−Removed: We are a clinical stage biotechnology company developing first-in-class immunology therapeutic product candidates focused on emerging immune control mechanisms applicable to inflammation and immuno-oncology indications.
−Removed: We develop our product candidates using our proprietary antibody discovery technology platform, which is based upon a breakthrough understanding of the natural process of antibody generation, known as somatic hypermutation (“SHM”), and replicates this natural process of antibody generation in vitro .
−Removed: Our strategy is to advance the development of our proprietary product candidates, and where applicable, establish partnerships with leading biopharmaceutical companies where we retain certain development and commercialization rights.
−Removed: Our most advanced wholly-owned antibody programs, imsidolimab, rosnilimab, previously referred to as ANB030, and ANB032, are designed to modulate therapeutic targets that are genetically associated with human inflammatory disorders.
−Removed: Imsidolimab, our IL-36R antibody previously referred to as ANB019, inhibits the interleukin-36 receptor (“IL-36R”), and is being developed for the treatment of multiple dermatological inflammatory diseases.
−Removed: We completed a Phase 1 clinical trial in healthy volunteers, which was presented at the European Academy of Allergy and Clinical Immunology in 2018, where imsidolimab was well-tolerated by all subjects, no dose-limiting toxicities were observed, and no serious adverse events were reported among any subjects in the clinical trial.
−Removed: In July 2020, the U.S.
−Removed: Food and Drug Administration (the “FDA”) granted Orphan Drug Designation for imsidolimab for the treatment of patients with GPP.
−Removed: We completed an open-label, multi-dose, single-arm Phase 2 clinical trial of imsidolimab in 8 GPP patients, also referred to as the GALLOP clinical trial, where top-line data through week 16 was presented at the European Academy of Dermatology and Venerology (EADV) Congress on October 2, 2021.
−Removed: In this trial, 6 of 8 (75%) patients treated with imsidolimab monotherapy achieved the primary endpoint of response on the clinical global impression (“CGI”) scale at week 4 and week 16, without requiring rescue medication.
−Removed: Two of 8 (25%) patients were considered to have not met the primary endpoint because they dropped out of the trial prior to Day 29.
−Removed: The Modified Japanese Dermatology Association severity index total score (mJDA-SI), which incorporates both dermatological and systemic aspects of GPP, decreased for patients on average by 29% at week 1, 54% at week 4 and 58% at week 16.
−Removed: Erythema with pustules, which clinically defines GPP, decreased by 60% at week 1, 94% by week 4 and 98% by week 16.
−Removed: Patients achieved a reduction in the Dermatology Life Quality Index (DLQI), which is a patient- reported measure, of 6 points at week 4 and 11 points by week 16, each of which exceeded the minimal clinically importance difference (MCID) of 4 points.
−Removed: GPP Physician Global Assessment (GPPPGA) scale was implemented by protocol amendment during the course of the trial and was assessed in 4 of the 8 enrolled patients, where zero (clear) or 1 (almost clear) response was achieved in 2 (50%) patients at week 4 and 3 (75%) patients at week 16.
−Removed: Genotypic testing, available for 7 of the 8 patients enrolled, indicated homozygous wild-type IL-36RN, CARD14 and AP1S3 alleles.
−Removed: Through week 16, anti-drug antibodies were only detected in one patient, which occurred at week 12 and did not impact imsidolimab pharmacokinetics or efficacy.
−Removed: Imsidolimab was generally well-tolerated, and most treatment-emergent adverse events were mild to moderate in severity and resolved without sequelae.
−Removed: No infusion or injection site reactions were observed.
−Removed: One patient dropped out of the clinical trial due to a diagnosis of Staphylococcal aureus bacteremia in the first week, which was a serious adverse event deemed to be possibly drug-related.
−Removed: Because the patient was symptomatic prior to dosing and had a prior medical history of bacteremia, a common comorbidity of GPP, we do not believe this event is likely attributable to imsidolimab.
−Removed: Another patient dropped out of the study on Day 22 due to investigator reported inadequate efficacy.
−Removed: One patient contracted COVID-19 during the course of the clinical trial, which was deemed a serious adverse event unrelated to imsidolimab, and did not lead to study discontinuation.
−Removed: While initial GPP epidemiology studies suggested at least 3,000 GPP patients in the United States, medical claims analyses conducted by IQVIA indicate approximately 37,000 unique patients were diagnosed with GPP at least once, and approximately 15,000 unique patients were diagnosed with GPP at least twice, by a physician between 2017 and 2019 using the International Classification of Diseases 10th Revision (ICD-10) billing code pertaining to GPP (L40.1).
−Removed: We met with the FDA during the second quarter of 2021 for an end-of-Phase 2 meeting to review an orphan disease registration plan for imsidolimab for the treatment of GPP.
−Removed: We initiated our first Phase 3 trial for imsidolimab for GPP, called GEMINI-1, during the third quarter of 2021.
−Removed: GEMINI-1 will enroll approximately 45 moderate-to-severe GPP patients, each undergoing an active flare at baseline, which will be randomized equally to receive a single dose of 750mg intravenous (IV) imsidolimab, 300mg IV imsidolimab or placebo.
−Removed: The primary endpoint of the Phase 3 program is the proportion of patients achieving clear or almost clear skin as determined by a Generalized Pustular Psoriasis Physician’s Global Assessment (GPPPGA) score of zero or 1 at week 4 of GEMINI-1.
−Removed: Patients completing the GEMINI-1 trial will subsequently be enrolled in GEMINI-2, our second Phase 3 trial for imsidolimab in GPP, where they will receive monthly doses of 200mg subcutaneous imsidolimab or placebo depending upon whether they are responders, partial responders or non-responders in treatment under GEMINI-1.
−Removed: The objective of GEMINI-2 is to assess the efficacy and safety of imsidolimab after 6 months of monthly dosing.
−Removed: We are conducting a global registry of GPP patients, also referred to as the RADIANCE study, which we anticipate will improve understanding of the patient journey and assist in enrollment of future GPP clinical trials.
−Removed: We are conducting clinical development of imsidolimab in moderate-to-severe acne.
−Removed: Acne is the most common skin disorder in the United States, with approximately 3 million patients diagnosed with moderate-to-severe disease.
−Removed: Moderate-to-severe acne typically presents with painful papules, pustules, nodules, cysts and scarring.
−Removed: A key contributing factor to the pathogenesis of acne is the immune response to Propionibacterium acnes, or P.
−Removed: acnes , which is associated with upregulated IL-36 cytokine activity, localized inflammation, and neutrophil infiltration of the skin.
−Removed: Existing therapies, including isotretinoin and systemic antibiotics, provide variable efficacy for moderate-to-severe acne patients and have practical limitations to their use given potential for clinically meaningful side effects.
−Removed: We are conducting a Phase 2 clinical trial of imsidolimab, called ACORN, where 120 patients will be randomized equally between two dose levels of imsidolimab and placebo, for the treatment of moderate-to-severe acne, and we anticipate top-line data during the first half of 2022.
−Removed: We are conducting clinical development of imsidolimab in hidradenitis suppurativa, also known as acne inversa, which is a chronic inflammatory skin disease characterized by painful nodules in intertriginous areas that can progress to abscesses, sinus tracks and scarring.
−Removed: Current treatment options for hidradenitis suppurativa, including antibiotics, corticosteroids and anti-TNF therapy, have variable efficacy in moderate-to-severe patients, which often leads to surgery for removal of hidradenitis suppurativa nodules.
−Removed: Human translational studies have demonstrated elevated IL-36 cytokine expression in hidradenitis suppurativa skin biopsies, and we believe treatment of moderate-to-severe hidradenitis suppurativa with imsidolimab may lead to therapeutic benefit for this patient population.
−Removed: Moderate-to-severe hidradenitis suppurativa affects approximately 150,000 adults in the United States.
−Removed: We are conducting a Phase 2 clinical trial of imsidolimab in moderate-to-severe hidradenitis suppurativa, called HARP, where 120 patients will be randomized equally between two dose levels of imsidolimab and placebo, and we anticipate top-line data during the second half of 2022.
−Removed: Our second wholly-owned program, rosnilimab, previously referred to as ANB030, is an anti-PD-1 agonist antibody program designed to augment PD-1 signaling through rosnilimab treatment to suppress T-cell driven human inflammatory diseases.
−Removed: Genetic mutations in the PD-1 pathway are known to be associated with increased susceptibility to human inflammatory diseases, and hence we believe that rosnilimab is applicable to diseases where PD-1 checkpoint receptor function may be under-represented.
−Removed: We presented preclinical data for rosnilimab at the Festival of Biologics Annual Meeting in March 2020, including translational data demonstrating i n vitro activity of rosnilimab in alopecia areata patient samples.
−Removed: We announced positive top-line data from a healthy volunteer Phase 1 clinical trial of rosnilimab in November 2021.
−Removed: A total of 144 subjects were enrolled in the randomized, double-blind, placebo-controlled healthy volunteer Phase 1 trial, where single ascending dose (SAD) cohorts were administered single subcutaneous or intravenous doses of rosnilimab ranging between 0.02mg to 600mg or placebo, while multiple ascending dose (MAD) cohorts received four weekly subcutaneous doses of rosnilimab ranging between 60mg and 400mg or placebo.
−Removed: Dose escalation was conducted subsequent to data safety monitoring board review of safety and tolerability parameters following each single and multiple ascending dose level.
+Added: We are a clinical-stage biotechnology company focused on delivering innovative immunology therapeutics.
+Added: We are developing immune cell modulating antibodies, including two wholly owned checkpoint agonists in clinical-stage development, for autoimmune and inflammatory disease:
+Added: rosnilimab, our PD-1 agonist, previously referred to as ANB030, in a planned Phase 2b trial for the treatment of moderate-to-severe rheumatoid arthritis (“RA”);
+Added: and ANB032, our BTLA agonist, in a planned Phase 2b trial for the treatment of moderate-to-severe atopic dermatitis (“AD”).
+Added: We also have other preclinical immune cell modulator candidates in our portfolio, including ANB033, an anti-CD122 antagonist antibody for the treatment of autoimmune and inflammatory diseases.
+Added: In addition, we have two cytokine antagonists that we are exploring options for out-licensing:
+Added: imsidolimab, our anti-IL-36R antibody, in a Phase 3 trial for the treatment of generalized pustular psoriasis (“GPP”), and etokimab, our anti-IL-33 antagonist that is Phase 2/3 ready.
+Added: We have also discovered multiple therapeutic antibodies licensed to GlaxoSmithKline, Inc.
+Added: (“GSK”) in a financial collaboration for immune-oncology, including an anti-PD-1 antagonist antibody (JEMPERLI (dostarlimab-gxly)), an anti-TIM-3 antagonist antibody (cobolimab, GSK4069889) and an anti-LAG-3 antagonist antibody (GSK4074386).
+Added: We currently recognize revenue from milestones and royalties achieved under our immuno-oncology collaboration with GSK.
+Added: Our Wholly Owned Product Candidate Pipeline
+Added: Our immune cell modulating antibodies, including anti-inflammatory checkpoint agonists for PD-1 and BTLA, treat inflammatory disorders by down regulating immune responses mediated by multiple immune cell types including T-cells, B-cells, and dendritic cells.
+Added: We believe these molecules have potential applicability across a broad range of autoimmune and inflammatory disorders including dermatology, rheumatology, gastroenterology, respiratory, and neurology therapeutic areas.
+Added: Rosnilimab is designed to suppress aberrant T cell driven inflammation by augmenting signaling through PD-1 or targeted depletion of PD-1+ T cells.
+Added: Rosnilimab binds to PD-1 on a membrane proximal epitope that is on the opposite side of the receptor to that utilized by PD-L1 for binding, and thus preserves the ability of PD-L1 to agonize PD-1.
+Added: In the setting of T cell activation, rosnilimab binding has been shown to induce agonistic signaling and the recruitment of SHP2 to PD-1, in a manner similar to that by PD-L1.
+Added: In preclinical assays, rosnilimab prevented T cell expansion in antigen-specific response assays to numerous antigens, demonstrating prevention of T cell expansion and reduction in the secretion of inflammatory cytokines associated with multiple T cell types implicated in inflammatory pathology when dysregulated.
+Added: In addition to direct agonistic activity, rosnilimab is an IgG1k antibody with effector function that can drive targeted depletion of PD-1+ T cells via the induction of antibody-dependent cellular cytotoxicity (ADCC).
+Added: We believe this component of the mechanism of rosnilimab may provide more durable immune modulation by effectively eliminating the most pathogenic antigen-specific T cells in the setting of autoimmunity and inflammation.
+Added: Genetic mutations in the PD-1 pathway are known to be associated with increased susceptibility to human inflammatory diseases, and hence we believe that rosnilimab is applicable to diseases where PD-1 checkpoint receptor function may be insufficient to maintain immune homeostasis.
+Added: We announced positive top-line data from a healthy volunteer Phase 1 trial of rosnilimab in November 2021.
+Added: A total of 144 subjects were enrolled in the randomized, double-blind, placebo-controlled healthy volunteer Phase 1 trial, where single ascending dose (SAD) cohorts were administered single subcutaneous or intravenous (“IV”) doses of rosnilimab up to 600mg or placebo, while multiple ascending dose (MAD) cohorts received four weekly subcutaneous doses of rosnilimab ranging up to 400mg or placebo.
Rosnilimab was generally well-tolerated and no dose limiting toxicities were observed.
−Removed: The most frequent adverse event reported among SAD cohorts was increased circulating C-reactive protein levels of mild severity in nine (10%) rosnilimab-dosed subjects occurring sporadically in a dose-independent manner and a severe occurrence in one (3.3%) placebo-dosed subject.
−Removed: MAD cohorts reported headache as the most frequent adverse event with mild occurrences in three (12.5%) rosnilimab-dosed subjects and none in placebo subjects.
−Removed: Mild injection site reactions were observed in two subjects (11.1%) administered with multiple subcutaneous rosnilimab doses.
−Removed: Two serious adverse events were reported in single dose cohorts, including obstructive pancreatitis in a placebo-dosed subject and COVID-19 infection in a rosnilimab-dosed subject leading to discontinuation which was deemed unrelated to treatment.
+Added: Two serious adverse events were reported in single dose cohorts, including obstructive pancreatitis in a placebo-dosed subject and COVID-19 infection in a rosnilimab-dosed subject leading to discontinuation.
+Added: The COVID-19 infection was deemed unrelated to treatment.
No serious adverse events were reported in subjects receiving multiple doses of rosnilimab or placebo.
−Removed: Pharmacokinetic analyses demonstrated a favorable profile for rosnilimab with an estimated two-week half-life for subcutaneous and intravenous routes of administration and approximately 80% bioavailability.
−Removed: Low-titer anti-drug antibodies were detected at low single dose levels in 19 (21%) rosnilimab-dosed subjects, but none were detected in high single dose or multiple dose subjects.
−Removed: Full PD-1 receptor occupancy was observed rapidly during the first week following single subcutaneous rosnilimab doses at or above 60mg, and was maintained for at least 30 days at or above 200mg single subcutaneous doses.
−Removed: These data support monthly subcutaneous dosing of rosnilimab for future patient trials.
−Removed: Rosnilimab’s pharmacodynamic activity resulted in rapid and sustained reduction in the quantity and functional activity of PD-1+ T cells, which are known to be pathogenic drivers of inflammatory diseases.
−Removed: Conventional T (Tcon) cells (CD3+, CD25 low) expressing PD-1, which represented approximately 25% of peripheral T cells at baseline, were reduced by 50%, including in both CD4+ and CD8+ subsets, in a dose-dependent manner and in correlation with receptor occupancy.
−Removed: This effect was maximized on high-PD-1 expressing Tcon cells, which represented approximately 5% of peripheral T cells, with 90% reduction relative to baseline.
−Removed: Conversely, total T cells (CD3+), total Tcon cells (CD3+, CD25low) and total regulatory T (Treg) cells (CD3+, CD4+, CD25 bright, CD127-) were unchanged (<5% change from baseline), resulting in a favorable shift in the ratio of PD-1+ Tcon cells to total Treg cells post-treatment.
+Added: Rosnilimab demonstrated a favorable pharmacokinetic profile with an estimated two-week half-life for subcutaneous and IV routes of administration.
+Added: Full PD-1 receptor occupancy was observed rapidly and was maintained for at least 30 days at or above 200mg following single subcutaneous rosnilimab doses.
+Added: Rosnilimab pharmacodynamic activity demonstrated rapid and sustained reduction in the quantity and functional activity of PD-1+ T cells, which are known to be pathogenic drivers of inflammatory diseases.
+Added: Conventional T (Tcon) cells (CD3+, CD25 low) PD-1+, which represented approximately 25% of peripheral T cells at baseline, were reduced by 50%, including in both CD4+ and CD8+ subsets, in a dose-dependent manner and in correlation with receptor occupancy.
+Added: This effect was maximized on high-PD-1+ Tcon cells, which represented approximately 5% of peripheral T cells, with 90% reduction relative to baseline.
+Added: Conversely, total T cells (CD3+), total Tcon cells (CD3+, CD25low) and total regulatory T (Treg) cells (CD3+, CD4+, CD25 bright, CD127-) were unchanged (<5% change from baseline), resulting in a
+Added: consistent ratio of PD-1+ Tcon cells to total Treg cells post-treatment in healthy volunteers.
No effect (<5% reduction from baseline) was observed on any of the aforementioned cell types in placebo-dosed subjects.
−Removed: In addition, an antigen-specific functional T cell recall response, measured as ex vivo interferon-
−Removed: gamma released in response to tetanus toxoid challenge, was inhibited in a receptor occupancy dependent manner and was consistent with the observed reduction of PD-1+ Tcon cells, to a maximum of approximately 90% relative to baseline within 30 days following single rosnilimab dose, while placebo administration had no effect.
−Removed: Based upon these data, we believe rosnilimab’s in vivo mechanism has the potential to treat T-cell driven human inflammatory diseases.
−Removed: During the fourth quarter of 2021, we initiated AZURE, a randomized placebo-controlled 45-patient Phase 2 trial of rosnilimab in moderate-to-severe alopecia areata patients with at least 50% scalp hair loss for at least 6 months prior to enrollment, where the primary endpoint is change in severity of alopecia tool (SALT) relative to baseline.
−Removed: We continue to assess clinical development opportunities for rosnilimab in additional indications, including vitiligo and rheumatoid arthritis, and will make decisions pending additional data.
−Removed: Our third wholly-owned program is an anti-BTLA modulator antibody, known as ANB032, which is broadly applicable to human inflammatory diseases associated with lymphoid and myeloid immune cell dysregulation.
−Removed: Mutations in the BTLA signaling pathway are associated with human inflammatory disease, and we believe ANB032 silences pro-inflammatory signaling by modulating BTLA binding to HVEM.
−Removed: We are conducting a healthy volunteer Phase 1 trial of ANB032, under an Australian Clinical Trial Notification (“CTN”) and anticipate top-line data from this trial during the first half of 2022.
−Removed: We presented preclinical data regarding ANB032 at the 2020 Federation of Clinical Immunology Societies (FOCIS) Virtual Annual Meeting in October 2020.
−Removed: In addition to our wholly-owned antibody programs, multiple Company-developed antibody programs have been advanced to preclinical and clinical milestones under our collaborations.
−Removed: We have received to date approximately $226.9 million in cash receipts from collaborations.
−Removed: Our collaborations include an immuno-oncology-focused collaboration with GlaxoSmithKline, Inc.
−Removed: (“GSK”) and an inflammation-focused collaboration with Bristol-Myers Squibb (“BMS”).
−Removed: A Biologics License Application (“BLA”) for our most advanced partnered program, which is an anti-PD-1 antagonist antibody called JEMPERLI (dostarlimab), was approved by the FDA in April 2021 for the treatment of advanced or recurrent deficient mismatch repair endometrial cancer (“dMMREC”).
−Removed: This is the first AnaptysBio-generated antibody, of eight currently under clinical development, to obtain FDA approval.
−Removed: We earned a $20.0 million milestone payment as a result of this FDA approval.
−Removed: In addition, in April 2021 the European Medicines Agency (“EMA”) granted conditional marketing authorization in the European Union (“EU”) for JEMPERLI for use in women with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) recurrent or advanced endometrial cancer who have progressed on or following prior treatment with a platinum containing regimen, which approval makes JEMPERLI the first anti-PD-1 therapy available for endometrial cancer in Europe.
−Removed: We earned a $10.0 million milestone payment as a result of this approval.
−Removed: A second BLA submitted by GSK was accepted by the FDA during the first quarter of 2021 for JEMPERLI in pan-deficient mismatch repair tumors (“PdMMRT”).
−Removed: We received a $10.0 million cash milestone payment upon the FDA acceptance of GSK’s second FDA BLA for JEMPERLI and received $20.0 million cash milestone payment in September 2021, upon FDA approval of this second FDA BLA of JEMPERLI in August.
−Removed: JEMPERLI is currently in clinical development for various solid tumor indications, including dMMREC, PdMMRT, colorectal cancer, ovarian cancer, non-small cell lung cancer, cervical cancer, rectal cancer, clear cell sarcoma and head-and-neck squamous cell carcinoma.
−Removed: GSK is conducting combination trials of dostarlimab with Zejula, belantamab mafodotin (BCMA ADC), GSK6097608 (anti-CD96) and GSK3745417 (STING agonist).
−Removed: In addition, under GSK’s collaboration with iTeos Therapeutics, dostarlimab is being developed in combination with EOS-448 (anti-TIGIT) and inupadenant (A2A receptor antagonist) in various solid tumor indications, including registration-directed trials combining dostarlimab and EOS-448 for first-line PD-L1 high non-small cell lung cancer (NSCLC) patients, head and neck squamous cell cancer (HNSCC) and a third undisclosed indication.
−Removed: In June 2021, GSK publicly disclosed estimated potential peak annual global JEMPERLI sales on a non-risk adjusted basis of £1-£2 billion, which is currently equal to approximately $1.4 to $2.7 billion based on the GBP to USD exchange rate as of December 31, 2021, for currently approved indications and first-line use in endometrial and ovarian cancer only.
−Removed: In October 2020, we amended our GSK collaboration to increase royalties on global net sales of JEMPERLI to 8% on annual global net sales below $1.0 billion and 12-25% of annual global net sales above $1.0 billion, add a 1% royalty rate on GSK’s global net sales of Zejula and received a one-time cash payment of $60.0 million.
−Removed: In October 2021, we signed a royalty monetization agreement (“Royalty Monetization Agreement”) with Sagard Healthcare Royalty Partners (“Sagard”).
−Removed: Pursuant to this transaction, we received a $250.0 million payment upon closing in December 2021, in exchange for JEMPERLI royalties due to us on annual commercial sales below $1.0 billion and certain future milestones starting in October 2021.
−Removed: The aggregate JEMPERLI royalties and milestones to be received by Sagard under the Royalty Monetization Agreement is capped at certain fixed multiples of the upfront payment based upon time.
−Removed: For more information about these collaborations, see “— Collaborations”.
−Removed: Following the closing of the Sagard royalty monetization transaction, we ended 2021 with $615.2 million in cash, cash equivalents and investments and intend to continue to operate in a capital-efficient manner.
+Added: We plan to conduct a randomized placebo-controlled multi-hundred patient global Phase 2b trial assessing three dose levels of subcutaneously administrated rosnilimab in moderate-to-severe RA for approximately six months on well-established endpoints including ACR 20/50/70 and DAS28.
+Added: We expect to initiate this trial in the third quarter of 2023 with top-line interim data anticipated by mid-year 2025.
+Added: We also plan to conduct a second global Phase 2 trial, in an indication to be announced, with trial initiation anticipated by the end of 2023.
+Added: During the fourth quarter of 2021, we initiated AZURE, a randomized placebo-controlled 45-patient Phase 2 trial of rosnilimab in moderate-to-severe alopecia areata patients.
+Added: We conducted an interim review of blinded data in December 2022 which demonstrated robust reductions in peripheral PD-1+ T cells, including PD-1 high T cells reduction of >80%, across blinded pooled rosnilimab patients and placebo patients, which is consistent with observations in the healthy volunteer Phase 1 trial of >90% in rosnilimab treated patients.
+Added: The blinded data suggests rosnilimab administration was generally safe and well tolerated.
+Added: Interim results suggest that target improvement in severity of alopecia tool (SALT) was not achieved potentially due to an inadequate tested dose level, limited duration of treatment, and/or complexity of disease biology including the hair growth cycle.
+Added: Further development in alopecia areata will not be pursued.
+Added: The unblinded final results will be available in second half of 2023.
+Added: ANB032 is designed to augment BTLA signaling, which is broadly applicable to human inflammatory diseases associated with lymphoid and myeloid immune cell dysregulation.
+Added: Genetic studies have demonstrated that BTLA pathway mutations increase human susceptibility to multiple autoimmune diseases and insufficient BTLA signaling can lead to dysregulated T or B cell responses and changes in the function of dendritic cells.
+Added: BTLA modulates signaling of HVEM, governing HVEM’s interaction with its natural ligands, including LIGHT.
+Added: Polymorphisms in BTLA or molecules in the BTLA pathway such as HVEM are associated with inflammatory diseases, including aberrant T cell activity, B cell activity and dysregulation of downstream humoral immune responses (IgE, IgG secretion).
+Added: Similarly, BTLA knockout animals have spontaneous or enhanced severity of inflammatory disease, demonstrating aberrant T cell activity, B cell activity and dysregulation of pathogenic antibody responses upon immunization.
+Added: ANB032 is anticipated to down-modulate the activity of T cells, B cells and dendritic cells via several potential mechanisms:
+Added: BTLA agonistic activity, stabilization of the interaction of BTLA and HVEM in cis which prevents pro-inflammatory signaling mediated by HVEM ligands such as LIGHT, and abrogation of pro-inflammatory HVEM signaling mediated by BTLA in trans.
+Added: We announced positive top-line data from a healthy volunteer Phase 1 trial of ANB032, under a CTN, in April 2022.
+Added: A total of 96 subjects were enrolled in the randomized, double-blind, placebo-controlled healthy volunteer Phase 1 trial, where single ascending dose (SAD) cohorts received subcutaneous or IV single doses of ANB032 or placebo, while multiple ascending dose (MAD) cohorts received four weekly subcutaneous doses of ANB032 or placebo.
+Added: ANB032 was generally well-tolerated and no dose limiting toxicities were observed.
+Added: No serious adverse events were reported.
+Added: ANB032 demonstrated a favorable pharmacokinetic profile with an estimated two-week half-life for subcutaneous and IV routes of administration.
+Added: Full PD-1 receptor occupancy was observed rapidly and was maintained for at least 30 days.
+Added: In in vitro studies, ANB032 pharmacodynamic activity demonstrated inhibition of T cell proliferation and reduction in inflammatory cytokine secretion (Th1, Th2, Th17).
+Added: While Th2 targeted therapies provide benefit to patients with chronic moderate-to-severe atopic dermatitis (AD), there is compelling evidence that AD is broader than a Th2 driven disease, as Th1, Th17 and other cell types, including dendritic cells, contribute significantly to the pathogenesis.
+Added: ANB032 inhibition of inflammatory Th1, Th2 and Th17 activity, and modulation of additional cell types such as B cells and dendritic cells, creates the potential for broader, deeper and more durable responses than more narrowly targeted interventions.
+Added: We plan to conduct a randomized placebo-controlled 160 patient Phase 2 trial assessing three dose levels of subcutaneously administrated ANB032 in moderate-to-severe AD for 12 weeks on well-established endpoints including EASI75 and IGA 0/1.
+Added: We expect to initiate this clinical trial in the second quarter of 2023 with top-line interim data anticipated by the end of 2024.
+Added: ANB033 targets CD122, the common beta subunit shared by the IL-15 and IL-2 receptors.
+Added: IL-15 signaling mediates the survival and maintenance of tissue resident memory T cells (T RM ).
+Added: The presence of long-lived and persistent T RM has been shown to drive tissue-specific immune-mediated inflammation.
+Added: T RM are present in the skin in dermatologic diseases, where defined borders of inflammation often recur.
+Added: T RM are also observed in other tissue-specific inflammatory disorders including gastroenterology, rheumatology and respiratory.
+Added: ANB033 is designed with an affinity to CD122 that inhibits IL-15 signaling, leading to death of pathogenic T RM cells in diseased tissue, with the potential to achieve and maintain remission of inflammation through the elimination of these disease-causing cells.
+Added: In addition, ANB033 inhibits IL-2 signaling through the
+Added: low affinity IL-2 receptor (comprised of CD122 and the common gamma subunit, CD132) expressed on T cells, while sparing regulatory T cells which express the high affinity IL-2 receptor (comprised of CD122, CD132 and the alpha receptor subunit for IL-2, CD25).
+Added: This drives reduction of pathogenic T cell numbers while sparing or potentially enhancing regulatory T cell numbers.
+Added: We anticipate submitting an IND for a Phase 1 clinical trial with ANB033 during the first half of 2024.
+Added: Imsidolimab inhibits the interleukin-36 receptor (IL-36R) and is being developed for the treatment of GPP.
+Added: We completed a Phase 1 clinical trial in healthy volunteers, which was presented at the European Academy of Allergy and Clinical Immunology in 2018, where imsidolimab was well-tolerated, no dose-limiting toxicities were observed, and no serious adverse events were reported.
+Added: In July 2020, the FDA granted Orphan Drug Designation for imsidolimab for the treatment of patients with GPP.
+Added: We completed an open-label, multi-dose, single-arm Phase 2 clinical trial of imsidolimab in 8 GPP patients, also referred to as the GALLOP clinical trial, where top-line data through week 16 was presented at the European Academy of Dermatology and Venerology (EADV) Congress in October 2021.
+Added: We have initiated two Phase 3 trials for imsidolimab for GPP.
+Added: The first, called GEMINI-1, will enroll approximately 45 moderate-to-severe GPP patients, each undergoing an active flare at baseline, which will be randomized equally to receive a single dose of 750mg IV imsidolimab, 300mg IV imsidolimab, or placebo.
+Added: The primary endpoint of the Phase 3 program is the proportion of patients achieving clear or almost clear skin as determined by a GPPPGA score of zero or 1 at week 4 of GEMINI-1.
+Added: Patients completing the GEMINI-1 trial will subsequently be enrolled in GEMINI-2, our second Phase 3 trial for imsidolimab in GPP, where they will receive monthly doses of 200mg subcutaneous imsidolimab or placebo depending upon whether they are responders, partial responders or non-responders to treatment under GEMINI-1.
+Added: The objective of GEMINI-2 is to assess the efficacy and safety of imsidolimab after 3 years of monthly dosing.
+Added: Top-line data from an interim analysis of GEMINI-1 is anticipated in the fourth quarter of 2023.
+Added: We announced in August 2022 that we intend to complete execution of our Phase 3 program in GPP and out-license imsidolimab prior to potential FDA approval.
+Added: Etokimab inhibits IL-33 function and acts upstream of key cell types involved in atopy and the subsequent release of Th2 cytokines.
+Added: IL-33 is a pro-inflammatory cytokine that signals through the ST2 receptor, which multiple studies suggest serves as a central mediator of various immune responses leading to Th2-type inflammatory disorders, including asthma, COPD and atopic diseases.
+Added: Individuals with asthma symptoms express higher levels of IL-33 than healthy control subjects.
+Added: IL-33 initiates a diverse array of cellular immune responses, including the activation of mast cells, basophils and eosinophils, leading to production of downstream cytokines, such as IL-4, IL-5 and IL-13, which are associated with atopic diseases.
+Added: IL-33 also acts on Th2 effector cells and Innate Lymphoid Cell Type 2 (ILC2), two types of white blood cells that initiate and orchestrate atopic responses.
+Added: We have no ongoing clinical trials of etokimab and announced in January 2023 that etokimab is available to out-license.
+Added: Multiple Company-discovered antibody programs have been advanced to preclinical and clinical milestones under our collaborations.
+Added: Our collaborations include an immuno-oncology-focused collaboration with GSK.
+Added: Under the GSK Agreement, a Biologics License Application (BLA) for our most advanced partnered program, which is an anti-PD-1 antagonist antibody called JEMPERLI (dostarlimab), was approved by the FDA in April 2021 for the treatment of advanced or recurrent deficient mismatch repair endometrial cancer (dMMREC).
+Added: In February 2023, the FDA granted full approval for this indication (from an accelerated approval).
+Added: In addition, in April 2021 the European Medicines Agency (“EMA”) granted conditional marketing authorization in the European Union (EU) for JEMPERLI for use in women with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) recurrent or advanced endometrial cancer who have progressed on or following prior treatment with a platinum containing regimen.
+Added: A second FDA approval was received in August 2021 for JEMPERLI in pan-deficient mismatch repair tumors (PdMMRT).
+Added: JEMPERLI is currently in Phase 3 trials for various solid tumor indications, including first-line advanced/recurrent endometrial cancer and first-line ovarian cancer.
+Added: In addition, under the collaboration, GSK is developing dostarlimab in combination with two other development programs from the GSK Agreement:
+Added: cobolimab, an anti-TIM-3 antibody, and GSK40974386, an anti-LAG-3 antibody for multiple solid tumor indications.
+Added: GSK is conducting a Phase 3 trial, COSTAR Lung, which is a randomized, open label 3-arm trial comparing cobolimab plus dostarlimab plus docetaxel to dostarlimab plus docetaxel to docetaxel alone in patients with advanced non-small-cell lung cancer (“NSCLC”) who have progressed on prior anti-PD-(L)1 therapy and chemotherapy.
+Added: In June 2021, GSK estimated potential peak annual global JEMPERLI sales on a non-risk adjusted basis of £1-£2 billion for currently approved indications and first-line use in endometrial and ovarian cancer only.
Our Product Candidates
−Removed: The following table summarizes certain key information about our wholly-owned and partnered product candidates:
−Removed: We are continuing to proactively monitor and assess the COVID-19 global pandemic.
−Removed: The full impact of the COVID-19 pandemic is inherently uncertain.
−Removed: Our ongoing clinical trials have been, and may continue to be, affected by the closure of offices, or country borders, among other measures being put in place around the world.
−Removed: The COVID-19 pandemic has caused us to modify our business practices (including but not limited to curtailing or modifying employee travel, moving to full remote work, and cancelling physical participation in meetings, events and conferences).
−Removed: While we have begun to re-open our offices, we continue to allow remote work, we continue to monitor developments of the COVID-19 pandemic and we may take further actions as may be required by government authorities or that we determine are in the best interests of our employees, patients, and business partners.
−Removed: We have implemented appropriate safety measures, following guidance from the Center for Disease Control and the Occupational Safety and Health Administration.
−Removed: The extent of the impact of the COVID-19 pandemic on our future liquidity and operational performance will depend on certain developments, including the duration and spread of the outbreak, including its variants, the availability and effectiveness of vaccines, the impact on our clinical trials, patients and collaboration partners, and the effect on our suppliers.
−Removed: We are a leading antibody development company with a pipeline of novel therapeutic antibodies, which is being further expanded by applying our technology platform to emerging biological targets.
+Added: The following table summarizes certain key information about our wholly-owned product candidates:
+Added: We are a clinical-stage biotechnology company focused on delivering innovative immunology therapeutics.
+Added: Our immune cell modulating antibodies, developed internally with our antibody research platform, modulate key nodes governing the body’s regulation of inflammation and autoimmunity.
+Added: Dysregulated immune responses may result in abnormal and pathological inflammation in disorders with large and substantially underserved patient populations in the therapeutic areas of dermatology, rheumatology, gastroenterology, respiratory and neurology.
The key elements of our strategy include:
−Removed: • Advancing our wholly-owned lead product candidates to clinical milestones.
−Removed: We are working to demonstrate the safety and efficacy of our wholly-owned pipeline programs.
−Removed: We are currently developing three wholly-owned programs to key 2022 milestones, including top-line data from our Phase 2 imsidolimab trials in moderate-to-severe acne and hidradenitis suppurativa in the first and second halves of 2022, respectively, and top-line data from our Phase 1 clinical trial of ANB032 in the first half of 2022.
−Removed: • Continuing to expand our proprietary pipeline by generating new product candidates using our technology platform.
−Removed: Using our proprietary SHM antibody generation platform, we are able to rapidly develop novel antibodies against biological targets.
−Removed: Our goal is to continue expanding our wholly-owned new therapeutic antibody program pipeline by innovating additional wholly-owned novel pipeline antibodies to potentially first-in-class immune-related targets.
−Removed: • Identifying emerging opportunities in key therapeutic areas.
−Removed: We intend to remain at the forefront of discovery and development of new therapeutic opportunities in inflammation by understanding and translating biological breakthroughs into first-in-class therapeutic antibodies.
−Removed: Our approach includes translational biology assessments, such as human genetics, ex vivo tissue pathology and target expression patterns, to understand the relevance of emerging targets to patients with unmet medical needs.
−Removed: We plan to leverage this knowledge to create new product candidates and position our current and future programs for initial efficacy assessment.
−Removed: • Retaining rights to strategic products in key commercial markets.
−Removed: We intend to retain ownership and control of our pipeline programs to key preclinical and clinical data inflection points.
−Removed: For certain programs, we plan to seek strategic collaborations that provide us with funding, infrastructure and marketing resources to advance through development and commercialization.
−Removed: Our Wholly-Owned Product Pipeline
−Removed: Our most advanced, wholly-owned pipeline programs, imsidolimab, rosnilimab and ANB032, are described below:
−Removed: Anti-IL-36R Antibody
−Removed: Imsidolimab is an antibody that inhibits the function of IL-36R, which we are initially developing as a potential first-in-class therapy for multiple inflammation-mediated dermatological patient populations.
−Removed: GPP is a life-threatening, rare systemic inflammatory disorder, with no currently approved therapies.
−Removed: While initial GPP epidemiology studies suggested at least 3,000 patients in the United States, recent medical claims analyses conducted by IQVIA indicate approximately 37,000 unique patients were diagnosed with GPP at least once, and approximately 15,000 unique patients were diagnosed with GPP at least twice, by a physician between 2017 and 2019 using the International Classification of Diseases 10th Revision (ICD-10) billing code pertaining to GPP (L40.1).
−Removed: Studies have shown that GPP can be associated with mutations in the gene encoding the IL-36R antagonist, or IL-36RA, or can be caused by excessive IL-36 cytokine levels, that lead to abnormally high signaling through the IL-36R and thereby cause the systemic inflammatory condition, GPP.
−Removed: We have obtained FDA Orphan Drug Designation for imsidolimab for the treatment of GPP, and plan to seek Orphan Drug Designation for additional indications in the future.
−Removed: We initiated a Phase 3 clinical trial in GPP, called GEMINI-1, during the third quarter of 2021.
−Removed: We are also developing imsidolimab for moderate-to-severe acne which affects approximately 3 million patients in the United States, for which we anticipate top-line data during the first half of 2022, and moderate-to-severe hidradenitis suppurativa affecting approximately 150,000 patients in the United States, for which we anticipate top-line data during the second half of 2022.
−Removed: IL-36R Target Biology
−Removed: The IL-36 subfamily of proteins consists of the IL-36 receptor antagonist, or IL-36RA, as well as three cytokines, IL-36 alpha, IL-36 beta and IL-36 gamma, each of which have agonistic characteristics and signal through IL-36R.
−Removed: These IL-36 proteins are mainly expressed in keratinocytes, the predominant cell type in the epidermis.
−Removed: The role of the IL-36RA is to dampen the inflammatory effects of IL-36 alpha, IL-36 beta and IL-36 gamma.
−Removed: Studies have demonstrated the relevance of IL-36 in regulating inflammation in the skin.
−Removed: Mice over-expressing the IL-36 alpha cytokine undergo a psoriasis-like condition when challenged with an inflammatory stimulus.
−Removed: Additionally, immuno-deficient mice transplanted with human psoriatic skin have been shown to require the IL-36R signaling to maintain disease.
−Removed: Recent human studies have demonstrated that mutations in the IL-36RA can lead to the occurrence of GPP by dysregulating the IL-36R signaling pathway .
−Removed: However, translational studies that we conducted have also demonstrated that a significant number of GPP patients do not have mutations in the IL-36RA but are likely to have excessive levels of IL-36 cytokines leading to the same disease as patients with mutations.
−Removed: These findings support our hypothesis that IL-36 signaling plays a significant role in GPP.
−Removed: In addition, studies have demonstrated that humans with genetic mutations that downregulate IL-36 receptor activity are otherwise normal with no specific clinical phenotype.
−Removed: We believe that imsidolimab has the potential to be the first-in-class therapeutic antibody targeting IL-36R, serving as a therapeutic opportunity for patients with IL-36 signaling mediated inflammatory diseases.
−Removed: Translational studies have indicated that IL-36 signaling is upregulated in GPP, hidradenitis suppurativa and acne.
−Removed: Imsidolimab Non-Clinical Development
−Removed: Imsidolimab was generated using our SHM technology platform and has demonstrated high functional potency in blocking human and cynomolgus monkey IL-36 signaling in preclinical studies.
−Removed: Imsidolimab blocks signal transduction through the human IL-36R and cynomolgus monkey IL-36R by inhibiting the interaction between the receptor and IL-36 alpha, IL-36 beta, and IL-36 gamma cytokines.
−Removed: The high potency and functional activity of imsidolimab for human and cynomolgus monkey IL-36R was measured using standard in vitro assays to determine equilibrium dissociation constant, or KD, and half-maximal inhibitory concentration values, or IC50.
−Removed: Imsidolimab has demonstrated potent KD values of approximately of 71 pM and 209 pM for human IL-36R and cynomolgus monkey IL-36R, respectively.
−Removed: The antibody exhibits high specificity for IL-36R, displaying no detectable binding to related proteins.
−Removed: Functional potency of imsidolimab is at least 100-fold greater than IL-36RA in human systems, which is measured as the IC50 of inhibition of interleukin-8, or IL-8, release from human keratinocytes.
−Removed: Imsidolimab functional activity has been demonstrated through inhibition of IL-8 secretion from human primary keratinocytes when stimulated by IL-36 gamma of approximately 0.15 nM and 1.2 nM, respectively.
−Removed: Lower KD and IC50 values indicate higher potency and functional activity, respectively.
−Removed: Similar IC50 values were observed in those same preclinical studies when keratinocytes were stimulated with IL-36 alpha or beta.
−Removed: To date, we have demonstrated that the half-life of imsidolimab in cynomolgus monkeys is more than nine days.
−Removed: Imsidolimab is well-expressed from Chinese hamster ovary cells, or CHO cells, and is readily purified using standard methodologies.
−Removed: In addition, the antibody retained full functional activity when incubated in normal human serum at 37 °C for one week.
−Removed: Clinical Development Plan
−Removed: We have completed, under an approved Clinical Trial Notification, or CTN, a Phase 1 clinical trial in healthy volunteers for which we announced positive top-line results from an interim analysis of this clinical trial and subsequently presented completed data from this clinical trial at the 2018 European Academy of Allergy and Clinical Immunology Congress.
−Removed: In the double-blinded, placebo-controlled healthy volunteer Phase 1 clinical trial, 36 subjects were administered a single subcutaneous or intravenous dose of imsidolimab ranging between 10 mg and 750 mg, 18 subjects were administered multiple ascending doses of imsidolimab intravenously ranging between 40 mg and 300 mg weekly for four consecutive weeks and 18 subjects were dosed with placebo.
−Removed: Imsidolimab was well-tolerated by all subjects, and no dose-limiting toxicities were observed.
−Removed: The most frequent treatment-emergent adverse events observed in the single ascending dose cohorts were upper respiratory tract infections in 10 of 36 (28%) subjects dosed with imsidolimab versus six of 12 (50%) subjects dosed with placebo and headache in 10 of 36 (28%) subjects dosed with imsidolimab versus three of 12 (25%) subjects dosed with placebo.
−Removed: In the multiple ascending dose cohorts, the most frequent treatment-emerging adverse events observed were headache in seven of 18 (39%) subjects dosed with imsidolimab versus one of six (17%) subjects dosed with placebo.
−Removed: No serious adverse events were reported among any subjects in the clinical trial.
−Removed: The in vivo half-life of imsidolimab was approximately 28 days for both subcutaneous and intravenous routes of administration, with bioavailability of approximately 90 percent.
−Removed: A single dose of imsidolimab at certain dose levels was able to completely suppress IL-36 cytokine function for 85 days, as measured by IL-36 cytokine-mediated release of IL-8 using an ex vivo pharmacodynamic assay.
−Removed: The favorable pharmacokinetics and pharmacodynamic properties of imsidolimab and other results demonstrated by this Phase 1 clinical trial supported advancement of imsidolimab into Phase 2 studies.
−Removed: We completed an open-label, multi-dose, single-arm Phase 2 clinical trial of imsidolimab in 8 GPP patients, also referred to as the GALLOP clinical trial, where top-line data through week 16 was presented at the European Academy of Dermatology and Venerology (EADV) Congress on October 2, 2021.
−Removed: In this trial 6 of 8 (75%) patients treated with imsidolimab monotherapy achieved the primary endpoint of response on the clinical global impression (“CGI”) scale at week 4 and week 16, without requiring rescue medication.
−Removed: Two of 8 (25%) patients were considered to have not met the primary endpoint because they dropped out of the clinical trial prior to Day 29.
−Removed: The modified Japanese Dermatology Association Severity Index (“mJDA-SI”) score, which incorporates both dermatological and systemic aspects of GPP, decreased for patients on average by 29% at week 1, 54% at week 4 and 58% at week 16.
−Removed: Erythema with skin pustules, which clinically defines GPP, decreased by 60% at week 1 and 94% by week 4 and 98% by week 16.
−Removed: Patients achieved a reduction in the Dermatology Life Quality Index (DLQI), which is a patient-reported measure, of 6 points at week 4 and 11 points by week 16, each of which exceeded the minimal clinically importance difference (MCID) of 4 points.
−Removed: GPP Physician Global Assessment (GPPPGA) scale was implemented by protocol amendment during the course of the trial and was assessed in 4 of the 8 enrolled patients, where zero (clear) or 1 (almost clear) response was achieved in 2 (50%) patients at week 4 and 3 (75%) at week 16.
−Removed: Genotypic testing
−Removed: indicated homozygous wild-type IL-36RN, CARD14 and AP1S3 alleles for all 8 patients.
−Removed: Through week 16, anti-drug antibodies were only detected in one patient, which occurred at week 12 and did not impact imsidolimab pharmacokinetics or efficacy.
−Removed: Imsidolimab was generally well-tolerated, and most treatment-emergent adverse events were mild to moderate in severity and resolved without sequelae.
−Removed: No infusion or injection site reactions were observed.
−Removed: One patient dropped out of the clinical trial due to a diagnosis of Staphylococcal aureus bacteremia in the first week, which was a serious adverse event deemed to be possibly drug-related.
−Removed: Because the patient was symptomatic prior to dosing and had a prior medical history of bacteremia, a common comorbidity of GPP, we do not believe this event is likely attributable to imsidolimab.
−Removed: Another patient dropped out of the study on Day 22 due to investigator reported inadequate efficacy.
−Removed: One patient contracted COVID-19 during the course of the clinical trial, which was deemed a serious adverse event unrelated to imsidolimab, and did not lead to study discontinuation.
−Removed: Data from the first two patients to have completed the Day 113 treatment period under this clinical trial, which we announced in September 2019, indicated sustained efficacy in these two patients through Day 113.
−Removed: We met with the FDA during the fourth quarter of 2020 to review an orphan disease registration plan for imsidolimab for the treatment of GPP and have initiated a Phase 3 clinical trial during the third quarter of 2021 following completion of protocol alignment and review of 16-week data from the GALLOP clinical trial by the FDA.
−Removed: In July 2020, the FDA granted Orphan Drug Designation for imsidolimab for the treatment of patients with GPP.
−Removed: GPP is a chronic, life-threatening, rare disease with no currently approved therapies.
−Removed: GPP is a systemic inflammatory disease characterized by the development of widespread pustules marked by idiopathic exacerbations.
−Removed: In severe cases, GPP patients can die from cardio-pulmonary failure, exhaustion, toxicity and/or infection subsequent to occurrences of pustular flares.
−Removed: Patients with GPP suffer without robust therapeutic options because currently approved psoriasis management therapies have not demonstrated clear efficacy in the treatment of this condition.
−Removed: While initial GPP epidemiology studies suggested at least 3,000 patients in the United States, recent medical claims analyses conducted by IQVIA indicate approximately 37,000 unique patients were diagnosed with GPP at least once, and approximately 15,000 unique patients were diagnosed with GPP at least twice, by a physician between 2017 and 2019 using the International Classification of Diseases 10th Revision (ICD-10) billing code pertaining to GPP (L40.1).
−Removed: We have initiated a global registry of GPP patients, also referred to as the RADIANCE study, which we anticipate will improve understanding of the patient journey in these two indications and assist in enrollment of future GPP clinical trials.
−Removed: We are conducting clinical development of imsidolimab in moderate-to-severe acne.
−Removed: Acne is the most common skin disorder in the United States, with approximately 3 million patients diagnosed with moderate-to-severe disease.
−Removed: Moderate-to-severe acne typically presents with painful papules, pustules, nodules, cysts and scarring.
−Removed: A key contributing factor to the pathogenesis of acne is the immune response to Propionibacterium acnes , or p.
−Removed: acnes , which is associated with upregulated IL-36 cytokine activity, localized inflammation and neutrophil infiltration of the skin.
−Removed: Existing therapies, including isotretinoin and systemic antibiotics, provide variable efficacy for moderate-to-severe acne patients and have practical limitations to their use given potential for clinically meaningful side effects.
−Removed: We are conducting a Phase 2 clinical trial of imsidolimab, called ACORN, where 120 patients will be randomized equally between two dose levels of imsidolimab and placebo, for the treatment of moderate-to-severe acne, and we anticipate top-line date during the first half of 2022.
−Removed: We are conducting clinical development of imsidolimab in hidradenitis suppurativa, also known as acne inversa, which is a chronic inflammatory skin disease characterized by painful nodules in intertriginous areas that can progress to abscesses, sinus tracks and scarring.
−Removed: Current treatment options for hidradenitis suppurativa, including antibiotics, corticosteroids and anti-TNF therapy, have variable efficacy in moderate-to-severe patients, which often leads to surgery for removal of hidradenitis suppurativa nodules.
−Removed: Human translational studies have demonstrated elevated IL-36 cytokine expression in hidradenitis suppurativa skin biopsies, and we believe treatment of moderate-to-severe hidradenitis suppurativa with imsidolimab may lead to therapeutic benefit for this patient population.
−Removed: Moderate-to-severe hidradenitis suppurativa affects approximately 150,000 adults in the United States.
−Removed: We are conducting a Phase 2 clinical trial of imsidolimab in moderate-to-severe hidradenitis suppurativa, called HARP, where 120 patients will be randomized equally between two dose levels of imsidolimab and placebo, and we anticipate top-line data during the second half of 2022.
+Added: • Enabling broad development of our immune cell modulator portfolio, including our checkpoint agonist programs, rosnilimab and ANB032, in indications including moderate-to-severe RA and AD, respectively.
+Added: • Generating in vitro and in vivo translational and clinical data to inform the potential differentiation of our molecules from in-class competitors and, relative to standard of care, treat patient populations most likely to have deeper and/or more durable responses by restoring immune balance.
+Added: • Facilitating the global commercialization of our checkpoint agonists while retaining rights in key therapeutic areas and/or commercial markets to enable us to become a fully integrated discovery, development and commercial organization.
+Added: • Continuing to leverage our research platform to generate potentially best-in-class antibodies against high-value immunological targets.
+Added: • Maximizing return on equity through execution against a multi-year capital and operating plan, including the potential for future royalty revenues from our GSK immuno-oncology collaboration and, where actionable, monetizing our legacy cytokine antagonist programs and enabling further external development and, potentially, commercialization.
As described in the section titled “Risk Factors” and elsewhere in this report, the clinical development of drug product candidates is subject to a wide range of risks and uncertainties, any of which could cause our actual development strategy or timeframes to vary.
−Removed: Checkpoint Receptor Modulator Programs
−Removed: We are developing anti-inflammatory checkpoint receptor antibodies to PD-1 and BTLA, each of which are genetically associated with inflammatory disease when dysregulated in humans.
−Removed: Rosnilimab is an antibody that binds PD-1 in an agonistic manner, leading to reduced T cell activity and anti-inflammatory effects in vivo .
−Removed: PD-1 is a key inhibitory immune checkpoint receptor expressed by activated T cells.
−Removed: PD-1 activity contributes to downregulation of T cell mediated immune responses in healthy individuals.
−Removed: We believe insufficient PD-1 activity may be a key biological defect associated with human inflammatory diseases.
−Removed: According to a 2007 study, genetic mutations in the PD-1 pathway are associated with increased susceptibility to various inflammatory conditions.
−Removed: We hypothesize that augmenting PD-1 signaling by rosnilimab treatment has the potential to broadly suppress human inflammatory diseases.
−Removed: Rosnilimab was developed using our proprietary antibody discovery platform.
−Removed: We believe PD-1 agonist antibodies are challenging to discover due to the unique binding properties required to augment signaling through checkpoint receptors.
−Removed: Rosnilimab has been preclinically tested for key pharmacological properties (including binding potency, functional activity, epitope specificity, in vivo efficacy and pharmacokinetics) and manufacturability attributes (including expression and stability).
−Removed: Through translational biology, we plan to focus the clinical development of rosnilimab upon certain human autoimmune diseases where PD-1 checkpoint receptor function may be under-represented.
−Removed: We presented preclinical data for rosnilimab at the Festival of Biologics Annual Meeting in March 2020, including translational data demonstrating in vitro activity of rosnilimab in alopecia areata patient samples.
−Removed: We announced positive top-line data from a healthy volunteer Phase 1 clinical trial of rosnilimab in November 2021.
−Removed: A total of 144 subjects were enrolled in the randomized, double-blind, placebo-controlled healthy volunteer Phase 1 trial, where single ascending dose (SAD) cohorts were administered single subcutaneous or intravenous doses of rosnilimab ranging between 0.02mg to 600mg or placebo, while multiple ascending dose (MAD) cohorts received four weekly subcutaneous doses of rosnilimab ranging between 60mg and 400mg or placebo.
−Removed: Dose escalation was conducted subsequent to data safety monitoring board review of safety and tolerability parameters following each single and multiple ascending dose level.
−Removed: Rosnilimab was generally well-tolerated and no dose limiting toxicities were observed.
−Removed: The most frequent adverse event reported among SAD cohorts was increased circulating C-reactive protein levels of mild severity in nine (10%) rosnilimab-dosed subjects occurring sporadically in a dose-independent manner and a severe occurrence in one (3.3%) placebo-dosed subject.
−Removed: MAD cohorts reported headache as the most frequent adverse event with mild occurrences in three (12.5%) rosnilimab-dosed subjects and none in placebo subjects.
−Removed: Mild injection site reactions were observed in two subjects (11.1%) administered with multiple subcutaneous rosnilimab doses.
−Removed: Two serious adverse events were reported in single dose cohorts, including obstructive pancreatitis in a placebo-dosed subject and COVID-19 infection in a rosnilimab-dosed subject leading to discontinuation which was deemed unrelated to treatment.
−Removed: No serious adverse events were reported in subjects receiving multiple doses of rosnilimab or placebo.
−Removed: Pharmacokinetic analyses demonstrated a favorable profile for rosnilimab with an estimated two-week half-life for subcutaneous and intravenous routes of administration and approximately 80% bioavailability.
−Removed: Low-titer anti-drug antibodies were detected at low single dose levels in 19 (21%) rosnilimab-dosed subjects, but none were detected in high single dose or multiple dose subjects.
−Removed: Full PD-1 receptor occupancy was observed rapidly during the first week following single subcutaneous rosnilimab doses at or above 60mg, and was maintained for at least 30 days at or above 200mg single subcutaneous doses.
−Removed: These data support monthly subcutaneous dosing of rosnilimab for future patient trials.
−Removed: Rosnilimab’s pharmacodynamic activity resulted in rapid and sustained reduction in the quantity and functional activity of PD-1+ T cells, which are known to be pathogenic drivers of inflammatory diseases.
−Removed: Conventional T (Tcon) cells (CD3+, CD25 low) expressing PD-1, which represented approximately 25% of peripheral T cells at baseline, were reduced by 50%, including in both CD4+ and CD8+ subsets, in a dose-dependent manner and in correlation with receptor occupancy.
−Removed: This effect was maximized on high-PD-1 expressing Tcon cells, which represented approximately 5% of peripheral T cells, with 90% reduction relative to baseline.
−Removed: Conversely, total T cells (CD3+), total Tcon cells (CD3+, CD25low) and total regulatory T (Treg) cells (CD3+, CD4+, CD25 bright, CD127-) were unchanged (<5% change from baseline), resulting in a favorable shift in the ratio of PD-1+ Tcon cells to total Treg cells post-treatment.
−Removed: No effect (<5% reduction from baseline) was observed on any of the aforementioned cell types in placebo-dosed subjects.
−Removed: In addition, an antigen-specific functional T cell recall response, measured as ex vivo interferon-gamma released in response to tetanus toxoid challenge, was inhibited in a receptor occupancy dependent manner and was consistent with the observed reduction of PD-1+ Tcon cells, to a maximum of approximately 90% relative to baseline within 30 days following single rosnilimab dose, while placebo administration had no effect.
−Removed: Based upon these data, we believe rosnilimab’s in vivo mechanism has the potential to treat T-cell driven human inflammatory diseases.
−Removed: During the fourth quarter of 2021, we initiated AZURE, a randomized placebo-controlled 45-patient Phase 2 trial of rosnilimab in moderate-to-severe alopecia areata patients with at least 50% scalp hair loss for at least 6 months prior to enrollment, where the primary endpoint is change in severity of alopecia tool (SALT) relative to baseline.
−Removed: We continue to assess clinical development opportunities for rosnilimab in additional indications, including vitiligo and rheumatoid arthritis, and will make decisions pending additional data.
−Removed: ANB032 is an antibody that modulates BTLA in a manner that results in anti-inflammatory effects in vivo .
−Removed: BTLA is broadly expressed upon lymphoid (including T and B) cells and myeloid cells (including dendritic cells) and therefore involved in a spectrum of inflammatory responses.
−Removed: We believe that the binding of BTLA with LIGHT, a receptor also known as TSFSR14, results in pro-inflammatory signaling across various immune cells, and that stabilization of BTLA’s binding to
−Removed: HVEM, which is mediated by ANB032 treatment, leads to an anti-inflammatory effect in vivo .
−Removed: Genetic studies have demonstrated that dysregulated BTLA signaling, which favors pro-inflammatory activity, is associated with certain human inflammatory diseases (Lin et al.
−Removed: J Biomed Sci.
−Removed: ANB032 has demonstrated in vivo efficacy in an animal disease model.
−Removed: We are conducting a healthy volunteer Phase 1 trial of ANB032, under an Australian Clinical Trial Notification (“CTN”), and anticipate top-line data from this trial during the first half of 2022.
−Removed: We presented preclinical data regarding ANB032 at the 2020 Federation of Clinical Immunology Societies (FOCIS) Virtual Annual Meeting in October 2020.
−Removed: Our SHM Antibody Discovery Platform
Antibody Overview
2 unchanged sentences
Antibodies are structurally distinct Y-shaped proteins formed through the combination of two long proteins, called heavy chains, and two short proteins, called light chains.
−Removed: Each heavy and light chain pair forms a binding site where the antibody specifically binds its target, otherwise known as an antigen, at the Fab domain of the antibody molecule.
+Added: heavy and light chain pair forms a binding site where the antibody specifically binds its target, otherwise known as an antigen, at the Fab domain of the antibody molecule.
The specificity of each antibody to a target, and the potency of its binding strength to that target are defined by the amino acid sequences of heavy and light chains in the Fab domain of the antibody molecule.
The other end of the antibody, called the Fc domain, is responsible for communication between the antibody and the rest of the immune system.
−Removed: Fc domains bind to various receptors and cause immune system effector responses.
Therapeutic antibodies are typically non-naturally occurring, or recombinant, antibodies specifically developed to treat human diseases by binding to certain proteins, and thereby modulating key biological processes.
1 unchanged sentence
Therapeutic antibodies have the following key features that we believe make them more predictable than small molecules:
−Removed: • Target Specificity.
−Removed: Due to the large size and complex nature of the antibody Fab domain, antibodies generally bind with high specificity to the desired therapeutic target and tend to exhibit less off-target binding to unrelated proteins, which lowers the risk of unintended biological side effects such as toxicity.
+Added: • Fab Domain.
+Added: Due to the relatively large size and complex nature of the antibody Fab domain, antibodies generally bind with high specificity to the desired therapeutic target and tend to exhibit less off-target binding to unrelated proteins, which lowers the risk of unintended biological side effects such as toxicity.
+Added: Because target proteins are typically larger than antibody Fab domains, antibodies can be generated against a variety of specific binding epitopes on a given single protein, which can alter the functional activity of the protein.
+Added: For example, antibodies binding to unique epitopes on a single target protein can act as antagonists or agonists of the natural target protein function.
+Added: The Fc domain of an antibody is the tail region that interacts with cell surface receptors called Fc receptors and some proteins of the complement system.
+Added: In humans, there are five Fc domains referred to as isotypes (IgA, IgD, IgM, IgG, IgE) and numerous Fc receptors expressed on specialized immune cells.
+Added: Many therapeutic antibodies are subtypes of the IgG isotype and are chosen specifically to limit or induce immune system activity for therapeutic purposes.
+Added: Engagement of Fc domains by specific Fc receptors can modulate biological activity, for example, by clustering the target protein on the cell surface in an immune synapse, leading to modulation of the target protein activity and hence altering the function of the cell expressing the target protein.
+Added: Specific Fc domain and Fc receptor interactions may also trigger killing of a cell, often referred to as “effector function” of the antibody, via cytotoxic mechanisms depending on the cell type bearing the Fc receptor.
+Added: In some therapeutic settings, mutations can be made to the Fc domain to weaken or entirely abrogate Fc receptor interactions.
+Added: In creating the most efficacious therapeutic antibody, an appropriate Fc domain is often utilized to avoid or induce immune system activity that contributes to its broader mechanism of action.
+Added: We believe that therapeutic antibodies can be significantly de-risked preclinically for specificity, toxicology, pharmacokinetics, and modulation of immune system activity, which is not generally true for small molecule drugs.
• Pharmacokinetics and Dosing Frequency .
2 unchanged sentences
• Potency and Dose Quantities.
−Removed: Antibodies are typically highly potent in binding to their desired target, with binding dissociation constants in the low nanomolar to picomolar range.
+Added: Antibodies are typically highly potent in binding affinity to their desired target, with binding dissociation constants in the low nanomolar to picomolar range.
Hence, antibodies tend to be dosed at low amounts (less than 1 gram quantities per course of therapy).
−Removed: We believe that therapeutic antibodies can be significantly de-risked pre-clinically for specificity, toxicology and pharmacokinetics, which is not generally true for small molecule drugs.
Limitations of Competing Antibody Technologies
1 unchanged sentence
Such technologies have relied primarily on mouse immunization methodologies (such as wild-type or engineered mice), microbial antibody display libraries (such as phage or yeast cell display) or human B cell screening to generate antibodies against therapeutic targets of interest.
−Removed: We believe the key limitations of these competitive approaches include:
−Removed: • Insufficient Diversity .
−Removed: Each of the prior technologies has limited, and often static, diversity of antibodies available for selection.
−Removed: The number of therapeutic targets that can be addressed by the available antibodies is therefore limited.
−Removed: It is particularly difficult for mouse immunization approaches to identify therapeutics against conserved proteins that are homologous between human and mouse species;
−Removed: • Lack of Functional Activity Selection.
−Removed: Competing technologies have not been able to drive antibody selection on the basis of functional activity.
−Removed: Even if antibodies are available against a certain target, they may not bind the correct region or epitope of the protein to achieve the intended functional therapeutic effects;
−Removed: • Low Potency.
−Removed: Antibodies from competing technologies tend to demonstrate low binding potencies against their targets.
−Removed: Such incomplete binding may not result in therapeutic effect that is sufficient to change disease outcomes, or require impractically high doses to convey therapeutic benefit;
−Removed: • Unpredictable Manufacturing Properties.
−Removed: Using microbial display systems such as phage and yeast display libraries has resulted in unpredictable expression, stability and formulation when manufacturing is initiated using mammalian cells, thus leading to poor production yields and product stability.
−Removed: Mouse immunization methodologies .
−Removed: Mouse immunization methodologies involve the administration of human target antigen to mice with wild-type or engineered immune systems, with the assumption that their immune systems will generate antibodies with sufficient potency against the desired human antigen epitope to convey biological effect.
−Removed: A key limitation of this approach is that when the mouse is dosed with an antigen that is similar in the human and mouse, the antigen is seen by the mouse immune system as one of its own proteins, and very few, if any, antibodies are generated.
−Removed: In addition, the mouse immune system often generates mouse antibodies to epitopes that are not therapeutically relevant to humans, leading the resulting antibodies to bind the human target but failing to convey therapeutic effect.
−Removed: Microbial antibody display systems .
−Removed: Microbial antibody display systems require screening of antibodies, typically formatted as antibody fragments, from a static library diversity displayed on a bacterial or yeast microbial cell surface.
−Removed: The static nature of these libraries limits the range of antibody specificities to values around 10 9 or 10 10 , which is generally insufficient to avail high-affinity antibodies against many antigens.
−Removed: This can lead to suboptimal potency and subsequently require phage/yeast antibodies to be matured significantly, typically with random mutagenesis, to obtain therapeutic level potencies, which is a labor-intensive and inefficient process.
−Removed: In addition, antibodies selected using this approach are expressed through the microbial cell expression machinery, which differs significantly in terms of manufacturability (expression level, glycosylation, formulation and stability) from mammalian cell expression typically utilized for clinical and commercial manufacturing of therapeutic antibodies.
−Removed: Such differences typically lead to difficulties in mammalian cell manufacturing of microbial display-derived antibodies.
−Removed: Human B cell screening methodologies .
−Removed: Human B cell screening methodologies involve the screening and isolation of antibodies from peripheral human blood against therapeutic antigens of interest.
−Removed: The key limitation of this approach is that circulating human B cells generally do not develop antibodies against endogenous proteins because their function is to develop humoral immunity against foreign pathogens, such as bacteria and viruses.
−Removed: Therefore, it is challenging to obtain therapeutic antibodies against human antigens through this approach.
−Removed: Our Technology Solution
−Removed: Our innovative platform is designed to replicate the natural process of SHM embedded within the human immune system to rapidly develop a diverse range of therapeutic-grade antibodies in vitro .
−Removed: SHM is a critical, endogenous process that generates the essential antibody diversity required to develop a natural immune response to pathogens.
−Removed: Human genomes encode a limited number of antibody genes, which are insufficient to generate antibodies against the wide variety of foreign pathogens encountered from the external environment.
−Removed: SHM enables the human immune system to expand the limited diversity encoded within human genomes to the billions of antibody specificities required to defend against external pathogens.
−Removed: The key enzyme required for SHM is called activation-induced cytidine deaminase, or AID.
−Removed: AID has been genetically conserved throughout mammalian biology and is required for the non-random mutagenesis pattern associated with SHM.
−Removed: AID is specifically expressed by B cells after contact with a foreign pathogen and modifies antibody sequences in a non-random fashion.
−Removed: Through SHM, B cells evolve antibodies with the potency and specificity required to clear the foreign pathogen.
−Removed: However, within the in vivo environment, SHM does not generally progress to the creation of high potency antibodies or develop antibodies against the body’s own proteins.
−Removed: By coupling in vitro SHM with our mammalian cell system that simultaneously displays and secretes antibodies, we believe SHM is able to rapidly identify and mature antibodies with desired functional activity to high potency while simultaneously mitigating the risks associated with manufacturing.
−Removed: We introduce AID into mammalian cells to replicate the non-random mutagenesis SHM pattern observed within B cells in vivo .
−Removed: Starting with a library of either fully-human or humanized antibodies, our platform generates AID-based variants of the starting antibody library throughout the process.
−Removed: We have demonstrated that the pattern of mutagenesis we observe in vitro using our platform technology closely mimics the pattern observed among in vivo generated antibodies, thereby increasing confidence that antibodies generated by our platform will be tolerated when used as therapeutic drugs in humans.
−Removed: By selecting antibodies based on their antigen binding from the broad antibody library population SHM develops, we are able to evolve in an iterative fashion the binding potency and function of antibodies to levels that we believe will be required for therapeutic use.
−Removed: We believe this approach allows us to rapidly generate antibodies with high binding potency against a target.
−Removed: Through this approach, we have successfully generated therapeutic antibody product candidates to more than 25 targets, including targets that we believe have been challenging for competing antibody technology platforms to generate.
−Removed: Each evolving antibody is expressed within the SHM-active mammalian cell to concurrently display the evolved antibody on the cell surface to permit cell sorting selection for potency properties while the same antibody is secreted into the extracellular media at sufficient quantities to permit functional assays to be conducted.
−Removed: In this manner, the evolving antibodies
−Removed: expressed by each transfected cell are assessed in a high-throughput fashion for the desired functional activity relevant to the therapeutic mechanism.
−Removed: We believe our antibody discovery platform, as described above, has the following advantages over competing approaches:
−Removed: • Diversity against difficult targets.
−Removed: We are able to generate an unprecedented diversity of antibodies by applying SHM-based diversification outside of the constraints of an in vivo environment.
−Removed: This enables us to develop antibodies against human targets that we believe have not otherwise been accessible to prior technologies.
−Removed: • High potency.
−Removed: Because our platform generates highly-potent antibodies, we are potentially able to modulate every extracellular target associated with human disease, and believe only small therapeutic doses may be required to mediate therapeutic effect in vivo .
−Removed: • Functional activity selection.
−Removed: Our mammalian cell system simultaneously displays and secretes antibodies during the antibody discovery process, allowing us to incorporate functional assays throughout the process and focus on producing product candidates that are optimized for the desired therapeutic activity.
−Removed: Our platform technology has enabled us to generate therapeutic-grade antibodies and initiate subsequent preclinical manufacturing and toxicology studies, typically in less than 12 months.
−Removed: We believe this timeline is significantly shorter than conventional approaches based upon mouse immunization and microbial display systems.
−Removed: • Manufacturability.
−Removed: By utilizing our mammalian cell display system, we believe our approach increases the probability of success in manufacturing and commercialization by mitigating the risks associated with antibody expression, formulation and stability during the antibody generation process.
+Added: We believe the key limitations of these competitive approaches include insufficient diversity, lack of functional activity selection, and low potency.
+Added: Antibody discovery technologies are often not utilized in combination, or iteratively in combination, or utilized in the appropriate immunological setting that would be conducive to co-discovery of appropriate Fab and Fc domains that work together to accomplish more challenging therapeutic mechanisms of action, such as immune cell modulation.
+Added: Our Antibody Research Platform
+Added: Our innovative antibody research platform is designed to discover and optimize therapeutic antibodies that are tailored to modulate immune function, whether they may be antagonists or immune cell modulators.
+Added: Discovery and optimization occurs first on the Fab domain of the antibody where we often utilize a technology that replicates the natural process of somatic hyper mutation (“SHM”) employed by the human immune system through the expression of a key enzyme called activation-induced cytidine deaminase, (“AID”).
+Added: SHM is a critical, endogenous process that generates the essential antibody diversity required to develop a natural immune response to pathogens, expanding the limited diversity encoded within human genomes to billions of antibody specificities.
+Added: By coupling in vitro SHM with our mammalian cell system that simultaneously displays and secretes
+Added: antibodies, we believe SHM rapidly evolves in an iterative fashion the binding potency and function of antibodies to levels that we believe will be required for therapeutic use with high potency functional activity while simultaneously mitigating potential manufacturing liabilities.
+Added: In addition to optimizing the Fab domain of antibodies for therapeutic purposes using in vitro SHM, we also optimize the Fc domain of the antibody, when needed, to tailor it for specific activity.
+Added: Appropriate Fc domains are utilized to reduce Fc receptor interactions or to optimize Fc receptor interactions, in combination with the Fab domain of the antibody, to specifically modulate immune cell function, engage effector function that kills specific targeted immune cells, or leverage a combination of both activities.
+Added: We further optimize the overall antibody through humanization and removal of liabilities that could potentially affect the structure, stability, pharmacology, manufacturability or immunogenicity of the antibody.
+Added: Optimized antibodies are tested in an extensive suite of immune cell assays, using engineered cell lines, and more relevantly, primary human immune cells from healthy and diseased individuals that we believe most accurately recapitulates the conditions in which the antibody will need to have optimal activity in patients.
+Added: We believe that by combining the in vitro SHM discovery platform with an appropriate Fc domain, in combination with a suite of primary immune cell assays, and finally in vivo functional assessment, we effectively tailor antibody discovery to achieve a unique therapeutic benefit.
Collaborations
GlaxoSmithKline
−Removed: In March 2014, we entered into a Collaboration and Exclusive License Agreement (the “GSK Agreement”) with TESARO, Inc.
−Removed: (“Tesaro”), an oncology-focused biopharmaceutical company now a part of GlaxoSmithKline (Tesaro and GlaxoSmithKline are hereinafter referred to, collectively, as “GSK”).
−Removed: We executed an amendment in November 2014 to add an additional dual-reactive antibody product candidate.
−Removed: Under the terms of the GSK Agreement, as amended, we granted GSK an exclusive, royalty-bearing, sub-licensable worldwide license to research, develop, manufacture, market and sell products based on our proprietary technology for the discovery, generation and optimization of certain specified immunotherapy antibodies.
−Removed: We have granted GSK exclusive rights to three monospecific antibody product candidates targeting TIM-3 (TSR-022), LAG-3 (TSR-033) and PD-1 (TSR-042) and a bispecific antibody product candidates targeting PD-1 and LAG-3.
−Removed: Under the GSK Agreement, as amended, we are responsible for performing initial discovery and development of therapeutic antibodies with the goal of generating immunotherapy antibodies for use in the treatment of cancer.
−Removed: GSK is responsible for all subsequent preclinical, clinical, regulatory, manufacturing and other activities necessary to develop and commercialize antibodies selected under each of six development programs, and GSK is obligated to use commercially reasonable efforts to research, develop and commercialize at least one product to each of the four targets.
−Removed: During the term, other than under the collaboration, and except as amended by the October 23, 2020 amendment of the GSK Agreement (described below), both GSK and we are prohibited from developing and commercializing, independently or with a third party, any agents targeting LAG-3, PD-1 or TIM- 3, as single agents or in combination with other therapies.
−Removed: We completed our responsibilities under the terms of the GSK Agreement as of December 31, 2016 to generate and develop antibodies to certain defined stages of preclinical development.
−Removed: Under the terms of the GSK Agreement, as amended, GSK made up-front, non-creditable and non-refundable cash payments aggregating $19.0 million to us during 2014.
−Removed: GSK was also required to reimburse us on a quarterly basis for specified costs incurred by us in our initial discovery and development activities covered by the agreement.
−Removed: For each of the targets for which GSK is granted exclusive rights, GSK is required to make milestone payments to us of up to $18.0 million if certain research and development milestone events are achieved, up to an additional $90.0 million of milestone payments if certain U.S.
−Removed: regulatory submissions and approvals occur in initial and subsequent indications, and up to an additional $165.0 million upon the achievement of specified levels of annual worldwide net sales.
−Removed: GSK will also be required to pay us tiered royalties ranging from 4% to 8%, for each product developed under the agreement, except in the case of dostarlimab where the royalties payable will be 8% to 25% (as explained in more detail below in connection with the October 23, 2020 amendment of the GSK Agreement), on a product- by-product basis, on worldwide annual net sales, and additional commercial milestone payments if specified levels of annual net sales of a product are attained.
−Removed: On October 23, 2020, we again amended the GSK Agreement (the “2020 Amendment”).
−Removed: Under the 2020 Amendment, we agreed to permit GSK to conduct development and commercialization of Zejula in combination with any third-party molecules.
−Removed: Zejula is an oral, once-daily poly (ADP-ribose) polymerase (PARP) inhibitor, which has received U.S.
−Removed: approval for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy, has been approved for certain other indications, and is under development for additional cancer indications as well.
−Removed: In addition, under the 2020 Amendment, we were granted increased royalties upon sales of dostarlimab, an anti-PD-1 antagonist antibody under development by GSK for multiple oncological disorders, including endometrial cancer, non-small cell lung cancer, ovarian cancer, colorectal cancer and mismatch repair deficient solid tumors, equal to 8% of Net Sales (as defined in the GSK Agreement) below $1.0 billion and from 12% up to 25% of Net Sales above $1.0 billion.
+Added: In March 2014, we entered into a Collaboration and Exclusive License Agreement with GSK (the “GSK Agreement”) for the development and commercialization of therapeutic monospecific and bispecific antibodies that antagonize PD-1, TIM-3, LAG-3 and/or a fourth undisclosed checkpoint receptor.
+Added: We received $17.0 million in upfront fees from GSK in March 2014, and in November 2014, we amended the agreement with GSK to include the development and commercialization of bispecific antibodies to another undisclosed target, for an additional upfront fee of $2.0 million.
+Added: Both upfront fees were recognized over the same period that our research and development services for which we were reimbursed were performed, which was extended through December 31, 2016 by amendment of the GSK Agreement in February 2016.
+Added: For each of the targets under the GSK agreement, we are eligible to receive up to $273.0 million in milestone payments, which are comprised of $18.0 million for preclinical and clinical development milestone payments, $90.0 million upon certain regulatory events and $165.0 million upon worldwide commercial sales thresholds.
+Added: In addition, GSK is obligated to pay us tiered royalties, ranging from 4% to 8%, for each product developed under the agreement, except in the case of JEMPERLI where the royalties payable will be 8% to 25% as described below, on annualized net sales of each antibody commercialized from the collaboration.
+Added: On October 23, 2020, we amended the GSK Agreement (the “2020 Amendment”).
+Added: Under the 2020 Amendment, we were granted increased royalties upon sales of JEMPERLI (dostarlimab), an anti-PD-1 antagonist antibody under development by GSK for multiple oncological disorders, equal to 8% of Net Sales (as defined in the GSK Agreement) below $1.0 billion and from 12% up to 25% of Net Sales above $1.0 billion.
The 2020 Amendment also provided for a one-time non-refundable cash payment of $60.0 million that we received in the fourth quarter of 2020.
−Removed: GSK also agreed, starting January 1, 2021, to pay us a 1% royalty on all GSK Net Sales of Zejula.
The $1.1 billion in cash milestone payments due under the GSK Agreement remain unchanged.
−Removed: Additionally, under the terms of the 2020 Amendment, GSK has agreed to certain diligence commitments with respect to the future development of dostarlimab, and the parties have agreed to review such commitments under regular joint review committee meetings going forward.
+Added: Additionally, under the terms of the 2020 Amendment, GSK has agreed to certain diligence commitments with respect to the future development of JEMPERLI, and the parties have agreed to review such commitments under regular joint review committee meetings going forward.
+Added: In October 2021, we entered into the JEMPERLI Royalty Monetization Agreement (the “JEMPERLI Royalty Monetization Agreement”) with Sagard.
+Added: Under the terms of the JEMPERLI Royalty Monetization Agreement, we received $250.0 million, upon closing in December 2021, in exchange for royalties payable to us under the GSK collaboration on annual global net sales of JEMPERLI below $1.0 billion, as well as certain milestone payments, starting in October 2021.
+Added: The aggregate JEMPERLI royalties and certain future milestones to be received by Sagard under the JEMPERLI Royalty Monetization Agreement are capped at certain fixed multiples of the upfront payment based on time.
+Added: For more information see Note 5 — Sale of Future Royalties in the accompanying notes to the consolidated financial statements.
This GSK Agreement, as amended, expires when no further payments are due to us, unless earlier terminated.
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GSK may terminate the GSK Agreement, as amended, at any time upon 90 days’ prior written notice to us.
−Removed: In October 2021, we signed the Royalty Monetization Agreement with Sagard.
−Removed: Pursuant to this transaction, we received a $250.0 million payment upon closing in December 2021, in exchange for JEMPERLI royalties due to us on annual commercial sales below $1.0 billion and certain future milestones starting in October 2021.
−Removed: The aggregate JEMPERLI royalties and milestones to be received by Sagard under the Royalty Monetization Agreement is capped at certain fixed multiples of the upfront payment based upon time.
+Added: Under the GSK Agreement, a Biologics License Application (“BLA”) for our most advanced partnered program, which is an anti-PD-1 antagonist antibody called JEMPERLI (dostarlimab), was approved by the FDA in April 2021 for the treatment of advanced or recurrent deficient mismatch repair endometrial cancer (dMMREC).
+Added: In February 2023, the FDA granted full approval for this indication (from an accelerated approval).
+Added: In addition, in April 2021 the European Medicines Agency (“EMA”) granted conditional marketing authorization in the European Union (“EU”) for JEMPERLI for use in women with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) recurrent or advanced endometrial cancer who have progressed on or following prior treatment with a platinum containing regimen.
+Added: A second FDA approval was received in August 2021 for JEMPERLI in pan-deficient mismatch repair tumors (PdMMRT).
+Added: JEMPERLI is currently in Phase 3 trials for various solid tumor indications, including first-line advanced/recurrent endometrial cancer and first-line ovarian cancer.
+Added: In addition, under the collaboration, GSK is developing dostarlimab in combination with two other development programs from the GSK Agreement:
+Added: cobolimab, an anti-TIM-3 antibody, and GSK40974386, an anti-LAG-3 antibody for multiple solid tumor indications.
+Added: GSK is conducting a Phase 3 trial, COSTAR Lung, which is a randomized, open label 3-arm trial comparing cobolimab plus dostarlimab plus docetaxel to dostarlimab plus docetaxel to docetaxel alone in patients with advanced NSCLC who have progressed on prior anti-PD-(L)1 therapy and chemotherapy.
+Added: In June 2021, GSK estimated potential peak annual global JEMPERLI sales on a non-risk adjusted basis of £1-£2 billion for currently approved indications and first-line use in endometrial and ovarian cancer only.
Bristol-Myers Squibb
In December 2011, we entered into a license and collaboration agreement (the “BMS Agreement”) with Celgene, now a part of Bristol-Myers Squibb (Celgene and Bristol-Myers Squibb are hereinafter referred to, collectively, as “BMS”), to develop therapeutic antibodies against multiple targets.
−Removed: We completed our responsibilities under the terms of the BMS Agreement to generate antibodies against various mutually agreed biological targets during fiscal 2014.
−Removed: On a target-by-target basis, we provided BMS an option to obtain rights to develop and commercialize a defined number of antibodies against each target.
−Removed: We were successful in generating antibodies against multiple targets and BMS has exercised its option with respect to antibodies against three targets.
−Removed: BMS is currently advancing two anti-inflammatory antibodies, of which an anti-PD-1 agonist antibody, also known as CC-90006, is currently in a Phase 1 clinical trial, while the other program is currently in preclinical development.
−Removed: Upon execution of the BMS Agreement in 2011, BMS paid us a one-time, non-refundable, non-creditable initial fee of $6.0 million.
−Removed: BMS has reimbursed us for specified research costs in accordance with the research plans.
−Removed: BMS is also obligated, on a project-by-project basis, to pay us up to a total of an additional $18.0 million if certain research and development milestone events are achieved under such project and up to a total of an additional $35.0 million if certain regulatory milestone events are achieved under such project.
−Removed: BMS will also be required to pay us single digit royalties on net sales of products containing the delivered antibodies on a product-by-product and country-by-country basis until the later of the expiration of the last patent right that covers manufacture, use or sale of such product in such country, and in any case at least 10 years after the first commercial sale of the product in such country.
+Added: We granted BMS the option to obtain worldwide commercial rights to antibodies generated against each of the targets under the agreement, which option was triggered on a target-by-target basis by our delivery of antibodies meeting certain pre-specified parameters pertaining to each target under the agreement.
+Added: The BMS Agreement provided for an upfront payment of $6.0 million from BMS, which we received in 2011, and recognized through 2014, milestone payments of up to $53.0 million per target, low single-digit royalties on net sales of antibodies against each target, and reimbursement of specified research and development costs.
The BMS Agreement continues until our royalty rights on any BMS product resulting from the collaboration expire, which period will last at least ten years after any such product first goes to market.
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In-Licensing Agreements License Agreement with UKRI
−Removed: In 2006, we entered into an exclusive worldwide license agreement with the Medical Research Council, which has subsequently been acquired by United Kingdom Research and Innovation, or UKRI, to obtain rights to multiple patents and patent applications relating to fundamental discoveries with respect to SHM and AID by Dr.
−Removed: Michael Neuberger and his colleagues.
+Added: In 2006, we entered into an exclusive worldwide license agreement with the Medical Research Council, which has subsequently been acquired by United Kingdom Research and Innovation (“UKRI”), to obtain rights to multiple patents and patent applications relating to fundamental discoveries with respect to SHM and AID.
We since amended this license agreement to include additional subject matter and reflect the change in ownership.
−Removed: Under the terms of the agreement, or the UKRI Agreement, we obtained an exclusive, worldwide, sub-licensable license under specified patent rights to manufacture, use, sell and commercialize products and methods covered by such patents for all fields of use.
+Added: Under the terms of the agreement (the “UKRI Agreement”), we obtained an exclusive, worldwide, sub-licensable license under specified patent rights to manufacture, use, sell and commercialize products and methods covered by such patents for all fields of use.
We are responsible for prosecution of the licensed patents and the development of therapeutic products covered by the intellectual property.
−Removed: We are obligated to research and develop licensed methods and licensed products for the
−Removed: purpose of commercializing such methods and products at least as diligently as we research and develop our other products of similar market potential and stages of development.
We are responsible for paying UKRI an annual fee of $55,000.
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In May 2009, we signed a non-exclusive research and commercial license agreement with Millipore Corporation, or Millipore, to obtain a non-exclusive license to patents and patent applications directed to the ubiquitous chromatin opening elements technology for the expression of proteins, particularly antibodies, generated by us, which license may be sublicensed to our contractors and partners.
−Removed: Under the terms of the agreement, or the Millipore Agreement, we are obligated to pay Millipore $87,500 in annual license fees, adjusted annually for inflation using the Consumer Price Index.
+Added: Under the terms of the agreement, (the “Millipore Agreement”), we are obligated to pay Millipore $87,500 in annual license fees, adjusted annually for inflation using the Consumer Price Index.
Additionally, for each product developed and commercialized under the Millipore Agreement, we are obligated to pay Millipore up to an additional $750,000 upon the achievement of specified development milestone events and up to an additional $4.4 million upon the achievement of specified commercial milestone events.
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We may terminate the Millipore Agreement upon 90 days’ notice to Millipore.
−Removed: Australian Operations
−Removed: In March 2015, we established a wholly-owned Australian subsidiary called AnaptysBio Pty Ltd, in order to conduct various preclinical and clinical activities for etokimab and imsidolimab.
−Removed: By establishing operations in Australia, we are able to access an established network of manufacturing and clinical development support contractors located in Australia and benefit from Australia’s streamlined approval processes for the initiation of first-in human studies.
−Removed: We have few employees with experience advancing product candidates through the Australian regulatory review process and have therefore engaged Australian consultants with expertise in the regulatory requirements and clinical development of therapeutic products in Australia.
−Removed: We are also working with established manufacturing and clinical development support contractors located in Australia, who are familiar with Australian regulatory and product development processes.
Intellectual Property
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The patent portfolios for our internal programs and platform technology are outlined below:
+Added: As of December 31, 2022, we owned 16 patent applications in various countries directed to the antibody sequence of rosnilimab and its variants, methods of use and related matters.
+Added: We intend to prosecute our pending applications and pursue patent issuance and protection in key commercial markets where significant product sales may occur.
+Added: Patents that may issue from our pending applications could provide protection until June 2040.
+Added: As of December 31, 2022, we owned one international (PCT) patent application and one U.S.
+Added: provisional patent application directed to the antibody sequence of ANB032 and its variants, methods of use and related matters.
+Added: We intend to prosecute the pending international patent application and file additional patent applications claiming priority to the U.S.
+Added: provisional patent application, and pursue patent issuance and protection in key commercial markets where significant product sales may occur.
+Added: Patents that may issue from our pending applications, or other patent applications claiming priority thereto, could provide protection until April 2043.
+Added: As of December 31, 2022, we owned one pending U.S.
+Added: provisional patent application directed to the antibody sequence of ANB033 and its variants, methods of use and related matters.
+Added: We intend to file additional patent applications claiming priority to the U.S.
+Added: provisional patent application, and pursue patent issuance, in key commercial markets where significant product sales may occur.
+Added: Patents that may issue claiming priority to our provisional patent application could provide protection until November 2043.
As of December 31, 2022, we owned 24 patents and patent applications in various countries directed to the antibody sequence of imsidolimab and its variants, methods of use and related matters.
We intend to prosecute our pending applications and pursue patent issuance and protection in key commercial markets where significant product sales may occur.
−Removed: Patents that may issue from our pending applications would provide protection until July 2041.
−Removed: As of December 31, 2021, we owned 15 patent applications in various countries directed to the antibody sequence of rosnilimab and its variants, methods of use and related matters.
+Added: Patents that have issued or may issue from our pending applications could provide protection until May 2042.
+Added: As of December 31, 2022, we owned 17 patents and patent applications in various countries directed to the antibody sequence of etokimab and its variants, methods of use and related matters.
We intend to prosecute our pending applications and pursue patent issuance and protection in key commercial markets where significant product sales may occur.
−Removed: Patents that may issue from our pending applications would provide protection until June 2040.
−Removed: As of December 31, 2021, we owned one international (PCT) patent application directed to the antibody sequence of ANB032 and its variants, methods of use and related matters.
−Removed: We intend to prosecute this pending application and, perhaps, other patent applications, and pursue patent issuance and protection in key commercial markets where significant product sales may occur.
−Removed: Patents that may issue from our pending application would provide protection until October 2041.
+Added: Patents that have issued or may issue from our pending applications could provide protection until January 2035.
Dostarlimab (GSK4057190)
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We intend to prosecute our pending applications and pursue patent issuance and protection in key commercial markets where significant product sales may occur.
−Removed: Patents that may issue from our pending applications would provide protection until June 2038.
+Added: Patents that have issued or may issue from our pending applications could provide protection until June 2038.
Cobolimab (GSK4069889)
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We intend to prosecute our pending applications and pursue patent issuance and protection in key commercial markets where significant product sales may occur.
−Removed: Patents that may issue from our pending applications would provide protection until November 2037.
+Added: Patents that have issued or may issue from our pending applications could provide protection until November 2037.
As of December 31, 2022, we owned or co-owned 37 patents and patent applications in various countries directed to the antibody sequence of GSK4074386, an anti-LAG-3 antagonist, and its variants, methods of use and related matters.
We intend to prosecute our pending applications and pursue patent issuance and protection in key commercial markets where significant product sales may occur.
−Removed: Patents that may issue from our pending applications would provide protection until April 2038.
+Added: Patents that have issued or may issue from our pending applications could provide protection until April 2038.
Platform Technology
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Patents relating to our platform technology that have been issued to date provide protection through May 2033.
+Added: Other Intellectual Property Matters
The patent positions of biotechnology companies like ours are generally uncertain and involve complex legal, scientific and factual questions.
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In most countries in which we file, the patent term is 20 years from the earliest date of filing a non-provisional patent application related to the patent.
−Removed: patent also may be accorded a patent term adjustment, or PTA, under certain circumstances to compensate for delays in obtaining the patent from the U.S.
−Removed: Patent and Trademark Office, or USPTO.
+Added: patent also may be accorded a patent term adjustment (“PTA”) under certain circumstances to compensate for delays in obtaining the patent from the U.S.
+Added: Patent and Trademark Office (“USPTO”).
In some instances, such a PTA may result in a U.S.
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In addition, the term of a U.S.
−Removed: patent that covers an FDA-approved drug may also be eligible for patent term extension, which permits patent term restoration as compensation for the patent term lost during the
−Removed: FDA regulatory review process.
+Added: patent that covers an FDA-approved drug may also be eligible for patent term extension, which permits patent term restoration as compensation for the patent term lost during the FDA regulatory review process.
The Hatch-Waxman Act permits a patent term extension of up to five years beyond the expiration of the patent.
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Patent term extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval and only one patent applicable to an approved drug may be extended.
−Removed: Similar provisions are available in Europe and other foreign jurisdictions to extend the term of a patent that covers an approved drug.
+Added: Similar provisions are available in Europe and
+Added: other foreign jurisdictions to extend the term of a patent that covers an approved drug.
In the future, if and when our products receive FDA approval, we expect to apply for patent term extensions on patents covering those products.
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Manufacturing
−Removed: We must manufacture drug product for clinical trial use in compliance with current good manufacturing practices, or cGMP.
+Added: We must manufacture drug product for clinical trial use in compliance with current good manufacturing practices (“cGMP”).
The cGMP regulations include requirements relating to organization of personnel, buildings and facilities, equipment, control of components and drug product containers and closures, production and process controls, packaging and labeling controls, holding and distribution, laboratory controls, records and reports, and returned or salvaged products.
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We do not have and we do not currently plan to acquire or develop the facilities or capabilities to manufacture cGMP drug substance or filled drug product for use in human clinical trials.
−Removed: We rely on third-party manufacturers to generate cGMP-grade cell lines and will rely on them to produce cGMP drug product required for our planned clinical trials, and we expect to continue to rely on third parties to manufacture clinical trial drug supplies for the foreseeable future.
+Added: We rely on third-party manufacturers to generate cGMP-grade cell lines and will rely on them to produce cGMP drug product required for our clinical trials, and we expect to continue to rely on third parties to manufacture clinical trial drug supplies for the foreseeable future.
We also contract with additional third parties for the filling, labeling, packaging, storage and distribution of investigational drug products.
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Specifically, there are several companies developing or marketing treatments that may be approved for the same indications and/or diseases as our product candidates, including major pharmaceutical companies.
−Removed: For GPP, our competitors include marketed therapies such as secukinumab (Cosentyx;
−Removed: Novartis), which binds IL-17A;
−Removed: ustekinumab (Stelara;
−Removed: Janssen), which blocks IL-12 and 23 cytokine function;
−Removed: and acitretin (Soriatane;
−Removed: GSK), as well as therapies in development such as guselkumab (Janssen), which blocks IL-23 cytokine function, gevokizumab (Xoma 052) and canakinumab (Ilaris, Novartis), which binds IL-1 beta, anakinra (Kineret;
−Removed: Swedish Orphan Biovitrum AB), a recombinant form of the IL-1 receptor antagonist,an anti-IL-36 receptor antibody called spesolimab or BI-655130 (Boehringer Ingelheim) and an anti-IL-36 receptor antibody called REGN6490 (Regeneron).
−Removed: For acne, our competitors include retinoids and retinoid-like drugs, including tretinoin (Avita, Retin-A, adapalene (Differin) and tazarotene (Tazorac, Avage), antibiotics including clindamycin (Benzaclin, Duac) and erythromycin (Benzamycin) and isotretinoin (Amnesteem, Claravis, Accutane) and oral antibiotics including sarecycline (Seysara).
−Removed: For hidradenitis suppurativa, our competitors include adalimumab (Humira;
−Removed: Abbvie) which is approved for the treatment of moderate to severe hidradenitis suppurativa for patients 12 years of age or older.
−Removed: For our PD-1 agonist antibody program, our competitors include CC-90006 (BMS), which is an anti-PD-1 agonist antibody developed under our partnership with BMS, a BTLA modulator antibody called LY3361237 being developed by Eli Lilly, a PD-1 agonist antibody called LY3462817 also being developed by Eli Lilly, a PD-1 agonist antibody called JNJ-67484703 (Janssen), two PD-1 agonist antibodies called PT627 and PT001 being developed by Pandion Therapeutics, which has been acquired by Merck and a PD-1 agonist antibody under preclinical development by MiroBio.
−Removed: Our competitors in moderate-to-severe alopecia areata include topical and oral corticosteroids, topical immunotherapy (diphencyprone, dinitrochlorobenzene, squaric acid dibutyl ester), calcineurin inhibitors (tacrolimus, pimecrolimus), prostaglandins and janus kinase inhibitors (tofacitinib, rixolitinib) currently in development.
−Removed: Our BTLA agonist antibody program competitors include LY3361237 (Lilly) which has demonstrated efficacy in treatment of systemic lupus erythematous as measured by the cutaneous lupus erythematosus disease area and severity index (CLASI), and a preclinical antibody under development at MiroBio.
+Added: For our anti-PD-1 agonist antibody program, our competitors include other anti-PD-1 agonist antibodies peresolimab (Eli Lilly) in Phase 2b development for the treatment of rheumatoid arthritis, JNJ-67484703 (Janssen) in Phase 2 development, a PD-1 agonist antibody (Boehringer Ingelheim) in Phase 1 development, PT627 and PT001 (Pandion Therapeutics, which has been acquired by Merck) in preclinical development, and MB151 (MiroBio, which has been acquired by Gilead) in preclinical development.
+Added: Our competitors in moderate-to-severe rheumatoid arthritis include monoclonal antibodies targeting anti-TNF (Humira;
+Added: Abbvie), IL-6 (Actemra;
+Added: Roche and Kevzara;
+Added: Regeneron), CD-80/86 (Orencia;
+Added: BMS), CD-20 (Rituxan;
+Added: Roche), and janus kinase inhibitors (Rinvoq;
+Added: AbbVie, Olumiant;
+Added: Eli Lilly, and Xeljanz;
+Added: For our anti-BTLA agonist antibody program, our competitors include other anti-BTLA agonist antibodies LY3361237 (Eli Lilly) in Phase 2 development, which has demonstrated efficacy in treatment of systemic lupus erythematosus as measured by the cutaneous lupus erythematosus disease area and severity index (CLASI), and MB272 (MiroBio, in Phase 1 development which has been acquired by Gilead).
+Added: Our competitors in moderate-to-severe atopic dermatitis include topical and oral corticosteroids, calcineurin inhibitors (Protopic;
+Added: LEO Pharma and Elidel;
+Added: Bausch Health), monoclonal antibodies targeting IL-4/13 (Dupixent;
+Added: Regeneron/Sanofi), IL-13 (Adbry;
+Added: LEO Pharma and lebrikizumab;
+Added: Eli Lilly), IL-31 (nemolizumab;
+Added: Galderma), OX-40L (amlitelimab;
+Added: Sanofi), and janus kinase inhibitors (Rinvoq;
+Added: AbbVie and abrocitinib;
+Added: For our anti-CD122 antagonist antibody program, our competitors include one other anti-CD122 antagonist antibody, auremolimab (Villaris Therapeutics, which has been acquired by Incyte), currently in preclinical development, and an anti-IL-15 monoclonal antibody, AMG 714 (Amgen), currently in Phase 2 development for the treatment of vitiligo.
+Added: For imsidolimab in the treatment of GPP, our competitors include one other anti-IL-36 receptor antibody called SPEVIGO or spesolimab (Boehringer Ingelheim), recently approved for GPP flares in adults.
Government Regulation and Product Approval
−Removed: Government authorities in the United States, at the federal, state and local level, and in other countries and jurisdictions, including the European Union, extensively regulate, among other things, the research, development, testing, manufacture, quality control, approval, packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, marketing, post-approval monitoring and reporting, and import and export of pharmaceutical products.
+Added: Government authorities in the United States, at the federal, state and local level, and in other countries and jurisdictions, including the EU, extensively regulate, among other things, the research, development, testing, manufacture, quality control, approval, packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, marketing, post-approval monitoring and reporting, and import and export of pharmaceutical products.
The processes for obtaining regulatory approvals in the United States and in foreign countries and jurisdictions, along with subsequent compliance with applicable statutes and regulations and other regulatory authorities, require the expenditure of substantial time and financial resources.
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In the United States, pharmaceutical products are subject to extensive regulation by the FDA.
−Removed: The Federal Food, Drug, and Cosmetic Act, or the FDC Act, and other federal and state statutes and regulations, govern, among other things, the research, development, testing, manufacture, storage, recordkeeping, approval, labeling, promotion and marketing, distribution,
−Removed: post-approval monitoring and reporting, sampling, and import and export of pharmaceutical products.
−Removed: Biological products used for the prevention, treatment, or cure of a disease or condition of a human being are subject to regulation under the FDC Act, except the section of the FDC Act which governs the approval of new drug applications, or NDAs.
−Removed: Biological products are approved for marketing under provisions of the Public Health Service Act, or PHSA, via a BLA.
+Added: The Federal Food, Drug, and Cosmetic Act (“FDC Act”), and other federal and state statutes and regulations, govern, among other things, the research, development, testing, manufacture, storage, recordkeeping, approval, labeling, promotion and marketing, distribution, post-approval monitoring and reporting, sampling, and import and export of pharmaceutical products.
+Added: Biological products used for the prevention, treatment, or cure of a disease or condition of a human being are subject to regulation under the FDC Act,
+Added: except the section of the FDC Act which governs the approval of new drug applications (“NDAs”).
+Added: Biological products are approved for marketing under provisions of the Public Health Service Act (“PHSA”), via a BLA.
However, the application process and requirements for approval of BLAs are similar to those for NDAs, and biologics are associated with similar approval risks and costs as drugs.
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requirements may subject a company to a variety of administrative or judicial sanctions, such as clinical hold, FDA refusal to approve pending NDAs or BLAs, warning or untitled letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, civil penalties, and criminal prosecution.
−Removed: Biological product development for a new product or certain changes to an approved product in the United States typically involves preclinical laboratory and animal tests, the submission to the FDA of an IND, which must become effective before clinical testing may commence in the United States, and adequate and well-controlled clinical trials to establish the safety and effectiveness of the drug for each indication for which FDA approval is sought.
+Added: Biological product development for a new product or certain changes to an approved product in the United States typically involves preclinical laboratory and animal tests, the submission to the FDA of an investigational new drug application (“IND”), which must become effective before clinical testing may commence in the United States, and adequate and well-controlled clinical trials to establish the safety and effectiveness of the drug for each indication for which FDA approval is sought.
Satisfaction of FDA premarket approval requirements typically takes many years and the actual time required may vary substantially based upon the type, complexity, and novelty of the product or disease.
Preclinical tests include laboratory evaluation of product chemistry, formulation, and toxicity, as well as animal trials to assess the characteristics and potential safety and efficacy of the product.
−Removed: The conduct of the preclinical tests must comply with federal regulations and requirements, including good laboratory practices, or GLPs.
+Added: The conduct of the preclinical tests must comply with federal regulations and requirements, including good laboratory practices (“GLPs”).
The results of preclinical testing are submitted to the FDA as part of an IND along with other information, including information about product chemistry, manufacturing and controls, and a proposed clinical trial protocol.
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(i) in compliance with federal regulations;
−Removed: (ii) in compliance with good clinical practices, or GCPs, an international standard meant to protect the rights and health of patients and to define the roles of clinical trial sponsors, administrators, and monitors;
+Added: (ii) in compliance with good clinical practices (“GCPs”), an international standard meant to protect the rights and health of patients and to define the roles of clinical trial sponsors, administrators, and monitors;
as well as (iii) under protocols detailing the objectives of the trial, the parameters to be used in monitoring safety, and the effectiveness criteria to be evaluated.
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The FDA may order the temporary, or permanent, discontinuation of a clinical trial at any time, or impose other sanctions if it believes that the clinical trial either is not being conducted in accordance with FDA requirements or presents an unacceptable risk to the clinical trial patients.
−Removed: The trial protocol and informed consent information for patients in clinical trials must also be submitted to an institutional review board, or IRB, for approval.
+Added: The trial protocol and informed consent information for patients in clinical trials must also be submitted to an institutional review board (“IRB”) for approval.
An IRB may also require the clinical trial at the site to be halted, either temporarily or permanently, for failure to comply with the IRB’s requirements, or may impose other conditions.
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These fees are typically increased annually.
−Removed: The FDA has 60 days from its receipt of a BLA to determine whether the application will be accepted for filing based on the agency’s threshold determination that it is sufficiently
−Removed: complete to permit substantive review.
+Added: The FDA has 60 days from its receipt of a BLA to determine whether the application will be accepted for filing based on the agency’s threshold determination that it is sufficiently complete to permit substantive review.
Once the submission is filed, the FDA begins an in-depth review.
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Most such applications for standard review biologic products are reviewed within 10 months of the date the BLA is filed with the FDA;
−Removed: most applications for priority review biologics are reviewed within six months of the date the BLA is filed with the FDA.
+Added: most applications for priority review biologics are reviewed within
+Added: six months of the date the BLA is filed with the FDA.
Priority review can be applied to a biologic that the FDA determines has the potential to treat a serious or life-threatening condition and, if approved, would be a significant improvement in safety or effectiveness compared to available therapies.
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An approval letter authorizes commercial marketing of the biologic with specific prescribing information for specific indications.
−Removed: As a condition of BLA approval, the FDA may require a risk evaluation and mitigation strategy, or REMS to help ensure that the benefits of the biologic outweigh the potential risks.
−Removed: REMS can include medication guides, communication plans for health care professionals, and elements to assure safe use, or ETASU.
+Added: As a condition of BLA approval, the FDA may require a risk evaluation and mitigation strategy (“REMS”) to help ensure that the benefits of the biologic outweigh the potential risks.
+Added: REMS can include medication guides, communication plans for health care professionals, and elements to assure safe use (“ETASU”).
ETASU can include, but are not limited to, special training or certification for prescribing or dispensing, dispensing only under certain circumstances, special monitoring, and the use of patient registries.
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• a statement on whether written commitments by investigators to comply with GCP and the protocol were obtained.
−Removed: Orphan Drug Designation
−Removed: Under the Orphan Drug Act, the FDA may grant Orphan Drug Designation to biological products intended to treat a rare disease or condition—generally a disease or condition that (i) affects fewer than 200,000 individuals in the United States, or (ii) affects more than 200,000 individuals in the United States and there is no reasonable expectation that the cost of developing and making a product available in the United States for such disease or condition will be recovered from sales of the product.
−Removed: Orphan Drug Designation must be requested before submitting a BLA.
−Removed: After the FDA grants Orphan Drug Designation, the generic identity of the biological product and its potential orphan use are disclosed publicly by the FDA.
−Removed: Orphan Drug Designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.
−Removed: The first BLA applicant to receive FDA approval for a biological product containing a particular active moiety to treat a particular disease with FDA Orphan Drug Designation is entitled to a seven-year exclusive marketing period in the United States for that product for that indication.
−Removed: During the seven-year exclusivity period, the FDA may not approve any other applications to market a biological product containing the same active moiety for the same disease, except in limited circumstances, such as a showing of clinical superiority to the product with orphan drug exclusivity.
−Removed: A product is clinically superior if it is safer, more effective or makes a major contribution to patient care.
−Removed: Orphan drug exclusivity does not prevent the FDA from approving a different drug or biological product for the same disease or condition, or the same biological product for a different disease or condition.
−Removed: Among the other benefits of Orphan Drug Designation are tax credits for certain research and a waiver of the BLA user fee.
Disclosure of clinical trial information
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Pediatric information
−Removed: Under the Pediatric Research Equity Act, or PREA, NDAs or BLAs or supplements to NDAs or BLAs must contain data to assess the safety and effectiveness of the biological product for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the biological product is safe and effective.
+Added: Under the Pediatric Research Equity Act (“PREA”), NDAs or BLAs or supplements to NDAs or BLAs must contain data to assess the safety and effectiveness of the biological product for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the biological product is safe and effective.
The FDA may grant full or partial waivers, or deferrals, for submission of data.
Unless otherwise required by regulation, the PREA does not apply to any biological product for an indication for which Orphan Drug Designation has been granted.
−Removed: The Best Pharmaceuticals for Children Act, or BPCA, provides sponsors of NDAs with an additional six-month period of market exclusivity for all unexpired patent or non-patent exclusivity on all forms of the drug containing the active moiety if the sponsor submits results of pediatric studies specifically requested by the FDA under BPCA within required timeframes.
+Added: The Best Pharmaceuticals for Children Act (“BPCA”), provides sponsors of NDAs with an additional six-month period of market exclusivity for all unexpired patent or non-patent exclusivity on all forms of the drug containing the active moiety if the sponsor submits results of pediatric studies specifically requested by the FDA under BPCA within required timeframes.
The BPCA provides sponsors of BLAs an additional six-month extension for all unexpired non-patent market exclusivity on all forms of the biological containing the active moiety pursuant to the BPCA if the conditions under the BPCA are met.
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After a BLA is approved, the product may also be subject to official lot release as a condition of approval.
−Removed: As part of the manufacturing process, the manufacturer is required to perform certain tests on each lot of the product before it is released for
−Removed: distribution.
+Added: As part of the manufacturing process, the manufacturer is required to perform certain tests on each lot of the product before it is released for distribution.
If the product is subject to official release by the FDA, the manufacturer submits samples of each lot of product to the FDA together with a release protocol showing a summary of the history of manufacture of the lot and the results of all of the manufacturer’s tests performed on the lot.
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Interim patent extensions are not available for a drug or biologic for which an NDA or BLA has not been submitted.
−Removed: The Biologics Price Competition and Innovation Act of 2009, or BPCIA, created an abbreviated approval pathway for biological products shown to be highly similar to or interchangeable with an FDA licensed reference biological product.
+Added: The Biologics Price Competition and Innovation Act of 2009 (“BPCIA”), created an abbreviated approval pathway for biological products shown to be highly similar to or interchangeable with an FDA licensed reference biological product.
Biosimilarity sufficient to reference a prior FDA-approved product requires that there be no differences in conditions of use, route of administration, dosage form, and strength, and no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency.
Biosimilarity must be shown through analytical trials, animal trials, and a clinical trial or trials, unless the Secretary of the U.S.
−Removed: Department of Health and Human Services waives a required element.
+Added: Department of Health and Human Services (“HHS”) waives a required element.
A biosimilar product may be deemed interchangeable with a prior approved product if it meets the higher hurdle of demonstrating that it can be expected to produce the same clinical results as the reference product and, for products administered multiple times, the biologic and the reference biologic may be switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic.
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The FDA also may require post-marketing testing, known as Phase 4 testing, REMS, and surveillance to monitor the effects of an approved product, or the FDA may place conditions on an approval that could restrict the distribution or use of the product.
−Removed: In addition, quality control, biological product manufacture, packaging, and labeling procedures must continue to conform to
−Removed: cGMPs after approval.
+Added: In addition, quality control, biological product manufacture, packaging, and labeling procedures must continue to conform to cGMPs after approval.
Biologic manufacturers and certain of their subcontractors are required to register their establishments with the FDA and certain state agencies.
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The review of an in vitro companion diagnostic in conjunction with the review of a biologic involves coordination of review by the FDA’s Center for Biologics Evaluation and Research and by the FDA’s Center for Devices and Radiological Health.
−Removed: Pursuing FDA approval of an in vitro companion diagnostic would require us to obtain a premarket approval, or PMA.
+Added: Pursuing FDA approval of an in vitro companion diagnostic would require us to obtain a premarket approval (“PMA”).
The PMA process, including the gathering of clinical and preclinical data and the submission to and review by the FDA, can take several years or longer.
It involves a rigorous premarket review during which the applicant must prepare and provide the FDA with reasonable assurance of the device’s safety and effectiveness and information about the device and its components regarding, among other things, device design, manufacturing and labeling.
−Removed: PMA applications are subject to an application fee, which exceeds $250,000 for most PMAs.
+Added: PMA applications are
+Added: subject to an application fee, which exceeds $250,000 for most PMAs.
In addition, PMAs for certain devices must generally include the results from extensive preclinical and adequate and well-controlled clinical trials to establish the safety and effectiveness of the device for each indication for which FDA approval is sought.
In particular, for a diagnostic, the applicant must demonstrate that the diagnostic produces reproducible results when the same sample is tested multiple times by multiple users at multiple laboratories.
−Removed: As part of the PMA review, the FDA will typically inspect the manufacturer’s facilities for compliance with the Quality System Regulation, or QSR, which imposes elaborate testing, control, documentation and other quality assurance requirements.
+Added: As part of the PMA review, the FDA will typically inspect the manufacturer’s facilities for compliance with the Quality System Regulation (“QSR”), which imposes elaborate testing, control, documentation and other quality assurance requirements.
PMA approval is not guaranteed, and the FDA may ultimately respond to a PMA application submission with a not approvable determination based on deficiencies in the application and require additional clinical trial or other data that may be expensive and time-consuming to generate and that can substantially delay approval.
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health care laws and compliance requirements
−Removed: In the United States, our activities are potentially subject to regulation by various federal, state and local authorities in addition to the FDA, including but not limited to, the Centers for Medicare and Medicaid Services, or CMS, other divisions of the U.S.
−Removed: Department of Health and Human Services (such as the Office of Inspector General), the U.S.
−Removed: Department of Justice, or DOJ, and individual U.S.
+Added: In the United States, our activities are potentially subject to regulation by various federal, state and local authorities in addition to the FDA, including but not limited to, the Centers for Medicare and Medicaid Services (“CMS”), other divisions of the HHS (such as the Office of Inspector General), the U.S.
+Added: Department of Justice (“DOJ”), and individual U.S.
Attorney offices within the DOJ, and state and local governments.
−Removed: For example, sales, marketing and scientific/educational grant programs may have to comply with the anti-fraud and abuse provisions of the Social Security Act, anti-kickback statutes, false claims laws, the privacy and security provisions of the Health Insurance Portability and Accountability Act, or HIPAA, and similar state laws, each as amended, as applicable.
−Removed: The federal Anti-Kickback Statute prohibits, among other things, any person or entity, from knowingly and willfully offering, paying, soliciting or receiving any remuneration, directly or indirectly, overtly or covertly, in cash or in kind, to induce or in return for purchasing, leasing, ordering or arranging for the purchase, lease or order of any item or service reimbursable
−Removed: under Medicare, Medicaid or other federal health care programs.
+Added: For example, sales, marketing and scientific/educational grant programs may have to comply with the anti-fraud and abuse provisions of the Social Security Act, anti-kickback statutes, false claims laws, the privacy and security provisions of the Health Insurance Portability and Accountability Act (“HIPAA”), and similar state laws, each as amended, as applicable.
+Added: The federal Anti-Kickback Statute prohibits, among other things, any person or entity, from knowingly and willfully offering, paying, soliciting or receiving any remuneration, directly or indirectly, overtly or covertly, in cash or in kind, to induce or in return for purchasing, leasing, ordering or arranging for the purchase, lease or order of any item or service reimbursable under Medicare, Medicaid or other federal health care programs.
The term remuneration has been interpreted broadly to include anything of value.
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Our practices may not in all cases meet all of the criteria for protection under a statutory exception or regulatory safe harbor.
−Removed: Additionally, the intent standard under the Anti-Kickback Statute was amended by the Patient Protection and Affordable Care Act, or ACA, to a stricter standard such that a person or entity no longer needs to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.
+Added: Additionally, the intent standard under the Anti-Kickback Statute was amended by the Patient Protection and Affordable Care Act (“ACA”) to a stricter standard such that a person or entity no longer needs to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.
In addition, the ACA codified case law that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the federal False Claims Act (discussed below).
The civil monetary penalties statute imposes penalties against any person or entity that, among other things, is determined to have presented or caused to be presented a claim to a federal health program that the person knows or should know is for an item or service that was not provided as claimed or is false or fraudulent.
−Removed: Federal false claims and false statement laws, including the federal False Claims Act, prohibit, among other things, any person or entity from knowingly presenting, or causing to be presented, a false or fraudulent claim for payment to, or approval by, the federal health care programs, including Medicare and Medicaid, or knowingly making, using, or causing to be made or used a false record or statement material to a false or fraudulent claim to the federal government.
+Added: Federal false claims and false statement laws, including the federal False Claims Act, prohibit, among other things, any person or entity from knowingly presenting, or causing to be presented, a false or fraudulent claim for payment to, or approval
+Added: by, the federal health care programs, including Medicare and Medicaid, or knowingly making, using, or causing to be made or used a false record or statement material to a false or fraudulent claim to the federal government.
As a result of a modification made by the Fraud Enforcement and Recovery Act of 2009, a claim includes “any request or demand” for money or property presented to the U.S.
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We may be subject to data privacy and security regulations by both the federal government and the states in which we conduct our business.
−Removed: HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, or HITECH, and its implementing regulations, imposes requirements relating to the privacy, security and transmission of individually identifiable health information.
+Added: HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act (“HITECH”), and its implementing regulations, imposes requirements relating to the privacy, security and transmission of individually identifiable health information.
Among other things, HITECH makes HIPAA’s privacy and security standards directly applicable to business associates, independent contractors or agents of covered entities that receive or obtain protected health information in connection with providing a service on behalf of a covered entity.
1 unchanged sentence
In addition, many state laws govern the privacy and security of health information in specified circumstances, many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.
−Removed: Additionally, the federal Physician Payments Sunshine Act within the ACA, and its implementing regulations, require that certain manufacturers of drugs, devices, biological and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program (with certain exceptions) report annually to CMS information related to certain payments or other transfers of value made or distributed to physicians and teaching hospitals, or to entities or individuals at the request of, or designated on behalf of, the physicians and teaching hospitals and to report annually certain ownership and
−Removed: investment interests held by physicians and their immediate family members.
+Added: Additionally, the federal Physician Payments Sunshine Act within the ACA, and its implementing regulations, require that certain manufacturers of drugs, devices, biological and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program (with certain exceptions) report annually to CMS information related to certain payments or other transfers of value made or distributed to physicians and teaching hospitals, or to entities or individuals at the request of, or designated on behalf of, the physicians and teaching hospitals and to report annually certain ownership and investment interests held by physicians and their immediate family members.
Moreover, the Drug Supply Chain Security Act imposes new obligations on manufacturers of pharmaceutical products related to product tracking and tracing.
4 unchanged sentences
All of our activities are potentially subject to federal and state consumer protection and unfair competition laws.
−Removed: If our operations are found to be in violation of any of the federal and state health care laws described above or any other governmental regulations that apply to us, we may be subject to penalties, including without limitation, civil, criminal and/or administrative penalties, damages, fines, disgorgement, exclusion from participation in government programs, such as Medicare and Medicaid, injunctions, private “qui tam” actions brought by individual whistleblowers in the name of the government, or refusal to allow us to enter into government contracts, contractual damages, reputational harm, administrative burdens, diminished profits and future earnings, and the curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results of operations.
+Added: If our operations are found to be in violation of any of the federal and state health care laws described above or any other governmental regulations that apply to us, we may be subject to penalties, including without limitation, civil, criminal and/or administrative penalties, damages, fines, disgorgement, exclusion from participation in government programs, such as Medicare and Medicaid, injunctions, private “qui tam” actions brought by individual whistleblowers in the name of the government, or refusal to allow us to enter into government contracts, contractual damages, reputational harm, administrative
+Added: burdens, diminished profits and future earnings, and the curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results of operations.
Coverage, pricing and reimbursement
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Even if favorable coverage and reimbursement status is attained for one or more products for which we receive regulatory approval, less favorable coverage policies and reimbursement rates may be implemented in the future.
−Removed: Health care reform
+Added: Healthcare reform
Healthcare reforms that have been adopted, and that may be adopted in the future, could result in further reductions in coverage and levels of reimbursement for pharmaceutical products, increases in rebates payable under U.S.
government rebate programs and additional downward pressure on pharmaceutical product prices.
−Removed: On September 9, 2021, the Biden administration published a wide-ranging list of policy proposals, most of which would need to be carried out by Congress, to reduce drug prices and drug payment.
−Removed: The HHS plan includes, among other reform measures, proposals to lower prescription drug prices, including by allowing Medicare to negotiate prices and disincentivizing price increases, and to support market changes that strengthen supply chains, promote biosimilars and generic drugs, and increase price transparency.
−Removed: Many similar proposals, including the plans to give Medicare Part D authority to negotiate drug prices, require drug manufacturers to pay rebates on drugs whose prices increase greater than the rate of inflation, and cap out-of-pocket costs, have already been included in policy statements and legislation currently being considered by Congress.
−Removed: It is unclear to what extent these and other statutory, regulatory, and administrative initiatives will be enacted and implemented.
−Removed: In March 2010, President Obama enacted the ACA, which has begun to substantially change healthcare financing and delivery by both governmental and private insurers, and has also begun to significantly impact the pharmaceutical and biotechnology industry.
−Removed: The ACA will impact existing government healthcare programs and will result in the development of new programs.
+Added: Recently, healthcare reform initiatives culminated in the enactment of the Inflation Reduction Act (“IRA”), in August 2022, which will, among other things, allow the HHS to negotiate the selling price of certain drugs and biologics that CMS reimburses under Medicare Part B and Part D, although only high-expenditure single-source drugs that have been approved for at least 7 years (11 years for biologics) can be selected by CMS for negotiation, with the negotiated price taking effect two years after the selection year.
+Added: The negotiated prices, which will first become effective in 2026, will be capped at a statutory ceiling price.
+Added: Beginning in January 2023 for Medicare Part B and October 2022 for Medicare Part D, the IRA will also penalize drug manufacturers that increase prices of Medicare Part B and Part D drugs at a rate greater than the rate of inflation.
+Added: The IRA permits the Secretary of HHS to implement many of these provisions through guidance, as opposed to regulation, for the initial years.
+Added: Manufacturers that fail to comply with the IRA may be subject to various penalties, including civil monetary penalties.
+Added: The IRA also extends enhanced
+Added: subsidies for individuals purchasing health insurance coverage in ACA marketplaces through plan year 2025.
+Added: These provisions will take effect progressively starting in 2023, although they may be subject to legal challenges.
The Foreign Corrupt Practices Act
−Removed: The Foreign Corrupt Practices Act, or FCPA, prohibits any U.S.
+Added: The Foreign Corrupt Practices Act(“FCPA”), prohibits any U.S.
individual or business from paying, offering, or authorizing payment or offering of anything of value, directly or indirectly, to any foreign official, political party or candidate for the purpose of influencing any act or decision of the foreign entity in order to assist the individual or business in obtaining or retaining business.
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Certain countries outside of the United States have a similar process that requires the submission of a clinical trial application much like the IND prior to the commencement of human clinical trials.
−Removed: In the United Kingdom (“UK”) and countries in the EU, for example, a Clinical Trial Authorisation, or CTA, must be submitted to each country’s national health authority and an independent ethics committee, much like the FDA and IRB, respectively.
+Added: In the United Kingdom (“UK”) and countries in the EU, for example, a Clinical Trial Authorisation (“CTA”) must be submitted to each country’s national health authority and an independent ethics committee, much like the FDA and IRB, respectively.
Once the CTA is approved in accordance with a country’s requirements, clinical trial development may proceed.
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Conducting clinical trials for therapeutic drug candidates in Australia is subject to regulation by Australian governmental entities.
−Removed: Approval for inclusion in the Australian Register of Therapeutic Goods, or the ARTG, is required before a pharmaceutical drug product may be marketed in Australia.
+Added: Approval for inclusion in the Australian Register of Therapeutic Goods (the “ARTG”), is required before a pharmaceutical drug product may be marketed in Australia.
Typically, the process of obtaining approval of a new therapeutic drug product for inclusion in the ARTG requires compilation of clinical trial data.
−Removed: Clinical trials conducted using “unapproved therapeutic goods” in Australia, being those which have not yet been evaluated by the Therapeutic Goods Administration, or the TGA, for quality, safety and efficacy must occur pursuant to either the Clinical Trial Notification, or CTN, or Clinical Trial Exemption, or CTX, process.
−Removed: The CTN process broadly involves:
−Removed: • completion of pre-clinical laboratory and animal testing;
−Removed: • submission to a Human Research Ethics Committee, or the HREC, of all material relating to the proposed clinical trial, including the trial protocol.
−Removed: The TGA does not review any data relating to the clinical trial;
−Removed: • the institution or organization at which the clinical trial will be conducted, referred to as the “Approving Authority” gives the final approval for the conduct of the clinical trial at the site, having due regard to the advice from the HREC;
−Removed: • CTN clinical trials cannot commence until the clinical trial has been notified to the TGA.
−Removed: Under the CTX process:
−Removed: • a sponsor submits an application to conduct a clinical trial to the TGA for evaluation and comment;
−Removed: • a sponsor cannot commence a CTX clinical trial until written advice has been received from the TGA regarding the application and approval for the conduct of the clinical trial has been obtained from an ethics committee and the institution at which the clinical trial will be conducted.
−Removed: In each case, it is required that:
−Removed: • adequate and well-controlled clinical trials demonstrate the quality, safety and efficacy of the therapeutic product;
−Removed: • evidence is compiled which demonstrates that the manufacture of the therapeutic drug product complies with the principles of cGMP;
−Removed: • manufacturing and clinical data is derived to submit to the Australian Committee on Prescription Medicines, which makes recommendations to the TGA as to whether or not to grant approval to include the therapeutic drug product in the ARTG;
−Removed: • an ultimate decision is made by the TGA whether to include the therapeutic drug product in the ARTG.
−Removed: Pre-clinical studies include laboratory evaluation of the therapeutic drug product as well as animal studies to assess the potential safety and efficacy of the drug.
−Removed: The results of the pre-clinical studies form part of the materials submitted to the investigators HREC in the case of a CTN trial and part of the application to the TGA in the case of a CTX trial.
−Removed: Clinical trials involve administering the investigational product to healthy volunteers or patients under the supervision of a qualified principal investigator.
+Added: Clinical trials conducted using “unapproved therapeutic goods” in Australia, being those which have not yet been evaluated by the Therapeutic Goods Administration (the “TGA”), for quality, safety and efficacy must occur pursuant to either the Clinical Trial Notification (“CTN”), or Clinical Trial Exemption (“CTX”), process.
+Added: The CTN process broadly involves submission to a Human Research Ethics Committee (the “HREC”) of all material relating to the proposed clinical trial after completion of pre-clinical laboratory and animal testing.
+Added: The institution or organization at which the clinical trial will be conducted (the “Approving Authority”) then gives the final approval for the conduct of the clinical trial at the site, having due regard to the advice from the HREC.
+Added: After receiving final approval, CTN clinical trials cannot commence until the clinical trial has been notified to the TGA.
+Added: Following approval, responsibility for all aspects of the trial conducted under a CTN application remains with the HREC of each investigator’s institution.
+Added: Under the CTX process a sponsor submits an application to conduct a clinical trial to the TGA for evaluation and comment and a sponsor cannot commence a CTX clinical trial until written advice has been received from the TGA regarding the application and approval for the conduct of the clinical trial has been obtained from an ethics committee and the institution at which the clinical trial will be conducted.
+Added: In each of the CTN or CTX process, it is required that adequate and well-controlled clinical trials demonstrate the quality, safety and efficacy of the therapeutic product, evidence is compiled which demonstrates that the manufacture of the therapeutic drug product complies with the principles of cGMP and manufacturing and clinical data is derived to submit to the Australian Committee on Prescription Medicines.
+Added: The Australian Committee on Prescription Medicines then makes recommendations to the TGA and the TGA ultimately decides whether to include the therapeutic drug product in the ARTG.
The TGA has developed guidelines for a CTN.
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The TGA is formally notified by submission of a CTN application but does not review the safety of the drug or any aspect of the proposed trial.
−Removed: The approving authority of each institution gives the final approval for the conduct of the clinical trial, having due regard to advice from the HREC.
−Removed: Following approval, responsibility for all aspects of the trial conducted under a CTN application remains with the HREC of each investigator’s institution.
The standards for clinical research in Australia are set by the TGA and the National Health and Medical Research Council, and compliance with GCP is mandatory.
−Removed: Guidelines, such as those promulgated by the International Conference on
−Removed: Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, or ICH, are required across all fields, including those related to pharmaceutical quality, nonclinical and clinical data requirements and study designs.
+Added: Guidelines, such as those promulgated by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”), are required across all fields, including those related to pharmaceutical quality, nonclinical and clinical data requirements and study designs.
The basic requirements for preclinical data to support a first-in- human study under ICH guidelines are applicable in Australia.
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As of December 31, 2022, we had 96 full-time employees.
−Removed: Of these employees, 81 were primarily engaged in research and development activities and 30 have an M.D.
+Added: Of these employees, 65 were primarily engaged in research and development activities and 23 held a doctorate degree such as an M.D., Ph.D., or PharmD.
None of our employees are represented by a labor union or covered by collective bargaining agreements.
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Depending on the position, our recruitment reach can be local as well as national.
−Removed: We provide competitive compensation and best in class benefits that are tailored specifically to the needs and requests of our employees.
−Removed: During 2021, we worked to manage through the effects of the COVID-19 pandemic and entered 2022 stronger than ever.
−Removed: During 2021, all employees were retained at full salary and lab employees’ productivity and safety were a top priority.
−Removed: As appropriate, others were provided the option of working remotely or at our facilities with appropriate safeguards.
−Removed: We uphold our commitment to shareholders by working hard, being thoughtful about how we use resources and doing the right thing for the company at every turn.
+Added: We provide competitive compensation and benefits that are tailored specifically to the needs and requests of our employees.
Corporate Information
7 unchanged sentences
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.