About Mesoblast
Mesoblast Limited and its subsidiaries (Mesoblast) primarily engage in the development of regenerative medicine products. The company’s primary proprietary regenerative medicine technology platform is based on specialized cells known as mesenchymal lineage cells. Mesoblast has developed a range of late-stage product candidates derived from its first and second generation proprietary mesenchymal lineage cell therapy technology platforms. Remestemcel-L is the company’s first-generation mesenchymal lineage stromal cell (MSC) product platform and is in late stage development for the treatment of systemic inflammatory diseases including steroid refractory acute graft versus host disease (SR-aGVHD); acute respiratory distress syndrome (ARDS); and biologic refractory inflammatory bowel disease. Rexlemestrocel-L is the company’s second generation mesenchymal lineage precursor cell product platform and is in late stage development for the treatment of chronic heart failure (CHF); and chronic low back pain (CLBP) due to degenerative disc disease. Both platforms have life cycle management strategies with promising emerging pipelines. The company’s proprietary manufacturing processes yield industrial-scale, cryopreserved, off-the-shelf, cellular medicines. These cell therapies, with defined pharmaceutical release criteria, are planned to be readily available to patients worldwide upon receiving marketing authorizations. Mesoblast’s immuno-selected, culture expanded cellular medicines are based on mesenchymal precursor cells (MPCs) and their progeny, MSCs. These are rare cells (approximately 1:100,000 in bone marrow) found around blood vessels that are central to blood vessel maintenance, repair and regeneration. These cells have a unique immunological profile with immunomodulatory effects that reduce inflammation allowing healing and repair. This mechanism of action enables the targeting of multiple disease pathways across a wide spectrum of complex diseases with significant unmet medical needs. Mesenchymal lineage cells are collected from the bone marrow of healthy adult donors and proprietary processes are utilized to expand them to a uniform, well characterized, and highly reproducible cell population. This enables manufacturing at industrial scale for commercial purposes. Another key feature of Mesoblast’s cells is they can be administered to patients without the need for donor–recipient matching or recipient immune suppression. Mesoblast’s approach to product development is to ensure rigorous scientific investigations are performed with well-characterized cell populations in order to understand mechanisms of action for each potential indication. Extensive preclinical translational studies guide clinical trials that are structured to meet stringent safety and efficacy criteria set by international regulatory agencies. All trials are conducted under the continuing review of independent Data Safety Monitoring Boards comprised of independent medical experts and statisticians. These safeguards are intended to ensure the integrity and reproducibility of results, and to ensure that outcomes observed are scientifically reliable. Allogeneic, Off-the-Shelf, Commercially Scalable Products The company’s technology platform enables development of a diverse range of products derived from the mesenchymal cell lineage in adult tissues. MPCs constitute the earliest known cell type in the mesenchymal lineage in-vivo. MPCs can be isolated using monoclonal antibodies and culture-expanded using methods that enable efficient expansion without differentiation. MSCs are defined biologically in culture following density gradient separation from other tissue cell types and following culture by plastic adherence. MSCs presumably represent culture-expanded in-vitro progeny of the undifferentiated MPCs present in-vivo. The functional characteristics of each cell type enable product development for specific indications. The company’s proprietary mesenchymal lineage cell-based products have distinct biological characteristics enabling their use for allogeneic purposes. Immune Privilege: Mesenchymal lineage cells are immune privileged, in that they do not express specific cell surface co-stimulatory molecules that initiate immune allogeneic responses. Expansion: The company has developed proprietary methods that enable the large-scale expansion of its cells while maintaining their ability to produce the key biomolecules associated with tissue health and repair. This allows the company to produce a cellular product intended to demonstrate consistent and well-defined characterization and activity. Products Commercialized by Licensees Two allogeneic mesenchymal stromal cell (MSC) products developed and commercialized by Mesoblast licensees have been approved in Japan and Europe, with both licensees the first to receive full regulatory approval for an allogeneic cellular medicine in these major markets. Mesoblast’s licensee in Japan, JCR Pharmaceuticals Co. Ltd. (JCR), is marketing its MSC-based product in Japan for the treatment of aGVHD in children and adults. TEMCELL HS Inj. (TEMCELL) was the first allogeneic cellular medicine to receive full regulatory approval in Japan. Mesoblast receives royalty income on sales of TEMCELL in Japan. In 2017, Mesoblast granted TiGenix S.A.U (TiGenix), a wholly owned subsidiary of Takeda Pharmaceutical Co. Ltd. (Takeda), exclusive access to certain of its patents to support global commercialization of Alofisel, the first allogeneic MSC therapy to receive central marketing authorization approval from the European Commission. Mesoblast receives royalty income on Takeda’s worldwide sales of Alofisel in the local treatment of perianal fistulae. Remestemcel-L for the Treatment of Steroid Refractory Acute Graft Versus Host Disease Remestemcel-L is an intravenously delivered product candidate for the treatment of steroid-refractory acute graft versus host disease, or SR-aGVHD, following an allogeneic bone marrow transplant (BMT). In a bone marrow transplant, donor cells can attack the recipient, causing a-GVHD. The donor T-cell mediated inflammatory response involves secretion of TNF-alpha and IFN-gamma, resulting in activation of pro-inflammatory T-cells and tissue damage in the skin, gut and liver, which can be fatal. Remestemcel-L is suggested to have immunomodulatory properties to counteract the cytokine storm that is implicated in various inflammatory conditions. The mechanism of action is thought to involve down-regulating the production of pro-inflammatory cytokines, increasing production of anti-inflammatory cytokines, and enabling recruitment of naturally occurring anti-inflammatory cells to involved tissues. This life-threatening disease occurs in approximately 50% of patients who receive an allogeneic BMT. Over 30,000 patients worldwide undergo an allogeneic BMT annually, primarily during treatment for blood cancers, and these numbers are increasing. In patients with the most severe form of SR-aGVHD (Grade C/D or III/IV) mortality can be as high as 90% despite optimal best available therapy. There are no FDA-approved treatments in the United States for children under 12 with SR-aGVHD. Status and Anticipated Milestones Mesoblast submitted its completed BLA to the FDA for remestemcel-L in January 2020. The BLA was subsequently accepted for priority review by the FDA on March 30, 2020, with a Prescription Drug User Fee Act (PDUFA) action date set for September 30, 2020. In August 2020, the FDA’s Oncologic Drugs Advisory Committee(ODAC) voted overwhelmingly in favor (nine to one(1)) that the available data support the efficacy of remestemcel-L in pediatric patients with SR-aGVHD. FDA issued a CRL on September 30, 2020, noting deficiencies related to clinical and Chemistry, Manufacturing and Controls (CMC) data. Mesoblast has worked to address the issues noted in the Complete Response Letter, through multiple interactions with FDA for guidance. Mesoblast provided these new data to FDA to address all CMC outstanding items as required in January 2023. In March 2023, the FDA accepted the BLA resubmission considering the resubmission to be a complete response and set a PDUFA goal date of August 2, 2023. In August 2023, the FDA provided a CRL to the BLA resubmission for remestemcel-L for the treatment of pediatric SR-aGVHD requiring more data to support marketing approval, including potency assay or clinical data. Remestemcel-L for Moderate to Severe Acute Respiratory Distress Syndrome due to COVID-19 Infection Mesoblast has entered into a non-binding Memorandum of Understanding (MOU) with Vanderbilt University Medical Center, which coordinates and works closely with clinical investigators at over 40 sites across the United States focused on studying ARDS and other critical illnesses. The MOU proposes a collaboration toward the design and execution of a second COVID-19 trial for remestemcel-L; to jointly develop a trial protocol and seek FDA approval for the trial, the results from which Mesoblast may use to support regulatory filings (such as seeking Emergency Use Authorization from FDA); and to negotiate a written, cooperative agreement and proceeding with the trial upon receipt of FDA approval. Remestemcel-L for Inflammatory Bowel Disease (IBD) – Ulcerative Colitis (UC) and Crohn’s Colitis Strategically, Mesoblast views UC and Crohn’s colitis as a potentially important label extension for remestemcel-L given the gastrointestinal involvement common to acute graft versus host disease and inflammatory bowel disease. Gastrointestinal damage is the major driver of aGVHD mortality and is linked to systemic inflammation in aGVHD. Biomarkers that predict high mortality in aGVHD, such as blood levels of soluble suppression of tumorigenicity 2 (ST2) have shown to be significantly reduced in patients treated with remestemcel-L. ST2 has also been shown to be associated with active IBD (UC & Crohn’s). Rexlemestrocel-L for Chronic Low Back Pain (CLBP) associated with Degenerative Disc Disease (DDD) Rexlemestrocel-L (MPC-06-ID) for CLBP consists of a unit dose of 6 million MPCs administered by syringe directly into a damaged disc. Mesoblast has received feedback from FDA on the Phase 3 program for CLBP and plans to conduct an additional U.S. Phase 3 trial which may support submissions for potential approval in both the U.S. and EU. Following review of the completed Phase 3 trial data, FDA agreed with Mesoblast’s proposal for pain reduction at 12 months as the primary endpoint of the next trial, with functional improvement and reduction in opioid use as secondary endpoints. In February 2023, FDA granted Regenerative Medicine Advanced Therapy (RMAT) designation for rexlemestrocel-L in the treatment of CLBP associated with disc degeneration, in combination with HA as delivery agent for injection into the lumbar disc. RMAT designations aim to expedite the development of regenerative medicine therapies intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition where preliminary clinical evidence indicates that the drug has the potential to address unmet medical needs for the disease or condition. An RMAT designation for rexlemestrocel-L provides all the benefits of Breakthrough and Fast Track designations, including rolling review and eligibility for priority review on filing of a BLA. Rexlemestrocel-L for Chronic Heart Failure Mesoblast is developing rexlemestrocel-L to fill the treatment gap for chronic heart failure (CHF). Patients with CHF continue to represent high unmet medical need despite recent advances in new therapeutic agents for chronic heart failure. The American Heart Association (AHA) estimated in 2017 that prevalence is expected to grow 46% by 2030 in the U.S., affecting more than 8 million Americans. CHF causes severe economic, social, and personal costs. Program in End Stage Heart Failure Patients Requiring Mechanical Support Rexlemestrocel-L is also being evaluated in patients with end-stage HFrEF implanted with a left ventricular assist device (LVAD). Mesoblast reported that treatment with rexlemestrocel-L resulted in greater improvement in the pre-specified analysis of left ventricular ejection fraction (LVEF) at 12 months relative to controls after a single intervention in the Phase 3 trial in NYHA class II/III chronic heart failure. Improvement in LVEF was most pronounced in the setting of inflammation and preceded long-term reduction in the 3-point MACE of cardiovascular death, non-fatal heart attack or stroke. Effects on LVEF and MACE outcomes were even more pronounced in 301 HFrEF patients with high baseline levels of inflammation as measured by hsCRP. LVEF improvement at 12 months may be an appropriate early surrogate endpoint for long-term reduction in MACE. Rexlemestrocel-L has regenerative medicine advanced therapy (RMAT) designation from the FDA for the treatment of chronic heart failure with left ventricular systolic dysfunction in patients with an LVAD. Mesoblast intends to meet with FDA under the RMAT framework to discuss the totality of the data and the evidence of a common rexlemestrocel-L MOA across the broader HFrEF spectrum. Intellectual Property The company has a large patent portfolio of issued and pending claims covering compositions of matter, uses for its mesenchymal lineage cell-based technologies and other proprietary regenerative product candidates and technologies, as well as for elements of its manufacturing processes. As of July 2023, the patent portfolio comprises approximately 1,035 patents and patent applications across 54 patent families, with protection extending through to at least 2042 in all major markets. More specifically, the company’s patent estate includes issued patent and patent applications in major markets, including, but not limited to, the United States, Europe, Japan and China. The patents that it has obtained, and continue to apply for, These patents cover, among other technology areas, a variety of MLCs (including MPCs and MSCs), and the use of MLC for expansion of hematopoietic stem cells, or HSCs. Among the indication-specific issued or pending patents covering product candidates derived from the company’s mesenchymal lineage cells are those which are directed to its lead product candidates: aGVHD, ARDS, CLBP, CHF and chronic inflammatory conditions, such as RA. The company also has issued and pending patents covering other pipeline indications, including diabetic kidney disease, inflammatory bowel disease (e.g., Crohn’s disease), neurologic diseases, eye diseases and additional orthopedic diseases. In addition, the company has in-licensed patents covering complementary technologies, such as other types of mesenchymal lineage cells, cell surface modification technologies, pay-loading technology and protein and gene technologies, as part of its strategy to expand its targeted disease applications and manage the life-cycle of its lead programs. The company’s patent portfolio also includes issued and pending coverage of proprietary manufacturing processes that are being used with its current two-dimensional manufacturing platform, as well as the 3D bioreactor manufacturing processes under development. These cell manufacturing patents cover isolation, expansion, purification, scale up, culture conditions, aggregates minimization, cryopreservation, release testing and potency assays. In addition, the company maintains as a trade secret, among other things, its proprietary FBS-free media used in its 3D bioreactor manufacturing processes. As of July 2023, the company’s patent portfolio included the following patents and patent applications in the following major jurisdictions: 53 granted U.S. patents and 41 pending U.S. patent applications; 57 granted Japanese patents and 34 pending Japanese patent applications; 33 granted Chinese patents and 28 pending Chinese patent applications; 42 granted European patents and 32 pending European patent applications; and 50 granted Australian patents and 28 pending Australian patent applications. License and Collaboration Agreements Grünenthal arrangement In September 2019, Mesoblast entered into a strategic partnership with Grünenthal GmbH (Grünenthal) to develop and commercialize MPC-06-ID, the company’s Phase 3 allogeneic cell therapy candidate for the treatment of chronic low back pain due to degenerative disc disease in patients who have exhausted conservative treatment options. The agreement was amended by the parties in June 2021. Under the partnership, Grünenthal will have exclusive commercialization rights to MPC-06-ID for Europe and Latin America. JCR Pharmaceuticals Co., Ltd.—Hematological Malignancies and Hepatocytes Collaboration in Japan In October 2013, the company acquired all of Osiris Therapeutics, Inc.’s business and assets related to culture expanded MSCs. These assets included assumption of a collaboration agreement with JCR (JCR Agreement), which will continue in existence until the later of 15 years from the first commercial sale of any product covered by the agreement and expiration of the last Osiris patent covering any such product. JCR is a research and development oriented pharmaceutical company in Japan. Under the JCR Agreement the company assumed from Osiris, JCR has the right to develop its MSCs in two fields for the Japanese market: exclusive in conjunction with the treatment of hematological malignancies by the use of HSCs derived from peripheral blood, cord blood or bone marrow, or the First JCR Field; and non-exclusive for developing assays that use liver cells for non-clinical drug screening and evaluation, or the Second JCR Field. Under the JCR Agreement, JCR obtained rights in Japan to its MSCs, for the treatment of aGVHD. JCR also has a right of first negotiation to obtain rights to commercialize MSC-based products for additional orphan designations in Japan. The company retains all rights to those products outside of Japan. The company has the right to use all safety and efficacy data generated by JCR in Japan to support its development and commercialization plans for its MSC product candidate remestemcel-L in the United States and other major healthcare markets, including for GVHD, EB and HIE. Lonza—Manufacturing Collaboration In September 2011, the company entered into a manufacturing services agreement, or MSA, with Lonza Walkersville, Inc. and Lonza Bioscience Singapore Pte. Ltd., collectively referred to as Lonza, a global leader in biopharmaceutical manufacturing. In October 2019, the company entered into an agreement with Lonza for commercial manufacture of remestemcel-L for pediatric SR-aGVHD. This agreement will facilitate inventory build ahead of the planned the U.S. market launch of remestemcel-L and commercial supply to meet Mesoblast’s long-term market projections. Singapore Economic Development Board (EDB)—Singapore Operations In 2014, the Economic Development Board of Singapore, or EDB, granted the company certain financial incentives tied to revenues generated by its Singapore operations, among other things. Central Adelaide Local Health Network Incorporated—Mesenchymal Precursor Cell Intellectual Property In October 2004, the company, through its wholly-owned subsidiary, Angioblast Systems Inc., Mesoblast, Inc., acquired certain intellectual property relating to its MPCs, or Medvet IP, pursuant to an Intellectual Property Assignment Deed, or IP Deed, with Medvet Science Pty Ltd, or Medvet. Medvet’s rights under the IP Deed were transferred to Central Adelaide Local Health Network Incorporated, or CALHNI, in November 2011. Osiris Acquisition—Continuing Obligations In October 2013, the company and Osiris entered into a purchase agreement, as amended, or the Osiris Purchase Agreement, under which it acquired all of Osiris’ business and assets related to culture expanded MSCs. Pursuant to the Osiris Purchase Agreement, the company also agreed to make certain milestone and royalty payments to Osiris pertaining to remestemcel-L for the treatment of aGVHD and Crohn’s disease. Tasly Pharmaceutical Group — Cardiovascular Alliance for China In July 2018, the company entered into a Development and Commercialization Agreement with Tasly. The Development and Commercialization Agreement provides Tasly with exclusive rights to develop, manufacture and commercialize REVASCOR in China for the treatment or prevention of CHF and MPC-25-IC for the treatment or prevention of AMI. TiGenix NV – patent license for the treatment of fistulae In December 2017, the company entered into a Patent License Agreement with TiGenix, a wholly owned subsidiary of Takeda, which granted Takeda exclusive access to certain of its patents to support global commercialization of the adipose-derived MSC product Alofisel, previously known as Cx601, a product candidate of Takeda, for the local treatment of fistulae. The agreement includes the right for Takeda to grant sub-licenses to affiliates and third parties. Research and Development The company’s research and development expenses were $27.2million for the year ended June 30, 2023. Government Regulation Governmental authorities worldwide, including the U.S. Food and Drug Administration (FDA), are charged with the administration and enforcement of various laws and regulations that impact all aspects of the development, production, importing, testing, approval, labeling, promotion, advertising, and sale of products, such as the company. All of the company’s product candidates are regulated as biological products by the Center for Biologics Evaluation and Research in the FDA. Manufacturers of the company’s products are required to comply with applicable requirements in the good manufacturing practices regulations, including quality control and quality assurance and maintenance of records and documentation. History Mesoblast Limited was founded in 2004. The company was incorporated in 2004 as a public company in Australia under the Corporations Act 2001.
