based employees to work from home and provided support for fully remote work.
−Removed: In our offices, we follow health and safety protocols by providing mandatory masks for anyone entering the building, foot-dispensing hand sanitizer stations, and disinfecting wipes at each workstation.
−Removed: We purchased high efficiency air filters to ensure air is not recirculated in the facilities.
−Removed: We offer antibody testing and encourage employees to be tested for COVID-19 frequently.
Information about Segments
−Removed: We currently operate in a single business segment developing a portfolio of innovative, late-stage product candidates targeting neurological diseases, including rare disorders.
+Added: We currently operate in a single business segment developing a portfolio of treatments in therapeutic areas including neuroscience, immunology and oncology.
See additional information in our financial statements contained in Part II, Item 8 of this Annual Report.
3 unchanged sentences
Box 173, Road Town, Tortola, British Virgin Islands and our telephone number is +1 (284) 852-3000.
−Removed: office is located at 215 Church Street, New Haven, Connecticut 06510 and our telephone number is (203) 404-0410.
−Removed: Our website address is www.biohavenpharma.com.
+Added: subsidiary's office is located at 215 Church Street, New Haven, Connecticut 06510 and telephone number is (203) 404-0410.
+Added: Our website address is www.biohaven.com.
The information contained on our website is not incorporated by reference into this Annual Report, and you should not consider any information contained on, or that can be accessed through, our website as part of this Annual Report or in making an investment decision regarding our common shares.
1 unchanged sentence
Available Information
−Removed: Our internet website address is www.biohavenpharma.com.
+Added: Our internet website address is www.biohaven.com.
In addition to the information about us and our subsidiaries contained in this Annual Report, information about us can be found on our website.
Our website and information included in or linked to our website are not part of this Annual Report.
−Removed: Our annual reports on Form 10-K, quarterly reports on Form 10-Q, current reports on Form 8-K and amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended, are available free of charge through our website as soon as reasonably practicable after they are electronically filed with or
−Removed: furnished to the Securities and Exchange Commission ("SEC").
+Added: Our annual reports on Form 10-K, quarterly reports on Form 10-Q, current reports on Form 8-K and amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended, are available free of charge through our website as soon as reasonably practicable after they are electronically filed with or furnished to the Securities and Exchange Commission ("SEC").
A copy of these reports is also available at the SEC's website (www.sec.gov).
Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.