−Removed: We are a clinical ‑stage biopharmaceutical company focused on discovering and developing engineered monoclonal antibodies to treat severe and life ‑ threatening diseases with unmet medical needs.
−Removed: We use our proprietary XmAb technology platform to create next ‑generation antibody product candidates designed to treat autoimmune and allergic diseases, cancer and other conditions.
−Removed: In contrast to conventional approaches to antibody design, which focus on the portion of antibodies that interact with target antigens, we focus on the portion of the antibody that interacts with multiple segments of the immune system.
−Removed: This portion, referred to as the Fc domain, is constant and interchangeable among antibodies.
−Removed: Our engineered Fc domains, the XmAb technology, can be readily substituted for natural Fc domains.
−Removed: We believe our Fc domains enhance antibody performance by, for example, increasing immune inhibitory activity, improving cytotoxicity , extending circulating half ‑ life or stabilizing novel antibody structures , while maintaining 99.5% identity in structure and sequence to natural antibodies.
−Removed: By improving over natural antibody function, we believe that our XmAb ‑engineered antibodies offer innovative approaches to treating disease and potential clinical advantages over other treatments.
−Removed: Our business strategy is based on the plug ‑and ‑play nature of the XmAb technology platform to modify features of natural antibodies and create numerous differentiated antibody product candidates.
−Removed: We have internally generated a pipeline that has allowed us to selectively partner certain development programs while maintaining full ownership of other programs.
−Removed: We also have a number of technology licenses under which we have licensed the XmAb technology platform to pharmaceutical and biotechnology companies for use in a limited number of programs, providing multiple revenue streams that require no further resources from Xencor.
−Removed: There are currently eight antibody product candidates in clinical trials that have been engineered with XmAb technology, including six candidates being advanced by licensees and development partners.
−Removed: Our internally ‑generated pipeline includes the following three lead XmAb ‑ engineered antibodies that are currently in development:
−Removed: XmAb5871, our most recently advanced wholly-owned program recently completed a Phase 1b/2a clinical trial in rheumatoid arthritis (RA) and we are planning to initiate an open-label pilot clinical trial in IgG4-related disease (IgG4-RD) to assess disease control activity measured by the IgG4-RD Responder Index (Carruthers, et al., 2012, Int J Rheum) in 2015.
−Removed: XmAb5871 uses our XmAb Immune Inhibitor Fc Domain and targets B cells, an important component of the immune system.
−Removed: In January 2015 , we announced that in the Phase 2a part of the trial 15 XmAb5871 -t treated patients and eight placebo - treated patients were evaluable for RA disease activity at the protocol specified disease activity assessment time point of two weeks following the sixth biweekly infusion.
−Removed: 33% of patients (5 of 15) that received all six biweekly doses of XmAb5871 achieved DAS28-CRP remission or low disease activity compared to zero patients that were treated with the placebo achieving DAS28-CRP remission or low disease activity.
−Removed: Three ACR70 responses (20%) and six ACR50 responses (40%) occurred in the XmAb5871 group compared to zero and one (13%) respectively in the placebo group.
−Removed: ACR70 and ACR50 responses refer, respectively to 70% and 50% reductions in the American College of Rheumatology rheumatoid arthritis symptom scale, a common measure of RA disease activity.
−Removed: Across the entire Phase 1b/2a clinical trial, biweekly administration of XmAb5871 for 12 weeks was generally well tolerated.
−Removed: The most common XmAb5871 treatment related adverse related events (AEs) observed were predominantly mild to moderate gastrointestinal toxicities (nausea, vomiting, diarrhea) occurring during the first infusion of XmAb5871.
−Removed: These gastrointestinal AEs did not typically recur on subsequent infusions and no infusions were discontinued due to these AEs.
−Removed: Other treatment related AEs experienced in more than two XmAb5871 treated patients were pyrexia (fever) and headache.
−Removed: Treatment related serious adverse events (SAEs) occurred in two patients that received
−Removed: infusion related reaction and venous thrombosis (blood clot) .
−Removed: Two patients in the placebo treated group also reported SAEs.
−Removed: We believe XmAb5871 has the potential to address a key unmet need in autoimmune therapies due to its combination of potent B-cell inhibition without B-cell depletion and will be exploring other indications in 2015.
−Removed: In October 2014, we announced that we sought and regained all rights to XmAb5871from our partner, Amgen Inc.
−Removed: (Amgen), who had an option to acquire an exclusive worldwide license.
−Removed: In return, we granted Amgen a first right to negotiate a proposed license for XmAb5871 prior to seeking future partners.
−Removed: This right expires upon the earlier of the initiation of Phase 3 clinical testing of XmAb5871, a change of control of Xencor, or October 2019.
−Removed: XmAb7195 is our wholly-owned program being developed for the treatment of severe asthma and allergic diseases.
−Removed: It uses our XmAb Immune Inhibitor Fc Domain and is designed to reduce blood serum levels of IgE, which mediates allergic responses and allergic disease.
−Removed: Its three specific mechanisms of action give it potential advantages over current therapies:
−Removed: (i) increased IgE binding, (ii) inhibition of IgE production and (iii) rapid clearance of IgE from circulation.
−Removed: In 2014 we filed an IND for XmAb7195 for allergic asthma with the FDA and in May initiated a Phase 1a single ascending dose clinical trial in healthy volunteers and in allergen-sensitive subjects with high IgE levels.
−Removed: In January 2015 , we reported that interim data from the trial show rapid reduction of circulating free IgE levels to below the limit of detection at the end of the XmAb7195 infusion in 90% of XmAb7195 treated subjects that had detectable free IgE pre-dose, including those at the lowest dose evaluated of 0.3 mg/kg.
−Removed: Total IgE levels were also reduced in a parallel fashion.
−Removed: Two subjects with high pre-dose IgE levels (above 400 IU/mL) were treated with XmAb7195, one each at 0.75 mg/kg and 3.0 mg/kg doses, and both had reduction of free IgE levels to below the limit of detection lasting for at least one week.
−Removed: A dose limiting toxicity of transient, asymptomatic thrombocytopenia (low blood platelet count) was observed at the 3.0 mg/kg dose.
−Removed: The decrease in platelet count was transient with a minimum by 24 hours post-dose, recovery starting by 48 hours post-dose and near f ull platelet count recovery by study Day 8 in all cases, at which time serum drug concentrations still exceeded levels that eliminate detectable IgE .
−Removed: No evidence of thrombocytopenia has been observed in any of the clinical trials of XmAb5871, an anti-CD19 antibody with the identical XmAb Immune Inhibitor Fc domain as that of XmAb7195.
−Removed: Moderate urticaria (hives) was reported in a total of seven XmAb7195 treated subjects with an apparent correlation of dose with frequency of occurrence.
−Removed: In all cases regardless of dose, the signs/symptoms of urticaria were mild, non-diffuse and easily treated with oral antihistamine, and the study drug infusions were continued to completion without worsening of symptoms.
−Removed: Otherwise, there were no other adverse events that occurred in more than two XmAb7195 treated subjects.
−Removed: There were no serious adverse events reported and no subject discontinued Part 1 of trial early.
−Removed: XmAb5574/MOR208 is being developed by our partner MorphoSys AG (MorphoSys) for the treatment of blood ‑ based cancers and uses our XmAb Cytotoxic Fc Domain.
−Removed: In a Phase 1 clinical trial of XmAb5574/MOR208 completed by Xencor in patients with high-risk, heavily-pretreated chronic lymphocytic leukemia ( CLL ) , in which the antibody showed encouraging signs of preliminary anti-tumor activity and an acceptable safety profile and was well tolerated.
−Removed: The trial protocol was amended to include a period of extended dosing for a total of eight patients at the 12 mg/kg dose to study the effect of longer duration of exposure on safety and response rate.
−Removed: Overall response rate by IWCLL 2008 criteria was 29.6% (eight partial responses in 27 evaluable patients).
−Removed: Using NCI-WG CLL 1996, response criteria resulted in a response rate of 66.7% (18 partial responses).
−Removed: At the highest dose studied, 12 mg/kg, 12 of 16 patients (75%) had a partial response by NCI-WG CLL 1996 and six patients (37.5%) had a partial response using additional CT criteria (IWCLL 2008).
−Removed: Median progression free survival for all patients was 199 days and for the extended treatment arm (at 12 mg/kg) was 420 days.
−Removed: Blood disease cleared in most patients, with median reduction in absolute lymphocyte count from baseline of 90.8%.
−Removed: XmAb5574/ MOR208 was generally well tolerated with no maximum-tolerated dose identified.
−Removed: Clinically-significant, treatment-related adverse events (AEs) classified as Grade 3 or higher occurred in 5 out of twenty-seven patients.
−Removed: The most frequent treatment-related AEs were infusion-related reactions, which were reported for 66.7% of patients, all of which were grade 1 or 2, and no reactions were seen following the first infusion.
−Removed: Treatment-related AEs each reported for 18.5% of patients were ALT increased, AST
−Removed: increased, neutropenia and thrombocytopenia;
−Removed: all other treatment-related AEs were reported for ≤
−Removed: 15% of patients.
−Removed: These events resolved, generally without requiring treatment, and did not lead to discontinuation.
−Removed: MorphoSys is currently conducting two Phase 2 clinical trials of MOR208 in patients with B-cell acute lymphoblastic leukemia (B-ALL) and non-Hodgkin lymphomas (NHL).
−Removed: In 2014 our development efforts for XmAb bispecific antibodies expanded.
−Removed: Bispecific antibodies are designed with two different variable domains to elicit biological effects that require simultaneous binding to two targets.
−Removed: Previously, industry efforts at bispecific antibody design have generally been frustrated by poor molecular stability, difficulties in production and short in vivo half-life.
−Removed: Xencor’s XmAb®
−Removed: bispecific Fc domain technology is designed to maintain full-length antibody properties in a bispecific antibody, potentially enabling stable molecules with favorable in vivo half-life and allowing for the use of standard antibody production methods.
−Removed: These bispecific Fc domains are used to generate a broad array of novel drug candidates.
−Removed: In November 2014 , we announced preclinical data from three programs using our XmAb bispecific Fc technology showing that bispecific antibodies targeting CD123, CD20 and CD38 antigens each activated T-cells to rapidly kill target cells from a single dose IV bolus in cynomolgus monkeys and demonstrated prolonged half-life of approximately one week in mice.
−Removed: We also announced that we had selected our lead anti-CD123xCD3 bispecific antibody, XmAb14045, for IND-enabling studies and cGMP process development and manufacturing.
−Removed: In addition, we have licensed our XmAb technology to pharmaceutical and biotechnology companies for use in a limited number of their programs.
−Removed: These licensees include Boehringer Ingelheim International GmBH (Boehringer Ingelheim) , CSL Limited (CSL) , Janssen R&D, LLC (Janssen) , Merck , Sharp and Dohme, a subsidiary of Merck & Co., Inc.
−Removed: (Merck) , Alexion Pharmaceuticals, Inc.
−Removed: (Alexion) , and collec tively these licensees have five Phase 1 clinical dev elopment-stage programs and two pre-clinical development-stage programs.
−Removed: In December 2014, we announced a discovery-collaboration with Novo Nordisk A/S (Novo Nordisk) to jointly discover novel biologic drug candidates for an undisclosed target by combining multiple Xencor XmAb technologies, including our bispecific and immune inhibitor technologies.
−Removed: A summary of all our licensed programs is s h own below :
−Removed: Boehringer Ingelheim
−Removed: Phase 1 trials
−Removed: (two candidates)
−Removed: Autoimmune disease
−Removed: Hematological diseases
−Removed: Fc optimization
−Removed: Autoimmune disease
−Removed: Various, including Bi-specifics
−Removed: We were founded in 1997 based on protein engineering technology developed by our co-founders Bassil Dahiyat, Ph.D.
−Removed: and Stephen Mayo, Ph.D.
−Removed: at the California Institute of Technology.
−Removed: We began our first therapeutic monoclonal antibody engineering and discovery programs in 2002 and entered into our first XmAb technology license in 2004.
−Removed: Our goal is to become a leading biopharmaceutical company focused on developing and commercializing engineered monoclonal antibodies to treat severe and life-threatening diseases with unmet medical needs.
+Added: We are a clinical-stage biopharmaceutical company focused on discovering and developing engineered antibody therapeutics to treat patients with cancer and other serious diseases, who have unmet medical needs.
+Added: We use our protein engineering capabilities to increase our understanding of protein structures and interactions and to design new technologies and XmAb® drug candidates with improved properties.
+Added: We advance these candidates into clinical-stage development, where we are conducting Phase 1 and Phase 2 studies for a broad portfolio of programs, to determine which programs we advance into later stages of development and potentially commercialization, which programs we partner to access complementary resources to optimize development, and which programs we terminate.
+Added: Our approach to protein design includes engineering Fc domains, the parts of antibodies that interact with multiple segments of the immune system and control antibody structure.
+Added: The Fc domain is constant and interchangeable among antibodies, and our engineered XmAb Fc domains can be readily substituted for natural Fc domains.
+Added: Our protein engineering capabilities and Fc technologies enable us and our partners to develop XmAb antibodies and other types of biotherapeutic drug candidates with improved properties and functionality, which can provide innovative approaches to treating disease and potential clinical advantage over other treatment options.
+Added: For example, we have developed an antibody scaffold to rapidly create novel multi-specific antibodies that bind two or more different targets simultaneously, creating entirely new biological mechanisms.
+Added: Other applications of our protein engineering technologies enhance antibody performance by increasing immune inhibitory activity, improving cytotoxicity, extending circulating half-life and stabilizing novel protein structures, such as engineered cytokines.
+Added: Three marketed XmAb medicines have been developed with our protein engineering technologies.
+Added: Our protein engineering capabilities allow us to continually explore new functionality in the Fc region, which provides us with opportunities to:
+Added: • Create new technology platforms;
+Added: • Engineer new drug candidates to advance into development or as partnering opportunities;
+Added: • Provide collaboration and licensing opportunities with partners for application of our technologies, access to our technologies, access to our drug candidates, or combinations of each.
+Added: Our goal is to become a leading biopharmaceutical company that develops and commercializes engineered biologic medicines to treat patients with severe and life-threatening diseases with unmet medical needs.
Key elements of our strategy are to:
−Removed: Advance the clinical development of our lead Immune Inhibitor Fc Domain product candidates.
−Removed: We are developing XmAb5871for the treatment of autoimmune diseases, including IgG4-related disease, and are developing XmAb7195 for the treatment of asthma and allergic diseases.
−Removed: Build a large and diversified portfolio of product candidates.
−Removed: We aim to create new XmAb-engineered antibody product candidates that exploit the novel properties of our XmAb technology platform for preclinical and clinical development by us.
−Removed: Continue to monetize and expand the use of our XmAb technology platform.
−Removed: We are seeking additional licensing and partnering opportunities, similar to our collaborations with MorphoSys and Novo Nordisk with other leading pharmaceutical and biotechnology companies.
−Removed: Broaden the functionality of our XmAb technology platform.
−Removed: We are conducting further research into the function and application of antibody Fc domains in order to expand the scope of our XmAb technology platform.
−Removed: Our bispecific technology, which uses our heterodimeric Fc domain enabling molecules with dual target binding, is an example of the expanding functionality of our XmAb technology platform.
−Removed: Continue to expand our patent portfolio protecting our XmAb technology platform.
−Removed: We seek to expand and protect our development programs and product candidates by filing and prosecuting patents in the United States and other countries.
−Removed: Antibodies as Therapeutic Agents
−Removed: Antibodies are Y-shaped proteins that are produced by B cells and used by the immune system to target and neutralize foreign objects known as antigens.
−Removed: These objects may include tumor cells, bacteria and viruses.
−Removed: Antibodies are composed of two structurally independent parts, the variable domain (the Fv domain) and the constant domain (the Fc domain and the CH1 domain).
−Removed: The Fv domain is responsible for targeting a specific antibody to a specific antigen and is different for every type of antibody.
−Removed: The Fc domain interacts with various receptors on immune cells and other cells and, rather than binding antibodies to target antigens, it endows antibodies with properties beyond simple binding, such as immune response regulation and cytotoxicity.
−Removed: Importantly, Fc domains are the same and interchangeable from antibody to antibody.
−Removed: Most antibody research to date has been based on the ability to discover and improve antigen-selective antibody Fv domains.
−Removed: Many pharmaceutical and biotechnology companies have efforts to discover, develop and commercialize antibody drugs using such Fv-based tools.
−Removed: A number of successful products have resulted from these efforts and the
−Removed: global market for antibody therapeutics was estimated to be approximately $45 billion in 2011, of which the U.S.
−Removed: market was estimated to be $20 billion.
−Removed: Intense competition drives companies to develop differentiated antibody drugs, often because of the common pursuit of the same antigen Fv targets across the industry.
−Removed: Industry efforts have focused on engineering Fv domains since the mid-1980s to enhance performance.
−Removed: More recently, many efforts at differentiation have attempted to improve upon antibody performance by drastically changing the antibody structure or substituting new molecules altogether, for example, new antibody-like scaffolds, bi-specific antibodies and antibody-drug conjugates.
−Removed: A challenge to these efforts has been making these new drug molecules replicate the beneficial features of natural antibodies, including ease of production, safety, efficacy and simplicity.
−Removed: These efforts, however, have largely ignored the Fc domain.
−Removed: In contrast, in the last decade Xencor has focused on Fc engineering.
−Removed: Fc engineering involves additional complexities, particularly consideration of simultaneous interactions with multiple Fc receptors and immune cell types and requires significant expertise in structural biology and immunology.
−Removed: We developed the XmAb technology to create significantly enhanced antibody performance while preserving over 99.5% of the natural antibody structure because we believe that maintaining native antibody structure could retain these beneficial features in our highly differentiated antibody candidates.
−Removed: Our XmAb Technology Platform
−Removed: Our XmAb Fc domain technology is a platform of antibody components that enable the creation of therapeutic antibody candidates that have novel interactions with the human immune and antibody regulation systems.
−Removed: We developed the XmAb technology platform from a systematic effort to engineer the Fc domain of antibodies to manipulate its interactions with a variety of its natural receptors.
−Removed: We used our patented screening technology, consisting of algorithms and computer models of the three-dimensional structure of the Fc domain, to focus on, from the vast number of possibilities, manageable sets of possible amino acid changes that result in small modifications to the Fc domain structure which effect significant changes in antibody function and performance.
−Removed: We have identified a set of Fc domains, each of which is engineered to have a specific function based on its Fc receptor binding profile, including:
−Removed: Immune Inhibitor Fc Domain —selective immune inhibition and rapid target clearance, targeting the receptor FcγRIIb
−Removed: Cytotoxic Fc Domain —increased cytotoxicity, targeting the receptors FcγRIIIa on natural killer (NK) cells and FcγRIIa on other immune system cells
−Removed: Xtend Fc Domain —extended antibody half ‑life, targeting the receptor FcRn on endothelial cells
−Removed: Bispecific Domain –
−Removed: het e rodimeric Fc domains enabling molecules with dual target binding
−Removed: In addition, we have engineered XmAb Fc domains with other properties, including rapid antigen clearance, antibody stability and multiple ‑antigen specificity (heterodimer).
−Removed: Each XmAb Fc domain consists of a naturally occurring Fc domain with a small number of amino acid changes, usually two that we found to be critical for modulating interactions with the desired Fc receptors or manipulating Fc structural organization .
−Removed: With such limited modifications of the natural Fc domain, XmAb ‑engineered antibodies are typically over 99.5% identical in structure and sequence to natural antibodies, simplifying product development yet enhancing function.
−Removed: In contrast to other engineering approaches for next-generation antibodies, we believe this conservative design allows our engineered antibodies to retain the beneficial stability, pharmacokinetics, and ease of discovery of natural antibodies, as well as to allow well-validated methods for antibody manufacturing.
−Removed: We believe we can thereby avoid the problems many new antibody platforms have had in production and drug stability .
−Removed: XmAb Immune Inhibitor Fc Domain technology
−Removed: FcγRIIb is an inhibitory receptor that is expressed on B cells and other cells.
−Removed: FcγRIIb, when engaged by Fc domains, signals inside the cell to block immune response activation pathways, for example the B ‑cell receptor pathway that activates in response to antigen recognition and ultimately results in the production of antibodies to antigen.
−Removed: We have focused on this role as an important negative feedback regulator of the B ‑cell response, where its biology is well ‑valida ted.
−Removed: Its expression and signalin g characteristics have made it a difficult target for monoclonal antibodies, as targeting it by itself does not trigger its inhibitory properties.
−Removed: FcγRIIb must be associated with other specific partner proteins on the cell surface to activate its inhibitory properties.
−Removed: We have circumvented this problem by discovering variants of the Fc domain with enhanced binding to FcγRIIb and designed the Fv domain to target a B ‑cell protein.
−Removed: This coupling of the two target proteins, in some cases, will trigger the inhibitory properties of FcγRIIb.
−Removed: We have discovered a series of FcγRIIb immune inhibitor Fc variants with increased binding affinity to FcγRIIb of up to 400 ‑fold.
−Removed: The high affinity variant has two amino acid substitutions in the Fc domain and has been applied to create our first immune inhibitor product development candidate XmAb5871.
−Removed: This antibody, described in greater detail below, targets CD19 on B cells through its variable domain and recruits FcγRIIb to induce its inhibitory properties.
−Removed: We have demonstrated in several preclinical studies that XmAb5871 inhibits B ‑cell responses to a variety of stimuli .
−Removed: We have also applied this high affinity Immune Inhibitor Fc Domain to our anti ‑IgE antibody XmAb7195, which as a result inhibits activation of only IgE ‑positive B cells and hence prevents production of IgE, a key mediator of allergic response.
−Removed: Also, we have discovered an exciting new mechanism of action mediated by the XmAb Immune Inhibitor Fc Domains.
−Removed: High FcγRIIb binding causes very rapid clearance from the circulation of the complexes formed between XmAb7195 and IgE, a property that we believe is unique among IgE inhibitor antibodies.
−Removed: This provides another mechanism to lower the amount of circulating IgE.
−Removed: The rapid clearance mechanism of Immune Inhibitor Fc Domains offers a highly differentiating function for antibodies targeting soluble antigens, such as IgE, and opens opportunities for the technology beyond B ‑cell modulation.
−Removed: For example, we are generating discovery candidates using XmAb Immune Inhibitor Fc Domains to clear pathologic targets from circulation.
−Removed: XmAb Cytotoxic Fc Domain technology
−Removed: Our XmAb Cytotoxic Fc Domain technology consists of a series of variant Fc domains that improve binding to the activating Fcγ
−Removed: This binding improvement drives increased antibody ‑dependent cell cytotoxicity (ADCC), a primary mechanism of antibody cytotoxicity.
−Removed: The lead Fc variant used in nearly all of our Cytotoxic Fc Domain antibody candidates is an Fc domain with two amino acid substitutions that increase affinity for FcγRIIIa, the activating receptor expressed on natural killer (NK) cells, by approximately 40 ‑fold.
−Removed: NK cells are cytotoxic lymphocytes of the innate immune system and play a major role in elimination of tumor cells and virally infected cells.
−Removed: Our XmAb Cytotoxic Fc Domain also increases affinity for FcγRIIa by approximately five ‑fold, with potential for recruitment of other important effector cells such as macrophages, which play a role in both innate and adaptive immunity by engulfing and digesting foreign material.
−Removed: FcγRIIIa is considered an important mediator of the antitumor efficacy of antibodies such as Genentech’s Herceptin (trastuzumab) and BiogenIdec/Genentech’s Rituxan (rituximab).
−Removed: Numerous publications have demonstrated the importance of Fcγ
−Removed: receptors for anti ‑tumor efficacy in mouse models and also in clinical studies of Rituxan and Herceptin.
−Removed: We have applied our Cytotoxic Fc Domain to a large number of validated (e.g.
−Removed: Rituxan, Herceptin, Bristol ‑Myers Squibb and Eli Lilly and Company’s Erbitux (cetuximab)) and unvalidated antibodies, and in all cases we have seen a marked increase of ADCC measured in vitro.
−Removed: We have established that the Cytotoxic Fc Domain technology increases the anti ‑tumor efficacy of antibodies in a number of mouse models.
−Removed: In primate studies, we have shown that our anti ‑CD19 antibody XmAb5574/MOR208, which incorporates our XmAb Cytotoxic Fc Domain, depletes monkey B cells whereas a similar anti ‑CD19 antibody with an unmodified Fc domain did not successfully kill B cells.
−Removed: In Phase 1 clinical studies, antibodies incorporating our XmAb Cytotoxic Fc Domain, for example XmAb2513 targeting CD30 in Hodgkin’s lymphoma, have shown tumor reduction response rates comparable or superior to response rates in published reports of non ‑Fc engineered antibodies against the same target cells.
−Removed: Several partners and licensees are using our Cytotoxic Fc Domain in their oncology antibodies, including four programs currently in clinical trials.
−Removed: XmAb Xtend Fc Domain technology
−Removed: Our XmAb Xtend Fc Domain technology consists of Fc domains designed to increase binding affinity to the receptor FcRn.
−Removed: FcRn is present inside lysosomes in endothelial cells lining the blood vessels and functions to rescue antibodies from the degradation that makes most proteins short ‑lived in circulation.
−Removed: As a result of interactions with FcRn, all antibodies have half ‑lives ranging from a few days to a few weeks, allowing less frequent dosing for antibody drugs than most other biologics.
−Removed: We have engineered a series of Fc variants that increase binding of the Fc domain to FcRn to enhance FcRn ‑mediated rescue and thereby increase circulating half ‑life.
−Removed: Our lead XmAb Xtend Fc Domain has two amino acid substitutions and has shown up to three ‑fold increases of in vivo half ‑life for a number of different antibodies in monkey models.
−Removed: We believe extension of half ‑life can be exploited to improve therapeutic antibody performance in several ways:
−Removed: Increased dosing interval, providing superior patient convenience and likely compliance.
−Removed: Such a reduced frequency of dosing also results in lower drug use in aggregate, reducing cost of goods.
−Removed: Lower drug quantities at the same dosing interval as the parent antibody.
−Removed: This can simplify dosage formulation and sometimes enable subcutaneous formulation.
−Removed: Cost of goods is reduced as well.
−Removed: Higher drug levels using the same dose and dosing interval as the parent antibody, resulting in longer drug exposure and potentially translating to better efficacy.
−Removed: We have licensed XmAb Xtend Fc Domain technology to several biopharmaceutical companies who are using XmAb Xtend Fc Domains to both improve existing antibody drugs and to create new drugs with long half ‑lives.
−Removed: In the third quarter of 2014, our partner Alexion initiated a Phase 1 clinical trial with an undisclosed molecule to be used against an undisclosed target.
−Removed: It is the first human clinical trial with a molecule incorporating our XmAb Xtend Domain technology.
−Removed: XmAb Bispecific Domain t echnology
−Removed: Bispecific antibodies are designed with two different variable domains to elicit biological effects that require simultaneous binding to two targets.
−Removed: Previously, industry efforts at bispecific antibody design have generally been frustrated by poor molecular stability, difficulties in production and short in vivo half-life.
−Removed: Xencor’s XmAb®
−Removed: bispecific Fc domain technology is designed to maintain full-length antibody properties in a bispecific antibody, potentially enabling stable molecules with favorable in vivo half-life and allowing for the use of standard antibody production methods.
−Removed: These bispecific Fc domains are used to generate a broad array of novel drug candidates .
−Removed: We have created Fc variants that form heterodimeric Fc domains that enable the creation of bispecific antibodies that have different Fv domains on each side of the Fc domain in order to bind to a different antigen with each of their Fv domains.
−Removed: For example, we can readily create bispecific antibodies that bind both CD3 and a tumor antigen in order to recruit cytotoxic T cells to the tumor cell.
−Removed: Because of the Fc domain, these bispecific antibodies retain the long half-life and ease of production typical of standard antibodies.
−Removed: We have generated a number of bispecific antibody discovery programs using our XmAb heterodimer Fc domains and have dem onstrated that several bispecific antibod ies built on these Fc domains are highly active in primate models.
−Removed: In November 2014 , we announced preclinical dat a from three programs using our XmAb bispecific Fc technology showing that bispecific antibodies targeting CD123, CD20 and CD38 antigens each activated T-cells to rapidly kill target cells from a single dose IV bolus in cynomolgus monkeys and demonstrated prolonged half-life of approximately one week in mice.
−Removed: Our initial bispecific programs are tumor-targeted antibodies that contain both a tumor antigen binding domain (CD123, CD20, or CD38) and a cytotoxic T-cell binding domain (CD3).
−Removed: We also announced in November 2014 that we had selected our lead anti-CD123xCD3 bispecific antibody, XmAb14045, for IND-enabling studies and cGMP process development and manufacturing.
−Removed: We plan to initiate clinical trials in acute myeloid leukemia with XmAb14045 in 2016.
−Removed: Additional development candidates against additional tumor targets are in discovery.
−Removed: Additional XmAb Fc domains
−Removed: We continue to design Fc domain variants and have identified improved functions in addition to those described above.
−Removed: Our goal is to remain at the forefront of antibody engineering by using our expertise in Fc domain engineering to create new functions for use in antibody therapeutics.
−Removed: We have Fc variants that improve complement ‑dependent cytotoxicity.
−Removed: Other Fc variants have been engineered to eliminate binding to all Fcγ
−Removed: receptors, thereby creating Fc domains that have no cytotoxic effector function at all.
−Removed: Such domains have important use in therapeutics where no effector function is desired.
−Removed: Antibody Fv domain engineering capabilities
−Removed: We have developed tools to engineer humanized and fully human, high ‑affinity antibody Fv domains.
−Removed: Usually starting from a mouse antibody Fv domain, we analyze its amino acid sequence computationally to find the best matches with human antibody sequences, which we then substitute into the murine Fv domain to create antibodies with very high human sequence content.
−Removed: Our approach preserves the structural integrity of the antibody and maintains binding to antigen.
−Removed: We also perform antigen affinity enhancement by computationally filtering sequence changes and generating small, focused libraries of Fv variants that we screen for tighter binding.
−Removed: All of our internally discovered candidates, including XmAb5871, XmAb7195 and XmAb5574/MOR208, were generated using these tools.
−Removed: XmAb5871, a B ‑cell Inhibitor for the Treatment of Autoimmune Diseases
−Removed: Overview of XmAb5871
−Removed: XmAb5871 is a monoclonal antibody for the treatment of autoimmune diseases that uses our XmAb Immune Inhibitor Fc domain to target FcγRIIb, an inhibitory receptor expressed on B cells and other immune cells, and through its Fv domain targets CD19, which is expressed on all B cells.
−Removed: By simultaneously targeting the B ‑cell proteins, CD19 and FcγRIIb, XmAb5871 has an ability to engage the natural inhibitory pathway provided by FcγRIIb, preventing further activation of B cells by autoantigens and potentially also suppressing the ability of B cells to further provoke downstream autoimmune responses from T cells.
−Removed: CD19 and FcγRIIb are expressed broadly throughout B ‑cell development, so we expect that XmAb5871 will confer broad suppression of B ‑ cell activation and downstream events such as antibody production.
−Removed: We have demonstrated that XmAb5871 inhibits B ‑cell function in multiple animal models and in initial human clinical trials without destroying these important immune cells, in contrast to other B ‑cell targeting therapies, such as Rituxan, that attack and destroy B cells.
−Removed: We believe the combination of potent inhibition without B ‑cell depletion, which can lead to opportunistic infections, has the potential to address a key unmet need in autoimmune therapies.
−Removed: The coupling between CD19 and FcγRIIb, mediated by XmAb5871, promotes a strong negative signal in the B cell, preventing its activation and potentially blocking disease pathology in a variety of autoimmune and inflammatory conditions by broadly blocking all B ‑cell populations.
−Removed: XmAb5871 is the first potential therapy that we are aware of that targets FcγRIIb inhibition.
−Removed: Therapeutic Inhibition by XmAb5871 Mimics Natural Pathways.
−Removed: (A) B ‑cell responses against a ntigen lead to antibody secretion, resulting in immunity and in some cases autoimmunity.
−Removed: (B) Excess antibodies p roduced in the B ‑cell response can engage both the antigen and the inhibitory receptor FcγRIIb on the B ‑cell surface, acting to control the immune response.
−Removed: (C) XmAb5871 mimics the natural feedback inhibition by targeting CD19, rather than the antigen, on the B ‑cell surface and recruiting FcγRIIb to inhibit activation of the targeted B cell.
−Removed: In December 2010, we entered into a collaboration and option agreement with Amgen for XmAb5871.
−Removed: During the option period, which was to expire upon completion of a data review period following our planned Phase 2b proof ‑of ‑conc ept (POC) clinical trial, we le d research, development and manufacturing activities for XmAb5871 with collaborative input and development support from Amgen.
−Removed: Under the agreement, Amgen paid us an upfront payment and early development milestones and was obligated to pay additional milestones, both before and after payment of an
−Removed: option exercise fee, and royalties on sales following an exercise of the option by Amgen.
−Removed: In 2014 we approached Amgen to request an end to the collaboration to allow us to pursue a different clinical and commercial path from the original agreement.
−Removed: Amgen agreed and in October 2014 we announced that we had regained all rights to XmAb5871, subject to granting Amgen a right of first negotiation.
−Removed: The new agreement requires Xencor to first discuss with Amgen any proposed license prior to seeking other partners.
−Removed: This right expires upon the earlier of the initiation of Phase 3 clinical testing of XmAb5871, a change of control of Xencor, or October 2019.
−Removed: At that time we announced that we were not continuing development in RA and were planning clinical development in multiple autoimmune diseases where B-cell inhibition shows promise, including IgG4-RD.
−Removed: Clinical Development Summary
−Removed: The initial clinical trial application for XmAb5871 was approved by the United Kingdom Medicines and Healthcare Products regulatory agency in September 2011.
−Removed: To date, all clinical development for XmAb5871 has been conducted in western and central Europe.
−Removed: In December 2012, we completed a Phase 1a randomized, blinded, placebo-controlled, single ascending dose clinical trial to investigate the safety, tolerability and pharmacokinetics of XmAb5871 in healthy male adult volunteers.
−Removed: The primary objectives of this clinical trial were (1) to determine the safety and tolerability profile of single-dose intravenous administration of XmAb5871 and (2) to characterize the single-dose pharmacokinetics and immunogenicity of XmAb5871.
−Removed: We also included several biomarkers to evaluate the ability of XmAb5871 to suppress B-cell responses in treated subjects and we observed promising immunosuppressive activity against these biomarkers, including a tetanus antigen challenge, stimulated CD86 expression and B-cell count .
−Removed: XmAb5871 was well tolerated at all doses investigated.
−Removed: No subjects experienced a serious adverse event or a dose-limiting toxicity.
−Removed: The most frequently reported treatment related adverse events (AEs) were gastrointestinal AEs (including nausea, vomiting, abdominal pain, abdominal/epigastric discomfort and diarrhea) in 39% of subjects.
−Removed: All but one were of mild to moderate severity, with one subject experiencing severe nausea.
−Removed: All 48 subjects completed the clinical trial protocol.
−Removed: XmAb5871 ’s h alf-life averaged 3.63 ±
−Removed: A nti-drug antibodies (ADA) were detected in samples from 44% of the subjects.
−Removed: One subject with a positive ADA appeared to have an accelerated decline in XmAb5871 concentration.
−Removed: Other than this one subject there was no distinct evidence of ADA - mediated clearance of XmAb5871 in any other ADA positive subject .
−Removed: XmAb5871 was demonstrated to have promising immunosuppressive activity based on several biomarkers observed during the trial.
−Removed: In January 2013 , we initiated a Phase 1b/2a clinical trial in patients with active RA.
−Removed: This Phase 1b/2a clinical trial was a multi-center, randomized, placebo-controlled, double-blinded, multiple ascending dose study of the safety, tolerability, pharmacokinetics and pharmacodynamics of XmAb5871 in RA patients with active disease on stable non-biologic DMARD therapy.
−Removed: The primary objective of this clinical trial was to determine the safety and tolerability profile of biweekly, multiple-dose, intravenous administration of XmAb5871 in patients with RA.
−Removed: Secondary objectives were (1) to characterize the pharmacokinetics and immunogenicity of intravenously administered XmAb5871 in patients with RA and (2) to evaluate the effect of XmAb5871 on RA disease response as measured by changes in Disease Activity Score 28 using C-reactive protein (DAS28-CRP) at Week 13 for the Phase 2a part of this clinical trial.
−Removed: The clinical trial was conducted in two parts.
−Removed: In the Phase 1b part of this clinical trial , 29 RA patients with active disease on stable non-biologic DMARD therapy were enrolled into four consecutive dose cohorts (0.3 to 10.0 mg/kg) randomized approximately 6:2 (six XmAb5871 patients to two placebo patients), other than for the lowest dose, where it was 3:1.
−Removed: Each patient was administered XmAb5871 or placebo every 14 days for a total of six doses.
−Removed: In the Phase 2a part of this clinical trial , 27 patients were randomized 2:1 (two XmAb5871 patients to one placebo patient).
−Removed: The dose for this part of the trial was 10.0 mg/kg or placebo and patients were administered XmAb5871 or placebo every 14 days for a total of six doses .
−Removed: Data from the Phase 2a part of the trial show promising activity in patients with RA, including multiple DAS28-CRP remissions and ACR50 and ACR70 responses.
−Removed: In the Phase 2a cohort of the trial 15 XmAb5871 treated patients and eight placebo treated patients were evaluable for RA disease activity at the protocol specified disease activity assessment time point of two weeks following the sixth biweekly infusion.
−Removed: 33% of patients (5 of 15) that received all six biweekly doses of XmAb5871 achieved DAS28-CRP remission or low disease activity versus zero on placebo.
−Removed: Three ACR70 responses (20%) and six ACR50 responses (40%) occurred in the XmAb5871 group compared to zero and one (13%) respectively in the placebo group.
−Removed: Across the entire Phase 1b/2a clinical trial, bi weekly administration of XmAb5871 for 12 weeks was generally well tolerated.
−Removed: The most common XmAb5871 treatment
−Removed: related adverse events (AEs) observed were predominantly mild to moderate gastrointestinal toxicities (nausea, vomiting, diarrhea) occurring during the first infusion of XmAb5871.
−Removed: These gastrointestinal AEs did not typically recur on subsequent infusions and no infusions were discontinued due to these AEs.
−Removed: Other treatment related AEs experienced in more than two XmAb5871 treated patients were pyrexia (fever) and headache.
−Removed: Treatment related serious adverse events (SAEs) occurred in two patients that received XmAb5871:
−Removed: infusion related reaction and venous thrombosis.
−Removed: Two patients in the placebo treated group also reported SAEs.
−Removed: We have begun translational and mechanistic studies of XmAb5871 in the rare autoimmune disorder, immunoglobin G4-related disease, or IgG4-RD .
−Removed: In 2015 we plan to file an investigational new drug application (IND) with the FDA and to initiate an open-label pilot clinical trial in patients with IgG4-RD to assess disease control activity as measured by the IgG4-RD Responder Index (Carruthers, et al., 2012, Int J Rheum).
−Removed: IgG4 - RD is a rare fibro-inflammatory autoimmune disorder that impacts approximately 10,000-20,000 patients in the United States , based on the incidence rate reported in Japan .
−Removed: IgG4 - RD affects multiple organ systems and we believe is characterized by the presence of IgG4-positive plasmablast cells and the distinct histopathologic al appearance of diseased organs that is required for diagnosis.
−Removed: This objective histopathologic al diagnostic criterion is atypical for most autoimmune diseases and offers advantages for accurately identifying patients.
−Removed: Preclinical Development
−Removed: We have examined the ability of XmAb5871 to inhibit B cells in preclinical studies, including in vitro and in vivo studies.
−Removed: The observation s in our preclinical studies include:
−Removed: No depletion of human B cells in culture;
−Removed: Inhibition of human B cells, including B cells donated by lupus and arthritis patients, stimulated by a variety of agents;
−Removed: Suppression of antibody responses in humanized mouse models;
−Removed: Suppression of disease in mouse models of arthritis and multiple sclerosis without B-cell depletion;
−Removed: Well tolerated at high doses in monkeys.
−Removed: The lack of B-cell depletion is an important property of XmAb5871, giving it a potential safety advantage relative to B-cell depleting therapies like Rituxan.
−Removed: We have shown that XmAb5871 did not kill B cells in a culture of human blood cells over a wide concentration range.
−Removed: In contrast, Rituxan and XmAb5574, depleting antibodies for treating B-cell cancers, both significantly depleted B cells.
−Removed: The hallmark of B-cell activation is intracellular calcium mobilization.
−Removed: B cells taken from human donors can be stimulated in vitro resulting in a readily observable mobilization of calcium.
−Removed: In contrast, in the presence of XmAb5871, stimulation of the B cells leads to very slight calcium mobilization, barely detectable with our assays (figure below).
−Removed: XmAb5871 suppresses calcium mobilization, a hallmark of B-cell activation.
−Removed: Upon stimulation, B cells treated with placebo showed an increase in calcium flux.
−Removed: In contrast, B cells treated with Xm Ab5871 showed a low calcium signal.
−Removed: A second common measure of B-cell activation is their proliferation in response to various stimuli.
−Removed: In preclinical studies, we demonstrated XmAb5871 inhibits B-cell proliferation stimulated by anti-CD79b, IL-4, BLyS or lipopolysaccharide (LPS), a range of stimulants that signal through different pathways.
−Removed: The inhibition of the BLyS-mediated propagation is particularly notable given the recent approval of the anti-BLyS antibody Benlysta for treatment of lupus, suggesting that XmAb5871 inhibition includes the pathways blocked by Benlysta.
−Removed: Because most autoimmune diseases involve contributions from T cells in addition to B cells, we examined the ability of XmAb5871 to reduce the propensity of the B cell to activate T cells.
−Removed: CD86 is the ligand for CD28 on T cells and their interaction is a major stimulant of T cells.
−Removed: For example, the blockade of CD86 by Bristol-Myers Squibb's Orencia (abatacept) is used as a treatment for rheumatoid arthritis and is also being investigated for the treatment of lupus.
−Removed: Upon B-cell stimulation, CD86 is increased on the B-cell surface, promoting the ability of the B cell to engage and activate the T-cell response.
−Removed: In the presence of XmAb5871, however, we observed that CD86 was significantly diminished.
−Removed: This observation led subsequently to the use of a similar assay as an activity biomarker for our Phase 1a clinical trial.
−Removed: XmAb5871 was consistently immunosuppressive in mouse models of the human B-cell response.
−Removed: Because the antibody does not recognize mouse CD19 or mouse Fc 
−Removed: RIIb, we used humanized mouse models (huSCID), in which human peripheral-blood cells, including B cells and T cells, are engrafted into an immune compromised mouse.
−Removed: These are well-established models and the human immune cells will normally react to immunization with antigen.
−Removed: Assuming that most of our human donors would have been vaccinated with tetanus toxoid, we set up humanized mouse models with a tetanus booster vaccination to see if XmAb5871 could suppress the anti-tetanus response (figure below).
−Removed: We ran the model numerous times and observed a robust anti-tetanus antibody response in untreated mice (the placebo control group), which we did not observe in mice treated with XmAb5871, indicating effective B-cell inhibition.
−Removed: Rituximab was included as a control, showing only intermediate suppression of the anti-tetanus antibody response.
−Removed: XmAb5871's ability to prevent antibody responses in these humanized mouse models suggests it might be capable of inhibiting antibody responses in general and thus autoantibody responses in humans with autoimmune diseases.
−Removed: XmAb5871 inhibited anti-tetanus antibody responses in mice engrafted with human B cells and immunized with tetanus.
−Removed: We could not test XmAb5871 for activity in mouse disease models because of the lack of reactivity with the mouse CD19 and Fc 
−Removed: Accordingly, we created an XmAb5871 surrogate antibody called XENP8206, which has an Fv domain that recognizes mouse CD19 and an Fc domain identical to XmAb5871.
−Removed: We then used mice transgenic for human Fc 
−Removed: RIIb as a background system for disease models.
−Removed: In these mice, the mouse Fc 
−Removed: RIIb gene has been replaced with the human Fc 
−Removed: RIIb gene so their Fc 
−Removed: RIIb receptor can be recognized by the XENP8206 Immune Inhibitor Fc Domain.
−Removed: In vitro experiments with B cells taken from the transgenic mice showed us that XENP8206 was capable of mimicking XmAb5871's B-cell inhibition activity, and that the activity was dependent on engagement of human Fc 
−Removed: In a collagen-induced arthritis model, XENP8206-treated mice had little to no evidence of inflammation, whereas untreated mice had a 40% incidence of disease.
−Removed: XENP8206's ability to decrease symptoms in a mouse model of multiple sclerosis was at least as good as a Rituxan surrogate antibody, which caused complete depletion of the mouse B cells.
−Removed: XmAb5871's surrogate antibody XENP8206 did not cause significant B-cell depletion in our mouse studies.
−Removed: We completed both 12-week and 24-week, multiple- dose, preclinical monkey toxicology studies of XmAb5871 and found no adverse events in doses up to 200 mg/kg.
−Removed: Additional preclinical work has also shown that XmAb5871 is capable of suppressing B cells donated by lupus and rheumatoid arthritis patients in both in vitro and in vivo models.
−Removed: Market Opportunity
−Removed: The indication for which we are currently pursuing XmAb5871 development is IgG4-RD, a newly designated disorder.
−Removed: IgG4-RD is a rare fibro-inflammatory autoimmune disorder that impacts approximately 10,000-20,000 patients in the United States , based on the incidence rate reported in Japan .
−Removed: IgG4-RD affects multiple organ systems and
−Removed: we believe is characterized by the distinct microscopic appearance of diseased organs, including the presence of IgG4-positive plasmablast cells that is required for diagnosis.
−Removed: There are currently no approved therapies for IgG4-RD and glucocorticoids ( h ormone steroids) are the current standard of care treatment.
−Removed: The autoimmune disease therapeutic market generally presents a n opportunity in various small and large market indications, some of which may be appropriate for XmAb14045.
−Removed: C urrently marketed antibody-based products, include Rituxan (marketed under the trade name MabThera outside the United States), with 2012 worldwide sales for the treatment of several autoimmune indications of approximately $1.1 billion, and GlaxoSmithKline's Benlysta (belimumab), with 2012 worldwide sales of over $200.0 million for the treatment of lupus.
−Removed: We will continue to consider additional autoimmune diseases to determine whether XmAb5871 has potential as a treatment.
−Removed: XmAb7195, an IgE Inhibitor for the Treatment of Asthma and Allergic Diseases
−Removed: XmAb7195 is an anti ‑IgE antibody engineered to reduce IgE levels for the treatment of asthma and other atopic diseases.
−Removed: Its three specific mechanisms of action give it potential advantages over current therapies:
−Removed: increased IgE affinity, inhibition of the transition of B cells to IgE ‑secreting cells and rapid clearance of IgE from circulation.
−Removed: XmAb7195 is a humanized anti ‑IgE antibody with an Fv domain that targets the same IgE epitope as Genentech and Novartis AG’s Xolair (omalizumab) , which is validated to block IgE.
−Removed: XmAb7195’s affinity for IgE is approximately three times higher than that of Xolair.
−Removed: We believe that this contributes to the increased suppression of IgE observed in our preclinical studies.
−Removed: XmAb7195, in contrast to Xolair, has our XmAb Immune Inhibitor Fc Domain that has a 400 ‑fold higher affinity than natural antibodies for FcγRIIb.
−Removed: XmAb7195 and XmAb5871 have the same Fc domain, but XmAb7195, unlike XmAb5871, inhibits only IgE ‑positive B cells.
−Removed: By binding to FcγRIIb on IgE ‑positive B cells, XmAb7195 suppresses their activation and differentiation into IgE ‑secreting plasma cells.
−Removed: This binding reduces IgE production, a mechanism not seen with Xolair, and ultimately lowers IgE levels in the blood.
−Removed: XmAb7195 targets FcγRIIb, which results in rapid clearance of free and total IgE and inhibition of the function of IgE expressing B cells.
−Removed: Total IgE reduction differentiates XmAb7195 from other anti-IgE therapeutic antibodies, which actually increase total IgE levels.
−Removed: Because total IgE assays, unlike free IgE assays, are readily available to clinicians, the effect of XmAb7195 on total IgE levels could enable for the first time simple monitoring, and potentially adjustment of treatment effect.
−Removed: In our preclinical primate and other animal studies, we observed rapid reductions in IgE levels, even from the highly ‑elevated levels found in chimpanzees, and rapid clearance of IgE from circulation.
−Removed: We did not observe any clearance or such magnitude of reduction with Xolair.
−Removed: This suggests a new mechanism of action in which high FcγRIIb binding causes very rapid clearance of the complexes formed between XmAb7195 and IgE in the liver.
−Removed: We believe XmAb7195 binds to FcγRIIb expressed in cells lining the blood vessels in the liver which take up and degrade the XmAb7195 IgE complex.
−Removed: These three mechanisms lead to levels of serum IgE below quantifiable levels in preclinical chimpanzee studies and offer the potential for superior IgE control and superior clinical efficacy.
−Removed: We believe the limitations of current treatment with Xolair can be overcome with XmAb7195, and that superior IgE control means our product candidate can potentially treat a larger population with superior efficacy.
−Removed: Clinical Development Plans
−Removed: In 2014 we filed an IND for XmAb7195 for asthma with the FDA and in May 2014 initiated a Phase 1a single ascending dose clinical trial in healthy volunteers and in allergen-sensitive subjects with high IgE levels.
−Removed: Th is Phase 1a
−Removed: clinical trial is a randomized, double-blind, placebo-controlled, single ascending dose trial being conducted in two parts.
−Removed: In the completed Part 1, healthy subjects were enrolled into five consecutive dose cohorts of eight subjects each, randomized to receive a single intravenous (IV) administration of XmAb7195 or matching placebo 6:2 (six XmAb7195 patients to two placebo patients) .
−Removed: In the ongoing Part 2, otherwise healthy subjects with a history of allergic rhinitis and/or allergic conjunctivitis and/or atopic dermatitis with elevated serum IgE (> 300 IU/mL), will be enrolled into three consecutive dose cohorts of eight subjects each, randomized to a single intravenous (IV) administration of XmAb7195 or matching placebo 6:2 (six XmAb7195 patients to two placebo patients) .
−Removed: The primary and secondary objectives of the clinical trial are to determine the safety and tolerability profile of single-dose IV administration of XmAb7195 and to characterize the pharmacokinetics (PK) and immunogenicity of single-dose IV administration of XmAb7195 respectively.
−Removed: Exploratory objectives include the determination of the effect of XmAb7195 on serum free and total IgE and the effect on basophil surface IgE and basophil FcεRI expression levels.
−Removed: In January 2015, we reported interim data from th is Phase 1a clinical trial.
−Removed: XmAb7195 was administered to 30 subjects in Part 1 of the trial in single doses ranging from 0.3 to 3.0 mg/kg.
−Removed: 29 of 30 (97%) subjects had detectable free IgE levels pre-dose.
−Removed: Of these, 26 subjects (90%) had reduction of free IgE levels to below the detectable limit of the assay (<10 ng/ml) at the end of the XmAb7195 infusion with reduction lasting for at least one week following a single infusion, including those at the lowest dose evaluated of 0.3 mg/kg.
−Removed: Two subjects with high pre-dose IgE levels (above 400 IU/mL) were treated with XmAb7195, one each at 0.75 mg/kg and 3.0 mg/kg doses, and both had reduction of free IgE levels to below the limit of detection lasting for at least one week.
−Removed: Total IgE was reduced to below the limit of detection (<2.0 IU/mL) in 26 of 30 (87%) subjects with detectable total IgE pre-dose.
−Removed: Dosing through the first three cohorts (0.3, 1.0 and 3.0 mg/kg) resulted in observations of two apparent dose-related toxicities:
−Removed: urticaria and thrombocytopenia.
−Removed: There were no other AEs that occurred in more than two XmAb7195 treated subjects.
−Removed: There were no SAEs reported and no subject discontinued the trial early.
−Removed: Asymptomatic thrombocytopenia occurred in all six subjects receiving XmAb7195 in the 3.0 mg/kg dose cohort and thrombocytopenia was deemed a dose limiting toxicity.
−Removed: The decrease in platelet count was transient with a low point by 24 hours post-dose, recovery starting by 48 hours post-dose and near f ull platelet count recovery by study Day 8 in all cases, at which time serum drug concentrations still exceeded levels that eliminate detectable IgE .
−Removed: There was no apparent relationship of thrombocytopenia to known polymorphisms of Fcγ
−Removed: receptors IIa or IIb .
−Removed: Moderate urticaria was reported in a total of seven XmAb7195 treated subjects with an apparent correlation of dose with frequency of occurrence.
−Removed: In all cases regardless of dose, the signs/symptoms of urticaria were mild, non-diffuse and easily treated with oral antihistamine, and the study drug infusions were continued to completion without worsening of symptoms.
−Removed: We plan to initiate a Phase 1b multiple ascending dose trial, following successful Phase 1a trial safety assessment, that will include cohorts of mild to moderate allergic patients.
−Removed: Preclinical Development
−Removed: We have performed a variety of in vitro and in vivo studies to explore the ability of XmAb7195 to sequester IgE and inhibit its production.
−Removed: These preclinical studies have shown that XmAb7195 inhibits the production of IgE in a variety of settings, with greater and/or prolonged reductions of IgE compared to Xolair.
−Removed: We also have observed evidence of three different mechanisms of action.
−Removed: The observations from our preclinical studies include:
−Removed: Selective inhibition of IgE production in human B-cell assays;
−Removed: Prolonged reduction of free and total IgE in humanized mice compared to Xolair;
−Removed: Greater reduction of free and total IgE in chimpanzees compared to Xolair;
−Removed: Well tolerated at high doses in monkeys;
−Removed: Well tolerated in chimpanzees.
−Removed: Important for XmAb7195's mechanisms of action is the binding of circulating IgE and our in vitro and in vivo studies reflect this activity and its three-fold tighter binding to IgE than Xolair.
−Removed: In a preclinical study, we treated B cells to induce their transition into IgE-secreting plasma cells and observed that XmAb7195 reduced the total amount of IgE produced.
−Removed: This is consistent with our prediction that the incorporation of our Immune Inhibitor Fc Domain causes the inhibition of IgE B cells.
−Removed: In this respect, XmAb7195 behaves similarly to XmAb5871, which we have shown to have broad capacity to inhibit the production of all classes of antibodies by B cells.
−Removed: In the case of XmAb7195, however, the B-cell inhibition is restricted to B cells expressing IgE on their surface, and our preclinical studies confirm this selectivity.
−Removed: As with XmAb5871, XmAb7195's enhanced Fc domain does not bind well to mouse Fc 
−Removed: RIIb, so we used models of mice engrafted with human blood cells and examined IgE levels in response to XmAb7195.
−Removed: Compared to Xolair, XmAb7195 prolonged the reduction of free IgE levels, indicating an additional biological effect beyond that of simple IgE bin ding.
−Removed: Total IgE levels (which are the sum of IgE complexed with anti-IgE antibody plus any free IgE) were significantly reduced in XmAb7195-treated mice, but not reduced in the Xolair-treated mice.
−Removed: We interpret these data as further evidence that XmAb7195, through its Immune Inhibitor Fc Domain, engages Fc 
−Removed: RIIb on IgE B cells and prevents their transition into IgE-secreting plasma cells.
−Removed: In further studies in the humanized mice, we compared the activity of XmAb5871 to XmAb7195 and saw that the XmAb7195 suppression was restricted to IgE versus other immunoglobulins such as IgG and IgM.
−Removed: We have also tested the activity of XmAb7195 in chimpanzees, which we believe is the most predictive animal model of the effects of XmAb7195 in humans.
−Removed: Chimpanzees, including those in our study, normally have very high levels of IgE compared to humans, and humans with these levels would be considered ineligible for Xolair because their IgE levels exceed Xolair's effective range.
−Removed: We treated six chimpanzees, three with XmAb7195 and three with Xolair, and observed that both antibodies caused a reduction in circulating free IgE, as shown in the figures below.
−Removed: XmAb7195 reduces free IgE levels in chimpanzees to below the limits of quantification of our IgE assay, 0.004 
−Removed: Chimpanzees treated with Xolair had transient impact, briefly reducing free IgE to approximately 0.050 
−Removed: The plots show data from the same study at different time intervals.
−Removed: Xolair only transiently reduced the free IgE, however, and never achieved the low IgE levels generally believed necessary for efficacy (0.02 
−Removed: g/ml or lower).
−Removed: Xolair, consistent with human clinical studies, increased total IgE three to five fold.
−Removed: XmAb7195, on the other hand, reduced free IgE levels to below our limit of quantification (0.004 
−Removed: g/ml), amounting to at least 10-fold lower IgE than with Xolair.
−Removed: XmAb7195-treated chimpanzees had marked and rapid reductions in total IgE as well, once again consistent with the added mechanisms of action contributed by the Immune Inhibitor Fc Domain.
−Removed: We believe that the very rapid reduction in total IgE implicates a third mechanism of action, namely the ability to rapidly clear IgE bound to XmAb7195.
−Removed: A second chimpanzee study confirmed these findings, and additional preclinical studies with surrogate antibodies in Fc 
−Removed: RIIb transgenic mice closely resemble our observations in chimpanzees, indicating that the rapid clearance mechanism is a general phenomenon and a potential new application of
−Removed: the Immune Inhibitor Fc Domain platform.
−Removed: We have performed 12-week, multiple dose toxicology studies in cynomolgus monkeys up to 100 mg/kg and XmAb7195 is well tolerated with no adverse effects observed.
−Removed: Furthermore, although the chimpanzee studies were not designed as toxicology studies, XmAb7195 was well tolerated at the 5 mg/kg dose we tested at both single and multiple doses.
−Removed: Market Opportunity
−Removed: According to the CDC, asthma affects approximately one in 12 Americans, more than half of asthma sufferers have at least one attack each year and thousands of people die from asthma attacks each year.
−Removed: Disease severities cover a wide range, and the treatment landscape is multi-tiered for asthma patients.
−Removed: Patients with mild and moderate asthma are generally well controlled with inhaled corticosteroids and long-acting beta agonists.
−Removed: However, a small percentage of the estimated 25 million asthma patients in the United States have severe asthma and are refractory to high-dose combination therapy.
−Removed: This severe population is commonly treated with oral corticosteroids, which are associated with a host of undesirable side effects and are often insufficient to control the disease.
−Removed: IgE, the target of Xolair, is the direct mediator of allergies and the allergic asthma response.
−Removed: When IgE binds to allergens, it triggers an allergic response, which can ultimately result in the debilitating bronchoconstriction of asthma, and other systemic pathologies such as atopic dermatitis and chronic urticaria, also known as hives.
−Removed: Xolair's efficacy in severe asthma through the suppression of IgE has validated IgE as a therapeutic target.
−Removed: Xolair has been used to treat the severe asthma population, generating worldwide sales in 2012 of approximately $1.3 billion.
−Removed: While Xolair has demonstrated efficacy in severe asthma, its modest potency has led to two key limitations:
−Removed: Because Xolair's modest potency would require an impractically large dose to control high IgE levels, it is approved for use only in a limited number of asthma patients, leaving approximately 20% of asthma patients that have high body weight and high IgE levels ineligible;
−Removed: Of those patients treated with Xolair, approximately half do not reach target IgE reductions.
−Removed: XmAb5574/MOR208, a Cytotoxic B ‑cell Depleting Product Candidate for the Treatment of B ‑cell Cancers
−Removed: XmAb5574/MOR208 is a monoclonal antibody that targets CD19 and incorporates our Cytotoxic Fc Domain technology for killing of malignant B cells.
−Removed: XmAb5574/MOR208 was discovered by us and is now being developed by MorphoSys, pursuant to a collaboration and license agreement that we entered into in June 2010.
−Removed: Under this agreement, we granted MorphoSys an exclusive worldwide license to XmAb5574/MOR208 for all indications.
−Removed: We were responsible for completing a Phase 1 clinical trial of XmAb5574/MOR208 in chronic lymphocytic leukemia ( CLL ) , which was completed in January 2013.
−Removed: MorphoSys is solely responsible, at its own cost, for all other development and commercialization activities.
−Removed: MorphoSys commenced Phase 2 clinical trials in patients with B ‑ALL and Non-Hodgkin’s Lymphoma ( NHL ) , in April and May 2013, respectively.
−Removed: We humanized XmAb5574/MOR208 with our proprietary technology and applied our Cytotoxic Fc Domain to enhance binding to the human Fc receptors FcγRIIIa and FcγRIIa, thereby enhancing recruitment of natural killer (NK) cells and other FcγR ‑bearing effector cells.
−Removed: We applied further engineering to the CD19 ‑binding Fv domain of XmAb5574/MOR208 to enhance its affinity over 10 ‑fold for human CD19, and also increased its affinity for monkey CD19, enabling monkey toxicology and efficacy studies.
−Removed: CD19 is an alternative target to CD20 that can be used in salvage regimens for patients failing Rituxan.
−Removed: Further, CD19 is expressed on the B cell surface earlier in development and persists longer through B ‑cell maturation.
−Removed: Therefore, XmAb5574/MOR208 may be able to target a broader spectrum of lymphoid malignancies, such as acute lymphocytic lymphoma ( ALL ) or CLL, where Rituxan’s efficacy may be limited.
−Removed: Finally, we believe that combination therapy of XmAb5574/MOR208 with immunomodulatory agents, such as lenalidomide, and/or new chemotherapy agents, offers the potential for superior efficacy to existing therapies.
−Removed: XmAb5574 recruits Natural Killer cells to malignant B cells to promote their destruction .
−Removed: Clinical Development
−Removed: In January 2013 , we completed a Phase 1 clinical trial of XmAb5574/MOR208 in patients with high-risk, heavily-pretreated CLL, in which the antibody showed encouraging signs of preliminary anti-tumor activity and an acceptable safety profile and was well tolerated.
−Removed: The trial protocol was amended to include a period of extended dosing for a total of eight patients at the 12 mg/kg dose to study the effect of longer duration of exposure on safety and response rate.
−Removed: Overall response rate by IWCLL 2008 criteria was 29.6% (eight partial responses in 27 evaluable patients).
−Removed: Using NCI-WG CLL 1996, response criteria resulted in a response rate of 66.7% (18 partial responses).
−Removed: At the highest dose studied, 12 mg/kg, 12 of 16 patients (75%) had a partial response by NCI-WG CLL 1996 and six patients (37.5%) had a partial response using additional CT criteria (IWCLL 2008).
−Removed: Median progression free survival for all patients was 199 days and for the extended treatment arm (at 12 mg/kg) was 420 days.
−Removed: Blood disease cleared in most patients, with median reduction in absolute lymphocyte count from baseline of 90.8%.
−Removed: XmAb5574/ MOR208 was generally well tolerated with no maximum-tolerated dose identified.
−Removed: Clinically-significant, treatment-related adverse events (AEs) classified as Grade 3 or higher occurred in 5 out of twenty-seven patients.
−Removed: The most frequent treatment-related AEs were infusion-related reactions, which were reported for 66.7% of patients, all of which were grade 1 or 2, and no reactions were seen following the first infusion.
−Removed: Treatment-related AEs each reported for 18.5% of patients were ALT increased, AST increased, neutropenia and thrombocytopenia;
−Removed: all other treatment-related AEs were reported for ≤
−Removed: 15% of patients.
−Removed: Based on the Phase 1 clinical trial results, MorphoSys has continued the development of XmAb5574/MOR208 and has initiated two Phase 2 clinical trials of MOR208 in patients with ALL and NHL, respectively.
−Removed: The Phase 2 clinical trial in ALL began in April 2013 and is an open-label, multicenter, single-arm clinical trial designed to assess efficacy in patients suffering from relapsed or refractory B-ALL.
−Removed: Secondary outcome measures include response duration, safety and pharmacokinetics of XmAb5574/MOR208.
−Removed: In total, 30 patients are planned to be enrolled.
−Removed: The Phase 2 clinical trial in NHL began in May 2013 and is an open-label, multicenter, single-arm clinical trial designed to assess the efficacy of MOR208 in patients with relapsed or refractory NHL.
−Removed: Secondary outcome measures include response duration, safety and pharmacokinetics of MOR208.
−Removed: A total of up to 120 patients are planned to be enrolled in four separate sub-indications:
−Removed: follicular lymphoma (FL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLCBL), and other forms of indolent NHL (iNHL).
−Removed: In December 2014, MorphoSys reported interim data from the Phase 2 trial in NHL.
−Removed: Of 89 patients treated with the four different subtypes of relapsed or refractory NHL ;
−Removed: four complete responses ( two in DLBCL, one in FL, one in iNHL), 14 partial responses ( seven in DLBCL, six in FL, one in iNHL).
−Removed: In addition, an investigator-sponsored Phase 2 clinical trial in CLL as a combination therapy with lenalidomide began in January 2014.
−Removed: Additional clinical trials in other B-cell malignancies and in combination with chemotherapy are possible and will be conducted at the discretion of and under the control of MorphoSys.
−Removed: Preclinical Development Summary
−Removed: Our preclinical observations include:
−Removed: Cytotoxicity against multiple lymphoma cell lines;
−Removed: Cytotoxicity against malignant cells from ALL and MCL patients;
−Removed: Inhibition of tumor growth in mouse xenograft models;
−Removed: Rapid and sustained depletion of peripheral and tissue B cells in monkeys;
−Removed: Well tolerated at high doses in monkeys.
−Removed: In preclinical in vitro studies, we tested XmAb5574/MOR208 for ADCC activity against a large number of lymphoma-derived tumor cell lines.
−Removed: In these studies, XmAb5574/MOR208 was shown to mediate strong NK-mediated killing against the CD19-positive tumor cell lines tested.
−Removed: Similar tests were performed with tumor cells taken directly from patients with either ALL or MCL.
−Removed: In these studies, XmAb5574/MOR208 demonstrated substantial ADCC activity against both types of lymphomas.
−Removed: In all contexts examined, the control antibody, which is identical to XmAb5574/MOR208 except its Fc domain is an unmodified Fc domain (anti-CD19 IgG1), showed greatly reduced ADCC, in some cases with no detectable killing of tumor cells.
−Removed: This comparison highlights the impact of our Cytotoxic Fc Domain technology on the ability of anti-CD19 antibodies to recruit NK cells and attack tumor cells.
−Removed: In addition to NK-mediated killing, the presumed dominant mechanism of action, we also observed macrophage-mediated phagocytosis of tumor cells in vitro, and a direct anti-tumor effect (requiring no effector cells such as NK or macrophage) in which the antibody appears to slow the growth of some tumor lines.
−Removed: We used mouse xenograft models to examine the in vivo activity of XmAb5574/MOR208 against subcutaneously implanted lymphoma cells.
−Removed: The antibody inhibits lymphoma growth in both prophylactic (tumor-prevention) models and established tumor models.
−Removed: Notably, anti-CD19 antibodies with unmodified Fc domains had diminished anti-tumor activity compared to XmAb5574/MOR208.
−Removed: Although the precursor antibody does not react strongly with monkey CD19 or B cells, our affinity-enhanced Fv domain does react well with monkey B cells, and this enabled further POC and toxicology studies in cynomolgus monkeys.
−Removed: We performed an initial high-dose (10 mg/kg) study in monkeys and observed rapid depletion of peripheral B cells after a single dose of the antibody, ultimately reducing the B cells to less than five percent of their starting numbers.
−Removed: Significant B-cell reductions were also observed in the bone marrow, spleen and lymph nodes, notable because of Rituxan's relatively poor ability to impact tissue-resident B cells.
−Removed: The 10 mg/kg dose was well-tolerated by the monkeys, with no adverse effects.
−Removed: In additional monkey studies, we compared the ability of different doses of XmAb5574/MOR208 to deplete monkey B cells and observed significant B-cell reductions at lower doses, 1 and 3 mg/kg.
−Removed: In a final study to demonstrate the impact of our Cytotoxic Fc Domain technology on in vivo tumor cell killing, we compared the ability of XmAb5574/MOR208 to an unmodified IgG1 control antibody (anti-CD19 IgG1) to deplete monkey B cells at a 3 mg/kg dose (figure below).
−Removed: The XmAb5574/MOR208-treated animals displayed a marked drop in peripheral B-cell counts.
−Removed: The unmodified control antibody anti-CD19 IgG1, on the other hand, did not noticeably affect B-cell counts and was indistinguishable from the effects of treatment with vehicle alone.
−Removed: A single dose of XmAb5574/MOR208 depletes peripheral B cells in cynomolgus monkeys.
−Removed: A control anti-CD19 antibody containing an unmodified IgG1 Fc domain and placebo, consisting of the buffer vehicle, has no effect on B cells.
−Removed: Market Opportunity
−Removed: B-cell cancers include lymphomas such as NHL and leukemias such as CLL and ALL.
−Removed: Collectively, lymphomas represent about five percent of all cancers diagnosed in the United States.
−Removed: NHL is the most prevalent of all lymphoproliferative diseases, with the National Cancer Institute estimating that over 69,000 new cases will be reported in the United States in 2013 and 85% of NHLs are classified as B-cell disorders.
−Removed: The Leukemia and Lymphoma Society estimates that over 16,000 new cases of CLL and over 6,000 new cases of ALL will be reported in 2013.
−Removed: CD19, the target of XmAb5871's Fv domain, is a B-cell surface protein that is highly expressed on the tumor cells in NHL and many leukemias, including ALL and CLL.
−Removed: We believe that targeting CD19 with XmAb5574/MOR208 offers potential advantages over the current standard of care for B-cell malignancies, which is treatment with Rituxan plus chemotherapy.
−Removed: Rituxan, an anti-CD20 antibody, plus chemotherapy have successfully treated many B-cell NHLs and some B-cell leukemias, demonstrating the utility of antibodies targeting B-cell diseases.
−Removed: Although the Rituxan-chemotherapy regimen has led to major improvements in response rates and progression-free survival, the majority of patients relapse and many lose responsiveness to Rituxan treatment.
−Removed: In 2014, MorphoSys gained orphan drug in the US and orphan medicinal product status in the European Union for XmAb5574/MOR208 for the treatment of both DLBCL and CLL.
+Added: Advance the development of our XmAb antibody programs for oncology and other serious diseases.
+Added: Our modular bispecific technology and protein engineering capabilities enable us to rapidly advance multiple drug candidates into clinical development for ourselves and our partners.
+Added: We and our partners are enrolling patients in multiple clinical studies to evaluate our candidates.
+Added: Build and manage a diversified portfolio of XmAb drug candidates.
+Added: We advance multiple XmAb drug candidates into early stages of clinical development and evaluate data from studies in managing our portfolio of candidates.
+Added: Based on the evaluation of emerging data and the competitive environment for such portfolio programs, we make additional investments in those candidates that demonstrate encouraging proof of concept, partner certain drug candidates to third-party biotechnology and pharmaceutical companies, and stop development of some candidates due to emerging data and resource allocation across our pipeline.
+Added: Leverage our protein engineering capabilities, XmAb Fc domains, and XmAb drug candidates with partnerships, collaborations, and licenses to generate revenue streams, create new drug candidates and combination treatments, and identify new indications for our pipeline of drug candidates.
+Added: Generate revenue streams.
+Added: The plug-and-play nature of our Fc technologies and our ability to generate multiple drug candidates efficiently provides us opportunities to generate revenue from licensing and
+Added: collaboration arrangements.
+Added: In 2023, we received total proceeds of $111.7 million in upfront payments, milestone payments and royalties from such arrangements.
+Added: We also received $215.0 million for the sale of a portion of our royalties due to us under our Alexion and MorphoSys agreements, as defined and discussed below.
+Added: Create new XmAb drug candidates and investigate novel combination therapies .
+Added: We seek to leverage our XmAb Fc domains and protein engineering capabilities with partners to create novel XmAb drug candidates, and to evaluate our XmAb drug candidates in combination with other therapeutic agents, when applicable.
+Added: Identify new indications for our pipeline of drug candidates.
+Added: Broaden the functionality of our XmAb Fc technology platforms.
+Added: We are conducting further research into the function and application of antibody Fc domains in order to expand the scope of our XmAb Fc technology platforms.
+Added: We use the modularity of our XmAb bispecific Fc domains to engineer XmAb drug candidates in a variety of structural formats.
+Added: Continue to expand our patent portfolio protecting our Fc technologies and XmAb drug candidates.
+Added: We seek to expand our intellectual property estate and protect our proprietary Fc technologies, our development programs, and XmAb drug candidates by filing and prosecuting patents in the United States and other countries.
+Added: Where appropriate, we will seek expansion and extension of patents issued for our product candidates and for partnered product candidates that incorporate our Fc technologies.
+Added: XmAb Bispecific Fc Domain and New Multi-Specific Antibody Formats
+Added: Our modular approach to protein engineering is a distinguishing feature of our Fc technologies.
+Added: This inherent flexibility enables us to design multiple XmAb drug candidates with distinct and novel mechanisms-of-action and to seek out new applications of the XmAb Bispecific Fc Domain.
+Added: Our business, research, and clinical efforts are to develop and advance our Fc technologies and our portfolio of XmAb drug candidates in oncology and other serious diseases.
+Added: CD3 candidates:
+Added: CD3 T cell engaging bispecific antibodies are designed to redirect T cells to tumor cells through the engagement of an antigen on tumor cells and CD3, an activating receptor on T cells.
+Added: We have significantly expanded the potential of our CD3 T cell engagers with the multi-specific XmAb 2+1 bispecific antibody format, utilizing two identical tumor targeting domains and one CD3 targeting domain.
+Added: The affinities for antigen binding are engineered to enable selective engagement and killing of high antigen-expressing tumor cells over low antigen-expressing normal cells.
+Added: In preclinical models, XmAb 2+1 bispecific antibodies bound preferentially to tumor cells compared to normal cells and effectively recruited T cells to kill tumor cells selectively.
+Added: We believe that these properties will be particularly important when developing bispecific antibodies against many solid tumor targets, where standard monovalent targeting of tumor antigens could lead to poor tolerability because such targets are often expressed on a range of normal tissues, including critical organs.
+Added: Our XmAb819 and XmAb541 CD3 candidates have been designed using our CD3 2+1 format.
+Added: CD28 candidates:
+Added: T cells in the tumor microenvironment require both T cell receptor (TCR) and co-stimulatory receptor engagement to achieve full activation.
+Added: CD28 is a key immune co-stimulatory receptor on T cells;
+Added: however, the ligands that activate T cells through CD28 are often not expressed on tumor cells.
+Added: Targeted CD28 T cell engaging bispecific antibodies may provide conditional co-stimulation of T cells, for example, to T cells recognizing neoantigens or in concert with CD3 T-cell engaging bispecific antibodies.
+Added: Our XmAb808 CD28 candidate has been engineered to provide selective CD28 co-stimulation of T cells, activating them when bound to tumor cells.
+Added: TME activator candidate:
+Added: Our tumor microenvironment (TME) activator candidate, vudalimab, has been designed to promote tumor-selective T-cell activation by targeting multiple checkpoints.
+Added: Vudalimab also incorporates our Xtend™ technology for longer half-life.
+Added: Cytokine candidates:
+Added: Our engineered novel cytokine candidates are fusions of XmAb Bispecific Fc Domains and immune signaling proteins.
+Added: Our cytokine candidates efbalropendekin alfa (XmAb306), XmAb564 and XmAb662 have been designed with reduced potency to improve therapeutic index and with our Xtend technology for longer half-life.
+Added: We continue to invest in our protein engineering efforts to identify novel technologies and drug candidates.
+Added: Other XmAb Fc Domains
+Added: We have also created additional XmAb Fc domains, and we have successfully entered partnerships for these technologies and for XmAb drug candidates that incorporate them.
+Added: We continue to seek additional partnering and licensing opportunities for these Fc domains.
+Added: Additional XmAb Fc domains include:
+Added: Immune Inhibitor Fc Domain – selective immune inhibition and rapid target clearance, targeting the receptor FcγRIIb;
+Added: Cytotoxic Fc Domain – increased cytotoxicity, targeting the receptors FcγRIIIa on natural killer (NK) cells and FcγRIIa on other immune system cells;
+Added: Xtend™ Fc Domain – extended antibody half-life, targeting the receptor FcRn on endothelial cells.
+Added: Approved or Authorized Medicines Engineered with XmAb Fc Domains
+Added: Currently three medicines that have been developed with our XmAb Fc domains are now marketed or made available by our partners.
+Added: These medicines generated $55.8 million in royalty revenue for us in 2023, which has partially offset our internal development costs.
+Added: • Sotrovimab:
+Added: Vir Biotechnology, Inc.
+Added: and its partner GSK have made available sotrovimab, an antibody that targets the SARS-CoV-2 virus, which in May 2021 received an emergency use authorization (EUA) from the United States Food and Drug Administration (FDA) for the early treatment of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct SARS-CoV-2 viral testing, and at high risk for progression to severe COVID-19, including hospitalization or death.
+Added: In March 2022, the FDA deauthorized sotrovimab’s use in all U.S.
+Added: regions due to increases in the proportion of COVID-19 cases caused by the Omicron BA.2 subvariant.
+Added: Sotrovimab has obtained emergency authorization, temporary authorization or marketing approval (under the brand name Xevudy®) for early treatment of COVID-19 in more than 30 countries.
+Added: Sotrovimab incorporates our Xtend Fc domain for longer duration of action.
+Added: Xevudy is a registered trademark of GSK.
+Added: • Ultomiris ® (ravulizumab-cwvz) :
+Added: Alexion’s Ultomiris is approved in the U.S., Europe, and Japan for the treatment of certain patients with paroxysmal nocturnal hemoglobinuria (PNH), certain patients with atypical hemolytic uremic syndrome (aHUS) and certain patients with generalized myasthenia gravis (gMG).
+Added: In May 2023, Ultomiris was approved in the EU and Japan for the treatment of certain adult patients with neuromyelitis optica spectrum disorder (NMOSD).
+Added: Alexion is also evaluating Ultomiris in a broad late-stage development program across additional hematology and neurology indications.
+Added: Alexion used our Xtend™ Fc Domain to enhance the half-life of Ultomiris to allow for a longer duration of action, less frequent dosing and reduced patient burden of therapy compared to the previous generation therapy, Soliris®.
+Added: • Monjuvi ® (tafasitamab-cxix) :
+Added: In 2020, the FDA approved Monjuvi under accelerated approval.
+Added: Monjuvi is a humanized Fc-modified CD19 targeting immunotherapy indicated in combination with lenalidomide for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, including DLBCL arising from low grade lymphoma, and who are not eligible for autologous stem cell transplant (ASCT).
+Added: This indication is approved under accelerated approval based on overall response rate.
+Added: Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
+Added: In August 2021, the European Commission granted conditional marketing authorization for Minjuvi ® (tafasitamab) in combination with lenalidomide, followed by tafasitamab monotherapy, for the treatment of adult patients with relapsed or refractory DLBCL who are not eligible for autologous stem cell transplantation (ASCT).
+Added: In addition to its approved indication, tafasitamab is being evaluated as a therapeutic option in ongoing pivotal trials for first-line DLBCL, relapsed or refractory follicular lymphoma (FL) and relapsed or refractory marginal zone lymphoma (MZL).
+Added: Tafasitamab was created and initially developed by us.
+Added: Tafasitamab is marketed by Incyte under the brand name Monjuvi in the U.S.
+Added: and under the brand name Minjuvi in Europe and Canada.
+Added: Monjuvi ® and Minjuvi ® are registered trademarks of Incyte.
+Added: Drug Candidates in Clinical Development
+Added: There are currently 22 clinical-stage drug candidates or marketed medicines that have been developed with one or more of our XmAb technologies.
+Added: A partner is also advancing a drug candidate that incorporates our DN-TNF technology.
+Added: Wholly Owned Co-developed with Partners Developed by Partners Marketed by Partners
+Added: Vudalimab Plamotamab Obexelimab Ultomiris*
+Added: Teropavimab and zinlirvimab
+Added: Tobevibart (VIR-3434)
+Added: Xaluritamig (AMG 509)
+Added: Efbalropendekin alfa**
+Added: XmAb541 (IND open)
+Added: Novartis antibody
+Added: Xpro1595/INB03
+Added: * Alexion and Incyte are conducting additional Phase 3 studies in new indications with these candidates.
+Added: ** Beginning in June 2024, our collaboration regarding efbalropendekin alfa will convert from a cost and profit-sharing arrangement into a royalty and milestone payment-based arrangement in which Genentech will assume full responsibility for development of the program.
+Added: We are also supporting an investigator sponsored trial evaluating vibecotamab (CD123 x CD3).
+Added: We regularly evaluate our portfolio of candidates and make additional investments in candidates with promising early-stage clinical data, partner out other candidates, and stop development of candidates where early clinical data does not support further investment by us.
+Added: • We initiated a Phase 1b/2 study of vudalimab in combination with chemotherapy, as a first-line treatment in patients with advanced non-small cell lung cancer;
+Added: • We initiated a Phase 1 study for our XmAb662 program;
+Added: • We submitted an investigational new drug (IND) application for our XmAb541 program;
+Added: • We stopped development of the XmAb104 program, and we also closed gynecologic tumor cohorts in the Phase 2 vudalimab monotherapy study due to the rapidly changing competitive environment in these indications;
+Added: • We appointed Nancy Valente, M.D., as our Chief Development Officer, a role in which she is responsible for leading our clinical and medical strategy and execution.
+Added: XmAb Bispecific Antibody Drug Candidates in Clinical Development
+Added: Currently, 10 XmAb bispecific antibody drug candidates are in active clinical development internally or with our partners:
+Added: • Three candidates are wholly owned and are being evaluated by us in Phase 2 or Phase 1 studies;
+Added: one wholly owned candidate has an open IND and is pending Phase 1 study initiation;
+Added: • One candidate is being co-developed with partners;
+Added: • Five additional candidates are being advanced by partners.
+Added: Additional candidates are advancing through the preclinical stages of development.
+Added: XmAb bispecific antibody drug candidates in clinical development include:
+Added: Wholly Owned Development Candidates
+Added: Vudalimab is a bispecific antibody that targets PD-1 and CTLA-4, two immune checkpoint receptors, and is designed to promote tumor-selective T-cell activation.
+Added: Data from a Phase 1 study that enrolled heavily pretreated patients with multiple solid tumor types indicated that vudalimab was generally well-tolerated with encouraging clinical activity.
+Added: We continue to develop vudalimab for patients with metastatic castration-resistant prostate cancer (mCRPC) and patients with locally advanced or metastatic non-small cell lung cancer.
+Added: We are conducting two Phase 2 clinical studies of vudalimab in patients with mCRPC, a study of vudalimab as a monotherapy in the clinically defined high-risk patient population and a study of vudalimab in combination with chemotherapy, in the aggressive variant patient population.
+Added: In the Phase 2 monotherapy study, vudalimab has been generally well tolerated and associated with response to treatment in multiple patients who have visceral or lymph node metastases.We are also conducting a Phase 1b/2 study evaluating vudalimab as a first-line treatment in patients with locally advanced or metastatic non-small cell lung cancer.
+Added: XmAb819 is a first-in-class ENPP3 x CD3 XmAb 2+1 bispecific antibody that we are developing for patients with renal cell carcinoma (RCC).
+Added: The XmAb 2+1 multivalent format enables greater selectivity for ENPP3 expressing tumor cells compared to normal cells, which also express ENPP3 at lower levels.
+Added: We are conducting a Phase 1 study evaluating XmAb819 in patients with advanced clear cell RCC.
+Added: XmAb808 is a tumor-selective, co-stimulatory XmAb 2+1 bispecific antibody designed to bind to the broadly expressed tumor antigen B7-H3, and selectively to the CD28 T-cell co-receptor only when bound to tumor cells, which was demonstrated in in vitro studies.
+Added: In vivo studies further demonstrated strong potentiation of checkpoint and CD3 cytotoxic activity.
+Added: We are conducting a Phase 1 study of XmAb808 in combination with pembrolizumab in patients with advanced solid tumors.
+Added: XmAb541 is a Claudin-6 (CLDN6) x CD3 XmAb 2+1 bispecific antibody that we are developing for patients with ovarian cancer and other solid tumor types.
+Added: The XmAb 2+1 multivalent format enables greater selectivity for CLDN6 over similar Claudin family members, such as CLDN9, CLDN3 and CLDN4.
+Added: The investigational new drug (IND) application for XmAb541 has been allowed to proceed by the FDA, and we plan to initiate a Phase 1 study in the first half of 2024.
+Added: Candidates Co-Developed with Partners
+Added: Plamotamab is a bispecific antibody that targets CD20, an antigen on B-cell tumors, and CD3, an activating receptor on T cells.
+Added: In October 2021, we entered into a global collaboration and license agreement with Janssen Biotech, Inc.
+Added: (Janssen), a Johnson & Johnson company, to advance plamotamab and XmAb CD28 bispecific antibody combinations for the treatment of patients with B-cell malignancies (2021 J&J collaboration).
+Added: J&J received worldwide exclusive development and commercial rights to plamotamab, and we are collaborating with J&J on further clinical development of plamotamab, with us paying 20% of costs.
+Added: We conducted a Phase 1 study of plamotamab in patients with non-Hodgkin's lymphomas.
+Added: Results from the expansion portion of the study indicate that intravenous plamotamab monotherapy was well tolerated and demonstrated encouraging clinical activity in heavily pretreated patients at the recommended Phase 2 intravenous dose.
+Added: In 2023, we completed enrolling patients in subcutaneous dose escalation cohorts of this study.
+Added: Candidates Advanced by Partners
+Added: Xaluritamig (AMG 509) is a STEAP1 x CD3 2+1 bispecific antibody that our partner Amgen is advancing for the treatment of patients with prostate cancer.
+Added: The XmAb 2+1 multivalent format enables higher binding capability for STEAP1 expressing cells.
+Added: Amgen is completing patient enrollment in the dose expansion portion of a Phase 1 study of xaluritamig in patients with mCRPC.
+Added: In October 2023, at the European Society for Medical Oncology (ESMO) Congress, encouraging interim clinical results from the study were presented during an oral proffered paper session, validating the potential of the XmAb 2+1 format.
+Added: Amgen is planning two additional Phase 1 studies of xaluritamig to evaluate preliminary efficacy and safety in patients with early prostate cancer.
+Added: ASP2138 is a Claudin-18.2 x CD3 2+1 bispecific antibody that our partner Astellas is advancing for the treatment of patients with gastric, gastroesophageal and pancreatic cancers and is currently being evaluated in a Phase 1 study.
+Added: The XmAb 2+1 multivalent format enables higher binding capability for Claudin-18.2 expressing cells.
+Added: JNJ-9401 is a PSMA x CD28 bispecific antibody that J&J is advancing for the treatment of patients with prostate cancer and is currently being evaluated in a Phase 1 study.
+Added: JNJ-9401 was developed with J&J under our 2020 collaboration.
+Added: JNJ-1493 is a B-cell x CD28 bispecific antibody that J&J is advancing for the treatment of patients with B-cell malignancies and is currently being evaluated in a Phase 1 study.
+Added: JNJ-1493 was developed with J&J under our 2021 collaboration.
+Added: Novartis XmAb undisclosed antibody candidate.
+Added: Novartis is evaluating an undisclosed antibody drug candidate that was developed with our bispecific Fc technology under our collaboration with them.
+Added: Cytokine Drug Candidates in Clinical Development
+Added: Currently, 3 XmAb cytokine drug candidates are in active clinical development internally or with our partners, which include:
+Added: Efbalropendekin alfa (XmAb306/RG6323) is a potency-reduced IL15/IL15-receptor alpha complex fused to our bispecific Fc domain (IL15/IL15Rα-Fc).
+Added: We are co-developing the program in collaboration with Genentech, a member of the Roche Group.
+Added: Genentech is conducting a Phase 1 study of XmAb306 as a single agent and in combination with atezolizumab in patients with advanced solid tumors and is also conducting Phase 1 studies, evaluating XmAb306 in patients with relapsed/refractory multiple myeloma, either in combination with daratumumab (anti-CD38 antibody) or in combination with cevostamab (FcRH5 x CD3 bispecific antibody).
+Added: In the fourth quarter of 2023, we agreed with Genentech to convert our current development cost and profit-sharing arrangement into a royalty and milestone payment-based arrangement.
+Added: Pursuant to the terms of the amended agreement with Genentech, effective June 1, 2024, Genentech will assume sole responsibility over all clinical, regulatory and commercial activities.
+Added: Under the amended agreement, we will be eligible for up to $600 million in milestones and tiered royalties on approved products ranging from low double-digit to mid-teens percentages.
+Added: XmAb564 is a monovalent, potency-reduced interleukin-2 Fc (IL-2-Fc) fusion protein, engineered to selectively activate and expand regulatory T cells (Tregs) for the potential treatment of patients with autoimmune diseases.
+Added: XmAb564 is engineered with reduced binding affinity for IL-2's beta receptor and increased binding affinity for its alpha receptor.
+Added: In a Phase 1a clinical study of XmAb564, a single dose of XmAb564, administered subcutaneously in healthy volunteers, was well tolerated and generated durable, dose-dependent and selective expansion of Tregs.
+Added: We have been conducting a randomized, double-blind, placebo-controlled Phase 1b clinical study to evaluate the safety and tolerability of multiple ascending doses of XmAb564, administered subcutaneously in patients with atopic dermatitis or psoriasis.
+Added: We plan to conclude the Phase 1b study in the first half of 2024 and pause further development of XmAb564 until after assessment of future data from competitor programs in this class and review of safety and biomarker data in the Phase 1b study.
+Added: XmAb662 is a potency-reduced interleukin-12 Fc (IL12-Fc) fusion protein engineered to increase anti-tumor activity and immunogenicity in the tumor microenvironment by promoting high levels of interferon gamma secretion from T cells and NK cells.
+Added: In preclinical testing, our engineered IL12-Fc fusions demonstrated an improved pharmacokinetic profile and therapeutic window compared to a native IL12-Fc fusion, with superior exposure, a more gradual dose response and more sustained interferon gamma response.
+Added: XmAb662 demonstrated significant anti-tumor activity, along with increases in NK cells, T cells, serum IP-10 and interferon gamma, which were further enhanced when combined with an anti-PD-1 antibody.
+Added: We have been conducting a Phase 1 study to evaluate XmAb662 in patients with advanced solid tumors.
+Added: We plan to conclude the Phase 1 study in the first half of 2024 and pause further development of XmAb662 until after assessment of future data from competitor programs in this class and review of safety and biomarker data in the Phase 1 study.
+Added: Xtend and Cytotoxic Fc Drug Candidates in Clinical Development
+Added: Currently, two drugs engineered with our Xtend Fc Domain and one drug we engineered with our XmAb Cytotoxic Fc Domain are marketed commercially by partners.
+Added: In addition to these approved drugs, our partners are
+Added: advancing multiple clinical-stage programs with antibodies engineered with Xtend and/or Cytotoxic Fc Domains, including:
+Added: • Vir Biotechnology, Inc.:
+Added: Vir is advancing tobevibart (VIR-3434) in a Phase 2 combination study as a potential treatment for patients with hepatitis B virus infection and in a Phase 2 combination study as a potential treatment for patients with hepatitis Delta virus infection;
+Added: • Gilead Sciences, Inc.:
+Added: Gilead is advancing teropavimab and zinlirvimab, two broadly neutralizing antibodies, in combination with lenacapavir, as a long-acting treatment for virologically suppressed people living with HIV;
+Added: • Omeros Corporation:
+Added: Omeros is advancing multiple Phase 2 studies evaluating OMS906 for the treatment of patients with PNH and other alternative pathway disorders;
+Added: • Our partners are conducting preclinical studies of additional drug candidates engineered with these XmAb Fc domains.
+Added: Other Clinical Stage Drug Candidates
+Added: • Obexelimab targets CD19 with its variable domain and uses our XmAb Immune Inhibitor Fc Domain, which is designed to inhibit the function of B cells, an important component of the immune system.
+Added: In November 2021, we licensed this drug candidate to Zenas BioPharma, which is conducting a Phase 3 study in patients with immunoglobulin G4-related disease (IgG4-RD) and a Phase 2 study in patients with warm autoimmune hemolytic anemia (wAIHA).
+Added: • AIMab7195 (XmAb7195) uses our XmAb Immune Inhibitor Fc Domain and is designed to reduce blood levels of IgE, which mediates allergic responses and allergic disease.
+Added: In February 2020, we licensed this drug candidate to Aimmune Therapeutics, Inc., now a wholly owned subsidiary of Nestlé S.A., which is evaluating the candidate in clinical studies for allergic indications.
+Added: • Xpro1595 is a proprietary TNF inhibitor candidate which we licensed to INmune Bio, Inc., in October 2017.
+Added: INmune is currently advancing Xpro1595 through clinical development for patients with Alzheimer’s disease and treatment-resistant depression.
+Added: Collaborations, Partnerships and Licensing Arrangements
+Added: A key part of our business strategy is to leverage our protein engineering capabilities, XmAb technologies, and XmAb drug candidates with partnerships, collaborations, and licenses.
+Added: Through these arrangements we generate revenues in the form of upfront payments, milestone payments, and royalties.
+Added: For partnerships for our drug candidates, we aim to retain a major economic interest in these candidates through transactions that allow us to retain major geographic commercial rights, provide for profit-sharing on future sales of approved products, include co-development options, and also the right to conduct independent clinical studies with drug candidates developed in the collaboration.
+Added: Examples of arrangements we have entered with our partners include:
+Added: • Product Licenses:
+Added: Johnson & Johnson, Genentech, Incyte Corporation, Nestlé S.A., Zenas BioPharma, Inc., INmune Bio, Inc.
+Added: • Novel Bispecific Antibody Collaborations:
+Added: Johnson & Johnson, Astellas Pharma Inc., Amgen Inc., Novartis AG
+Added: • Technology Licensing Agreements:
+Added: Alexion Pharmaceuticals, Inc., Vir Biotechnology, Inc., Gilead Sciences, Inc., Omeros Corporation, Astria Therapeutics, Inc.
+Added: • Strategic Collaborations:
+Added: Caris Life Sciences
+Added: Product Licenses
+Added: Product licenses are arrangements in which we license to third parties partial or full rights to develop and commercialize our internally developed drug candidates.
+Added: We seek partners that can provide infrastructure and resources to successfully develop our drug candidates, have a track record of successfully developing and commercializing medicines, or have a portfolio of development-stage candidates and commercialized medicines which could potentially be developed in rational combinations with our drug candidates.
+Added: Janssen Biotech, Inc., a Johnson & Johnson company
+Added: In October 2021, we entered into an agreement with Janssen Biotech, Inc., a Johnson & Johnson company, to develop, manufacture, and commercialize plamotamab and to conduct research and development activities to discover novel CD28 bispecific antibodies against undisclosed B cell tumor targets.
+Added: J&J will receive exclusive worldwide rights, subject to certain of our opt-in rights, to develop, manufacture and commercialize pharmaceutical products that contain one or more of such CD28 bispecific antibodies.
+Added: Pursuant to the agreement, we are collaborating with J&J on further clinical development of plamotamab with J&J paying 80% and the Company paying 20% of costs.
+Added: With respect to the CD28 bispecific antibody collaboration, we are generally responsible for conducting research activities, and J&J is generally responsible for all development, manufacturing, and commercialization activities for CD28 bispecific antibodies that are advanced.
+Added: In the first quarter of 2023, J&J selected a CD28 candidate that we developed under the collaboration for further development.
+Added: In the third quarter of 2023, J&J exercised its option on two additional CD28 candidates that were developed under the agreement.
+Added: In the fourth quarter of 2023, J&J initiated a Phase 1 study with a CD28 candidate that was developed under the agreement.
+Added: In 2023, we received $30.0 million of milestones related to the CD28 collaboration, and we are eligible to receive additional milestone payments up to a total of $640.0 million, which include an aggregate of $139.4 million in development milestones and $240.6 million in regulatory milestones.
+Added: For any CD28 bispecific antibodies approved, we are eligible to receive $260.0 million in sales milestones and tiered royalties in the high-single to low-double digit range on net sales.
+Added: In February 2019, we entered into an agreement with Genentech to develop and commercialize novel IL-15 cytokine therapeutics that use our bispecific Fc technology, including efbalropendekin alfa (XmAb306), declared as a Collaboration Product under the agreement.
+Added: Under the current agreement, we are sharing in 45% of development and commercialization costs of Collaboration Products, and we are eligible to share in 45% of net profits and losses from the sale of approved products.
+Added: However, in the fourth quarter of 2023, we agreed with Genentech to convert our current development cost and profit-sharing arrangement into a royalty and milestone payment-based arrangement.
+Added: Pursuant to the terms of the amended agreement with Genentech, effective June 1, 2024, Genentech will assume sole responsibility over all clinical, regulatory and commercial activities.
+Added: Under the amended agreement, we are eligible to receive up to $600.0 million in milestones, including $115.0 million in development milestones, $185.0 million in regulatory milestones and $300.0 million in sales-based milestones and tiered royalties ranging from low double-digit to mid-teens percentages.
+Added: Incyte Corporation
+Added: In July 2020, the FDA approved Monjuvi® (tafasitamab-cxix) in combination with lenalidomide for treating certain patients with DLBCL, and the European Commission granted conditional marketing authorization to tafasitamab for treating certain patients with DLBCL, which is marketed as Minjuvi® in Europe, in August 2021.
+Added: In 2010, we licensed exclusive worldwide rights to develop and commercialize tafasitamab (formerly MOR208 and XmAb5574) to MorphoSys AG.
+Added: In February 2024, Incyte acquired exclusive global development and commercialization rights to tafasitamab.
+Added: Tafasitamab, which we engineered with an XmAb Cytotoxic Fc Domain, is the second XmAb medicine to be approved by the FDA.
+Added: In 2023, we earned royalties of $8.7 million on net sales.
+Added: We are also eligible to receive up to $85.5 million in additional milestones for development of tafasitamab in additional oncology indications and $50.0 million in sales milestones across all indications.
+Added: We are entitled to receive tiered royalties in the high-single digit to low-double digit percent range on net sales.
+Added: Tafasitamab is marketed by Incyte under the brand name Monjuvi® in the U.S.
+Added: and is marketed under the brand name Minjuvi® in Europe and Canada.
+Added: In 2023, we sold a portion of the royalties due to us under the MorphoSys agreement for $22.5 million.
+Added: Nestlé S.A./Aimmune Therapeutics, Inc.
+Added: In February 2020, we granted Aimmune Therapeutics, Inc., an exclusive worldwide license to develop and commercialize XmAb7195, which was renamed AIMab7195.
+Added: Aimmune was subsequently acquired by Nestlé S.A.
+Added: received an upfront payment, and we are eligible to receive development, regulatory and sales milestones and tiered royalties in the high-single to mid-teen percent range on net sales of approved products.
+Added: Nestlé is responsible for all further development of AIMab7195.
+Added: INmune Bio, Inc.
+Added: In October 2017, we entered into an agreement with INmune Bio, Inc., for an exclusive license to our Xpro1595 drug candidate.
+Added: In connection with the license, we received shares of INmune common stock.
+Added: We are also eligible to receive a percentage of sublicensing revenue received for Xpro1595 and royalties in the mid-single digit percentage range on the sale of approved products.
+Added: INmune is currently conducting Phase 2 studies in early Alzheimer’s disease and treatment resistant depression.
+Added: Zenas BioPharma, Inc.
+Added: In November 2020, we entered into an agreement with Zenas BioPharma (Cayman) Limited, now Zenas BioPharma, Inc., (Zenas) to which we licensed the exclusive worldwide rights to develop and commercialize three preclinical-stage Fc-engineered drug candidates for autoimmune disease:
+Added: XmAb6755 (ZB002), XPro9523 (ZB004), and XmAb10171 (ZB003).
+Added: These programs incorporate an Xtend Fc Domain, a Cytotoxic Fc Domain, or both.
+Added: We received an equity interest in Zenas, and we will also receive royalties on net sales of approved products in the mid-single digit to mid-teen percentage range.
+Added: In November 2021, we entered into a second agreement with Zenas to which we licensed the exclusive worldwide rights to develop and commercialize obexelimab, a bifunctional antibody that targets CD19 with its variable domain and uses our XmAb Immune Inhibitor Fc Domain.
+Added: Zenas issued a warrant giving us the right to acquire additional Zenas equity, such that our total equity in Zenas would be 15% of its fully diluted capitalization following the closing of Zenas’ next round of equity financing, subject to certain requirements.
+Added: In 2022, Zenas completed a financing transaction, and we received additional shares in Zenas in exchange for the warrant such that our total ownership is equal to 15% of the fully diluted outstanding shares of Zenas.
+Added: We are eligible to receive up to $470.0 million based on the achievement of certain clinical development, regulatory and commercialization milestones and are eligible to receive tiered, mid-single digit to mid-teen percent royalties upon commercialization of obexelimab, dependent on geography.
+Added: Zenas will have sole responsibility for advancing the research, development, regulatory and commercial activities of obexelimab worldwide.
+Added: In 2023, Zenas initiated a Phase 3 study in patients with immunoglobulin G4-related disease (IgG4-RD) and a Phase 2 study in patients with warm autoimmune hemolytic anemia (wAIHA), and we received a milestone payment in additional equity in Zenas with a fair value of $10.0 million.
+Added: Novel Bispecific Antibody Collaborations
+Added: Novel bispecific antibody collaborations are arrangements in which our partner seeks to create an XmAb bispecific antibody using one or more of our bispecific technologies.
+Added: Our partners provide an antibody or an antigen against tumors, and we conduct limited research and development activities to create potential bispecific antibody candidates for further development and commercialization by our partners.
+Added: Janssen Biotech, Inc., a Johnson & Johnson company
+Added: In November 2020, we entered into an agreement, with J&J to develop XmAb bispecific antibodies against CD28 and a prostate tumor target, for the potential treatment of patients with prostate cancer.
+Added: Under the agreement, we conducted research activities to develop CD28 bispecific drug candidates for further development by J&J.
+Added: Upon development of a bispecific candidate by J&J through proof of concept, the agreement provides us the right to opt-in to fund 20% of development costs and to perform up to 30% of detailing efforts in the U.S.
+Added: If we exercise this right, we will be eligible to receive tiered royalties in the low-double digit to mid-teen digit percentage range.
+Added: We, along with J&J, have the right to access predefined agents from each other’s portfolios to evaluate potential combination therapies in prostate cancer, subject to certain limitations.
+Added: In 2021, J&J selected JNJ-9401, a PSMA x CD28 bispecific antibody developed under the agreement, for further development, and we received a milestone payment.
+Added: In 2023, J&J submitted an IND and initiated a clinical trial, and we
+Added: received another milestone payment.
+Added: J&J is conducting a Phase 1 study evaluating JNJ-9401 in patients with mCRPC.
+Added: In 2023, we received $17.5 million in milestones under the agreement, and we are eligible to receive an additional $139.4 million in development milestones in addition to tiered royalties on approved products ranging from high-single to low-double digit range as the program advances.
+Added: Astellas Pharma Inc.
+Added: In March 2019, we entered into an agreement with Astellas Pharma Inc., under which we applied our XmAb bispecific Fc technology to an antigen pair provided by Astellas and generated bispecific antibody candidates for further certain characterization and testing.
+Added: Astellas was granted a worldwide exclusive license, with the right to sublicense products in the field created by the research activities.
+Added: Astellas selected ASP2138, a CLDN18.2 x CD3 XmAb 2+1 bispecific antibody developed under the collaboration, for further development and is conducting a Phase 1 study of ASP2138 in patients with gastric, gastroesophageal, and pancreatic cancers.
+Added: We are eligible to receive an additional $232.5 million in milestones which include, $25.0 million in development milestones, $57.5 million in regulatory milestones and $150.0 million in sales milestones and tiered royalties from the high-single to low-double digit range as the program advances.
+Added: In September 2015, we entered into an agreement with Amgen Inc.
+Added: to develop and commercialize bispecific antibody product candidates using our proprietary XmAb bispecific Fc technology.
+Added: Amgen applied our XmAb bispecific Fc technology to create xaluritamig (AMG 509), a STEAP1 x CD3 XmAb 2+1 bispecific antibody.
+Added: We have received a total of $60.5 million in upfront and milestone payments and are eligible to receive up to $255.0 million in future development, regulatory and sales milestone payments in total for xaluritamig and tiered royalties in the mid-to-high single digit percentage range on the sale of approved products.
+Added: Amgen is currently completing enrollment in a Phase 1 study of xaluritamig in patients with mCRPC.
+Added: In October 2023 at the European Society for Medical Oncology (ESMO) Congress, encouraging interim clinical results from the study were presented during an oral proffered paper session, which we believe validates the potential of the XmAb 2+1 format.
+Added: Amgen is planning two additional Phase 1 studies of xaluritamig to evaluate preliminary efficacy and safety in patients with early prostate cancer.
+Added: In connection with our June 2016 agreement with Novartis, we applied our XmAb bispecific Fc technology to a target pair antibody selected by Novartis.
+Added: Novartis is responsible for development and commercialization of the program.
+Added: We are eligible to receive development, regulatory and sales milestone payments and royalties in the mid-single digit percent range on net sales of approved products.
+Added: Novartis is evaluating an undisclosed XmAb bispecific antibody candidate.
+Added: Technology Licensing Agreements
+Added: We enter into technology licensing agreements in which we license access to one or more of our XmAb Fc technologies on a restricted basis, typically to our XmAb Cytotoxic Fc Domain and/or our Xtend Fc Domain.
+Added: Our partners are responsible for all research, development and commercialization activities of the drug candidates.
+Added: The plug-and-play nature of XmAb Fc domains allows us to license access to our platforms with no internal research and development activities required of us.
+Added: Alexion Pharmaceuticals, Inc.
+Added: Ultomiris® (ravulizumab-cwvz) was the first antibody incorporating XmAb Fc technology to be approved by the FDA for commercial marketing.
+Added: It is approved in the U.S.
+Added: and multiple global markets for the treatment of certain patients with paroxysmal nocturnal hemoglobinuria (PNH), certain patients with atypical hemolytic uremic syndrome (aHUS) and certain patients with generalized myasthenia gravis (gMG).
+Added: It is approved in the EU and Japan for the treatment of certain
+Added: adult patients with neuromyelitis optica spectrum disorder (NMOSD).
+Added: Ultomiris is commercialized by Alexion Pharmaceuticals, Inc.
+Added: In 2013, we licensed Alexion the right to access our Xtend Fc domain, which Alexion used to develop an improved version of Alexion’s commercialized Soliris product.
+Added: The Xtend technology increased the circulating half-life of Ultomiris by over three-fold compared to Soliris and extended the dosing schedule to bimonthly for Ultomiris compared to biweekly for Soliris.
+Added: We are eligible to receive a low-single digit percent royalty on the sale of approved products.
+Added: During 2023, we recorded royalty revenue of $44.9 million and a $20.0 million sales milestone.
+Added: In the fourth quarter of 2023, we sold a portion of the royalties due us under the Alexion agreement for $192.5 million.
+Added: Vir Biotechnology, Inc.
+Added: In March 2020, we entered into an agreement in which we provided Vir a non-exclusive license to our Xtend technology to extend the half-life of novel antibodies, including sotrovimab, that Vir has investigated as potential treatments for patients with COVID-19.
+Added: Vir, along with alliance partner GSK, is responsible for all research, development, regulatory and commercial activities for COVID-19 antibodies, and we are eligible to receive royalties on the net sales of approved products in the mid-single digit percentage range.
+Added: During 2023, we recorded royalty revenue of $2.2 million.
+Added: In August 2019, we entered into an agreement with Vir Biotechnology, Inc., in which we provided Vir a non-exclusive license to our Xtend technology for two targets in infectious disease.
+Added: Tobevibart (VIR-3434) is being evaluated in a Phase 2 combination study as a potential treatment for patients with hepatitis B virus infection and in a Phase 2 combination study as a potential treatment for patients with hepatitis Delta virus infection.
+Added: Gilead Sciences, Inc.
+Added: In January 2020, we entered into an agreement with Gilead Sciences, Inc., in which we provided Gilead an exclusive license to our Cytotoxic Fc and Xtend Fc technologies for broadly neutralizing anti-HIV antibodies.
+Added: Gilead is responsible for all development and commercialization activities.
+Added: For each licensed antibody, we are eligible to receive up to $67.0 million in milestones, which includes $10.0 million in development milestones, $27.0 million in regulatory milestones, and $30.0 million in sales milestones.
+Added: We are also eligible to receive royalties in the low-single digit percentage range on net sales of approved products.
+Added: In 2023, Gilead initiated a Phase 2 study including two antibody candidates developed with our Fc technologies, teropavimab and zinlirvimab, and we received $6.0 million in milestone payments.
+Added: Omeros Corporation
+Added: In August 2020, we entered into an agreement with Omeros Corporation, in which we provided Omeros a non-exclusive license to our Xtend Fc technology, an exclusive license to apply our Xtend Fc technology to an initial identified antibody, OMS906, and options to apply our Xtend Fc technology to three additional antibodies.
+Added: Omeros is responsible for all development and commercialization activities.
+Added: In 2023, Omeros initiated a Phase 2 study of OMS906, a MASP-3 targeted antibody, in patients with PNH, and we received a $5.0 million milestone.
+Added: We are eligible to receive up to an additional $60.0 million in development, regulatory and sales milestones and royalties in the mid-single digit percentage range on net sales of approved products.
+Added: Astria Therapeutics, Inc.
+Added: In May 2018, we entered into an agreement with Astria Therapeutics, Inc (formerly Quellis Biosciences, Inc.), in which we provided Astria a non-exclusive license to our Xtend Fc technology to apply to an identified antibody.
+Added: Astria is responsible for all development and commercialization activities.
+Added: Our upfront payment included common stock in Astria.
+Added: In addition to equity shares in Astria, we are eligible to receive development, regulatory and sales milestones and we are also eligible to receive royalties in the mid-single digit percentage range on net sales of approved products.
+Added: Strategic Collaborations
+Added: We enter into strategic collaborations where we can create synergies between our partners’ capabilities and assets and our own protein engineering capabilities, Fc technologies and XmAb drug candidates.
+Added: Through these arrangements we seek to create new drug candidates, investigate novel combination therapies and potentially identify additional indications for our portfolio of XmAb drug candidates.
+Added: Caris Life Sciences
+Added: In July 2022, we entered into a research discovery agreement with Caris Life Sciences (Caris).
+Added: We received exclusive options to research, develop and commercialize products directed up to three targets.
+Added: Caris received an upfront payment and will be eligible to receive licensing fees, discovery, development, regulatory and sales-based milestones and royalty payments on net sales of each product commercialized by us and future rights for molecular profiling and companion diagnostics for drug candidates developed under the collaboration.
+Added: In December 2022, we expanded our Caris collaboration with a second agreement.
+Added: We paid Caris an upfront payment and Caris is eligible for additional licensing fees, milestones and royalty payments on net sales of each product commercialized by us.
+Added: Technology License Agreement and Service Agreement with Gale Therapeutics Inc.
+Added: In the fourth quarter of 2023, we formed a subsidiary, Gale Therapeutics Inc.
+Added: (Gale), to develop novel drug candidates that incorporate our XmAb technologies.
+Added: In December 2023, we entered into a Technology License Agreement (Gale License Agreement) with Gale, in which Gale received an exclusive worldwide, royalty-bearing, non-transferable license to preclinical assets in exchange for royalties on future sales and an option on future drug candidates that Gale will develop.
+Added: Concurrently, we entered into a Services Agreement (Gale Services Agreement) to provide research and development services and administrative support to Gale.
+Added: In exchange for $7.5 million of funding, we acquired a majority stake in Gale.
Our Research and Development Pipeline
−Removed: We have used our various Fc platforms and antibody optimization capabilities to produce a growing pipeline of development candidates.
−Removed: These include new XmAb Immune Inhibitor Fc Domain candidates designed to remove target antigens from circulation and multiple oncology candidates using our CD3 bispecifics platform.
−Removed: We will continue to progress these candidates as additional options for clinical development by us or as out ‑licensing opportunities to generate additional revenue.
−Removed: Bispecific Antibodies for Oncology
−Removed: We have created Fc variants that form heterodimeric Fc domains that enable the creation of bispecific antibodies that have different Fv domains on each side of the Fc domain in order to bind to a different antigen with each of their Fv domains.
−Removed: We have focused our initial bispecific candidate discovery work on building a pipeline of bispecific antibodies that bind both CD3 and a tumor antigen in order to recruit cytotoxic T cells to the tumor cell.
−Removed: Because of the Fc domain, these bispecific antibodies retain the long half-life and ease of production typical of standard antibodies.
−Removed: Our lead bispecific programs are tumor-targeted antibodies that contain both a tumor antigen binding domain (CD123, CD20, or CD38) and a cytotoxic T-cell binding domain (CD3).
−Removed: In November 2014 , we announced preclinical data from these three lead programs showing that each activated T-cells to rapidly kill target cells from a tolerated single dose IV bolus in cynomolgus monkeys and demonstrated prolonged half-life of approximately one week in mice.
−Removed: Data released included the following:
−Removed: XmAb Anti-CD123 x Anti-CD3 Bispecific Antibodies in Acute Myleogenous Leukemia
−Removed: Depletion of over 99% of circulating CD123+ cells in monkeys for over a week
−Removed: Bone marrow CD123+ cells were depleted by over 95% at all doses in monkeys
−Removed: Prolonged serum half-life in mice of 6.2 days
−Removed: XmAb Anti-CD20 ×
−Removed: Anti-CD3 Bispecific Antibodies in B-cell Lymphomas and Leukemia
−Removed: Depletion of over 97% of circulating B cells in monkeys for over a week
−Removed: B cells in the more resistant lymph nodes and bone marrow were depleted by over 90% at all doses in monkeys
−Removed: Prolonged serum half-life in mice up to 6.7 days
−Removed: Anti-CD38 ×
−Removed: Anti-CD3 Bispecific Antibodies in Multiple Myeloma
−Removed: Depleted circulating CD38+ cells by greater than 95%
−Removed: Prolonged half-life in mice up to 8 days
−Removed: Applying the rapid clearance property of the Immune Inhibitor Fc Domain
−Removed: We are exploring multiple new candidate concepts for application of our Immune Inhibitor Fc Domain, in particular capitalizing on the newly discovered rapid clearance property, which builds off the natural scavenging role of FcγRIIb on liver sinusoidal endothelial cells , a type of cell in the blood vessels of the liver that filters antigens out of the circulation .
−Removed: For example, building on our lead anti ‑IgE product candidate, XmAb7195, we are now characterizing a second ‑generation antibody with a modified version of the IIb immune inhibitor domain.
−Removed: The new Fc domain has intermediate affinity enhancement for FcγRIIb, which we have discovered promotes IgE control in mouse models with a longer dosing interval than XmAb7195.
−Removed: We are also exploring approaches to clear pathologic immune complexes from circulation.
−Removed: Antibody-antigen complexes are central to the kidney pathology in lupus nephritis and a variety of other conditions and form when antigens present in the circulation are recognized by antibodies of the immune system.
−Removed: Second Generation Biologics
−Removed: Our Xtend Fc Domain technology can potentially improve the performance of commercially successful therapeutic antibodies by enhancing their half ‑life and improving dosing convenience.
−Removed: We have produced several enhanced versions of antibodies, in some cases by applying the Xtend Fc Domain mutations, and in other cases also modifying other features.
−Removed: AbbVie’s Humira (adalimumab) is the industry ‑leading anti ‑TNF antibody for the treatment of rheumatoid arthritis, reaching global sales above $5 billion.
−Removed: We have produced and characterized a half ‑life enhanced version of Humira that we call Xtend ‑ TNF (also known as XmAb 6755).
−Removed: It has approximately twice the in vivo half ‑life of Humira, which is dosed on a biweekly schedule, and we believe Xtend ‑TNF has the potential to achieve monthly dosing in rheumatoid arthritis patients without loss of efficacy.
−Removed: A stable cell line has been created and we have a business relationship with Boehringer Ingelheim to manufacture Xtend ‑TNF drug supply for preclinical toxicology and clinical studies.
−Removed: Collaboration Agreements and Technology Licenses
−Removed: We use product development partnerships with pharmaceutical and biotechnology companies to complement our internal drug discovery and development capabilities, to assist the efficient global commercialization of our products
−Removed: and technology and to generate near and long ‑term funding.
−Removed: To date, the revenue generated from upfront fees, license fees, option fees and milestone payments associated with these arrangements, combined with the development expenses assumed by our partners, have allowed us to better manage our operating expenses and continue to invest in building new opportunities.
−Removed: Below is a table summarizing all of our technology licenses:
−Removed: Boehringer Ingelheim
−Removed: Phase 1 trials
−Removed: (two candidates)
−Removed: Autoimmune disease
−Removed: Hematological diseases
−Removed: Fc optimization
−Removed: Autoimmune disease
−Removed: Various, including Bi-specifics
−Removed: Collaboration Agreement with Novo Nordisk A/S
−Removed: In December 2014 we entered into a collaboration and licensing agreement with Novo Nordisk A/S (Novo) to jointly discover novel biologic drug candidates for an undisclosed target by combining multiple Xencor XmAb®
−Removed: technologies, including bispecific and immune inhibitor technologies.
−Removed: Under the terms of the agreement, we granted Novo a license to use and access these technologies over the research term that is initially a two year period.
−Removed: We will also provide research support in collaboration with Novo to the agreed upon research plan to discover potential drug candidates.
−Removed: Novo will have an exclusive right to develop and commercialize any candidates that are identified during the research discovery period.
−Removed: Xencor and Novo will use Xencor's XmAb®
−Removed: technologies, including our bispecific technology to build a variety of molecular formats that can engage the target and also modulate desired immune functions using Xencor's XmAb immune inhibitor technology.
−Removed: XmAb immune inhibitor Fc domains target FcγRIIb (also known as CD32b ).
−Removed: In addition to its proprietary technologies, Xencor will also contribute expertise in studying immune functions of biologics and immune system modulation.
−Removed: Novo will collaborate by using its proprietary technology during the research discovery period and will have all development and commercial rights.
−Removed: Under the terms of the agreement , in January 2015, we received an upfront payment of $2.5 million and will receive funded research support of $1.6 million per year for each year of the research term, which initially is two years.
−Removed: Novo has an option to extend the research term to a third year by providing written notice and payment of another year of research funding.
−Removed: If certain pre-established discovery milestones are achieved during the research term, we are eligible to receive $2.0 million in milestone payments.
−Removed: Upon completion of the research term, Novo will have development and commercial rights to any compounds identified.
−Removed: If certain developmental, regulatory and sales milestones are achieved by Novo in developing the compound, we are eligible to receive up to an additional $167.3 million in milestone payments for a product developed.
−Removed: The $167.3 million in milestone payments is comprised as follows:
−Removed: $36.3 million relates to clinical development milestone events, $51.0 million relates to the filing and completion of regulatory approvals and an additional $80.0 million of aggregate milestone payments relate to the achievement of certain product sale goals.
−Removed: If licensed products are commercialized, we are also entitled to receive royalties in the mid-single digits based on net sales of products sold by Novo, its affiliates and its sublicenses in a calendar year.
−Removed: Novo’s royalty obligations continue on a licensed product-by-product and country-by-country basis until the later to occur of the expiration of the last valid claim in a patent covering a product in such country, or 10 years after the date of the first commercial sale of such product in such country.
−Removed: The term of this agreement will continue until the earlier of expiration of all royalty payment obligations under the agreement or, upon completion of the research term if Novo does not identify a compound for continued
−Removed: The agreement provides that it may be terminated by either party upon written notice to the other party in the event of the other party’s bankruptcy or insolvency, or the other party’s material breach of the agreement if such breach remains uncured for 90 days, or 20 days for any non-payment breach.
−Removed: Novo may terminate this agreement at any time following the expiration of the research term for any reason upon delivery of at least 90 days’
−Removed: prior written notice to us.
−Removed: Upon such termination, all licenses granted by us to Novo shall terminate.
−Removed: Collaboration and Option Agreement with Amgen
−Removed: In December 2010, we entered into a collaboration and option agreement with Amgen Inc.
−Removed: (Amgen) pursuant to which we agreed to collaborate with Amgen to research, develop and commercialize XmAb5871, an Fc-engineered monoclonal antibody that targets CD19 via its Fv domains and Fc 
−Removed: RIIb via its XmAb Fc domain, and products based thereon.
−Removed: Under the terms of the agreement, we granted to Amgen an option to obtain an exclusive license to research, develop, manufacture and commercialize XmAb5871 and certain related products worldwide .
−Removed: Under the terms of the agreement, we received an initial upfront payment of $11.0 mi llion and a $2.0 million milestone payment upon the initiation of our Phase 1b/2a clinical trial of XmAb5871 in January 2013 in patients with moderate to severe rheumatoid arthritis.
−Removed: In October 2014, we announced that we sought and regained all rights to XmAb5871from Amgen.
−Removed: In return for terminating the collaboration and option agreement, we granted Amgen a first right to negotiate a proposed license for XmAb5871 prior to seeking future partners.
−Removed: This right expires upon the earlier of the initiation of Phase 3 clinical testing of XmAb5871, a change of control of Xencor, or October 2019.
−Removed: Collaboration and License Agreement with MorphoSys AG
−Removed: In June 2010, we entered into a collaboration and license agreement with MorphoSys AG (MorphoSys) which we subsequently amended in March 2012.
−Removed: We granted to MorphoSys an exclusive worldwide license under certain of our patents and know ‑how to research, develop and commercialize XmAb5574/MOR208, as well as other anti ‑CD19 antibodies that incorporate our cytotoxic Fc domain technology, with the right to sublicense under certain conditions.
−Removed: Under the terms of the agreement, we agreed to collaborate with MorphoSys to develop and commercialize XmAb5574/MOR208, a high potency cytotoxic monoclonal antibody developed by us for the treatment of B ‑cell malignancies and other diseases.
−Removed: Under the terms of the agreement, we initiated and sponsored a Phase 1 clinical trial for XmAb5574/MOR208 in patients with chronic lymphocytic leukemia in December 2010 which was completed in January 2013.
−Removed: Following such completion, MorphoSys is responsible for all further clinical development and commercialization of licensed antibodies and licensed products under the agreement and is required to use commercially reasonable efforts to achieve certain developmental and regulatory milestones and other diligence obligations under the agreement.
−Removed: In addition, MorphoSys is responsible for all costs relating to the development and commercialization of XmAb5574/MOR208, or other antibodies covered by the agreement, including manufacturing, regulatory, clinical and registration costs.
−Removed: Under the terms of the agreement, we received an upfront payment of $13.0 million and received $3.0 million for development milestones in 2013.
−Removed: If certain developmental, regulatory and sales milestones are achieved, we are also eligible to receive up to an additional $299.0 million in milestone payments.
−Removed: The $299.0 million of milestone payments is comprised as follows:
−Removed: $62.0 million relates to clinical development milestone events, $187.0 million relates to the filing and completion of regulatory approvals and an additional $50.0 million of aggregate milestone payments relate to the achievement of certain product sale goals.
−Removed: If licensed products are commercialized, we are also entitled to receive tiered royalties in the high single ‑digit to low ‑teen percent range based upon net sales of products sold by MorphoSys, its affiliates and its sublicensees in a calendar year.
−Removed: MorphoSys’
−Removed: royalty obligations continue on a licensed product ‑by ‑licensed product and country ‑by ‑country basis until the later to occur of the expiration of the last valid claim in the licensed patent covering a licensed product in such country, or 11 years after the first sale of a licensed product following marketing authorization in such country.
−Removed: The term of this agreement will continue until all of MorphoSys’
−Removed: royalty payment obligations have expired unless terminated earlier.
−Removed: The agreement provides that it may be terminated by either party upon written notice to the other party in the event of the other party’s insolvency or the other party’s material breach of the agreement if such breach remains uncured for 120 days, or 30 days in the case of a non ‑payment breach.
−Removed: MorphoSys may terminate the agreement without cause upon 90 days’
−Removed: advance written notice to us.
−Removed: In the event that MorphoSys terminates this
−Removed: agreement for convenience or we terminate due to MorphoSys’
−Removed: material breach, worldwide rights to develop, manufacture and commercialize XmAb5574/MOR208, as well as any other antibodies covered by the agreement, revert back to us completely.
−Removed: Along with these rights, MorphoSys is obligated to transfer all regulatory documents, clinical data and know how, and we are granted a license from MorphoSys to allow us to develop, manufacture and commercialize XmAb5574/MOR208, or other antibodies covered by the agreement, worldwide, subject to reimbursing MorphoSys a portion of their development costs out of future revenue generated from the development and commercialization of XmAb5574/MOR208.
−Removed: Option and License Agreement with Alexion
−Removed: In January 2013, we entered into an option and license agreement with Alexion Pharmaceuticals, Inc.
−Removed: Under the terms of the agreement, we granted to Alexion an exclusive research license, with limited sublicensing rights, to make and use our Xtend technology to evaluate and advance compounds against six different target programs during a five ‑year research term under the agreement, up to completion of the first multi ‑dose human clinical trial for each target compound.
−Removed: Alexion may extend the research term for an additional three years upon written notice to us and payment of an extension fee of $2.0 million.
−Removed: Alexion is responsible for conducting all research and development activities under the agreement at its own expense .
−Removed: In the third quarter of 2014, Alexion initiated a Phase 1 clinical trial with an undisclosed molecule to be used against an undisclosed target.
−Removed: It is the first human clinical trial with a molecule incorporating our Xtend Fc Domain technology.
−Removed: In addition, we granted to Alexion an exclusive option, on a target ‑by ‑target basis, to obtain an exclusive commercial, worldwide, royalty ‑bearing license, with sublicensing rights, under our Xtend technology to develop and commercialize products that contain the target for which the option is exercised.
−Removed: In order to exercise this option, Alexion must pay a $4.0 million option fee with respect to each target for which the option is exercised.
−Removed: Alexion may exercise this option at any time during the research term but must exercise an option prior to the initiation of a second clinical trial.
−Removed: Under the agreement, we received an upfront payment of $3.0 million.
−Removed: Alexion is also required to pay an annual maintenance fee of $0.5 million during the research term of the agreement and $1.0 million during any extension of the research term.
−Removed: In addition, if certain development, regulatory and commercial milestones are achieved we are eligible to receive up to $66.5 million for the first product to achieve such milestones on a target ‑by ‑target basis.
−Removed: If licensed products are successfully commercialized, we are also entitled to receive royalties based on a percentage of net sales of such products sold by Alexion, its affiliates or its sublicensees, which percentage is in the low single digits.
−Removed: Alexion’s royalty obligations continue on a product ‑by ‑product and country ‑by ‑country basis until the expiration of the last ‑to ‑expire valid claim in a licensed patent covering the applicable product in such country.
−Removed: Absent early termination, the term of the agreement will continue until the expiration of Alexion’s royalty payment obligations or until the expiration of the research term if Alexion has not exercised its option for a product license under the agreement.
−Removed: Either party may terminate the agreement for a material breach of the agreement by the other party if such breach remains uncured for 60 days, or 30 days in the case of a non ‑payment breach.
−Removed: Alexion may terminate the agreement without cause on a target ‑by ‑target basis upon 90 days’
−Removed: advance written notice to us.
−Removed: Other Technology Licenses
−Removed: In addition to the product development partnerships and technology license agreement described above, we also enter into non-exclusive relationships whereby we license our intellectual property around a specific XmAb technology to a pharmaceutical or biotechnology company to use in one or more of their own products.
−Removed: By accessing our technology, our partners hope to improve the pharmacology of their antibodies and create potential commercial differentiation for their product candidates.
−Removed: Under these technology licenses, we generally grant rights to our licensees that are limited to the specific XmAb Fc domains that are required and also limited to a specific program or set of programs of the partner that are outside of our core strategic areas.
−Removed: This approach allows us to maintain control over the vast majority of the rights to our platform while still disseminating our technology for broad use.
−Removed: The plug-and-play nature of XmAb technology allows us to structure nearly all of these licenses without any work commitment on our part;
−Removed: hence, these licenses allow us to generate revenue to support our own internal programs with no additional obligations
−Removed: The revenue we generate from these licenses comes in the form of license fees, annual maintenance fees, milestone payments and royalties.
+Added: We have used our XmAb Fc platforms and protein engineering capabilities to produce a growing pipeline of drug candidates in clinical and preclinical development.
+Added: These include multiple oncology candidates using our bispecific Fc domain.
+Added: We continue to advance these candidates as additional options for clinical development by us or as out-licensing opportunities.
+Added: We also from time to time in-license antibody technologies and compounds from other companies which we believe may allow us to create potential product candidates by incorporating our own proprietary technologies.
+Added: These licenses may require us to pay upfront fees, development, and commercial milestone payments, and if commercial products are approved, royalties on net sales.
+Added: Human Capital Management
+Added: Our Employees and Commitment to Diversity, Equity, and Inclusion
+Added: Our ability to develop XmAb technologies, advance our programs into late-stage development, position our programs for commercialization and identify successful business partnerships is dependent on attracting, retaining, and developing our employees.
+Added: We seek and support a diverse population of employees without regard to race, gender or sexual orientation.
+Added: As of December 31, 2023, we had 280 full-time employees, of which 231 were engaged in research and development activities, and 49 were engaged in business development, information systems, facilities, human resources, or administrative support.
+Added: Of these employees, 68 hold Ph.D.
+Added: degrees, and 9 hold M.D.
+Added: None of our employees are represented by any collective bargaining unit.
+Added: We believe we maintain good relations with our employees.
+Added: We are an equal opportunity employer and maintain policies that prohibit unlawful discrimination based on race, color, religion, gender, sexual orientation, gender identity/expression, national origin/ancestry, age, disability, marital and veteran status.
+Added: We are proud to employ a diverse workforce that, as of December 31, 2023, was 58% non-white and 57% women.
+Added: In addition, as of December 31, 2023, women made up 33% of our senior leadership team.
+Added: We strive to build and nurture a culture where all employees feel empowered to be their authentic selves.
+Added: In January 2024, in connection with re-prioritization of our development programs, we completed a reduction in force (RIF) affecting approximately 10% of the total employee headcount.
+Added: The RIF was applied across all functional areas.
+Added: As of February 1, 2024, we had 256 full-time employees.
+Added: We seek to provide human capital and employee health and safety policies that provide for the health, safety, and welfare of our employees.
+Added: We continue practices that address the COVID-19 pandemic consistent with government
+Added: guidelines to mitigate and prevent the spread of disease, such as masking, social distancing, providing hybrid work opportunities where possible, contact tracing, and encouraging vaccinations.
+Added: Compensation, Benefits, and Development
+Added: We provide compensation packages designed to attract, retain, and motivate high-quality employees.
+Added: All of our employees are eligible for cash bonuses and grants of equity awards.
+Added: We regularly evaluate our compensation programs with an independent compensation consultant and utilize industry benchmarking in an effort to ensure they are competitive compared to similar biotechnology and biopharmaceutical companies with which we compete for talent and that they are fair and equitable across our workforce with respect to gender, race, and other personal characteristics.
+Added: All employees are eligible to participate in the Employee Stock Purchase Plan where they can purchase shares of our common stock at a discounted price.
+Added: This plan, and our other equity compensation plans, assists us in building long-term relationships with our employees and aligns the interest of employees with stockholders.
+Added: We also deliver a benefits program that is designed to keep our employees and their families healthy, which includes not only medical, dental and vision benefits, but also dependent care, mental health, and other wellness benefits.
+Added: In addition, we provide a variety of programs and services to help employees meet and balance their needs at work, at home and in life.
+Added: We value career development for all employees, and we provide reimbursement and time for employees to attend professional development courses ranging from technical training, competency-based workshops, and leadership development programs.
+Added: Direct managers also take an active role in identifying individualized development plans to assist their employees in realizing their full potential and creating opportunities for promotions and added responsibilities that enhance the engagement and retention of our workforce.
+Added: Market Opportunity
+Added: Our wholly owned drug candidates that use the XmAb bispecific Fc domain, which we are actively advancing in clinical development, including vudalimab, XmAb819, XmAb808 and XmAb541 :
+Added: We are developing these bispecific antibody drug candidates to treat cancer.
+Added: Cancer is a broad group of diseases in which cells divide and grow in an uncontrolled fashion, forming malignancies that can invade other parts of the body, and it is the second leading cause of death in the United States (U.S.).
+Added: The American Cancer Society estimates that in 2024 there will be approximately 2.0 million new cases of cancer and approximately 611,720 deaths from cancer.
+Added: The National Institutes of Health (NIH) has estimated that based on growth and aging of the U.S.
+Added: population, medical expenditures for cancer in the year 2030 are projected to reach at least $245.6 billion.
Intellectual Property
−Removed: The foundation for XmAb technology and our product candidates and partnering is the generation and protection of intellectual property for novel antibody therapeutics.
−Removed: We combine proprietary computational methods for amino acid sequence design with laboratory generation and testing of new antibody compositions.
+Added: The foundation for our XmAb technology and our product candidates and partnering is the generation and protection of intellectual property for novel antibody and cytokine therapeutics.
+Added: We combine proprietary computational methods for amino acid sequence design with laboratory generation and testing of new antibody and cytokine compositions.
Our design and engineering team prospectively assesses, with patent counsel, the competitive landscape with the goal of building broad patent positions and avoiding third-party intellectual property.
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We have filed additional patent applications derived from these applications as we discover new properties of the Fc variants and as new business opportunities arise.
−Removed: We continually seek to expand the intellectual property coverage of our technology and candidates, and invest in discovering new Fc domain technologies and antibody product candidates.
−Removed: As of December 31, 201 4 , our patent estate, on a worldwide basis, includes more than 150 issued patents (of which at least 40 are in the United States) and over 170 pending patent applications (of which at least 60 are in the United States) which we own or for which we have a fully-paid exclusive license, with claims directed to XmAb Fc domains, all of our clinical and preclinical stage antibodies and our computational protein design methods, called the PDA, protein design platform.
−Removed: Over 100 issued patents and 150 pending patent applications have claims directed specifically to our XmAb technology and candidates.
−Removed: Ou r XmAb Fc domain, patents and patent applications, with claims directed to their incorporation into antibodies, Fc domain engineering and compositions of matter are expected to expire in the United States between 2023 and 2031.
−Removed: Our three lead product candidates are covered by issued U.S.
−Removed: composition of matter patents relating to both the XmAb Fc domains and the individual product candidates.
−Removed: The composition of matter patents relating to our lead product candidates are expected to expire in the United States between 2027 and 2030, one of which relates to XmAb5574/MOR208, two relate to XmAb5871 and two relate to XmAb7195.
+Added: We continually seek to expand the intellectual property coverage of our technology and candidates and invest in discovering new Fc domain technologies, antibody product candidates, and cytokine product candidates.
+Added: Our patent estate, on a worldwide basis, includes over 1,500 issued patents and pending patent applications which we own, with claims directed to XmAb Fc domains, all of our clinical and preclinical stage product candidates and our computational protein design methods and platforms.
+Added: We also have a large number of issued patents and pending patent applications with claims directed specifically to our XmAb technology and candidates.
+Added: The patent expiration in the U.S.
+Added: and major foreign countries (ex-U.S.) for our key technologies and drug candidates is set forth below.
+Added: We have pending applications filed that may extend the exclusivity of some of our technology and products:
+Added: Technology Patent Expiry
+Added: Cytotoxic 2025 U.S.;
+Added: Immune Inhibitor 2028 U.S.;
+Added: Xtend 2025 U.S.;
+Added: Bispecific 2034 U.S.
+Added: CD3 T Cell Engagers 2035 U.S.
+Added: CD28 T Cell Engagers 2041 U.S.
+Added: Company Products Patent Expiry
+Added: XmAb808 2041 U.S, and Ex-U.S.
+Added: Vudalimab, XmAb104 2037 U.S.
+Added: XmAb564 2038 U.S.
+Added: XmAb819 2040 U.S.
+Added: XmAb306 2038 U.S.;
+Added: Partnered Products Patent Expiry
+Added: Monjuvi (tafasitamab) 2029 U.S.;
+Added: Ultomiris 2025 U.S.;
+Added: AIMab7195 (XmAb7195) 2029 U.S.
+Added: Sotrovimab 2025 U.S.;
+Added: Obexelimab (XmAb5871) 2029 U.S.;
+Added: Plamotamab 2035 U.S.
+Added: The Hatch-Waxman Act permits a patent term extension for FDA-approved drugs, including biological products, of up to five years beyond the expiration of the patent.
+Added: The length of the patent term extension is related to the length of time the drug is under regulatory review.
+Added: Patent 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.
+Added: Similar provisions are available in Europe and other jurisdictions to extend the term of a patent that covers an approved drug.
+Added: In the future, if and when our pharmaceutical product candidates receive FDA approval, we expect to apply for patent term extensions on patents covering those products.
+Added: We intend to seek patent term extensions to any of our issued patents in any jurisdiction where these are available;
+Added: however, there is no guarantee that the applicable authorities, including the FDA in the United States, will agree with our assessment of whether such extensions should be granted, and even if granted, the length of such extensions.
+Added: The Patient Protection and Affordable Care Act, as amended by the Healthcare and Education Affordability Reconciliation Act (collectively the ACA) created a regulatory scheme authorizing the FDA to approve biosimilars via an abbreviated licensure pathway.
+Added: In many cases, this allows biosimilars to be brought to market without conducting the full suite of clinical trials typically required of originators.
+Added: Under the ACA, a manufacturer may submit an application for licensure of a biologic product that is "biosimilar to" or "interchangeable with" a previously approved biological product or "reference product." The "biosimilar" application must include specific information demonstrating bio similarity based on data derived from:
+Added: (1) analytical studies, (2) animal studies, and (3) a clinical study or studies that are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed, except that FDA may waive some of these requirements for a given application.
+Added: Under this new statutory scheme, an application for a biosimilar product may not be submitted to the FDA until four years after the date of first licensure.
+Added: The FDA may not approve a biosimilar product until 12 years from the date on which the reference product was first licensed.
+Added: The law does not change the duration of patents granted on biological products.
+Added: Even if a product is considered to be a reference product eligible for exclusivity, another company could market a competing version of that product if the FDA approves a full Biologics License Application (BLA) for such product containing the sponsor's own preclinical data and data from adequate and well-controlled clinical trials to demonstrate the safety, purity, and potency of their product.
+Added: There have been recent proposals to repeal or modify the ACA, and it is uncertain how any of those proposals, if approved, would affect these provisions.
In addition to patent protection, we rely on trade secret protection and know-how to expand our proprietary position around our technology and other discoveries and inventions that we consider important to our business.
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Further, we seek trademark protection in the United States and in certain other jurisdictions where available and when we deem appropriate.
−Removed: We have obtained registrations for the Xencor trademark, as well as certain other trademarks, which we use in connection with our pharmaceutical research and development services and our clinical-stage products, including XmAb, PDA and Protein Design Automation.
−Removed: We currently have registrations for Xencor and PDA in the United States, Australia, Canada, the European Community and Japan, for Protein Design Automation in the United States, Australia, Canada and the European Community, and for XmAb in the United States, Australia and the European Community.
−Removed: Manufacturing
+Added: We have obtained registrations for the Xencor trademark, as well as certain other trademarks, which we use in connection with our pharmaceutical research and development services and our clinical-stage products, including XmAb.
+Added: We currently have registrations for Xencor and XmAb in the United States, Australia, Canada, the European Union, the United Kingdom, and Japan, and for Proteins by Design in the United States, Australia, Canada, and the European Union and the United Kingdom.
+Added: Third Party Vendors and Suppliers
+Added: Our internal research activities are focused on early research stage and preclinical activities and studies.
+Added: We rely on third party vendors, suppliers and contractors for all other research, development and clinical activities.
We are able to internally manufacture the quantities of our product candidates required for relatively short preclinical animal studies.
−Removed: We believe that this allows us to accelerate the drug development process by not having to rely on third parties for all of our manufacturing needs.
−Removed: We have adopted a manufacturing strategy of contracting with third parties in accordance with cGMP for the manufacture of drug substance and product, including XmAb5871, XmAb7195 and our bispecific development candidate, XmAb14045.
+Added: We believe that this allows us to accelerate the drug development process by not relying on third parties for all of our manufacturing needs.
+Added: We have adopted a manufacturing strategy of contracting with third parties in accordance with current good manufacturing practices (cGMPs) for the manufacture of drug substance and product, including our pipeline of bispecific antibody and cytokine development candidates.
+Added: We have used third party manufacturers for all our bispecific antibody and cytokine candidates which include:
+Added: plamotamab, vudalimab, XmAb104, XmAb306, XmAb564, XmAb819 XmAb808, XmAb662 and, XmAb541.
Additional contract manufacturers are used to fill, label, package and distribute investigational drug products.
−Removed: This allows us to maintain a more flexible infrastructure
−Removed: while focusing our expertise on developing our products.
−Removed: XmAb5871and XmAb7195 are produced by mammalian cell culture of a Chinese hamster ovary cell line that expresses the antibody, followed by multiple purification and filtration steps typical of those used for monoclonal antibodies.
−Removed: We have no long term manufacturing agreements and will ultimately depend on contract manufacturers for the manufacture of our products for commercial sale, as well as for process development.
−Removed: We are currently in the process of developing subcutaneous formulations for XmAb5871 and XmAb7195 with third party contract manufacturers.
−Removed: Development and Manufacturing Services Agreement with Catalent
−Removed: In September 2005, we entered into a development and manufacturing services agreement (the Catalent Manufacturing Agreement) with Catalent Pharma Solutions LLC (formerly Cardinal Health PTS, LLC) (Catalent).
−Removed: Under the terms of the agreement, Catalent may, from time to time, provide development and manufacturing services for us related to our XmAb technology.
−Removed: Catalent is currently performing services related to the manufacture under cGMP of drug substance of XmAb5871 and XmAb7195 under the agreement.
−Removed: We pay for services performed by Catalent under the agreement pursuant to statements of work entered into from time to time.
−Removed: Under the terms of the agreement, if Catalent develops one or more cell lines using its proprietary GPEx product expression technology (GPEx Technology) in the course of performing services under the agreement, we have the option to license any such cell line for non ‑cGMP research for a license fee of $30,000 per year for a period of up to 10 years and on other terms to be agreed upon by Catalent and us.
−Removed: In addition, we have the option to license any cell line developed by Catalent in the course of performing services under the agreement that incorporates the GPEx Technology for use in the production of clinical and commercial supplies of gene expression products by us or any of our manufacturers for 10 years for an upfront fee that ranges between $0 and $0.3 million per cell line, an annual license fee of $30,000, and development and regulatory milestones up to as much as an aggregate of $ 2 .
−Removed: 9 million per cell line licensed, and on other terms to be agreed upon by Catalent and us.
−Removed: This agreement will remain in effect unless either party terminates it in accordance with its terms.
−Removed: We may unilaterally terminate the agreement or activities under any statement of work entered into pursuant to the agreement upon 90 days written notice to Catalent.
−Removed: Catalent may unilaterally terminate the agreement upon 24 months written notice to us.
−Removed: Either party may terminate the agreement upon written notice to the other party upon the other party’s insolvency or the other party’s material breach of the agreement if such breach remains uncured for 30 days following notice thereof.
−Removed: Cell Line Sale Agreement with Catalent
−Removed: In December 2011, we entered into a GPEx ‑derived cell line sale agreement with Catalent pursuant to which we purchased a cell line (the GPEx Cell Line) developed by Catalent under the Catalent Manufacturing Agreement for use in the manufacture of XmAb7195.
−Removed: As consideration for the purchase and sale of the GPEx Cell Line under the agreement, we paid an initial upfront fee of $125,000.
−Removed: In addition, we are required to pay an annual fee to Catalent and royalties based on a percentage of net sales for products that are derived from or utilize the GPEx Cell Line.
−Removed: Such percentage is less than 1.0%.
−Removed: We are also required to make payments to Catalent based upon the achievement of certain developmental and regulatory milestones totaling up to approximately $2.9 million.
−Removed: We have the unilateral right to terminate the agreement upon 30 days written notice to Catalent.
−Removed: In addition, either party may terminate the agreement upon written notice to the other party in the event of the other party’s insolvency or the other party’s material breach of the agreement if such breach remains uncured for 60 days following notice thereof.
−Removed: Absent early termination, the agreement will remain in effect.
−Removed: If we terminate the agreement without cause or if Catalent terminates the agreement for our material breach of the agreement, our ownership rights in the GPEx ®
−Removed: Cell Line will automatically terminate, and title thereto will revert to Catalent.
−Removed: Upon acquisition of the GPEx cell line we transferred XmAb7195 manufacturing to Cook Pharmica, LLC (Cook) under which Cook has produced drug substance and drug product for use in our XmAb7195 clinical studies and
−Removed: performed related services, Cook continues to provide services under the agreement, however, we have transferred further manufacturing and development efforts for XmAb7195 back to Catalent under the Catalent Manufacturing Agreement.
−Removed: Boehringer Ingelheim International GmBH
−Removed: In February 2012, we entered into a collaboration agreement with Boehringer Ingelheim International GmbH (B oehringer I ngelheim ) for the establishment of certain manufacturing processes and the production of our next generation monoclonal anti ‑TNF antibody for use in our preclinical and Phase 1 clinical development.
−Removed: Under the terms of the agreement, we are required to use commercially reasonable efforts to complete Phase 1 clinical testing of the product and to find a licensing partner for the further development and commercialization of the antibody into a therapeutic product.
−Removed: We will be required to pay for services performed and products provided by B oehringer I ngelheim under the agreement pursuant to project plans entered into from time to time.
−Removed: In addition, we are required to reimburse B oehringer I ngelheim for all out ‑of ‑pocket expenses, including the cost of raw materials, incurred in connection with the project plan.
−Removed: B oehringer I ngelheim has agreed to delay all payments due to them under the agreement, including an annual interest rate which is a low double digit percentage, until (A) in the case where we have entered into a license agreement with a third party, the later of (1) the effective date of such license agreement or (2) the earlier of (i) completion of the clinical summary report for a Phase 1 clinical trial of the product or (ii) February 10, 2017 or (B) in the case where we decide to continue to develop the product on our own, on or before five years from the earlier of (i) completion of the clinical summary report for a Phase 1 clinical trial of the product or (ii) February 10, 2017.
−Removed: Any payments due by us in the situation described in clause (A) of the preceding sentence will be made in installments each of which will be limited to a maximum percentage of any licensing revenue that we receive under the applicable third ‑party license.
−Removed: We are not obligated to pay B oehringer I ngelheim any or all of the amounts owed under the agreement, including interest payments if we:
−Removed: (a) are not able to further develop the product for technical or scientific reasons or (b) do not decide to proceed with the further development of the product without a business partner and are unable to enter into a partnership agreement within an agreed upon period of time after Phase 1 clinical development.
−Removed: Pursuant to the agreement, we have granted B oehringer I ngelheim a first right to negotiate to manufacture and supply the products for use in any future Phase 2 and Phase 3 clinical trials, and should B oehringer I ngelheim exercise such right, B oehringer I ngelheim has a first right to negotiate to manufacture and supply commercial product as our principal supplier for an agreed upon period following the first commercial launch of the products.
−Removed: In the event that we desire to produce the products using the process developed and performed by B oehringer I ngelheim outside the agreement or any manufacturing agreement which we may enter into with B oehringer I ngelheim , we will be required to pay B oehringer I ngelheim a one - time technology access fee of $3.5 million in exchange for a worldwide, irrevocable, exclusive and royalty free license, with sublicensing rights, to use the process developed by B oehringer I ngelheim under the agreement to produce the products.
−Removed: Absent early termination, the agreement will terminate upon completion of all projects set forth in the agreement.
−Removed: Either party may terminate the agreement upon 180 days prior written notice to the other party if such party will not be able to carry out the project contemplated by the agreement for scientific, technical or business reasons.
+Added: This allows us to maintain a more flexible infrastructure while focusing our expertise on developing our products.
+Added: We do not have any long-term manufacturing agreements in place and will ultimately depend on contract manufacturers for the manufacture of our products for commercial sale, as well as for process development.
KBI Biopharma, Inc.
In July 2014, we entered into a master services agreement (KBI Agreement) with KBI Biopharma, Inc.
−Removed: We have engaged KBI under the KBI Agreement for process development, clinical scale-up, analytical method development, formulation development and other services related to drug substance and drug product for our first bispecific development candidate, XmAb14045, in accordance with cGMP regulations.
−Removed: Under the KBI Agreement, Xencor will pay up to approximately $ 3 .5 million as services are incurred over the term of the Agreement.
+Added: We have engaged KBI under the KBI Agreement for process development, clinical scale-up, analytical method development, formulation development, and other services related to drug substance and drug product for our bispecific antibody and cytokine development candidates:
+Added: plamotamab, vudalimab, XmAb104, XmAb306, XmAb564 and XmAb541 in accordance with cGMP regulations.
+Added: For each bispecific program, we have entered into a separate agreement with the terms and conditions of services and payment.
The KBI Agreement is for a three-year term but is automatically extended on an annual basis until the services are completed.
−Removed: The KBI Agreement may be terminated by either party for a breach that is not remedied within thirty days after notice or sixty days after notice of the existence of an uncurable scientific or technical issue that renders KBI unable to render services under the KBI Agreement, by Xencor after sixty day notice, or i n the event of a bankruptcy of a party.
−Removed: For termination
−Removed: other than a material breach by KBI, we must pay for all services conducted prior to the termination and to wind down the activities.
+Added: The KBI Agreement may be terminated by either party for a breach that is not remedied within 30 days after notice or 60 days after notice of the existence of an incurable scientific or technical issue that renders KBI unable to render services under the KBI Agreement, by after 60-day notice, or in the event of a bankruptcy of a party.
+Added: For termination other than a material breach by KBI, we must pay for all services conducted prior to the termination and to wind down the activities.
+Added: Cell Line Agreements with Selexis
+Added: In December 2015, we entered into a master service agreement (Selexis Agreement) with Selexis SA (Selexis) for the manufacture of Selexis cell lines.
+Added: Under the terms of the Selexis Agreement, Selexis will manufacture cell lines for the antibody candidates provided by us and upon completion of the cell lines, we have the option to take an unrestricted commercial license to the cell line.
+Added: The terms of each commercial license require us to make payments upon achievement of certain development and regulatory milestones and we will also pay royalties based on a percentage of net sales for products that are derived from or utilize the Selexis cell line.
+Added: The royalty is less than 1%.
+Added: Selexis has manufactured cell lines for certain of our bispecific antibody and cytokine drug candidates, and we currently have rights to obtain commercial licenses to the Selexis cell line for the following bispecific antibody and cytokine candidates:
+Added: plamotamab, vudalimab, XmAb104, XmAb306, XmAb564, and XmAb819.
+Added: License Agreement with BIO-TECHNE
+Added: In April 2021, we entered into an agreement with BIO-TECHNE for a non-exclusive license to a certain recombinant monoclonal antibody reactive with human Claudin-6 (CLDN6).
+Added: We are using this protein in our XmAb541 drug candidate.
+Added: Under the terms of this agreement, we made an upfront payment and are obligated to make payments upon the achievement of certain development, regulatory and sales milestones, and royalties based on a percentage of net sales from products that are derived from the CLDN6 antibody.
+Added: The royalty is less than 1%.
+Added: Umbrella Development Services Agreement with Patheon Biologics LLC
+Added: In September 2018, we entered into an Umbrella Development Services Agreement (Patheon Agreement) with Patheon Biologics LLC (Patheon).
+Added: Under the terms of the Patheon Agreement, any of the affiliates within the global network of service sites in Thermo Fisher Scientific Inc.’s Pharma Services Group may perform clinical manufacturing and development services for us in accordance with cGMP regulations.
+Added: The Patheon Agreement may be terminated by either party for a breach or default that is not remedied within 30 days, or such other time period as may be reasonably necessary to remedy such breach after receiving notice of the breach from the non-breaching party or if the other party is subject to an insolvency event.
+Added: We have the unilateral right to terminate the Patheon Agreement upon 30 days written notice to Patheon for any business reason, subject to cancellation fees.
+Added: Patheon has the unilateral right to terminate the Patheon Agreement if we request to reschedule work beyond 120 days, the project work is not progressing according to our expectations and we cannot agree on appropriate changes, after six months of inactivity on a project at our request or if Patheon determines it is unable to perform its obligations in a safe and effective way in compliance with applicable regulatory requirements.
+Added: Patheon is currently manufacturing drug substance material for our XmAb819 program and drug product for our plamotamab program.
+Added: Master Services Agreement with WuXi Biologics (Hong Kong) Limited
+Added: In February 2021, we entered into a Master Services Agreement (WuXi Agreement) with WuXi Biologics (Hong Kong) Limited (WuXi).
+Added: Under the terms of the WuXi Agreement, WuXi and its affiliates will perform manufacturing, analytical, development and other services for Xencor in accordance with applicable regulations.
+Added: The WuXi Agreement includes customary rights to replacement of non-conforming products.
+Added: The WuXi Agreement may be terminated by either party for a breach by the other party that is not remedied within 45 days (or 10 days for a non-payment breach), or if the other party is subject to an insolvency event.
+Added: We have the unilateral right to terminate the WuXi Agreement upon 90 days’ prior written notice to WuXi for any reason, subject to applicable cancellation fees.
+Added: WuXi has the unilateral right to terminate the WuXi Agreement only if the services cannot be performed due to technical difficulties or the performance of the services is not permitted under applicable law.
+Added: WuXi is currently manufacturing drug substance and drug product for our XmAb808 and XmAb662 programs.
+Added: Master Clinical Services Agreement with ICON Clinical Research Limited
+Added: In April 2016, we entered into a Master Clinical Services Agreement (ICON Agreement) with ICON Clinical Research Limited (ICON) which was amended in April 2021.
+Added: Under the terms of the ICON Agreement, ICON and its affiliates will perform clinical trial services (including site selection, study design, site monitoring, management and training, and patient selection) for Xencor in accordance with applicable regulations.
+Added: The ICON Agreement may be terminated by either party for a breach by the other party that is not remedied within 30 days, or if the other party is subject to an insolvency event.
+Added: Each party may terminate the ICON Agreement upon 30 days’ prior written notice to the other party for any reason, however such termination would not affect any ongoing project under the ICON Agreement.
+Added: We may unilaterally terminate any project under the ICON Agreement upon 30 days’ prior written notice to ICON for any reason, subject to applicable close-out costs.
+Added: ICON is currently providing services to us in connection with ongoing Xencor-sponsored clinical trial that target oncology indications.
+Added: Master Services Agreement with Innovaderm Research, Inc.
+Added: In April 2022, we entered into a Master Services Agreement (Innovaderm Agreement) with Innovaderm Research, Inc.
+Added: (Innovaderm).
+Added: Under the terms of the Innovaderm Agreement, Innovaderm will perform clinical trial management and
+Added: clinical development services (including site selection, study design, site monitoring, management and training, and patient selection) for Xencor in accordance with applicable regulations.
+Added: The Innovaderm Agreement may be terminated by either party for a breach upon 15 days' written notice, if such breach is not cured within 30 days.
+Added: We may terminate the Innovaderm Agreement upon 30 days' written notice to Innovaderm for any reason;
+Added: however, we will be obligated for any costs incurred through the cancellation date and any non-refundable and non-cancellable commitments incurred by Innovaderm.
+Added: Innovaderm is currently conducting clinical studies for our XmAb564 program.
+Added: Master Services Agreement with PPD Development, L.P.
+Added: In June 2015, we entered into a Master Services Agreement (PPD Agreement) with PPD Development, L.P.(PPD).
+Added: Under the terms of the PPD Agreement, PPD will perform clinical trial management and clinical development services (including site selection, study design, site monitoring, management and training, and patient selection) for Xencor in accordance with applicable regulations.
+Added: The PPD Agreement may be terminated by either party for a breach upon 30 days' written notice, if such breach is not cured within 30 days.
+Added: We may terminate the PPD Agreement upon 30 days' written notice to PPD for any reason;
+Added: however, we will be obligated for any costs incurred through the cancellation date and any non-refundable and non-cancellable commitments incurred by PPD.
+Added: PPD is currently conducting clinical studies for our vudalimab program.
+Added: Master Services Agreement with Vetter Pharma International GmbH
+Added: In October 2020, we entered into a master services agreement (Vetter Agreement) with Vetter Pharma International GmbH (Vetter).
+Added: We have engaged Vetter under the Vetter Agreement for clinical scale-up, analytical method development, formulation development, and other services related to manufacturing drug product for our bispecific antibody candidates vudalimab and XmAb541 in accordance with cGMP regulations.
+Added: For each bispecific program, we have entered into a separate agreement with the terms and conditions of services and payment.
+Added: The Vetter Agreement is for a eight-year term but is automatically extended on an annual basis until the services are completed.
+Added: The Vetter Agreement may be terminated by either party for a breach that is not remedied within 60 days after notice or 60 days after notice of the existence of an incurable scientific or technical issue that renders Vetter unable to render services under the Vetter Agreement.
+Added: For termination other than a material breach by Vetter, we must pay for all services conducted prior to the termination and to wind down the activities.
+Added: Vetter is currently manufacturing drug product for our vudalimab and XmAb541 programs.
+Added: Master Services Agreement with OncoBay Clinical, Inc.
+Added: In August 2023, we entered into a Master Services Agreement (OncoBay Agreement) with OncoBay Clinical, Inc.
+Added: Under the terms of the OncoBay Agreement, OncoBay will perform Contract Research Organization (CRO) services including clinical trial management and clinical development services (including site selection, study design, site monitoring, management and training, and patient selection) for Xencor in accordance with applicable regulations.
+Added: The OncoBay Agreement may be terminated by either party for a breach upon 30 days' written notice, if such breach is not cured within thirty (30) days.
+Added: We may terminate the OncoBay Agreement upon 60 days' written notice to OncoBay for any reason;
+Added: however, we will be obligated for any costs incurred through the cancellation date and any non-refundable and non-cancellable commitments incurred by OncoBay.
+Added: OncoBay is currently conducting clinical studies for our XmAb541 program.
We compete in an industry that is characterized by rapidly advancing technologies, intense competition, and a strong emphasis on proprietary products.
Our competitors include pharmaceutical companies, biotechnology companies, academic institutions, and other research organizations.
−Removed: We compete with these parties for promising targets for antibody ‑based therapeutics, new technology for optimizing antibodies and in recruiting highly qualified personnel.
+Added: We compete with these parties for promising targets for antibody-based therapeutics, new technology for optimizing antibodies and cytokines, and in recruiting highly qualified personnel.
Many competitors and potential competitors have substantially greater scientific, research, and product development capabilities as well as greater financial, marketing and sales, and human resources than we do.
−Removed: In addition, many specialized biotechnology firms have formed collaborations with large, established companies to support the research, development and commercialization of products that may be competitive with ours.
+Added: In addition, many specialized biotechnology firms have formed collaborations with large, established companies to support the research,
+Added: development, and commercialization of products that may be competitive with ours.
Accordingly, our competitors may be more successful than we may be in developing, commercializing, and achieving widespread market acceptance.
−Removed: In addition, our competitors’
−Removed: products may be more effective or more effectively marketed and sold than any treatment we or our development partners may commercialize and may render our product candidates obsolete or noncompetitive before we can recover the expenses related to developing and commercializing any of our product candidates.
−Removed: Competition in autoimmune disease drug development is intense and includes multiple monoclonal antibodies, other biologics and small molecules approved for the treatment of autoimmune diseases, many of which are being developed or marketed by large multinational pharmaceutical companies such as Glaxo SmithKline plc, AbbVie Inc., Janssen Pharmaceuticals, Inc., Genentech Inc.
−Removed: and Amgen Inc.
−Removed: Benlysta is currently the only monoclonal antibody that we are aware of that is approved for the treatment of lupus, although we believe that Rituxan is prescribed, off label, for this indication.
−Removed: In addition, these and other pharmaceutical companies have monoclonal antibodies or other biologics in clinical development for the treatment of autoimmune diseases.
−Removed: There are currently no approved therapies for IgG4-related disease, a newly recognized disorder, and glucocorticoids are the current standard of care.
−Removed: Many companies have approved therapies or are developing drugs for the treatment of asthma including multinational pharmaceutical companies such as GlaxoSmithKline, Novartis AG and AstraZeneca plc.
−Removed: Monoclonal antibody drug development has primarily focused on allergic asthma.
−Removed: Xolair is currently the only monoclonal antibody that we are aware of that is approved for the treatment of severe asthma.
−Removed: In addition, we are aware that Novartis and Genentech each have an antibody targeting IgE in Phase 1 or 2 clinical development for asthma.
−Removed: Other monoclonal antibodies in development target cytokines such as IL ‑13, IL ‑4, IL ‑5, IL ‑9, GM ‑CSF or their receptors.
−Removed: Although these drugs function differently from our products, if successfully developed, these drugs will compete in the asthma market.
−Removed: We are not aware of any companies developing drugs that target FcγRIIb for the treatment of asthma.
−Removed: Competition in blood cancer drug development is intense, with more than 250 compounds in clinical trials by large multinational pharmaceutical companies and Rituxan is just one of many monoclonal antibodies approved for the treatment of NHL or other blood cancers.
−Removed: In addition, we are aware of a number of other companies with development stage programs that may compete with XmAb5574/MOR208 in the future.
−Removed: We anticipate that we will face intense and increasing competition as new treatments enter the market and advanced technologies become available , such as Gavyaza for CLL and NHL marketed by Roche, Blincyto for ALL marketed by Amgen and engineered T-cell therapies targeting blood cancers from companies such as Novartis .
+Added: In addition, our competitors’ products may be more effective, more effectively developed, or more effectively marketed and sold than any treatment we or our development partners may commercialize, which may render our product candidates obsolete or noncompetitive before we can recover the expenses related to developing and commercializing any of our product candidates.
+Added: Competition in the field of cancer drug development is intense, with hundreds of compounds in clinical trials.
+Added: Many large pharmaceutical companies and other smaller biotechnology companies are developing competing bispecific antibody platforms, and many of these companies have advanced multiple drug candidates into clinical development, including Amgen Inc.;
+Added: Macrogenics, Inc.;
+Added: Regeneron Pharmaceuticals, Inc.;
+Added: and Roche Holding AG.
+Added: We are developing bispecific antibody drug candidates engineered to direct cytotoxic T cell killing of solid tumor cells, by engaging the CD3 or CD28 receptor on T cells and an antigen on tumor cells.
+Added: Other companies conducting clinical trials to evaluate CD3 or CD28 bispecific antibodies directed to antigens expressed on solid tumors include Amgen Inc.;
+Added: Astellas Pharma Inc.;
+Added: BioAtla, Inc.;
+Added: CytomX Therapeutics, Inc.;
+Added: Immunocore Holdings plc;
+Added: Janux Therapeutics, Inc.;
+Added: Johnson & Johnson;
+Added: Regeneron Pharmaceuticals, Inc.;
+Added: Roche Holding AG;
+Added: and Takeda Pharmaceutical Co.
+Added: Other antibodies, antibody drug conjugates and cell therapies are in development or approved to treat patients with cancer.
+Added: We are also developing several bispecific antibody drug candidates engineered to selectively engage the immune system in order to treat patients with cancer.
+Added: Immuno-oncology is a competitive field within the biotechnology and pharmaceutical industries, and most large pharmaceutical companies are developing drug candidates, have marketed medicines in this space, or both:
+Added: AstraZeneca plc;
+Added: Bristol-Myers Squibb Company;
+Added: GlaxoSmithKline plc;
+Added: Merck & Co., Inc.;
+Added: Roche Holding AG;
+Added: and Sanofi S.A.
+Added: While tuning the binding affinities plays a crucial role in designing the mechanism of action for this class of bispecific antibody, smaller companies advancing clinical programs that, like vudalimab, dually target the immune checkpoint receptors PD-1 and CTLA-4 include Akeso, Inc.
+Added: and Macrogenics, Inc.
+Added: In addition, we are aware of a number of other companies with development-stage programs that may compete with the drug candidates we and our licensees are developing in the future.
+Added: We anticipate that we will face intense and increasing competition as new treatments enter the market and advanced technologies become available.
Regulatory Overview
2 unchanged sentences
The FDA and comparable regulatory authorities in state and local jurisdictions and in other countries impose substantial and burdensome requirements upon companies involved in the clinical development, manufacture, marketing, and distribution of drugs and biologics.
−Removed: These agencies and other federal, state and local entities regulate research and development activities and the testing, manufacture, quality control, safety, effectiveness, labeling, storage, recordkeeping, approval, advertising and promotion and export and import of our product candidate.
+Added: These agencies and other federal, state and local entities regulate research and development activities and the testing, manufacture, quality control, safety, effectiveness, labeling, storage, recordkeeping, approval, advertising and promotion, and export and import of our product candidates.
Government Regulation
+Added: We are subject to extensive regulation by the U.S.
+Added: and other countries.
+Added: Regulation by government authorities is a significant factor in development, manufacture, distribution and ongoing research activities.
+Added: All our products in development will require regulatory approval by government agencies prior to commercialization.
+Added: In particular, drugs and biologic products are subject to rigorous preclinical studies and clinical trials and other approval procedures of the FDA and similar regulatory authorities in foreign countries.
+Added: The process of obtaining these approvals and the subsequent compliance with appropriate federal and state statutes and regulations require the expenditure of substantial time and financial resources.
+Added: Various federal and state statutes and regulation also govern or influence testing, manufacturing, safety, labeling, storage, tracking, tracing and record-keeping of drugs and biologic products and their marketing.
Drug Development Process
−Removed: In the United States, the FDA regulates drugs and biologic products under the Federal Food, Drug and Cosmetic Act (FDCA) (21 U.S.C.
−Removed: §301, et seq), its implementing regulations and other laws, including, in the case of biologics, the Public Health Service Act.
−Removed: Our antibody product candidates are subject to regulation by the FDA as a biologic.
+Added: In the United States, the FDA regulates drugs and biologic products under the Federal Food, Drug and Cosmetic Act (FDCA), its implementing regulations, and other laws including, in the case of biologics, the Public Health Service Act.
+Added: Our product candidates are subject to regulation by the FDA as a biologic.
Biologics require the submission of a Biologics License Application (BLA) to the FDA and approval of the BLA by the FDA before marketing in the United States.
The process of obtaining regulatory approvals for commercial sale and distribution and the subsequent compliance with applicable federal, state, local and foreign statutes and regulations require the expenditure of substantial time and financial resources.
−Removed: Failure to comply with the applicable U.
−Removed: requirements at any time during the product development process, approval process or after approval, may subject an applicant to administrative or judicial civil or criminal sanctions.
−Removed: These sanctions could include the FDA’s refusal to approve pending applications, license suspension or revocation, withdrawal of an approval, imposition of a clinical hold on clinical trials, warning letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement or civil and/or criminal penalties.
+Added: Failure to comply with the applicable requirements at any time during the product development process, approval process or after approval, may subject an applicant to administrative or judicial civil or criminal sanctions.
+Added: These sanctions could include the FDA’s refusal to approve pending applications, license suspension or revocation, withdrawal of an approval, imposition of a clinical hold on clinical trials, warning letters, product recalls, product seizures, total or partial suspension of production, or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement or civil and/or criminal penalties.
The process required by the FDA before a biologic may be marketed in the United States generally involves the following:
−Removed: completion of preclinical laboratory tests, animal studies and formulation studies performed in accordance with the FDA’s current Good Laboratory Practices (GLP) regulations;
−Removed: submission to the FDA of an investigational new drug application (IND) which must become effective before human clinical trials in the United States may begin;
−Removed: performance of adequate and well ‑controlled human clinical trials in accordance with the FDA’s current good clinical practices (GCP) regulations to establish the safety and efficacy of the product candidate for its intended use;
−Removed: submission to the FDA of a BLA;
−Removed: satisfactory completion of an FDA inspection (if the FDA deems it as a requirement) of the manufacturing facility or facilities where the product is produced to assess compliance with the FDA’s cGMP regulations to assure that the facilities, methods and controls are adequate to preserve the product’s identity, strength, quality and purity;
+Added: completion of preclinical laboratory tests, animal studies, and formulation studies performed in accordance with the FDA’s current Good Laboratory Practices (GLP) regulations;
+Added: submission to and acceptance by the FDA of an IND which must become effective before human clinical trials in the United States may begin;
+Added: performance of adequate and well-controlled human clinical trials in accordance with the FDA’s current Good Clinical Practices (GCP) regulations to establish the safety and efficacy of the product candidate for its intended use;
+Added: submission to and acceptance by the FDA of a BLA;
+Added: satisfactory completion of an FDA inspection (if the FDA deems it as a requirement) of the manufacturing facility or facilities where the product is produced to assess compliance with the FDA’s cGMP regulations to assure that the facilities, methods, and controls are adequate to preserve the product’s identity, strength, quality, and purity;
potential audits by the FDA of the nonclinical and clinical trial sites that generated the data in support of the BLA;
−Removed: review of the BLA by an external Advisory Committee to the FDA, whose recommendations are not binding on the FDA;
+Added: potential review of the BLA by an external Advisory Committee to the FDA, whose recommendations are not binding on the FDA;
FDA review and approval of the BLA prior to any commercial marketing or sale.
1 unchanged sentence
Preclinical tests include laboratory evaluations of product chemistry, stability, and formulation, as well as animal studies to assess the potential toxicity and activity of the product candidate.
−Removed: The conduct of the preclinical tests must comply with federal regulations and requirements including GLPs.
−Removed: The sponsor must submit the results of the preclinical tests, together with manufacturing information, analytical data, any available clinical data or literature and a proposed clinical protocol, to the FDA as part of the IND.
−Removed: The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA raises concerns or questions about the conduct of the clinical trial, including concerns that human research subjects will be exposed to unreasonable health risks.
−Removed: In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin.
−Removed: The FDA may also
−Removed: impose clinical holds on a product candidate at any time before or during clinical trials due to safety concerns or non ‑compliance, or for other reasons.
−Removed: Clinical trials involve the administration of the product candidate to human patients under the supervision of qualified investigators, generally physicians not employed by or under the clinical trial sponsor’s control.
+Added: Clinical trials involve the administration of the product candidate to human patients under the supervision of qualified investigators, generally physicians not employed by or under the clinical trial sponsor’s control.
Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria, and the parameters to be used to monitor subject safety and effectiveness.
−Removed: Each protocol must be submitted to the FDA as part of the IND.
−Removed: Clinical trials must be conducted in accordance with GCPs.
−Removed: Further, each clinical trial must be reviewed and approved by an IRB at or servicing each institution at which the clinical trial will be conducted.
−Removed: An IRB is charged with protecting the welfare and rights of clinical trial participants and considers such items as whether the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits.
−Removed: The IRB also approves the form and content of the informed consent that must be signed by each clinical trial subject or his or her legal representative and must monitor the clinical trial until completed.
−Removed: Human clinical trials are typically conducted in three sequential phases that may overlap or be combined:
−Removed: The product candidate is initially introduced into a limited population of healthy human subjects and tested for safety, dosage tolerance, absorption, metabolism, distribution and excretion.
+Added: The FDA or responsible Institutional Review Board may place a trial on hold at any time related to perceived risks to patient safety.
+Added: Phases of clinical development include:
+Added: The product candidate is initially introduced into a limited population of healthy human subjects, or in some cases, patients with the disease for which the drug candidate is intended, and tested for safety, dosage tolerance, absorption, metabolism, distribution, and excretion.
In the case of some products for some diseases, or when the product may be too inherently toxic to ethically administer to healthy volunteers, the initial human testing is often conducted in patients with the disease or condition for which the product candidate is intended to gain an early indication of its effectiveness.
1 unchanged sentence
Clinical trials are undertaken to further evaluate dosage and provide substantial evidence of clinical efficacy and safety in an expanded patient population (such as several hundred to several thousand) at geographically dispersed clinical trial sites.
−Removed: Phase 3 clinical trials are typically conducted when Phase 2 clinical trials demonstrate that a dose range of the product candidate is effective and has an acceptable safety profile.
−Removed: These trials typically have at least 2 groups of patients who, in a blinded fashion, receive either the product or a placebo.
Phase 3 clinical trials are intended to establish the overall risk/benefit ratio of the product and provide an adequate basis for product labeling.
Generally, two adequate and well-controlled Phase 3 clinical trials are required by the FDA for approval of a BLA.
−Removed: Annual progress reports detailing the results of the clinical trials must be submitted to the FDA and written IND safety reports must be promptly submitted to the FDA and the investigators for serious and unexpected adverse events or any finding from tests in laboratory animals that suggests a significant risk for human subjects.
+Added: Post Approval.
+Added: Clinical trials or other post-approval commitments may be conducted after initial marketing approval.
+Added: These studies are used to gain additional experience from the treatment of patients in the intended therapeutic indication and may be required by the FDA as a condition of approval.
Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the biologic and finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.
−Removed: The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other things, must develop methods for testing the identity, strength, quality and purity of the final biologic product.
−Removed: Additionally, appropriate packaging must be selected and tested and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life.
Review and Approval Processes
The results of product development, preclinical studies and clinical trials, along with descriptions of the manufacturing process, analytical tests, proposed labeling, and other relevant information are submitted to the FDA in the form of a BLA requesting approval to market the product for one or more specified indications.
−Removed: If the FDA determines that the BLA is substantially complete it will accept the BLA for filing.
−Removed: This process generally takes eight months to a year but in some cases may take much longer.
−Removed: The FDA reviews the BLA to determine, among other things, whether the proposed product is safe and effective for its intended use, and whether the product is being manufactured in accordance with cGMP to assure and preserve the product’s identity, strength, quality and purity and it may inspect the manufacturing facilities to assure cGMP compliance and clinical sites used during the clinical trials to assure cGMP compliance.
−Removed: During the approval process, the FDA also will determine whether a risk evaluation and mitigation strategy (REMS) is necessary to assure the safe use of the product.
+Added: The standard time for the FDA to accept a BLA submission is two months.
+Added: If the FDA determines that the BLA is substantially complete, it will accept the BLA for review.
+Added: Once accepted, the FDA reviews the BLA to determine, among other things, whether the proposed product is safe and effective for its intended use, and whether the product is being manufactured in accordance with cGMP to assure and preserve the product’s identity, strength, quality, and purity, and it may inspect the manufacturing facilities to assure cGMP compliance and clinical sites used during the clinical trials to assure cGMP compliance.
+Added: The standard FDA review process is 10 months once a BLA is accepted for review, but it can take longer.
+Added: During the review process, the FDA also will determine whether a risk evaluation and mitigation strategy (REMS) is necessary to assure the safe use of the product.
If the FDA concludes a REMS is needed, the sponsor of the BLA must submit a proposed REMS prior to approval.
A REMS can substantially increase the costs of obtaining approval.
+Added: In addition, under the Pediatric Research Equity Act, a BLA or supplement to a BLA must contain data that are adequate to assess the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.
+Added: The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements.
The FDA will issue a complete response letter describing deficiencies in the BLA and recommend actions if the agency decides not to approve the BLA.
3 unchanged sentences
Post-Approval Requirements
−Removed: Any biologic products for which we or our collaborators receive FDA approvals are subject to continuing regulation by the FDA, including, among other things, record ‑keeping requirements, reporting of adverse experiences with the product, providing the FDA with updated safety and efficacy information, product sampling and distribution requirements, complying with certain electronic records and signature requirements and complying with FDA promotion and advertising requirements, which include, among others, restrictions on direct ‑to ‑ consumer advertising, promoting biologics for uses or in patient populations that are not described in the product’s approved labeling (known as “off ‑ label use”), industry ‑sponsored scientific and educational activities and promotional activities involving the internet.
−Removed: Failure to comply with these or other FDA requirements can subject a manufacturer to possible legal or regulatory action, such as warning letters, suspension of manufacturing, seizure of product, injunctive action, mandated corrective advertising or communications with healthcare professionals, possible civil or criminal penalties or other negative consequences, including adverse publicity.
−Removed: We will rely, and expect to continue to rely, on third ‑parties for the production of clinical and commercial quantities of our products.
−Removed: Our collaborators may also utilize third ‑parties for some or all of a product we are developing with such collaborator.
−Removed: Manufacturers are required to comply with applicable FDA manufacturing requirements contained in the FDA’s cGMP regulations and other laws .
−Removed: cGMP regulations require among other things, quality control and quality assurance as well as the corresponding maintenance of records and documentation.
−Removed: Drug manufacturers and other entities involved in the manufacture and distribution of approved biologics are subject to periodic inspections by the FDA and certain state agencies for compliance.
+Added: Any biologic products for which we or our collaborators receive FDA approvals are subject to continuing regulation by the FDA, including, among other things, cGMP compliance for product manufacture, record-keeping requirements, reporting of adverse experiences with the product, providing the FDA with updated safety and efficacy information, product sampling and distribution requirements, complying with certain electronic records and signature requirements, and complying with FDA promotion and advertising requirements, which include, among others, restrictions on direct-to-consumer advertising, promoting biologics for uses or in patient populations that are not described in the product’s approved labeling (known as “off-label use”), industry-sponsored scientific and educational activities, and promotional activities involving the internet.
+Added: Failure to comply with these or other FDA requirements can subject a manufacturer to possible legal or regulatory action, such as product reclass, warning letters, suspension of manufacturing,
+Added: seizure of product, injunctive action, mandated corrective advertising or communications with healthcare professionals, possible civil or criminal penalties, or other negative consequences, including adverse publicity.
Patent Term Restoration and Marketing Exclusivity
−Removed: Depending upon the timing, duration and specifics of the FDA approval of any of our biologic product candidate s , we may apply for limited patent term extension under the Drug Price Competition and Patent Term Restoration Act of 1984, commonly referred to as the Hatch-Waxman Amendments.
+Added: Depending upon the timing, duration and specifics of the FDA approval of any of our biologic product candidates, we may apply for limited patent term extension under the Drug Price Competition and Patent Term Restoration Act of 1984, commonly referred to as the Hatch-Waxman Amendments.
The Hatch-Waxman Amendments permit a patent restoration term of up to five years for one patent per product as compensation for patent term lost during product development and the FDA regulatory review process of that product.
Patent and Trademark Office, in consultation with the FDA, reviews and approves the application for any patent term extension or restoration.
−Removed: Market exclusivity provisions under the FDCA can also delay the submission or the approval of certain applications of other companies seeking to reference another company’s BLA.
−Removed: Specifically, the Biologics Price Competition and Innovation Act (BPCIA) established an abbreviated pathway for the approval of biosimilar and interchangeable biological products generally not earlier than 12 years after the original BLA approval, although it can be shortened to four years if the biosimilar contains certification of patent invalidity or non-infringement to one of the
−Removed: patents listed with the FDA by the innovator BLA holders .
−Removed: The new abbreviated regulatory pathway establishes legal authority for the FDA to review and approve biosimilar biologics, including the possible designation of a biosimilar as “interchangeable”
−Removed: based on their similarity to existing brand product.
−Removed: Foreign Corrupt Practices Act
−Removed: Foreign Corrupt Practices Act, to which we are subject, prohibits corporations and individuals from engaging in certain activities to obtain or retain business or to influence a person working in an official capacity.
−Removed: It is illegal to pay, offer to pay or authorize the payment of anything of value to any foreign government official, government staff member, political party or political candidate in an attempt to obtain or retain business or to otherwise influence a person working in an official capacity.
+Added: Market exclusivity provisions under the FDCA can also delay the submission or the approval of certain applications of other companies seeking to reference another company’s BLA.
+Added: Specifically, the Biologics Price Competition and Innovation Act established an abbreviated pathway for the approval of biosimilar and interchangeable biological products generally not earlier than 12 years after the original BLA approval.
+Added: The abbreviated regulatory pathway establishes legal authority for the FDA to review and approve biosimilar biologics, including the possible designation of a biosimilar as “interchangeable” based on their similarity to existing brand product.
Pharmaceutical Coverage, Pricing and Reimbursement
1 unchanged sentence
We expect that the pharmaceutical industry will experience pricing pressures due to the trend toward managed healthcare, the increasing influence of managed care organizations and additional legislative proposals.
−Removed: Significant uncertainty exists and will continue to exist as to the coverage and reimbursement status of any product candidate for which we obtain regulatory approval.
−Removed: In the United States and markets in other countries, sales of any product for which we receive regulatory approval for commercial sale will depend in part on the availability of coverage and adequate reimbursement from third party payors.
−Removed: Third-party payors include government payor programs at the federal and state levels, including Medicare and Medicaid, managed care providers, private health insurers and other organizations.
−Removed: Third ‑party payors are increasingly challenging the price and examining the medical necessity and cost ‑effectiveness of medical products and services, in addition to their safety and efficacy.
−Removed: Formulary placement by third-party payors is very competitive and can lead to lower prices and may effectively restrict patient access to our drugs.
−Removed: We may need to conduct expensive pharmacoecon o m i c studies in order to demonstrate the medical necessity and cost-effectiveness of our products, in addition to the costs required to obtain the FDA approvals.
−Removed: Our product candidates may not be considered medically necessary or cost-effective.
−Removed: government, state legislatures and foreign governments have shown significant interest in implementing cost containment programs to limit the growth of government-paid healthcare costs, including price controls, restrictions on reimbursement and requirements for substitution of generic products for branded prescription drugs.
−Removed: Different pricing and reimbursement schemes exist in other countries.
−Removed: In the European Community, governments influence the price of pharmaceutical products through their pricing and reimbursement rules and control of national healthcare systems that fund a large part of the cost of those products to consumers.
−Removed: The downward pressure on healthcare costs in general, and particularly prescription drugs, has become very intense.
−Removed: As a result, increasingly high barriers are being erected to the entry of new products.
−Removed: In addition, in some countries, cross ‑border imports from low ‑priced markets exert a commercial pressure on pricing within a country.
−Removed: There can be no assurance that any country that has price controls or reimbursement limitations for drug products will allow favorable reimbursement and pricing arrangements for any of our products.
Healthcare Reform
2 unchanged sentences
In the United States, the pharmaceutical industry has been a particular focus of these efforts and has been significantly affected by major legislative initiatives.
−Removed: In March 2010, the Patient Protection and Affordable Health Care Act, as amended by the Health Care and Education Affordability Reconciliation Act (collectively, PPACA) was enacted, which significantly change s the way healthcare is financed by both governmental and private insurers.
−Removed: Among other cost containment measures, PPACA establishes:
−Removed: an annual, nondeductible fee on any entity that manufactures or imports certain branded prescription drugs
−Removed: and biologic agents;
−Removed: a new Medicare Part D coverage gap discount program;
−Removed: and a new formula that increases the rebates a manufacturer must pay under the Medicaid Drug Rebate Program.
−Removed: In addition, other legislative changes have been adopted and proposed since PPACA was enacted including legislation reducing Medicare payments to providers and reductions to payments under other government programs .
−Removed: Additional new laws may result in additional reductions in Medicare and other healthcare funding, which could have a material adverse effect on our customers and accordingly, our financial operations.
Other Healthcare Laws and Compliance Requirements
−Removed: In the United States, the research, manufacturing, distribution, sale and promotion of drug products and medical devices are potentially subject to regulation by various federal, state and local authorities in addition to the FDA, including CMS, other divisions of HHS (e.g., the Office of Inspector General), the U.S.
+Added: In the United States, the research, manufacturing, distribution, sale and promotion of drug products and medical devices are potentially subject to regulation by various federal, state and local authorities in addition to the FDA, including the Centers for Medicare & Medicaid Services, other divisions of Health and Human Services (e.g., the Office of Inspector General), the U.S.
Department of Justice, state Attorneys General, and other state and local government agencies.
−Removed: For example, sales, marketing and scientific/educational grant programs must comply with fraud and abuse laws such as the federal Anti ‑Kickback Statute, as amended, the federal False Claims Act, as amended, and similar state laws.
−Removed: Pricing and rebate programs must comply with the Medicaid Drug Rebate Program requirements of the Omnibus Budget Reconciliation Act of 1990, as amended, and the Veterans Health Care Act of 1992, as amended.
−Removed: If products are made available to authorized users of the Federal Supply Schedule of the General Services Administration, additional laws and requirements apply.
−Removed: All of these activities are also potentially subject to federal and state consumer protection and unfair competition laws.
−Removed: The federal Anti ‑Kickback Statute prohibits any person, including a prescription drug manufacturer (or a party acting on its behalf), from knowingly and willfully soliciting, receiving, offering or providing remuneration, directly or indirectly, to induce or reward either the referral of an individual, or the furnishing, recommending or arranging for a good or service, for which payment may be made under a federal healthcare program such as the Medicare and Medicaid programs.
−Removed: Additionally, many states have adopted laws similar to the federal Anti ‑Kickback Statute, and some of these state prohibitions apply to referral of patients for healthcare items or services reimbursed by any third ‑ party payor, not only the Medicare and Medicaid programs .
−Removed: The federal False Claims Act imposes liability on any person or entity that, among other things, knowingly presents or causes to be presented, a false or fraudulent claim for payment by a federal healthcare program.
−Removed: The qui tam provisions of the False Claims Act allow a private individual to bring civil actions on behalf of the federal government alleging that the defendant has submitted a false claim to the federal government, and to share in any monetary recovery.
−Removed: In recent years, the number of suits brought by private individuals has increased dramatically.
−Removed: In addition, various states have enacted false claims laws analogous to the False Claims Act.
−Removed: Also, the Health Insurance Portability and Accountability Act of 1996 (HIPAA) created several new federal crimes, including healthcare fraud, and false statements relating to the delivery of or payments for healthcare benefits, items or services.
−Removed: HIPAA and its implementing regulations also established uniform federal standards for certain “covered entities”
−Removed: (healthcare providers, health plans and healthcare clearinghouses) governing the conduct of certain electronic healthcare transactions and protecting the security and privacy of protected health information.
−Removed: Many states also have similar laws.
−Removed: Under a federal “sunshine law”
−Removed: manufacturers are required to track and report to the federal government certain payments and other transfers of value made to physicians and other healthcare professionals and teaching hospitals and ownership or investment interests held by physicians and their immediate family members.
−Removed: There are also an increasing number of state “sunshine”
−Removed: laws that require manufacturers to make reports to states on pricing and marketing information.
−Removed: Several states have enacted legislation requiring pharmaceutical companies to, among other things, establish marketing compliance programs, file periodic reports with the state, make periodic public disclosures on sales, marketing, pricing, clinical trials and other activities and/or register their sales representatives and prohibiting or limiting certain other sales and marketing practices.
−Removed: Because of the breadth of these laws and the narrowness of available statutory and regulatory exemptions, it is possible that some of our business activities could be subject to challenge under one or more of such laws.
−Removed: If our operations are found to be in violation of any of the federal and state laws described above or any other governmental regulations that apply to us, we may be subject to penalties, including criminal and significant civil monetary penalties, damages, fines, imprisonment, exclusion from participation in government healthcare programs, injunctions, recall or seizure of products, total or partial suspension of production, denial or withdrawal of pre ‑ marketing product approvals, private “qui tam”
−Removed: actions brought by individual whistleblowers in the name of the government or refusal to allow us to
−Removed: enter into supply contracts, including government contracts, 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.
Europe / Rest of World Government Regulation
2 unchanged sentences
The requirements and process governing the conduct of clinical trials, product licensing, pricing and reimbursement vary from country to country.
−Removed: In addition, we and our collaborators may be subject to foreign laws and regulations and other compliance requirements, including, without limitation, anti ‑kickback laws, false claims laws and other fraud and abuse laws, as well as laws and regulations requiring transparency of pricing and marketing information and governing the privacy and security of health information, such as the European Union’s Directive 95 / 46 on the Protection of Individuals with regard to the Processing of Personal Data.
+Added: In addition, we and our collaborators may be subject to foreign laws and regulations and other compliance requirements, including, without limitation, anti-kickback laws, false claims laws and other fraud and abuse laws, as well as laws and regulations requiring transparency of pricing and marketing information and governing the privacy and security of health information, such as the European Union’s Directive 95/46 on the Protection of Individuals with regard to the Processing of Personal Data.
If we, or our collaborators, fail to comply with applicable foreign regulatory requirements, we may be subject to, among other things, fines, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions and criminal prosecution.
−Removed: As of December 31, 2014, we had 3 9 employees, 3 7 of whom were full ‑time , 16 of whom hold Ph.D.
−Removed: degrees, 2 8 of whom were engaged in research and development activities and 1 1 of whom were engaged in business development, finance, information systems, facilities, human resources or administrative support.
−Removed: None of our employees are represented by any collective bargaining unit.
−Removed: We believe that we maintain good relations with our employees.
+Added: Corporate Information
We were incorporated in California in August 1997 under the name Xencor.
−Removed: In September 2004, we reincorporated the state of Delaware under the name Xencor, Inc.
−Removed: Our principal offices are located at 111 West Lemon Avenue, Monrovia, CA 91016, and our telephone number (626) 305 ‑5900.
+Added: In September 2004, we reincorporated in the state of Delaware under the name Xencor, Inc.
+Added: Our principal offices are located at 465 North Halstead Street, Suite 200 , Pasadena, CA, 91107, and our telephone number is (626) 305-5900.
Our website address is www.xencor.com.
−Removed: Our website and the information contained on, or that can be accessed through, the website will not be deemed to be incorporated by reference in, and are not considered part of, this Annual Report on Form 10 ‑K.
−Removed: Our Annual Reports on Form 10 ‑K, Quarterly Reports on Form 10 ‑Q, Current Reports on Form 8 ‑K and amendments to reports filed or furnished pursuant to Section 13(a) and 15(d) of the Securities Exchange Act of 1934, as amended, are available free of charge of the Investor Relations portion of our web site at www.xencor.com as soon as reasonably practical after we electronically file such material with, or furnish it to, the Securities and Exchange Commission (SEC).
−Removed: We have a single operating segment and substantially all of our operating assets are located in the United States.
−Removed: For information regarding our revenue and research and development expenses for the last three fiscal years, see Item 7, ‘Management’s Discussion and Analysis of Financial Conditions and Results of Operations.”
+Added: Our website and the information contained on, or that can be accessed through, the website will not be deemed to be incorporated by reference in and are not considered part of this Annual Report.
+Added: Our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and amendments to reports filed or furnished pursuant to Section 13(a) and 15(d) of the Exchange Act, are available free of charge on the Investor Relations portion of our web site at www.xencor.com as soon as reasonably practical after we electronically file such material with, or furnish it to, the Securities and Exchange Commission (SEC).
+Added: The SEC maintains an internet site at www.sec.gov that contains reports, proxy and information statements, and other information regarding issuers that file electronically with the SEC.
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.