10-K
Table of Contents
UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM
10-K
(Mark One)
For the fiscal year ended
December 31
, 2021
OR
For the transition period from
to
Commission file number:
001-38541
Magenta Therapeutics, Inc.
(Exact name of registrant as specified in its charter)
100 Technology Square Cambridge, Massachusetts 02139
(Address of principal executive offices) (Zip Code)
(857)
242-0170
(Registrant’s telephone number, including area code)
Securities registered pursuant to Section 12(b) of the Act:
Title of each class Trading Symbol(s) Name of each exchange on which registered
Common Stock, $0.001 Par Value MGTA The Nasdaq Global Market
Securities registered pursuant to Section 12(g) of the Act:
None
Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☐ No ☒
Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act. Yes ☐ No ☒
Indicate by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. Yes ☒ No ☐
Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation
S-T
(§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit such files). Yes ☒ No ☐
Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a
non-accelerated
filer, a smaller reporting company
,
or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and “emerging growth company” in Rule
12b-2
of the Exchange Act.
Large accelerated filer ☐ Accelerated filer ☐
Non-accelerated filer ☒ Smaller reporting company ☒
Emerging growth company ☒
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐
Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report. ☐
Indicate by check mark whether the registrant is a shell company (as defined in Rule
12b-2
of the Exchange Act). Yes ☐ No ☒
The aggregate market value of Common Stock held
by non-affiliates of
the registrant computed by reference to the price of the registrant’s Common Stock as of June 30, 2021, the last business day of the registrant’s most recently completed second fiscal quarter, was approximately $436.0 million (based on the last reported sale price on the Nasdaq Global Market as of such date). For this computation, the registrant has excluded the market value of all shares of Common Stock reported as beneficially owned by its executive officer and directors; such exclusion shall not be deemed to constitute an admission that any such person is an affiliate of the registrant.
As of January 31, 2022, there were 58,799,157 shares of the registrant’s Common Stock, $0.001 par value per share, outstanding.
DOCUMENTS INCORPORATED BY REFERENCE
Portions of the registrant’s Proxy Statement for its 2022 Annual Meeting of Stockholders, which the registrant intends to file with the Securities and Exchange Commission not later than 120 days after the registrant’s fiscal year ended December 31, 2021, are incorporated by reference into Part III of this Annual Report on Form
10-K.
Table of Contents
Magenta Therapeutics, Inc.
Index
Page
PART I
Item 1. Business 6
Item 1A. Risk Factors 61
Item 1B. Unresolved Staff Comments 120
Item 2. Properties 120
Item 3. Legal Proceedings 120
Item 4. Mine Safety Disclosures 120
PART II
Item 7A. Quantitative and Qualitative Disclosures About Market Risk 131
Item 8. Financial Statements and Supplementary Data 132
Item 9A. Controls and Procedures 153
Item 9B. Other Information 153
PART III
Item 10. Directors, Executive Officers and Corporate Governance 157
Item 11. Executive Compensation 157
Item 14. Principal Accounting Fees and Services 157
PART IV
Item 15. Exhibits, Financial Statement Schedules 158
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FORWARD-LOOKING STATEMENTS
This Annual Report on Form
10-K
of Magenta Therapeutics, Inc. (the “Company”) contains or incorporates statements that constitute forward-looking statements within the meaning of the federal securities laws. Any express or implied statements that do not relate to historical or current facts or matters are forward-looking statements. In some cases, you can identify forward-looking statements by terminology such as “may,” “will,” “could,” “should,” “expects,” “intends,” “plans,” “anticipates,” “believes,” “estimates,” “predicts,” “projects,” “seeks,” “endeavor,” “potential,” “continue” or the negative of these terms or other comparable terminology. Forward-looking statements appear in a number of places in this Annual Report on Form
10-K
and include, but are not limited to, statements about:
• the outcomes of our preclinical studies;
• our reliance on third parties to conduct our clinical trials;
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• our ability to retain and recruit key personnel;
• our financial performance; and
• developments and projections relating to our competitors or our industry.
Although we believe that the expectations reflected in these forward-looking statements are reasonable, these statements relate to our strategy, future operations, future financial position, future revenue, projected costs, prospects, plans, objectives of management and expected market growth, and involve known and unknown risks, uncertainties and other factors including without limitation, risks, uncertainties and assumptions regarding the continuing impact of the novel coronavirus, or
COVID-19, pandemic
on our business, operations, strategy, goals and anticipated timelines, our ongoing and planned preclinical activities, our ability to initiate, enroll, conduct or complete ongoing and planned clinical trials, our timelines for regulatory submissions and our financial position that may cause our actual results, levels of activity, performance or achievements to be materially different from any future results, levels of activity, performance or achievements expressed or implied by these forward-looking statements. You are urged to carefully review the disclosures we make concerning these risks and other factors that may affect our business and operating results under “Item 1A. Risk Factors” in this Annual Report on Form
10-K,
as well as our other reports filed with the Securities and Exchange Commission (the “SEC”). Any public statements or disclosures by us following this Annual Report on
Form 10-K
that modify or impact any of the forward-looking statements contained in this Annual Report on
Form 10-K
will be deemed to modify or supersede such statements in this Annual Report on Form
10-K.
You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date of this document. The Company does not intend, and undertakes no obligation, to update any forward-looking information to reflect events or circumstances after the date of this document or to reflect the occurrence of unanticipated events, unless required by law to do so.
RISK FACTOR SUMMARY
The risk factors detailed in Item 1A entitled “Risk Factors” in this Annual Report on Form
10-K
are the risks that we believe are material to our investors and a reader should carefully consider them. Those risks are not all of the risks we face and other factors not presently known to us or that we currently believe are immaterial may also affect our business if they occur. The following is a summary of the risk factors detailed in Item 1A:
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This section contains forward-looking statements. You should refer to the explanation of the qualifications and limitations on forward-looking statements beginning on page three.
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PART I
Except where the context otherwise requires or where otherwise indicated, the terms “Magenta,” “we,” “us,” “our,” “our company,” “the company,” and “our business” refer to Magenta Therapeutics, Inc. and its consolidated subsidiary.
ITEM 1. BUSINESS
Overview
Magenta Therapeutics, Inc. is a clinical-stage biotechnology company developing novel medicines designed to bring the curative power of stem cell transplants to more patients with blood cancers, genetic diseases and autoimmune diseases.
Magenta’s drug development pipeline includes multiple clinical and preclinical product candidates designed to improve stem cell transplants. We are developing product candidates that are designed to deplete targeted cells in the bone marrow to make space for the bone marrow to receive newly transplanted stem cells, a process known as conditioning. Our targeted conditioning programs are intended to enhance the efficacy of and/or reduce the dosing levels, intensity or, in some cases, even the need for chemotoxic agents. Our first targeted conditioning program,
MGTA-117,
has entered clinical development in a Phase 1/2 trial, and our second program, a CD45-antibody drug conjugate, or
CD45-ADC,
is advancing in preclinical development. In addition to our conditioning programs, we are also developing a product candidate,
MGTA-145,
to improve the process by which stem cells are stimulated out of the bone marrow and into the bloodstream so they are available for collection for future reinfusion, known as mobilization, which is required for all transplants and gene therapy applications.
MGTA-145
is a Phase 2 clinical stage program intended to enable rapid, reliable, predictable and safe mobilization and collection of high numbers of functional stem cells for transplant.
Stem cell transplant is a well-established and potentially curative medical procedure that can reset a patient’s blood and immune system after the patient has received treatment for certain blood cancers, genetic diseases, or autoimmune diseases. Over 90,000 patients globally received a stem cell transplant in 2020. Stem cell transplants involve a three-step process: (i) stem cells are mobilized out of the patient’s or donor’s bone marrow and collected from the blood (or, in rare cases, surgically extracted from their bone marrow); (ii) the patient’s bone marrow is cleared of any remaining stem cells in order to make space to receive new transplanted stem cells; and (iii) the stem cells are transplanted into the patient via infusion where they fasten to, or engraft in, the bone marrow and grow into the blood cells and platelets that form the basis of a reset and rebuilt blood and immune system. All transplants are categorized as either autologous or allogeneic depending on the source of the new stem cells for the transplant. In an autologous transplant, the patient’s own stem cells are used. In an allogeneic transplant, patients receive cells from a stem cell donor.
Stem cell transplant, whether autologous or allogeneic, has broad applicability across disease settings, including blood cancers, gene therapies for genetic diseases and autoimmune diseases. It is the current standard of care for certain blood cancers such as acute myeloid leukemia, or AML, myelodysplastic syndromes, or MDS, multiple myeloma and
non-Hodgkin’s
lymphoma.
Hematopoietic stem cell, or HSC, based gene therapies also rely on the same steps of the stem cell transplant process with an additional step where collected stem cells are gene-corrected or modified to address the underlying disease prior to transplant. Such gene therapy approaches that leverage the stem cell transplant procedure are being investigated by numerous companies in a variety of diseases, including sickle cell disease, beta-thalassemia and lysosomal storage disorders. Autoimmune diseases such as multiple sclerosis and systemic sclerosis may also benefit from resetting the immune system through stem cell transplant.
In addition to our product candidates, Magenta’s research efforts are evaluating several early-stage targets that include a program for targeted lymphodepletion prior to therapies such as chimeric antigen receptor
T-cells
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or
CAR-T.
We also have a cell therapy program, E478, which is a small molecule aryl hydrocarbon receptor, or AHR, antagonist designed to increase the numbers of gene-modified HSCs for stem cell-based gene therapy and genome editing.
Magenta intends to become a fully integrated discovery, development, and commercial company in the field of stem cell transplant. We are developing our product candidates to be used individually or, in some cases, in combination with each other or together with other therapies. As a result, our portfolio could be tailored to the patient’s disease, such that a patient may receive more than one Magenta therapy as part of his or her individual stem cell transplant.
Our goal is to advance our product candidates through regulatory approval and bring them to the commercial market based on the data from our clinical trials and communications with regulatory agencies and payer communities. We expect to continue to advance our portfolio and innovate through our productive research programs.
Stem Cell Transplant: The Process and Current Opportunities
A stem cell transplant procedure involves three main steps: (i) stem cells are mobilized out of the patient’s or donor’s bone marrow and collected from the blood (or, in rare cases, surgically extracted from their bone marrow); (ii) the patient’s bone marrow is cleared of any remaining stem cells in order to make space to receive new transplanted stem cells; and (iii) the stem cells are transplanted into the patient via infusion where they fasten to, or engraft in, the bone marrow and grow into the blood cells and platelets that form the basis of reset and rebuilt blood and immune systems. All transplants are categorized as either autologous or allogeneic, depending on the source of the new stem cells for the transplant.
In an autologous transplant—used for conditions such as multiple myeloma,
non-Hodgkin’s
lymphoma and autoimmune diseases—the patient’s own stem cells are used. In the case of autologous stem cell gene therapy and genome editing in certain
non-malignant
diseases such as sickle cell disease, beta-thalassemia, and severe combined immunodeficiencies, the cells are collected from the patient and are modified to insert a functioning gene or correct a defective gene within the cell. Modified cells are then transplanted into the patient via infusion.
In an allogeneic transplant—used for conditions such as acute leukemias and myelodysplastic syndromes—patients receive cells from a stem cell donor. The preferred source of stem cells for an allogeneic transplant is a donor from a biological relative who has a well-matched immune system. Patients without a matched related donor have the option of finding a matched unrelated donor identified through a bone marrow donor registry. For patients without a matched related or unrelated donor, other options include mismatched donors, who can either be unrelated or related; however, transplant outcomes are not optimal with these donor types.
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Our Strategy
Magenta’s mission and culture are centered around the goal of enabling more patients with severe or life-threatening diseases to have access to the transformative benefit of stem cell transplant. We intend to provide transplant physicians with a tailored, multi-product treatment regimen based on the disease setting and the individual needs of patients. Our strategic priorities are as follows:
Bring the curative power of blood and immune reset through stem cell transplant to all patients who can benefit by advancing an integrated product portfolio
:
We believe we are the only company that is committed to addressing both conditioning and mobilization opportunities in stem cell transplant and
HSC-based
gene therapies. We are focused on creating a comprehensive portfolio of therapies to optimize the blood and immune reset process. Our initial focus is on blood cancers, genetic diseases, and autoimmune diseases, and we also plan to address other diseases for which blood and immune reset could represent a
one-time,
curative treatment.
Build on our deep expertise in stem cell biology to lead a new era in blood and immune reset through stem cell transplant
:
We have assembled a group of experts in the fields of stem cell biology, biotherapeutics and transplant medicine. With this team, we plan to convert recent scientific breakthroughs into a pipeline of product candidates for blood and immune reset therapies.
Create a fully integrated patient-focused biotechnology company
:
We are building a fully integrated biotechnology company with
end-to-end
capabilities in research, development, and commercialization, and we believe the broad and synergistic nature of our portfolio will allow us to address many of the significant limitations of stem cell transplant and transplant-based therapies.
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Commercialize our drug products to bring tailored blood and immune reset solutions to patients and physicians
:
Our commercial planning centers around hospital-based prescribers, and this is consistent across all product candidates in our portfolio. Stem cell transplants are performed in approximately 450 accredited medical centers in the U.S. and Europe, with more than half of the U.S. procedures performed at 20% of transplant centers. We have established relationships with key stakeholders within many of these top transplant centers. We believe the synergies among our programs and the well-defined structure of the current stem cell transplant provider network will allow us to commercialize our therapeutics through a focused, targeted commercial and medical affairs organization.
Strategically collaborate to realize the full potential of our portfolio
:
We own all product rights across our conditioning and mobilization programs, including
MGTA-117
and
MGTA-145.
We will evaluate additional collaborations when available to:
Our Pipeline of Product Candidates
We are developing a portfolio of novel product candidates that we believe have the potential to meaningfully improve stem cell transplant for patients with blood cancers, genetic diseases, and autoimmune diseases. Additionally, we believe our product candidates have the potential to allow more patients with debilitating or life-threatening diseases to access a
one-time,
transformative blood and immune reset through stem cell transplant with better outcomes and reduced risk of toxicities and mortality.
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We are applying our expertise in stem cell biology and biotherapeutics discovery to bring innovative product candidates to the stem cell transplant field through our programs, specifically designed to address each of the key opportunities in the stem cell transplant journey for patients:
Targeted Conditioning Programs
Targeted conditioning refers to agents that can selectively deplete stem and/or immune cells. These product candidates are designed to lessen the need for high-dose or high-intensity chemotherapeutic agents or, in the case of gene therapy applications, potentially eliminate the need for chemotherapeutic agents altogether, and make stem cell transplant more effective.
Opportunity
After a sufficient number of stem cells have been mobilized and collected, patients must be prepared, or conditioned, for transplant. Conditioning is intended to remove the disease-causing cells and make room for the new stem cells that will rebuild the healthy blood and immune system.
Conditioning for stem cell transplant and gene therapy is currently burdensome and risky for both pediatric and adult patients. The agents used today are
non-targeted
and involve high doses of systemic, toxic chemotherapy and/or radiation, which are known carcinogens and cause cancer. Most of these chemotherapy agents, including derivatives of mustard gas, were discovered more than 50 years ago, and were never intended for stem cell transplant conditioning. The current treatments eradicate the stem cells, immune cells, and diseased cells but also indiscriminately damage DNA and kill normal, healthy cells in the body. These conditioning regimens can cause long-term lung injury and liver toxicity, serious infections, organ failure, infertility, secondary cancers and even death. Nearly all transplant patients experience complications as a result of current conditioning treatments, and conditioning toxicity is responsible for up to 35% of mortality following allogeneic transplants.
Whenever possible, physicians use the most aggressive conditioning regimens, known as myeloablative conditioning, or MAC, to generate optimal efficacy outcomes for oncology and gene therapy patients. For oncology patients who can tolerate these high-intensity conditioning regimens to prepare them for stem cell transplant, over 50% are alive and without disease relapse, known as relapse-free survival, at five years post-transplant, an impressive survival rate in these high-risk patient populations. However, approximately 20% of patients receiving MAC regimens die from complications related to the transplant procedure, known as transplant-related mortality, and a significant majority experience serious short- and long-term side effects.
For the many patients that cannot tolerate such intense and toxic regimens due to advanced age or
co-morbidities,
such as decreased organ function, recent efforts have focused on reducing chemotherapy doses in
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regimens known as reduced intensity conditioning, or RIC. While significantly better tolerated, these RIC regimens, when used alone, lack the potency to adequately deplete a sufficient number of leukemic cells and therefore RIC regimens have significantly poorer disease outcomes (due to relapse) at five years post-transplant. Over 50% of patients receiving RIC relapse and only approximately 30% of patients are alive without relapse at five years following stem cell transplant. Therefore, physicians and patients must currently choose between either the superior long-term efficacy of MAC or the improved safety and tolerability of RIC.
Multiple clinical trials, including multi-center Phase 3 trials, have also shown that certain autoimmune diseases can be cured with an immune system reset through autologous stem cell transplant, with data in multiple sclerosis and scleroderma. When compared to the standard of care in relapsing remitting multiple sclerosis, clinical trials have shown that the proportion of patients with clinical benefit at two years appears to be double that of the next best treatment and that transplant prolongs the time to disease progression compared with disease modifying therapies. However, the toxicity of the required conditioning regimens has historically led many physicians to conclude that the risks of transplant in these patient populations outweigh the benefits. Currently only approximately 6% of eligible patients with multiple sclerosis and scleroderma receive a stem cell transplant, in part due to these significant risks. Magenta believes we can significantly expand the number of autoimmune patients who can benefit from immune reset with effective and safe targeted conditioning.
Our Targeted Conditioning Programs
Our targeted conditioning programs are designed to selectively eliminate stem cells and/or immune cells from a patient prior to transplant or gene therapy, and to be far less toxic than the current radiation and chemotherapy-based treatments. These programs focus on developing targeted products that remove specific cell types, with an approach that is tailored to the patient’s disease and transplant requirements.
We are developing a suite of novel ADCs for targeted conditioning. While ADCs are an established treatment for certain cancers, we believe this is the first time that ADC technology has been harnessed for transplant medicine. ADCs are a technology developed over the past 20 years where a monoclonal antibody specific for a cell surface protein is coupled to a payload via a molecule known as a linker. The ADC binds the receptor on the target cell, is internalized and degraded to release the payload into the target cell. Coupling the payload to the antibody increases the specificity of payload delivery to the target cell, reducing systemic exposure and increasing the safety and efficacy compared to delivering the payload alone or the antibody without the payload attached. Today, most ADCs are directed toward treating cancer cells expressing specific target receptors enriched on tumor cells. Our programs build on this clinically validated modality and adapt it for preparing patients for blood and immune reset through stem cell transplant.
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In our development of ADCs for use in conditioning, we are seeking to optimize several key parameters:
We are addressing each of these requirements through careful selection of the appropriate target receptor as well as antibody properties, including binding site, affinity, half-life and linker-payload chemistry.
Our targeted conditioning programs include both our ADC programs and earlier-stage research programs that leverage alternate modalities for targeted cell depletion. This is achieved by tuning the antibodies to specific cellular markers or receptors that are expressed on the particular cell types. These drugs are designed to specifically remove only the cell types required for a successful transplant, with an approach that is tailored to the patient’s disease and transplant requirements:
MGTA-117
Clinical Candidate
Our most advanced conditioning product candidate,
MGTA-117,
has entered a Phase 1/2 clinical trial in patients with relapsed/refractory AML or MDS.
MGTA-117
is an anti-CD117 antibody conjugated to an amanitin payload, and it targets CD117, also known as
c-Kit,
which is highly expressed on HSCs and leukemia cells. If clinically proven to target and safely deplete these types of cells,
MGTA-117
could improve conditioning across broad sets of diseases where stem cell transplant is either already the standard of care or could be expanded to benefit more patients.
For stem cell transplant in AML/MDS, we believe that
MGTA-117,
in combination with RIC, has the potential to demonstrate clinical outcomes that preserve the safety and tolerability of RIC while achieving the efficacy of MAC. Likewise, gene therapy is a promising approach to treat a variety of
non-malignant
diseases, including inherited metabolic disorders, sickle cell disease and beta-thalassemia, but the risks and toxicity associated with current chemotherapy-based conditioning approaches (e.g. busulfan) may limit the utility of this approach. In gene-therapy stem cell transplant,
MGTA-117
may enable single-agent conditioning and replace the use of busulfan.
Preclinical Data Supporting Clinical Development
We believe that it is critical for successful clinical development and commercialization of
MGTA-117
that we demonstrate selective target engagement, robust cell depletion and rapid clearance from the body with an
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acceptable safety profile. Our preclinical experiments have supported each of these concepts and informed our clinical trial plans.
Selective Target Engagement and Cell Depletion
In the hematopoietic system, CD117 is primarily expressed on HSC/progenitor, or HSPC, cells and mast cells but not expressed on mature immune cells such as B cells or T cells. We have demonstrated this selectivity in vitro by incubating cells with increasing concentrations of
MGTA-117.
Cells expressing CD117 were dose-dependently depleted by
MGTA-117,
while it had no depletion effect on cells lacking CD117, demonstrating the selectivity of
MGTA-117.
Based on: Nobili et.al., Long
non-coding
RNAs in normal and malignant hematopoiesis. Oncotarget (2016)
CD117 is expressed on stem cells and their progenitors and mast cells only within the hematopoetic system.
CD117-expressing cells are selectively depleted when cultured with increasing concentrations of
MGTA-117,
while CD117-negative cells are unaffected.
Cell Depletion
In humanized mice, single dose administration of
MGTA-117
engaged CD117-expressing cells with
on-target
depletion of human stem and progenitor (CD34+) cells in the bone marrow. Importantly, cells that did
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not express CD117, for example T cells, were not depleted and functional immunity was preserved. Additionally, cell depletion was payload dependent because the stand alone, or naked, antibody was shown to have no effect in the same experiment. These data collectively demonstrate that
MGTA-117
selectively engages the CD117 receptor on stem cells and their progenitors and once internalized the release of the amanitin payload results in effective potent targeted HSC depletion, while sparing non CD117 expressing cells of the immune system.
Administration of a single dose of
MGTA-117
to humanized mice results in significant depletion of CD117-positive HSC/HSPC but is without effect on CD117-negative
T-cells.
The monoclonal or naked antibody is ineffective in depleting stem cells.
In healthy primate studies, a single dose of
MGTA-117
showed dose-dependent HSC depletion in the bone marrow at seven days post-dosing with doses ≥ 0.3 mg/kg achieving ≥ 90% HSC depletion as measured by CD34+CD90+CD45RA- cells. These data demonstrate that in normal healthy primates,
MGTA-117
selectively targeted and depleted bone marrow stem cells and their progenitors. In the same studies, we observed dose-dependent depletion of peripheral blood reticulocytes. Reticulocytes do not express CD117 and therefore this sensitive depletion of these red blood cell precursors indicates the sensitivity of bone marrow erythro-progenitor cells to
MGTA-117.
Peripheral reticulocytes in the blood may therefore serve as a sensitive biomarker of
MGTA-117
effectiveness in depleting HSC/HSPC in the bone marrow compartment.
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MGTA-117
has also been shown to be effective in killing human acute myeloid leukemia cells
in vitro
. To extend these data, we assessed the ability of
MGTA-117
to reduce tumor burden and therefore extend survival in mice bearing two different human AML tumor types. We selected patient-derived AML tumor cells from a patient prior to treatment and compared that with human tumor cells from a recurrent/relapsed AML that was resistant to multiple lines of therapy. Tumor-bearing mice treated with a single dose of
MGTA-117
showed improved survival regardless of tumor-type, compared to mice left untreated or those treated with isotype control ADC (which does not bind to CD117) or multiple doses of standard aracytidine chemotherapy.
Mice bearing human tumor explants from naïve patients (PDX1) or from recurrent/relapsed patients (PDX2) showed improved survival following treatment with
MGTA-117
compared with either the isotype-control antibody or aracytidine.
Rapid Clearance
In preclinical studies, we utilized an experimental
CD117-ADC
with a full length human IgG1 antibody that had been engineered to have rapid clearance from the body which enables safe graft infusion within five days after dosing. As shown in the graphic below, the engineered half-life experimental
CD117-ADC
(that has the
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same engineered antibody as
MGTA-117
with a different
non-amanitin
payload) demonstrated rapid clearance in
non-human
primates with a half-life suitable for transplant (n=3/group). The half-life of the wild type CD117 antibody is approximately three days. The experimental
CD117-ADC
drops below limit of detection for the assay after two days and modeled pharmacokinetics (gray line) predicts the ADC will be below cytotoxic concentrations after five days.
An Experimental
CD117-ADC
Successfully Supports Transplant in a Gene Therapy Model
HSC-based
gene therapies also require conditioning of the transplant recipient prior to infusion with stem cells that have been gene-corrected or modified to address the underlying disease prior to transplant. Such gene therapy approaches that leverage the stem cell transplant procedure are being investigated by numerous companies in a variety of diseases, including sickle cell disease, beta-thalassemia and lysosomal storage disorders.
In a preclinical study, an experimental
CD117-ADC
that has the same engineered antibody with a different
non-amanitin
payload, enabled engraftment of autologous gene-modified HSCs in a
non-human
primate, or NHP, model. CD34+ cells were harvested from two rhesus NHPs and transduced with a lentiviral vector encoding beta-globin. The transduced cells were transplanted into the same animals six days after a single dose of experimental
CD117-ADC.
The neutrophil counts before and after transplantation of the transduced cells are shown for animal #1 (magenta line) and animal #2 (teal line). The animals recovered their neutrophils on day eight (animal #1) and day ten (animal #2) demonstrating that (1) the conditioning regiment was successful in depleting stem cells reflected by the severe depletion of neutrophils and (2) that the neutrophil count recovered demonstrating recovery from the conditioning and transplant.
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The success of the transplants in both animals were confirmed by measurement of vector copy number, or VCN, in the immune cells which are derived from the infused gene modified stem cells.
The VCN was stable beyond three months, the longest time point in the study, demonstrating that the gene-modified cells persisted in the body indicating the gold-standard of a durable transplant. This was comparable to historical data with four doses of busulfan conditioning, but without observation of the side effects associated with busulfan such as veno-occlusive disease, weight loss, diarrhea, mucositis, vomiting, pulmonary fibrosis or seizures.
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The graphic above shows that the VCN in the peripheral neutrophils (granulocytes) was equivalent with conditioning with one dose of the experimental
CD117-ADC
versus four doses of toxic busulfan even though the transduced CD34+ cell dose and VCN infused for the experimental
CD117-ADC
conditioned animals was lower compared to the busulfan conditioned animals
.
This indicates the conditioning with the experimental
CD117-ADC
is sufficient to enable engraftment of gene modified HSCs.
Well-Tolerated
A critical characteristic of our next generation conditioning agent
MGTA-117
is that it demonstrates safety and tolerability that supports advancement into human testing.
We determined the safety of
MGTA-117
by conducting a four-week good laboratory practices, or GLP, toxicology study in primates where a no observable adverse event level dose level was identified. There were only two target organs identified. At lower doses the target organ identified was the bone marrow with the intended pharmacological effect of stem cell depletion. At higher doses the target organ identified was the liver with transient enzyme elevations and transient histopathological changes observed. No histopathological changes were observed in kidney, reproductive organs and any other major organ. The GLP toxicology study enabled the advancement of
MGTA-117
into a Phase 1/2 clinical trial.
Clinical development of
MGTA-117
We have an ongoing Phase 1/2 clinical trial to evaluate
MGTA-117
in a multi-center, open-label, single-ascending-dose trial with patients with relapsed/refractory AML and
MDS-excess
blasts, or
MDS-EB
Dose escalation in the trial will be determined in accordance with a modified Fibonacci sequence. The primary outcomes for the clinical trial will be the evaluation of the safety profile, pharmacokinetics and pharmacodynamics of
MGTA-117
as a single dose.
The dosing cohorts expected to enroll in 2022 will allow for evaluation of
MGTA-117’s
ability to:
• selectively target CD117 as measured by receptor occupancy;
Magenta will assess data from each cohort and, after collection of adequate safety, pharmacokinetic and pharmacodynamic data, Magenta intends to engage with the U.S. Food and Drug Administration, or FDA, to transition to the primary target population of patients eligible for stem cell transplantation. In addition, Magenta plans to explore
MGTA-117
as a targeted conditioning agent for stem cell gene therapies.
We have entered into two research and clinical collaborations to evaluate the potential utility of
MGTA-117
for conditioning of patients prior to stem cell-based gene therapies:
CD45-ADC
Program
Our second
ADC-based
conditioning program is
CD45-ADC,
which targets the CD45 receptor that is expressed on both HSCs and disease-causing immune cells. For many stem cell transplant applications, it is
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important to eliminate both HSCs and immune cells in the patient prior to transplant. This is especially important as immune cell depletion is a key feature of the use of autologous stem cell transplant in patients with severe autoimmune disease. In this case, our goal is to eliminate the disease-causing auto-reactive immune cells that perpetuate the underlying autoimmune disease. Similarly, in the allogeneic blood cancer transplant setting, host immune cells must be depleted because they can elicit an immune-mediated rejection of the incoming foreign stem cells. Lastly, for cancer patients with tumors expressing CD45, there may also be a direct anti-tumor effect providing additional therapeutic benefit. For these reasons, we are developing a
CD45-ADC
product candidate that simultaneously targets both HSCs and immune cells.
Preclinical Data Supporting Development
Mouse Models of Autoimmune Disease
Data presented at the Transplant and Cellular Therapy, or TCT, and the European League Against Rheumatism, or EULAR, annual meetings in 2020 showed that a single dose of an experimental
CD45-ADC
removed disease-causing reactive T cells, enabled successful blood and immune reset, and rebuild of the immune system and was well tolerated in a reliable murine model of autoimmune disease, proteoglycan-induced arthritis. Further, a single dose of the
CD45-ADC
significantly reduced disease incidence and delayed disease onset in this model that has successfully provided preclinical proof of concept for many clinically validated
standard-of-care
therapies.
Conditioning with
CD45-ADC
Enables Immune Reset via Bone Marrow Transplant and results in halt of disease progression in a murine model of Rheumatoid Arthritis.
BALB/c mice (CD45.2
+
) were given three immunizations (study day 0, 21, and 42) with recombinant human core G1 aggrecan (60 μg in 2 mg DDA) to trigger rheumatoid arthritis (
A
). Animals were treated on day 11 post the final immunization (study day 53) and conditioned animals were transplanted with Balb/c CD45.1
+
congenic bone marrow 48 hours later (study day 55). Animals treated with a neutralizing monoclonal antibody to murine TNF α received 500 μg/mouse IP weekly starting on study day 53. Treatment with 2 mg/kg of
CD45-ADC,
but not
Isotype-ADC,
enabled full congenic donor chimerism in peripheral blood (
B
) at three weeks post-transplant. Representative paws from control and
CD45-ADC
–treated animals are shown in (
C
). Scores for the treatment groups over time are graphed in (
D
).
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Mouse Models of Allogeneic Transplant
Data presented at the European Society for Blood and Marrow Transplantation, or EMBT, and American Society of Hematology, or ASH, annual meetings in 2020 and at the TCT annual meeting in February 2021 showed that a single dose of
CD45-ADC
is fully myeloablative and enables complete chimerism in a full mismatch allogeneic stem cell transplant model without the need for additional conditioning agents.
A single dose of 5 mg/kg
CD45-ADC
is sufficient to enable allogeneic transplant of Balb/c CD45.1 donor cells into C57BL/6 recipients.
(A-D)
C57BL/six mice were conditioned with 5 mg/kg
Isotype-ADC
or
CD45-ADC.
CD45-ADC
enables ≥ 95% donor chimerism
(A)
and peripheral donor engraftment is multilineage through week 20.
(B-D)
. Terminal splenic
(E)
and thymic
(F)
chimerism in
CD45-ADC
conditioned mice were similar to TBI. *p<0.05 versus TBI; #p<0.05 versus
CD45-ADC;
ANOVA with post hoc Tukey’s multiple comparisons test.
Oncology Model Results
Data presented at the TCT annual meeting in 2020 demonstrated that a single dose administration of a short half-life
CD45-ADC
is well tolerated and is capable of reducing tumor burden by potently targeting leukemia cells in xenograft models. It significantly prolonged the median survival of animals harboring an established AML cell line and patient derived tumor cells as compared to both untreated controls and a multi-dose regimen of aracytidine, or
ARA-C,
a
standard-of-care
chemotherapy.
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A single dose of a short half-life
CD45-ADC
increases survival (A)
and effectively decreases tumor burden (B)
of human acute myeloid leukemia cells in two patient derived xenograft models compared to vehicle (PBS) or
isotype-ADC,
and comparable to a multi-dose regimen of
ARA-C,
a
standard-of-care
chemotherapy.
Treatment began when
2-16%
tumor blasts were detected in the periphery
(n=3-5
mice/group/AML PDX model). Mice were treated with a single intravenous dose of anti-human
CD45-ADC,
isotype-ADC,
or vehicle (PBS).
ARA-C
chemotherapy was administered intravenously once daily for five consecutive days. (A) Survival of CD45+CD117+ PDX AML mice treated with a single intravenous dose of
CD45-ADC
was significantly increased as compared to PBS or
isotype-ADC
controls (B).
CD45-ADC
significantly delayed tumor burden (expressed as %hCD45) in the peripheral blood of treated mice compared to PBS,
isotype-ADC
and standard of care controls.
Development plans
We plan to develop
CD45-ADC
for use in patients with autoimmune diseases, such as multiple sclerosis and scleroderma, and patients with leukemias and myelodysplastic syndromes. We have identified a lead antibody and progressed this program into
IND-enabling
studies. Magenta expects to have preclinical data from a dose ranging toxicology study in the second half of 2022.
Stem Cell Mobilization & Collection Program
Stem cell mobilization is a process by which stem cells are stimulated out of the bone marrow and into the bloodstream so they are available for collection for future reinfusion. The cells are then preserved, frozen, and stored until the time of transplant. We are developing
MGTA-145
as a new medicine intended to transform the process of mobilization and collection of stem cells.
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Opportunity
Once the patient and physician agree that stem cell transplant is the best treatment option, the source of stem cells must be identified and then the cells are collected. There are three methods of collecting stem cells from either patients or healthy donors for transplant:
Successful stem cell transplant requires collection of HSCs in both sufficient number and functionality, whether from the patient or a donor, to allow for robust engraftment and rebuilding of the blood and immune systems. Higher cell doses are associated with better outcomes and are especially important for gene therapy applications, which require processing of the stem cells following collection.
Mobilizing stem cells from the bone marrow to the blood has been shown to be an effective way to collect stem cells for transplant. Approximately 85% of the approximately 90,000 stem cell transplants performed globally each year use mobilized peripheral blood from either donors or patients as a source of stem cells.
Current approaches for stem cell mobilization include granulocyte colony-stimulating factor, or
G-CSF,
which mobilizes stem cells indirectly, requires repeated daily injections and is associated with significant side effects, including bone pain and, in some cases, splenic rupture and death. The
multi-day
regimen requires at least five days of injections of
G-CSF,
and side effects can be disruptive for both patients having their cells collected for autologous transplants and for healthy volunteers donating their cells for allogeneic transplants. For patients who are unable to mobilize a sufficient number of functional stem cells with
G-CSF,
physicians may add another drug, known as plerixafor. Plerixafor is a small molecule CXCR4 antagonist that blocks a pathway that otherwise plays an essential role in attracting and retaining HSCs in the bone marrow. It is approved for use in combination with
G-CSF
for multiple myeloma, and
non-Hodgkin’s
lymphoma patients who fail to achieve sufficient mobilization of stem cells with
G-CSF
alone.
G-CSF
can mobilize stem cells as a single agent but not to sufficient levels to be effective as a standalone agent in most disease settings.
The current unpredictability and inefficiency of stem cell mobilization and collection can also pose a significant logistical burden on transplant and apheresis centers. When planning for a patient’s transplant, transplanting physicians cannot reliably predict at the outset how long it will take to collect the number of cells required. In addition, each day scheduled for attempted mobilization and collection can cause an accumulation of both the direct costs associated with the repeated use of mobilization agents and other healthcare resources, including personnel time, and the indirect costs associated with the need to block time in the limited number of chairs in transplant centers that are used to collect stem cells. It is difficult to predict whether mobilization with
G-CSF
will be successful, especially in heavily treated blood cancer patients. Many patients require multiple collections, including approximately 40% of blood cancer patients. Finally, patients with sickle cell disease can have severe side effects with
G-CSF,
including potentially fatal complications, and therefore, plerixafor is the only available mobilization option for sickle cell disease patients. However, because of its poor efficacy as a standalone agent and the high number of stem cells required for a transplant in sickle cell disease, multiple doses of plerixafor and collections are needed in approximately 75% of sickle cell disease patients.
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Our
MGTA-145
Product Candidate
Magenta is developing
MGTA-145
as a potential first-line standard of care for stem cell mobilization in a broad range of diseases, for both autologous and allogeneic transplants.
MGTA-145,
a CXCR2 agonist, works in combination with plerixafor, a CXCR4 antagonist, to harness the physiological mechanism of stem cell mobilization. Our goal is for
MGTA-145
is to be the preferred first-line mobilization option for all patients and donors through rapid, reliable, predictable and safe mobilization and collection of high numbers of functional stem cells. We received Orphan Drug Designation from the FDA, for
MGTA-145
for the mobilization of HSCs to the peripheral blood for collection and subsequent transplant.
Mechanism of action
CXCR2 is a chemokine receptor expressed on the surface of neutrophils. Binding of
MGTA-145
to the receptor results in neutrophil activation. Published data from Magenta founders and scientists show that a key event for mobilization of stem cells is the
MGTA-145-mediated
release of proteases from activated neutrophils, which together with the actions of the CXCR4 antagonist, plerixafor, results in the rapid release of HSCs from the bone marrow into the blood. Blocking CXCR4 using plerixafor and activating neutrophils with
MGTA-145
has been shown clinically to produce an effective and synergistic untethering and release of HSCs from bone marrow into the blood, resulting in rapid, reliable, predictable and well-tolerated mobilization of HSCs.
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MGTA-145
in combination with plerixafor harnesses the natural mechanism of stem cell mobilization.
MGTA-145
Phase 1 Clinical Data – Healthy Subjects
We have completed a Phase 1 clinical trial of
MGTA-145
plus plerixafor in healthy subjects. The trial met all primary and secondary endpoints. Clinical endpoints included safety and tolerability, pharmacokinetics, target engagement and pharmacodynamic effects. Data from the trial presented at the ASH annual meeting in December 2020 showed that
MGTA-145
was safe and well tolerated as a single agent and in combination with plerixafor, and that
MGTA-145
in combination with plerixafor demonstrated rapid,
single-day
mobilization and collection of sufficient numbers of functional stem cells.
MGTA-145
was shown to engage CXCR2 on neutrophils to mobilize CD34+ stem cells into peripheral blood with limited neutrophil activation, which may minimize risk of vaso-occlusive crises in patients with sickle cell disease.
MGTA-145
Phase 2 Clinical Data – Phase 2 Investigator-Initiated Trial in Multiple Myeloma
A Magenta supported Phase 2 investigator-initiated clinical trial at Stanford University with 25 multiple myeloma patients showed that
MGTA-145,
in combination with plerixafor, mobilized a sufficient number of stem cells for transplantation and met the trial’s primary endpoint in 88% of patients (22/25). In addition, all patients transplanted with cells mobilized by
MGTA-145
plus plerixafor as of the data
cut-off
date had successful engraftment (18/18 patients) with prolonged durability through the
100-day
follow-up
period (13/13 patients) which were two key exploratory endpoints. The regimen was generally well-tolerated.
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MGTA-145
Clinical Data Confirms Potential Clinical Benefit, as Demonstrated in Multiple Myeloma from Single-Center Phase 2 Investigator-Initiated Trial (n=25 patients)
Next Steps in
MGTA-145
Clinical Development
Phase 2 Dosing and Administration Optimization Clinical Trial.
Building upon the encouraging cell collection data from the Phase 2 investigator-initiated clinical trial in multiple myeloma patients, Magenta plans to pursue a company-sponsored Phase 2 clinical trial to evaluate identified possible adjustments in the dosing and administration regimen that are expected to further increase the number of stem cells mobilized for collection. This evaluation will be performed in healthy subjects which we believe will enable expedited enrollment and reduced patient variability. This clinical trial approach is intended to inform our clinical development plans in autologous transplant, including multiple myeloma, and allogeneic stem cell transplant.
Phase 2 Sickle Cell Disease Stem Cell Mobilization and Collection (Cell Characterization;
Pre-Clinical
Gene Modification Model).
We entered into a Phase 2 clinical collaboration with bluebird bio, Inc. to evaluate the safety and potential utility of
MGTA-145,
in combination with plerixafor, for the mobilization and collection of stem cells in patients with sickle cell disease. Under the agreement, the companies will
co-fund
the clinical trial. Each party will characterize the collected cells and Magenta plans to gene- modify the cells and transplant them into established
pre-clinical
models to evaluate engraftment. Data from this clinical trial could provide
proof-of-concept
for
MGTA-145,
in combination with plerixafor, as the preferred mobilization regimen for patients with sickle cell disease and, more broadly, across all HSC gene therapy applications.
Phase 2 Allogeneic Donor Stem Cell Mobilization and Collection for Stem Cell Transplant in AML, ALL and MDS Patients.
We entered into a clinical trial collaboration with National Marrow Donor Program (as successor in interest to Be the Match Biotherapies, LLC, or Be the Match, to evaluate the potential utility of
MGTA-145,
in combination with plerixafor, to mobilize and collect stem cells from allogeneic donors for transplant in patients with AML, acute lymphocytic leukemia, or ALL, and MDS. The clinical trial commenced in 2021 and, after review of initial clinical data from the trial in parallel with the review of the multiple myeloma clinical data, we decided to close the allogeneic donor clinical trial in favor of exploring the dosing and administration adjustments described above. We decided that the dosing and administration optimization clinical trial would be more beneficial to the overall
MGTA-145
program due to its applicability to both allogeneic and autologous mobilization.
Research Programs
Our research efforts currently focus on future
ADC-based
conditioning programs. Our most advanced research program targets a receptor that is expressed on T cells, a type of immune cell. T cell depletion is
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currently performed with highly toxic,
non-specific
drugs which can lead to immune deficiency, infections and other complications, including secondary autoimmune reactions. We are pursuing targets expressed on the surfaces of T cells with the goal of offering a safer and more optimized targeted conditioning approach through T cell depletion before cell therapy such as