Mesoblast Limited (Mesoblast) is a clinical stage biotechnology company.
The company works in close collaborative associations with leading cell therapy research centers, as well as having the company’s own in-house R&D laboratories and specialists. The company ensures rigorous scientific investigations are performed with well characterized cell populations in order to understand mechanisms of action for each potential medical application. The company undertakes extensive pre-clinical translati...
Mesoblast Limited (Mesoblast) is a clinical stage biotechnology company.
The company works in close collaborative associations with leading cell therapy research centers, as well as having the company’s own in-house R&D laboratories and specialists. The company ensures rigorous scientific investigations are performed with well characterized cell populations in order to understand mechanisms of action for each potential medical application. The company undertakes extensive pre-clinical translational studies to guide subsequent clinical trials.
Mesoblast has developed a range of late-stage product candidates derived from the company’s 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); and
Biologic refractory inflammatory bowel disease, including Crohn's 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 consisted 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 the company’s 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’), now 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.
Mesoblast Product Candidates
Ryoncil (remestemcel-L) for the Treatment of Steroid Refractory Acute Graft Versus Host Disease
Ryoncil (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.
Current Status and Anticipated Milestones
Mesoblast submitted its completed BLA to the FDA for RYONCIL 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) that the available data support the efficacy of RYONCIL 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 RYONCIL for the treatment of pediatric SR-aGVHD requiring more data to support marketing approval, including potency assay or clinical data. As part of the BLA review, FDA completed the PLI of the manufacturing facility, did not issue any Form 483, and found no objectionable conditions.
In February 2024, ahead of a scheduled meeting with FDA, Mesoblast provided new data from a second potency assay for RYONCIL that provided additional product characterization as requested by FDA. In March 2024, FDA informed Mesoblast that following additional consideration the available clinical data from its Phase 3 study MSB-GVHD001 appears sufficient to support submission of the proposed BLA for remestemcel-L for the treatment of pediatric patients with SR-aGVHD. In July 2024, Mesoblast resubmitted the BLA for approval. FDA considered the resubmission to be a complete response and provided a Prescription Drug User Fee Act (‘PDUFA’) goal date of January 7, 2025.
There are no FDA-approved treatments in the U.S. for children under 12 with SR-aGVHD and only one FDA-approved treatment in the U.S. for other SR-aGVHD patients.
Mesoblast intends to conduct a targeted, controlled study in the highest-risk adults with the greatest mortality. This adult study is in line with the company’s overall commercial strategy, which envisioned a sequenced progression from pediatric to adult SR-aGVHD indications. Adults comprise 80% of the SR-aGVHD market. Mesoblast is collaborating with Blood and Marrow Transplant Clinical Trials Network (BMT CTN) in the United States, a body that is funded by the National Institutes of Health (NIH) and is responsible for approximately 80% of all U.S. allogeneic BMTs, to conduct a pivotal trial in adults with SR-aGVHD.
The U.S. adult and pediatric SR-aGVHD market requires a small, targeted commercial footprint. The target call point for SR-aGVHD will primarily be physicians in hematology/oncology who perform hematopoietic stem cell transplants. In the U.S., there are approximately 80 centers that perform pediatric transplants, with 50% of all transplants occurring at approximately 15 centers. Similarly, there are approximately 110 centers that perform adult transplants with half of those transplants occurring at approximately 20 centers.
The company has put in place a lifecycle extension strategy to generate evidence-based clinical outcomes to maximize the value of remestemcel-L in other pediatric and adult rare diseases that do not require large distribution channels. In addition, the company plans to expand investigator-initiated clinical trials for chronic GVHD and other indications that are underway or planned for the near future.
Remestemcel-L for Inflammatory Bowel Disease (IBD) – Ulcerative Colitis (UC) and Crohn’s Colitis
Current Status
A small investigator-initiated randomized, controlled study of remestemcel-L delivered by an endoscope directly to the areas of inflammation and tissue injury with medically refractory Crohn’s disease and ulcerative colitis was undertaken at Cleveland Clinic. The study is the first in humans using local cell delivery in the gut and will enable Mesoblast to compare clinical outcomes using this delivery method with results from an ongoing randomized, placebo-controlled trial in patients with biologic-refractory Crohn’s disease where remestemcel-L was administered intravenously. Results from the randomized, controlled study of remestemcel-L by direct endoscopic delivery to areas of inflammation in patients with medically refractory Crohn’s colitis were published in the peer-reviewed journal British Journal of Surgery.
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.
In CLBP, damage to the disc is the result of a combination of factors related to aging, genetics, and micro-injuries, which compromises the disc’s capacity to act as a fluid-filled cushion between vertebrae and to provide anatomical stability. Damage to the disc also results in an inflammatory response with ingrowth of nerves which results in chronic pain. This combination of anatomic instability and nerve ingrowth results in CLBP and functional disability.
With respect to mechanisms of action in CLBP, extensive pre-clinical studies have established that MLCs have anti-inflammatory effects and secrete multiple paracrine factors that stimulate new proteoglycan and collagen synthesis by chondrocytes in vitro and by resident cells in the nucleus and annulus in vivo.
Current Status and Anticipated Milestones
The Phase 3 clinical trial for CLBP completed enrollment in March 2018 with 404 patients enrolled across 48 centers in the United States and Australia randomized 1:1:1 to receive either 6 million MPCs with hyaluronic acid (MPC+HA), 6 million MPCs without hyaluronic acid (MPC) or saline control. Although the trial's composite outcomes of pain reduction together with functional responses to treatment were not met by either MPC group; the MPC+HA treatment group achieved substantial and durable reductions in pain compared to control through 24 months across the entire evaluable study population (n=391) compared with saline controls. Greatest pain reduction was observed in the pre-specified population with CLBP of shorter duration than the study median of 68 months (n=194) and subjects using opioids at baseline (n=168) with the MPC+HA group having substantially greater reduction at all time points (1, 3, 6, 12, 18 and 24 months) compared with saline controls. There was no appreciable difference in the safety of MPC groups compared to saline control over the 24-month period of follow-up in the entire study population. In subjects using opioids at baseline, the MPC+HA demonstrated a reduction in the average opioid dose over 24 months, while saline control subjects had essentially no change.
In July 2024, enrollment commenced at multiple sites across the United States in a confirmatory Phase 3 trial of rexlemestrocel-L in patients with CLBP due to inflammatory degenerative disc disease of less than five years duration. The FDA has previously confirmed alignment with Mesoblast on the design of the 300-patient randomized, placebo-controlled trial and the 12-month primary endpoint of pain reduction as an approvable indication. Key secondary measures include improvement in quality of life, function, and reduced opioid usage.
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.
Revascor (rexlemestrocel-L) for Chronic Heart Failure with Reduced Ejection Fraction (HFrEF)
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. In the U.S., it is estimated that CHF results in direct costs of $60.2 billion annually when identified as a primary diagnosis and $115.0 billion as part of a disease milieu. Mesoblast believes that targeting high-risk chronic patients with the highest unmet clinical needs provides the company with the most efficient path to market.
Revascor (rexlemestrocel-L) for HFrEF consists of 150 million mesenchymal precursor cells (MPCs) administered by direct cardiac injection. MPCs release a range of factors when triggered by specific receptor-ligand interactions within damaged tissue. Based on preclinical data, the factors released from the MPCs induce functional cardiac recovery by simultaneous activation of multiple pathways, including induction of endogenous vascular network formation, reduction in harmful inflammation, reduction in cardiac fibrosis, and reversal of endothelial dysfunction through activation of intrinsic tissue precursors.
Program in End Stage Heart Failure Patients Requiring Mechanical Support
REVASCOR is being evaluated in patients with end-stage HFrEF implanted with a left ventricular assist device (‘LVAD’).
Every year in the United States over 100,000 patients progress to end-stage HFrEF. In these patients, more than 2,500 life prolonging LVADs are implanted in the U.S. annually, of whom approximately 80% undergo the procedure as destination or permanent therapy. Most patients receiving LVADs as destination therapy have an ischemic HFrEF etiology. Compared to patients with non-ischemic HFrEF, patients with ischemic HFrEF have a 76% lower likelihood of LV functional recovery following LVAD implantation, and increased mortality over the initial 1-2 years. Resistance to functional recovery in ischemic HFrEF patients is thought to be due to excessive inflammation and microvascular insufficiency in the ischemic myocardium.
A Phase 2 trial was conducted by a multi-center team of researchers within the United States National Institutes of Health (‘NIH’)-funded Cardiothoracic Surgical Trials Network (‘CTSN’), led by Icahn School of Medicine at Mount Sinai, New York. The National Institute of Neurological Disorders and Stroke, and the Canadian Institutes for Health Research also supported this trial. Results of this Phase 2 trial were released in November 2018. The trial was a prospective, multi-center, double-blind, placebo controlled, 2:1 randomized (MPC to placebo), single-dose cohort trial to evaluate the safety and efficacy of injecting a dose of 150 million MPCs into the native myocardium of LVAD recipients. Patients with advanced CHF, implanted with an FDA-approved LVAD as bridge-to-transplant or destination therapy, were eligible to participate in the trial. All patients were followed until 12 months post randomization.
Across the 159 patients in this Phase 2 trial, the trial did not show a significant difference in the ability for patients to tolerate a wean for a period of 60 minutes. In the 70 patients with end-stage ischemic HFrEF the key findings were:
Ischemic controls were characterized by persistently elevated levels of the inflammatory cytokine IL-6, by reduced ability to be weaned from LVAD support, and by high mortality.
In contrast, in ischemic patients treated with rexlemestrocel-L, IL-6 levels returned to normal by 2 months and remained low through 12 months.
63% of ischemic patients who received a single administration of rexlemestrocel-L successfully underwent temporary weaning from full LVAD support as early as month 2 as compared with 36% of controls (p = 0.008).
The cumulative incidence of successful temporary weans off the LVAD device over 6 months was also increased by 1.55-fold over control in ischemic patients who received rexlemestrocel-L ([95% CI 1.01, 2.36]; p=0.02).
Only 4.9% of ischemic patients treated with a single administration of rexlemestrocel-L died from month 2 through month 12, as compared with 26.9% of ischemic controls, an 82% reduction (p = 0.02).
Current Status and Anticipated Milestones
In March 2024, FDA provided this feedback in formal minutes to the company following the Type B meeting held with FDA in February, 2024 for rexlemestrocel-L (Revascor) under the existing Regenerative Medicine Advanced Therapy (RMAT) designation. The FDA supported an accelerated approval pathway for rexlemestrocel-L in patients with end-stage ischemic HFrEF and a left ventricular assist device (LVAD).
In feedback provided to Mesoblast regarding potential pathways to licensure for rexlemestrocel-L, FDA’s comments indicated that the presented results may support a reasonable likelihood of clinical benefit of MPCs against mortality in LVAD patients, consistent with the criteria for accelerated approval.
Mesoblast intends to request a pre-BLA meeting with FDA to discuss data presentation, timing and FDA expectations for an accelerated approval filing in end-stage ischemic HFrEF patients with LVAD implantation.
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.
Program for Class II/III CHF patients
A multicenter, double-blinded, 1:1 randomized, sham-procedure-controlled Phase 3 study of remestemcel-L was completed across North America with 565 NYHA Class II/III patients at high risk of repeated heart failure hospitalizations or a terminal cardiac event (cardiac death, LVAD placement, heart transplant or insertion of an artificial heart). The enrollment criteria for this trial included a prior decompensated heart failure event (e.g. hospitalization) within the previous nine months and/or very high level of NT-proBNP, a protein used in diagnosis and screening of CHF. These inclusion criteria were designed for enrichment in patients with substantial left ventricular contractile abnormality, advanced CHF due to left ventricular systolic dysfunction and higher risk of recurrent decompensated heart failure hospitalizations and TCEs. This target patient population was shown to respond effectively to treatment with rexlemestrocel-L in the company’s previous Phase 2 trial.
Topline results from the 537 patients who met the criteria which allowed for treatment to occur on a 1:1 randomization basis between rexlemestrocel-L and sham control were announced in December 2021. Over a mean 30 months of follow-up, patients with advanced chronic heart failure who received a single endomyocardial treatment with rexlemestrocel-L on top of maximal therapies had 60% reduction in incidence of heart attacks or strokes and 60% reduction in death from cardiac causes when treated at an earlier stage in the progressive disease process. Despite significant reduction in the pre-specified endpoint of cardiac death, there was no reduction in study primary end point of recurrent non-fatal decompensated heart failure events, which was the trial’s primary endpoint.
The combination of the three pre-specified outcomes of cardiac death, heart attack or stroke into a single composite outcome - called the three-point major adverse cardiovascular event (MACE) is a well-established endpoint used by the FDA to determine cardiovascular risk. Rexlemestrocel-L reduced this three-point MACE by 30% compared to controls across the population of 537 patients. In the NYHA class II subgroup of 206 patients, rexlemestrocel-L reduced the three-point MACE by 55% compared to controls.
DREAM-HF Phase 3 trial results were published in the premier peer-reviewed journal for cardiovascular medicine, the Journal of the American College of Cardiology (JACC) in February 2023.
Complementary Technologies
In addition to having the most mature and diverse allogeneic cell therapy product pipeline and technology platform in the field of cellular medicines, the company has strategically targeted the acquisition of rights to technologies that are complementary to and synergistic with the company’s mesenchymal lineage cell technology platform. The aim of this activity is to maintain the company’s technology leadership position in the regenerative medicine space, while simultaneously expanding the company’s targeted disease applications and managing the life-cycle of the company’s lead programs.
The company’s complementary technologies and additional product candidates include other types of mesenchymal lineage cells, cell surface modification technologies, pay-loading technology and protein and gene technologies.
Manufacturing and Supply Chain
As of June 30, 2024, the company’s product candidates had been manufactured in two-dimensional, or 2D, planar, 10-layer cell factories, using media containing fetal bovine serum, or FBS.
The relatively small patient numbers and orphan drug designation for remestemcel-L lead the company to believe that 2D manufacturing will be adequate to meet demand for this product candidate if fully approved. The company also believe that 2D manufacturing process and facilities are commercially feasible for Phase 3 trial supply and the initial launch of MPC-06-ID for CLBP.
However, to build up commercial supply for certain of the company’s product candidates long-term, the company is developing novel manufacturing processes using three-dimensional, or 3D, bioreactors with greater capacity to improve efficiency and yields, with resulting lower-cost of goods. The company intends to evaluate products produced in 3D bioreactors in pre-clinical and potentially clinical studies, which may serve as FDA required comparability studies to 2D if successful.
The company is also focusing on the introduction of FBS-free media which has the potential to result in efficiency and yield improvements to the current 2D process. The company intends to conduct comparability studies to illustrate that products produced with this media are equivalent to those produced using FBS based media. While the company remains confident in its ability to deliver successful outcomes from each of these activities, any unexpected issues or challenges faced in doing so could delay the company’s programs or prevent the company from continuing its programs.
The company’s manufacturing activities to date have met stringent criteria set by international regulatory agencies, including the FDA. By using well-characterized cell populations, the company’s manufacturing processes promote reproducibility and batch-to-batch consistency for the company’s allogeneic cell product candidates. The company has developed robust quality assurance procedures and lot release assays to support this reproducibility and consistency.
Intellectual Property
As of July 2024, the patent portfolio comprised approximately 1,085 patents and patent applications across 66 patent families, with protection extending through to at least 2045 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 the company has obtained, and continue to apply for, cover mesenchymal lineage cell technologies and product candidates derived from these technologies, irrespective of the tissue source, including bone marrow, adipose, placenta, umbilical cord and dental pulp.
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 the company’s 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 the company’s strategy to expand its targeted disease applications and manage the life-cycle of the company’s lead programs.
The company’s patent portfolio also includes issued and pending coverage of proprietary manufacturing processes that are being used with the company’s 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 the company’s 3D bioreactor manufacturing processes.
As part of the company’s strategy, the company seeks patent protection for its product candidates and technologies in major jurisdictions, including the United States, Europe, Japan, China, and Australia; and files independent and/or counterpart patents and patent applications in other jurisdictions globally that the company deems appropriate under the circumstances, including India, Canada, Hong Kong, Israel, Korea and Singapore. As of July 2024, the company’s patent portfolio included the following patents and patent applications in the following major jurisdictions: 67 granted U.S. patents and 51 pending U.S. patent applications; 64 granted Japanese patents and 35 pending Japanese patent applications; 31 granted Chinese patents and 32 pending Chinese patent applications; 50 granted European patents and 37 pending European patent applications; and 51 granted Australian patents and 32 pending Australian patent applications.
License and Collaboration Agreements
All of the company’s revenue relates to upfront, royalty and milestone payments recognized under the license and collaboration agreements below.
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 the company’s 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 the company’s 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.
JCR received full approval in September 2015 for its MSC-based product for the treatment of children and adults with aGVHD, TEMCELL. TEMCELL is the first culture-expanded allogeneic cell therapy product to be approved in Japan. It was launched in Japan in February 2016.
The company expanded its partnership with JCR in Japan for two new indications: for wound healing in patients with EB in October 2018, and for neonatal hypoxic ischemic encephalopathy (‘HIE’), a condition suffered by newborns who lack sufficient blood supply and oxygen to the brain, in June 2019.
The company will receive royalties on TEMCELL product sales for licensed indications, if and when such indications receive marketing approval in Japan.
The company has the right to use all safety and efficacy data generated by JCR in Japan to support the company’s development and commercialization plans for the company’s 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.
The company has agreed to order a certain percentage of the company’s clinical requirements and commercial requirements for MPC products from Lonza. Lonza has agreed not to manufacture or supply commercially biosimilar versions of any of the company’s product candidates to any third party, during the term of the MSA, subject to the company’s meeting certain thresholds for sales of the company’s products.
The company relies on Lonza for the manufacture of its product candidates for preclinical and clinical testing, as well as for commercial manufacture of the company’s product candidates if marketing approval is obtained.
In October 2019, the company entered into an agreement with Lonza for commercial manufacture of remestemcel-L for pediatric SR-aGVHD. This agreement has facilitated inventory build ahead of the planned U.S. market launch of remestemcel-L and commercial supply to meet Mesoblast’s long-term market projections. The agreement provides for Lonza to expand its Singapore cGMP facilities if required to meet long-term growth and capacity needs for the product. Additionally, it anticipates introduction of new technologies and process improvements which are expected to result in significant increases in yields and efficiencies.
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 the company’s Singapore operations, among other things.
For example, in order to obtain full financial benefits from the EDB for the company’s manufacturing-related incentives, the company must manufacture at least 50% of the global volume of the company’s first three commercial products in Singapore (subject to certain exceptions), and the company would be required to construct and operate a manufacturing facility in Singapore, and hire and maintain a specified number of professionals (including supply chain personnel) in connection with the operation of that facility. The activities under the company’s MSA with Lonza could be used to fulfill all or part of the requirements to obtain the EDB financial incentives.
Central Adelaide Local Health Network Incorporated—Mesenchymal Precursor Cell Intellectual Property
In October 2004, the company, through its wholly-owned subsidiary, Angioblast Systems Inc., now Mesoblast, Inc., acquired certain intellectual property relating to the company’s 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. Under the IP Deed, the company also granted to Medvet a non-exclusive, royalty-free license to the Medvet IP for non-commercial, internal research and academic research.
Pursuant to the IP Deed, the company was assigned the rights in three U.S. patents or patent applications (including all substitutions, continuations, continuations-in-part, divisional, supplementary protection certificates, renewals, all letters patent granted thereon, and all reissues, reexaminations, extensions, confirmations, revalidations, registrations and patents of addition and foreign equivalents thereof) and all future intellectual property rights, including improvements, that might arise from research conducted at CALHNI related to MPCs and methods of isolating, culturing and expanding MPCs and their use in any therapeutic area. The company also acquired all related materials, information and know-how.
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 the company 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. Tasly will fund all development, manufacturing and commercialization activities in China for REVASCOR and MPC-25-IC.
TiGenix NV – patent license for the treatment of fistulae
In December 2017, the company entered into a Patent License Agreement with TiGenix, now a wholly owned subsidiary of Takeda, which granted Takeda exclusive access to certain of the company’s 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.
The agreement will continue in full force in each country (other than the United States) until the date upon which the last issued claim of any licensed patent covering Alofisel expires in such country (expected to be 2029) or, with respect to the United States, until the later of (i) the date upon which the last issued claim of any licensed patent covering Alofisel in the United States expires (expected to be around 2031) or (ii) the expiration of the regulatory exclusivity period in the United States with an agreed maximum term.
Either the company or Takeda may terminate the agreement for any material breach that is not cured within 90 days after notice thereof. The company also has the right to terminate the agreement, with a written notice in the event that Takeda file a petition in bankruptcy or insolvency or Takeda makes an assignment of substantially all of its assets for the benefit of its creditors.
Government Regulation
All of the company’s product candidates are regulated as biological products by the Center for Biologics Evaluation and Research in the FDA.
The company also must comply with the FDA’s advertising and promotion requirements, such as those related to direct- to-consumer advertising, the prohibition on promoting products 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 and notably, social media.
After Marketing Authorizations have been granted, the company must submit periodic safety reports to the EMA (if approval was granted under the Centralized Procedure) or to the National Health Authorities (if approval was granted under the DCP or the MRP).
To obtain regulatory approval of an investigational biological product under EU regulatory systems, the company must submit a marketing authorization application.
Business Strategies
The company is focused on the following core strategic imperatives: continue to innovate and optimize the company’s disruptive technology platform for cell-based therapeutics; develop a portfolio of clinically distinct products; focus on bringing late-stage products to market and portfolio prioritization; enabling manufacturing scale-up to meet demands of the portfolio; leverage talent base to continue to establish a culture of shared leadership and accountability; focus on strategic partnerships; focus on prudent cash management; and continue to strengthen the company’s substantial and robust intellectual property estate.
Research and Development
The company’s research and development expenses were $25.4 million for the year ended June 30, 2024.
History
Mesoblast Limited was founded in 2004. The company was incorporated in 2004 as a public company in Australia under the Corporations Act 2001.
