Item 1A. Risk Factors 32
Item 1B. Unresolved Staff Comments 92
Item 2. Properties 92
Item 3. Legal Proceedings 92
Item 4. Mine Safety Disclosures 92
PART II
Item 6. [Reserved] 93
Item 7A. Quantitative and Qualitative Disclosures About Market Risk 109
Item 8. Financial Statements and Supplementary Data 109
Item 9A. Controls and Procedures 110
Item 9B. Other Information 110
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 110
PART III
Item 10. Directors, Executive Officers and Corporate Governance 111
Item 11. Executive Compensation 111
PART IV
Item 14. Principal Accountant Fees and Services 112
Item 15. Exhibit and Financial Statement Schedules 112
i
JASPER THERAPEUTICS, INC.
As used in this Annual Report on Form 10-K, unless
the context requires otherwise, references to the “Company”, “Jasper”, “we”, “us”, “our”,
and similar terms refer to Jasper Therapeutics, Inc., a Delaware corporation formerly known as Amplitude Healthcare Acquisition Corporation
(“AMHC”), and its consolidated subsidiary. References to “Old Jasper” refer to the private Delaware corporation
that is now our wholly-owned subsidiary and named Jasper Tx Corp. (formerly known as Jasper Therapeutics, Inc.).
On September 24, 2021, we consummated the previously
announced Business Combination (pursuant to the Business Combination Agreement, dated May 5, 2021, by and among AMHC, Ample Merger Sub,
Inc. (“Merger Sub”) and Old Jasper). Pursuant to the terms of the Business Combination Agreement, a business combination (herein
referred to as the “Business Combination” or “Reverse Recapitalization” for accounting purposes) between AMHC
and Old Jasper was effected through the merger of Merger Sub with and into Old Jasper with Old Jasper surviving as AMHC’s wholly-owned
subsidiary. In connection with the Business Combination, AMHC changed its name from Amplitude Healthcare Acquisition Corporation to Jasper
Therapeutics, Inc.
Unless otherwise noted or the context requires otherwise,
references to our “common stock” refer to our voting common stock, par value $0.0001 per share.
CAUTIONARY NOTE REGARDING FORWARD-LOOKING STATEMENTS
Certain statements contained in this Annual Report
on Form 10-K may constitute “forward-looking statements” for purposes of federal securities laws. Such statements can be identified
by the fact that they do not relate strictly to historical or current facts. In addition, any statements that refer to projections, forecasts
or other characterizations of future events or circumstances, including any underlying assumptions, are forward-looking statements. The
words “anticipate,” “believe,” “contemplate,” “continue,”
“could,” “estimate,” “expect,” “intends,” “may,”
“might,” “plan,” “possible,” “potential,” “predict,”
“project,” “should,” “will,” “would” and similar expressions
(including the negative of any of the foregoing) may identify forward-looking statements, but the absence of these words does not mean
that a statement is not forward-looking.
Forward-looking statements in this Annual Report
on Form 10-K may include, for example, but are not limited to, statements about:
● our ability to research, discover and develop additional product candidates;
● the potential attributes and benefits of our product candidates;
● our ability to obtain funding for our operations;
● our ability to maintain the listing of our public securities on Nasdaq;
● our public securities’ potential liquidity and trading;
ii
● our ability to grow and manage growth profitably;
● our ability to identify, in-license or acquire additional technology;
● the effect of the continuing COVID-19 pandemic on the foregoing.
These forward-looking statements are based on current
expectations and beliefs concerning future developments and their potential effects. There can be no assurance that future developments
affecting us will be those that we have anticipated. These forward-looking statements involve a number of risks, uncertainties (some of
which are beyond our control) or other assumptions that may cause actual results or performance to be materially different from those
expressed or implied by these forward-looking statements. These risks and uncertainties include, but are not limited to, those factors
described under the heading “Risk Factors” in this Annual Report on Form 10-K. Should one or more of these risks or uncertainties
materialize, or should any of our assumptions prove incorrect, actual results may vary in material respects from those projected in these
forward-looking statements. Some of these risks and uncertainties may in the future be amplified by the continuing COVID-19 pandemic,
and there may be additional risks that we consider immaterial or which are unknown. It is not possible to predict or identify all such
risks. Readers are cautioned not to place undue reliance on forward-looking statements because of the risks and uncertainties related
to them and to the risk factors. We do not undertake any obligation to update or revise any forward-looking statements, whether as a result
of new information, future events or otherwise, except as may be required under applicable securities laws.
iii
PART I
ITEM 1. BUSINESS
Overview
We are a clinical-stage biotechnology company dedicated to enabling
cures through therapeutics targeting mast and hemopoietic stem cells. We are focused on the development and commercialization of safer
and more effective therapeutic agents for diseases such as Chronic Spontaneous Urticaria (“CSU”), Lower to Intermediate Risk
Myelodysplastic Syndrome (“LR-MDS”) and novel conditioning regimens for stem cell transplantation and ex-vivo gene therapy,
a technique in which genetic manipulation of cells is performed outside of the body prior to transplantation.
Our drug development pipeline includes multiple product candidates
designed to target mast and/or hematopoietic stem cells. Our lead product candidate, briquilimab (formerly known as JSP191), is in clinical
development as a novel therapeutic antibody that targets mast and stem cells in various diseases and as a conditioning agent to clear
hematopoietic stem cells from bone marrow in patients prior to undergoing allogeneic stem cell therapy or stem cell gene therapy. We are
also developing engineered hematopoietic stem cells product candidates reprogrammed using mRNA delivery (“mRNA stem cell platform”)
and gene editing that have a competitive advantage over endogenous hematopoietic stem cells (“HSCs”) because they may permit
higher levels of engraftment without the need for toxic conditioning. We also plan to continue to expand our pipeline to include other
novel mast and stem cell therapies based on immune modulation, graft engineering or cell and gene therapies. Our goal is to expand the
use of therapeutic agents targeting mast and stem cells as well as to expand curative stem cell transplants and gene therapies for all
patients, including children and the elderly.
Mast cells are immune cells that play a key role
in the inflammatory response to pathogens or injury and are typically found in the skin, lungs, digestive track, conjunctiva of the eye
and the mucosal linings of the mouth and nose. Typically, mast cells are triggered by a specific antigen or antibody interaction to release
histamine, a variety of cytokines and other chemical mediators in order fight a potential infection and to recruit additional types of
immune cells to aid in the body’s response. However, with certain diseases, such as CSU, chronic inducible urticaria, allergic asthma,
prurigo nodularis and eosinophilic esophagitis, the mast cell response is dysregulated and may lead to unwanted responses such as hives,
airway constriction or conjunctivitis. Current therapeutic approaches to controlling mast cell response include anti-histamines to counteract
the release of histamine by activated mast cells and anti-IgE antibody therapy to try to eliminate the antibodies responsible for triggering
mast cell activation. We believe that new chronic therapies that target mast cells could be beneficial in treating many diseases that
are a function of mast cell dysfunction.
Myelodysplastic syndromes (“MDS”) are
a mixed group of hematological disorders characterized by decreased production of healthy blood and/or immune cells by the hematologic
stem cells and eventual progression to Acute Myeloid Leukemia (“AML”). Patients with LR-MDS are typically treated with blood
transfusions to augment poor bone marrow stem cell function or with growth factors, such as erythropoietin, to stimulate any remaining
healthy bone marrow cells to increase production of blood or immune cells. The goals of current treatments are to delay the progression
of the disease to AML and for an eventual donor stem cell transplant for eligible patients. We believe that novel approaches that directly
target the diseased stem cells in the bone marrow of MDS patients may lead to better clinical outcomes such as decreased need for blood
transfusions, decreased use of growth factors, and delayed disease progression.
Stem cell transplantation is among the most widely practiced forms
of cellular therapy and has the potential to cure a wide variety of diseases, including cancers, genetic disorders and autoimmune diseases.
A stem cell transplant procedure involves three main steps: (i) stem cells from the patient’s or donor’s bone marrow are collected;
(ii) the patient’s bone marrow is cleared of any remaining stem cells in order to make space to receive new transplanted stem cells,
which is known as conditioning; and (iii) the new stem cells are transplanted into the patient via infusion where they fasten to, or engraft
in, the bone marrow and grow into the blood and immune cells that form the basis of reset and rebuilt blood and immune systems. Transplants
are either allogeneic or autologous, depending on the source of the new stem cells for the transplant. In an allogeneic transplant, patients
receive cells from a stem cell donor. In an autologous transplant, the patient’s own stem cells are used. Autologous transplants
also include stem cell gene therapies, where cells are collected from the patient, edited to either enable a functioning gene or correct
a defective gene, and then transplanted into the patient via infusion.
Currently, patients must receive highly toxic
and potentially life-threatening conditioning agents to prepare their bone marrow for transplantation with either donor stem cells
or their own gene-edited stem cells. Younger, fitter patients capable of surviving these toxic side effects are typically given
myeloablative, or high-intensity, conditioning whereas older or less fit patients are typically given reduced intensity, but still
toxic, conditioning which leads to less effective transplants. These toxicities include a range of acute and chronic effects to the
gastrointestinal tract, kidneys, liver, lung, endocrine and neurologic tissues. Depending upon the conditioning regimen, fitness of
the patient, and compatibility between the donor and recipient, the risk of transplant-related mortality ranges from 10% to more
than 50% in older patients. Less toxic ways to condition patients have been developed to enable transplant for older patients or
those with major comorbidities, but these regimens risk less potent disease elimination and higher rates of disease relapse. Even
though stem cell therapy can be one of the most powerful forms of disease cure, these limitations of non-targeted conditioning
regimens have seen little innovation over the past decade. We believe that novel targeting approaches to stem cell conditioning have
the potential to reduce toxicities associated with current regimens and expand the use of allogeneic and gene modified transplant in
multiple diseases.
1
Our lead product candidate, briquilimab, is a monoclonal
antibody designed to block stem cell factor (“SCF”) from binding to and signaling through the CD117 receptor on mast and stem
cells. The SCF/CD117 pathway is a survival signal for mast and stem cells and we believe that blocking this pathway may lead to depletion
of these cells from skin and bone marrow environments. Currently, we are developing briquilimab as chronic therapy for CSU and LR-MDS.
We are also developing briquilimab as a one-time conditioning therapy in various stem cell transplant settings such as severe combined
immunodeficiency (“SCID”) for which we are currently conducting a Phase 1/2 clinical trial in patients who have failed a previous
stem cell transplant. Briquilimab is also being studied by our academic and institutional partners, Stanford University and National Institutes
of Health (“NIH”), in other transplant settings, including Fanconi Anemia (“FA”), sickle cell disease (“SCD”),
chronic granulomatous disease (“CGD”) and GATA-2 Type MDS.
We are planning to evaluate briquilimab as a therapeutic
in patients with CSU, a disorder of mast cells in the skin. Patients with CSU experience swelling, redness and itching of the skin that
lasts at least six weeks due to either an unknown cause, Type I autoimmunity with Immunoglobulin E antibodies (“IgE”) against
self or Type IIb autoimmunity with activating antibodies directed at mast cells. The U.S. Food and Drug Administration (the “FDA”)-approved
drug therapy for CSU includes second generation H1-antihistamines for first line use followed by consideration for use of omalizumab,
a monoclonal antibody directed at circulating IgE. The biologic rationale for both of these therapies is based on modulating mast cell
response. Antihistamines work to counteract the effects of histamine that is released from activated mast cells and omalizumab is designed
to reduce IgE, which are thought to trigger mast cell activation. Based on preclinical and human healthy volunteer clinical data showing
that briquilimab can deplete mast cells from the skin, we believe that briquilimab could be effective therapy for CSU patients. We intend
to study briquilimab monotherapy in CSU patients who are refractory to anti-histamine therapy.
We also plan to evaluate briquilimab as a therapeutic
for certain patients with proliferative disorders of hematopoietic stem cells. MDS is a heterogeneous disorder of the bone marrow that
typically occurs in an older population and can progress to AML. The Revised International Prognostic Scoring System (“IPSS-R”)
is a clinical assessment tool used to evaluate risk and prognosis of newly diagnosed patients. Patients with IPSS-R scores of low or very
low are not typically referred for a stem cell transplant due to the risk of transplant-related toxicities from current conditioning regiments,
infection and Graft vs Host Disease (“GvHD”) outweighing the patient’s expected survival with drug therapies. These
patients typically suffer from anemia, thrombocytopenia or neutropenia and are given drug therapies such as an erythropoiesis stimulating
agent (“ESA”) to stimulate production of new cells to correct their blood deficiency. However, these agents do not target
the diseased hematopoietic stem cell and patients who become refractory to ESA are dependent on routine blood transfusions, which are
associated with poor survival rates. ESA-refractory lower-risk MDS patients have few treatment options and are a clinical unmet need.
Briquilimab
and other anti-CD117 monoclonal antibodies have been shown to deplete normal and diseased MDS human hematopoietic stem cells in clinical
and pre-clinical studies. In studies of non-human primates (“NHPs”) and healthy human volunteers, administration of a single
dose of briquilimab resulted in depletion of healthy hematopoietic stem cells followed by recovery in approximately six weeks. Additional
recent clinical data in MDS patients undergoing stem cell transplants showed depletion of hematopoietic stem cells after administration
of briquilimab alone. By depleting diseased and healthy hematopoietic stem cells, we believe that briquilimab may allow for preferential
recovery of healthy hematopoietic stem cells and restoration of normal hematopoiesis. We intend to study briquilimab monotherapy in lower-risk
MDS patients with documented cytopenia who are refractory to ESA
therapy.
We are also developing briquilimab for SCID. Due
to genetic errors at birth, SCID patients do not possess fully functional immune systems, which results in chronic infections, failure
to thrive and significantly decreased lifespans. If available, these patients are typically given a transplant from a close relative with
the goal of allowing healthy donor stem cells to establish in the patient’s bone marrow, leading to production of normal immune
cells. However, stem cell transplants are not universally successful. SCID patients with poor transplant outcomes are typically dependent
on external therapies such as intravenous immunoglobin (“IVIG”) and often have poor immunity, leading to chronic infections
and decreased lifespans. SCID patients who fail transplant are not usually given a second transplant due to their fragile health and the
significant toxicities of current conditioning agents.
2
We are currently conducting an open label Phase 1/2 clinical trial
in SCID patients with a history of a prior allogeneic transplant for SCID but with poor graft outcomes. The primary goals of the study
are to evaluate the safety of briquilimab in this population and to assess successful donor transplantation leading to improved immune
function. Based on preliminary results from the ongoing trial, we believe briquilimab has demonstrated the ability to enable engraftment
of donor HSCs as a single agent as determined by donor chimerism, or the percentage of bone marrow cells in the patient that are of donor
origin after transplant. Seven out of the first ten T cell-negative, B cell-negative (“T-B-”) SCID patients with prior allogeneic
transplant achieved donor engraftment, naïve donor T cell production and demonstrated preliminary clinical improvement after
re-transplantation using briquilimab-only conditioning. No briquilimab treatment-related serious adverse events (“SAEs”) have
been reported to date and pharmacokinetics have been consistent with earlier studies in healthy volunteers. We expect to complete enrollment
in this Phase 1/2 clinical trial in 2023.
The FDA has granted rare pediatric disease designation to briquilimab
as a conditioning treatment for patients with SCID. In addition, both the FDA and the European Medicines Agency (“EMA”) have
granted orphan drug designation to briquilimab for conditioning treatment prior to hematopoietic stem cell transplantation.
We also are evaluating briquilimab in an open label Phase 1 clinical
trial of donor stem cell transplant in patients with MDS or AML. The primary endpoints are to evaluate the safety, tolerability and pharmacokinetic
parameters of briquilimab. In this clinical trial, 0.6 mg/kg briquilimab-based conditioning was well tolerated in all 31 MDS/AML patients
as of December 31, 2022. Furthermore, it led to successful engraftment as demonstrated by sustained blood neutrophil count of >500
x 10^6 / L (Wolff 2002) in all 31 patients. Additionally, at one year post-transplant, eight of the twelve AML patients on study were
alive and disease-free, without trace evidence of leukemic cells, or minimal residual disease (“MRD”) as detected by cytogenetics,
flow cytometry or next-generation sequencing, a secondary endpoint of the clinical study. No briquilimab-related SAEs have been reported.
Among the twelve AML patients, three patients had disease relapse and one patient came off study due to late onset Grade 3 acute GvHD.
We expect to present additional data from this study, including data from the MDS patients, in 2023.
We have entered into a clinical collaboration with Stanford University
(“Stanford”) to study briquilimab-based conditioning in patients with FA with
bone marrow failure and who are eligible for stem cell transplant. This study is currently open for patient recruitment. The first two
patients enrolled in this study have been transplanted and show 100% donor myeloid chimerism, a measurement of transplant efficacy, along
with recovery of normal blood counts. We are also collaborating with the NIH to conduct clinical trials of briquilimab-based conditioning
in patients with SCD, with CGD and with GATA-2 mutated MDS. The first three patients in the SCD study have shown full myeloid chimerism
and increased production of hemoglobin compared to their pre-transplant baseline. We believe that briquilimab may also be useful for conditioning
in allogenic transplant for other diseases beyond which we are currently studying, including autoimmune diseases. We also believe that
targeted briquilimab-based conditioning may improve the efficacy and safety of gene therapies.
Our mRNA stem cell platform is designed to overcome key limitations
of stem cell transplant and stem cell gene therapy. By using mRNA delivery and/or gene editing, we believe we can reprogram donor or gene
corrected stem cells to have a transient proliferative and survival advantage over the patient’s existing cells. We believe our
initial preclinical experiments demonstrate that multiple different mRNAs can be used to improve engraftment of modified stem cells. One
example is mRNA stem cell grafts that express certain variants of CXCR4, a cell surface protein involved in cellular homing to the bone
marrow, which may lead to improved stem cell homing and engraftment in the bone marrow. Another example includes expression of a modified
stem cell factor receptor that can lead to cell line proliferation independent of SCF concentration, enabling our mRNA stem cell grafts
to outcompete unmodified HSCs through better survival and engraftment. Also, since briquilimab only blocks signaling through the SCF receptor,
these mRNA stem cell grafts are not affected by briquilimab when used in combination. Other initial experiments have shown that mRNA can
be used to express these receptor variants on the cell surface. We have also identified other potential receptor modifications that prevent
the binding of briquilimab but retain the ability to bind SCF, therefore allowing the mRNA stem cell grafts to proliferate normally even
in the presence of briquilimab.
We intend to become a fully integrated discovery, development and
commercial company in the field of mast and stem cell therapeutics. We are developing our product candidates to be used individually or,
in some cases, in combination with one another. For example, we believe our pipeline could be tailored to the patient-specific disease
so that a patient may receive more than one of our therapies as part of his or her individual allogeneic or gene-edited stem cell therapy.
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 payor communities. We expect to continue to advance our pipeline and
innovate through our research platform.
We have an exclusive license agreement with Amgen Inc. (“Amgen”)
for the development and commercialization of the briquilimab monoclonal antibody in all indications and territories worldwide. We also
have an exclusive license agreement with Stanford for the right to use briquilimab in the clearance of stem cells prior to the transplantation
of HSCs. We also entirely own the intellectual property for our mRNA stem cell platform, which has been internally developed.
Our Product Pipeline
We are developing a portfolio of novel product candidates that
we believe have the potential to meaningfully improve chronic mast and stem cell therapy for patients with certain blood disorders 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 transplant with better outcomes and reduced risk of toxicity
and mortality versus current technologies. We are developing our product candidates so that they can be used individually or in combination
with one another, such that patients may receive more than one of our therapies as part of their individual transplant journey. In addition
to our first set of clinical product candidates, we are in the process of identifying several other potential candidates from our mRNA-modified
hematopoietic stem cell platform.
3
Briquilimab
We believe briquilimab is a unique, humanized,
monoclonal antibody that targets the underlying biology of mast cell and stem cell survival pathways to potentially improve the efficacy
and safety of hematopoietic stem cell transplantation. Briquilimab is in development as a chronic therapy in CSU and LR-MDS, as well as
a conditioning agent to clear hematopoietic stem cells from the bone marrow prior to transplant. Briquilimab binds to human CD117, a receptor
for SCF, which is expressed on the surface of mast cells and hematopoietic stem and progenitor cells. The interaction of SCF and CD117
is required for mast and stem cells to survive. By blocking SCF from binding to CD117 and disrupting critical survival signals, briquilimab
leads to the depletion of mast cells in the skin and stem cells in the bone marrow. Briquilimab is in development as a conditioning agent,
both as a single agent and in combination with existing agents depending on the need in a particular transplant setting.
Briquilimab as a Primary Therapeutic for Disorders of Mast
Cells
Mast cells are primary cells of the immune system
derived from hematopoietic stem cells in the bone marrow. Mast cells store a number of different chemical mediators such as tryptase,
histamine, interleukins and heparin in granules found throughout the cell. When triggered by an allergen specific to membrane-bound IgE
antibodies, the mast cells are activated and release the content of the granules into the surrounding tissue. These chemical mediators
attract other immune cells to help with any response as well as produce a local allergic reaction consisting of inflammation, swelling,
contraction of smooth muscle and increased mucus secretion. Mast cells are usually long-lived and found at boundaries to the external
environment such as the skin, mucosal surfaces of the gut and lungs and eye.
Dysfunctional regulation and activation of mast
cells is thought to be a significant driver of multiple diseases, including urticarias, asthma, prurigo nodularis, allergic eye disease
and others. Each of these diseases has been shown to have local concentrations of mast cells, cellular response consistent with mast cell
degranulation and disease modification with use of anti-histamines. Unfortunately, currently approved agents targeting mast cells in these
diseases are ineffective in many patients, leading to continued high disease burden.
Briquilimab blocks signaling on the CD117 receptor by inhibiting the binding of SCF, the
ligand for the CD117 receptor. The interaction of SCF/CD117 on mast cells is critical for development, proliferation and survival. Without
continued signaling through CD117, mast cells will undergo apoptosis and die. We have shown that a subcutaneous dosing of briquilimab
leads to depletion of mast cells in the skin of healthy human volunteers for at least 29 days after a single administration. We believe
that depletion of mast cells in the skin of patients with urticaria or prurigo nodularis and in the lungs of patients with allergic asthma
has the potential to lead to improved disease control for those patients without adequate response to current therapies.
We intend to study briquilimab monotherapy in patients
with CSU who are refractory to second generation anti-histamine agents. We plan to file an investigational new drug (“IND”)
application with the FDA in the second quarter of 2023 with a potential study start in the third quarter of 2023.
Briquilimab
as a Primary Therapeutic for Proliferative Disorders of the Stem Cells
A transforming event in hematopoietic stem cells
can produce several different malignancies. Cancer stem cells can self-renew, have a prolonged survival rate and have the ability to give
rise to cells with more differentiated characteristics. The idea that cancer is primarily driven by a smaller population of stem cells
has important implications. For instance, many chemotherapies can shrink tumors or deplete downstream differentiated cells, but if the
chemotherapies do not kill the cancer stem cells, the tumor will grow back.
It has been shown that HSCs are the disease-initiating
cells in cancers like MDS and that these pathogenic MDS HSCs outcompete normal HSCs present in the bone marrow of affected patients. Furthermore,
these disease-initiating HSCs express CD117 and anti-CD117 antibodies can target and eradicate these pathogenic cells. This is especially
significant in a disease like MDS where available therapies either lack disease-modifying activity or possess off-target toxicity, which
prevents their use in older and/or fragile individuals who comprise most of the patients affected by MDS. Development of anti-CD117 monoclonal
antibodies, which might be safely used to target MDS clones, would represent a major step forward for the treatment of this disease.
4
We plan to evaluate briquilimab as a therapeutic for certain MDS patients.
The IPSS-R is a clinical assessment tool used to evaluate risk and prognosis of newly diagnosed patients. Patients with IPSS-R scores
of low or very low are not typically referred to stem cell transplant due to the risk of transplant-related toxicities from current conditioning
regiments, infection and GvHD outweighing the patient’s expected survival with drug therapies. These patients typically suffer from
anemia, thrombocytopenia or neutropenia and are given drug therapies such as an ESA to stimulate production of new cells to correct their
blood deficiency. However, these agents do not target the diseased hematopoietic stem cell and patients who become refractory to ESA are
dependent on routine blood transfusions, which are associated with poor survival rates. ESA refractory lower-risk MDS patients have few
treatment options and are a clinical unmet need.
Briquilimab and other anti-CD117 monoclonal antibodies have been shown
to deplete normal and diseased MDS human hematopoietic stem cells in clinical and pre-clinical studies. In studies in NHPs and healthy
human volunteers, administration of a single dose of briquilimab resulted in depletion of healthy hematopoietic stem cells followed by
recovery in approximately six weeks. Dr. Wendy Pang demonstrated at Stanford that briquilimab is capable of depleting MDS HSCs in vivo
in a xenografted mouse model. New data from our MDS/AML trial of briquilimab as a conditioning agent have revealed that the antibody can
have a direct depletion effect on CD34+CD45RA-CD117+ cells prior to administration of fludarabine or radiation. By depleting diseased
and healthy hematopoietic stem cells, we believe that briquilimab may allow for preferential recovery of healthy hematopoietic stem cells
and restoration of normal hematopoiesis.
We intend to study briquilimab monotherapy in lower-risk
MDS patients with documented cytopenia who are refractory to ESA therapy. We plan to run the primary treatment study under the existing
new drug application for MDS/AML and anticipate enrollment to begin in this single arm clinical trial in the first half of 2023.
mRNA Stem Cell Platform
Our mRNA stem cell grafts are designed to overcome
key limitations of allogeneic donor and autologous gene-edited stem cell transplants. By delivering mRNA or modifying DNA, leading to
expression of a modified receptor or protein, we can reprogram donor or gene-edited stem cells to have a transient proliferative and survival
advantage over the patient’s existing cells to permit higher levels of engraftment without the need for toxic conditioning of the
patient. mRNA stem cell grafts have the potential to eliminate the need for donor T-cells, B-cells and NK-cells which are needed in unmodified
donor HSC grafts to permit robust engraftment but can lead to GvHD, where the donor cells attack the patient’s tissues, resulting
in the need for long-term immunosuppression therapies.
Our Strategy
Our goal is to bring curative allogeneic and autologous hematopoietic cell transplant (“HCT”) and gene therapy to more people by developing compounds that can make it safer and more effective.
As part of our strategy, we aim to:
Build a leading biotechnology company to
enable cures via immune modulation, graft engineering and cell and gene therapies. We are bringing together a team of biotech
veterans, leading academic institutions and a strong syndicate of healthcare-focused investors to achieve our vision of developing improved
therapeutics for mast and stem cell diseases and improved stem cell transplantation.
Advance the development of briquilimab as
a chronic therapeutic targeted at mast and stem cell diseases. We are targeting disorders of mast and stem cells, including CSU
and LR-MDS, with briquilimab as a repeat dose therapy. We believe that briquilimab may also be effective in other diseases of the mast
or stem cell and we may consider expanding our efforts in additional indications.
Continue to develop briquilimab as a novel,
targeted pre-transplant conditioning agent enabling more efficacious and safer HCT. Starting with our lead product candidate,
briquilimab, we are advancing the field of HCT to address effective and safe pre-transplant conditioning in hematologic monogenic and
malignant disorders as well as in autoimmune disease and gene therapy. Our initial focus is on SCID, AML, MDS and autologous gene-edited
stem cell transplants.
Advance our mRNA platform to overcome the
limitations of current allogeneic and autologous gene-edited stem cell transplants. We are developing enhanced stem cell therapies
with transient proliferative advantages, which we believe may translate to superior efficacy and reduced GvHD compared to current standard
of care therapies in allogenic and autologous gene therapy transplants.
Commercialize our product candidates to expand
the use of effective and safe mast and stem cell therapies for patients and physicians in our target markets. If approved, we
plan to bring our product candidates to the American, European and Japanese markets, focusing on the top physicians and accredited transplant
centers and hospital-based prescribers who administer the majority of mast and stem cell therapies.
Form and strengthen strategic collaborations
with leading industry and academic organizations to further develop our pipeline, unlock the commercial potential of our portfolio and
provide enabling technologies for gene therapy collaborators. We intend to continue collaborations with our existing partners
and enter new strategic partnerships to develop additional candidates, generate evidence, and commercialize new products in the field
of mast and stem cell therapies.
5
Our History and Team
Jasper was founded by Dr. Judith Shizuru, Professor of Medicine
and Pediatrics at Stanford University, and Dr. Susan Prohaska, a Stanford-trained immunologist, stem cell biologist and drug developer,
with the goal of bringing curative hematopoietic stem cell transplantation to more people by making it safer and more effective. We unite
technologies from Stanford University and Amgen via expertise in stem cell transplantation, stem cell biology and drug development. Building
on bone marrow niche-clearing technology from Stanford and with our lead compound briquilimab, Dr. Shizuru initiated a clinical program
funded by the California Institute for Regenerative Medicine to safely condition patients with SCID prior to hematopoietic cell transplantation.
We have assembled a management team of experienced biopharma industry
veterans. With this leadership, we believe we are well positioned to achieve our vision of revolutionizing hematopoietic cell transplantation
with safer conditioning regimens. Ron Martell, our Chief Executive Officer, is an experienced biopharma veteran who has extensive experience
in cellular therapies and oncology drug development. Prior to joining Jasper, Mr. Martell served as the President and CEO of MorphImmune,
Inc., a private platform company advancing a highly specific targeting technology that uses a ligand-linked payload to reprogram the immune
system. Previously, he was President and CEO of Nuvelution Pharma. He was also Co-Founder and Executive Chairman of Indapta, Orca Bio
and Co-Founder and CEO of Achieve Life Sciences, where he led the merger of the company with Oncogenex. Mr. Martell has served as the
CEO of three public biopharmaceutical companies, including Sevion and NeurogesX, and has overseen billions of dollars in industry transactions.
Earlier in his career, Mr. Martell served as Senior Vice President of Commercial Operations at ImClone Systems, where he was instrumental
in deals with Bristol-Myers Squibb and Merck KGaA and built ImClone Systems’ worldwide operations to market and commercialize Erbitux®.
He also served in various leadership positions with Genentech where, as Group Manager, Oncology, he was responsible for building the company’s
oncology franchise, including the launch of Herceptin® and Rituxan®.
Members of our management team have held leadership
positions at companies that have successfully discovered, developed, and commercialized therapies for various cancers and devastating
rare diseases. These companies include Roche, Johnson & Johnson, Genentech, Bristol-Myers Squibb, Imclone, Amgen, Portola, Alexion
and many others.
Background on Hematopoietic Stem Cell Therapy
HCT is among the most widely practiced forms of
cellular therapy and has the potential to cure a wide variety of diseases. Currently, its use is limited to patients with severe disease
burden due to the toxicities of current non-targeted conditioning regimens and the limitations of the transplant grafts themselves.
Stem cell transplants first require identification
of a suitable donor and collection of the donor’s stem cells, typically from blood. Then chemotherapy or radiation-based conditioning
is used to clear the patient’s bone marrow of existing diseased stem cells in order to make space to receive new transplanted stem
cells. Finally, the donor or gene corrected stem cells are infused into the patient where they engraft into the bone marrow and produce
new blood and immune cells 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, which is used for conditions
such as multiple myeloma, non-Hodgkin’s lymphoma and certain autoimmune diseases, the patient’s own stem cells are used. Autologous
transplants also include stem cell gene therapies, in which cells are collected from the patient, edited to either insert a functioning
gene into, or correct a defective gene within, such cells and then such cells are transplanted into the patient via infusion.
In an allogeneic transplant, used for conditions such as acute
leukemias, MDS, genetic diseases and certain autoimmune diseases, patients receive cells from a stem cell donor. The preferred donor is
a biological relative who has a well-matched immune system. The second option is a matched unrelated donor identified through a bone marrow
donor registry. Transplant outcomes are not optimal with mismatched donors.
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Current State of Conditioning Regimens
Currently, patients must receive highly toxic, potentially
life-threatening and non-specific conditioning agents to prepare their bone marrow for transplantation with either donor stem cells or
their own gene-edited stem cells. Current conditioning agents are genotoxic and are associated with major toxicities and adverse events
such as oral mucositis, sepsis, veno-occlusive disease, bacteremia, pulmonary fibrosis, and GvHD in the near term. In the long term, patients
must be counseled against risk of infertility of up to 70% and risk of secondary cancers of 5-10% after chemotherapy conditioning. Additionally,
there is a treatment-related mortality risk associated with current conditioning regimens that ranges from 10% to more than 50% in older
patients. Other limitations of chemotherapy-based conditioning include incomplete engraftment, transplant ineligibility and prolonged
hospitalization.
Current State of Hematopoietic Stem Cell Grafts
Hematopoietic stem cell grafts currently have limitations
around failed or poor engraftment with the risk of clinical relapse. Furthermore, GvHD is a high-risk short- and long-term adverse event
associated with HCT as a result of donor T-cells, B-cells and NK-cells which are needed in unmodified donor HSC grafts to permit robust
engraftment. Donor immune cells may react to the patient’s tissues as foreign leading to GvHD whereas newly produced immune cells
are trained by the patient’s body to not act against the patient’s own cells. Due to this risk, patients also need to undergo
long-term immunosuppression.
Our Solution and Product Candidates
We are developing briquilimab as a conditioning agent that could
significantly expand the eligible patient population for both allogeneic and autologous gene edited hematopoietic stem cell therapies
in addition to our mRNA engineered hematopoietic stem cells that could result in better transplant efficacy with reduced complications.
Currently, approximately 20,000 patients receive allogeneic and autologous gene therapy transplants each year in the major global markets
(the United States, the United Kingdom, France, Germany, Spain, Italy and Japan), and we believe this may grow to 80,000 patients with
safe conditioning and more effective grafts.
Briquilimab is a targeted anti-CD117 (stem cell factor receptor)
antibody which we are currently evaluating in two clinical trials for conditioning prior to stem cell transplant in patients with SCID
or with MDS/AML. Briquilimab is designed to bind to CD117 with a greater affinity than SCF. By blocking signaling of the stem cell factor
receptor, briquilimab may lead to depletion of stem cell from the bone marrow. Briquilimab was also designed to minimize any interaction
with the immune system thereby reducing the risk of immune activation via mast cells or other pathways normally activated by antibodies.
We believe these attributes will allow briquilimab
to potentially be used as a monotherapy or in combination to deplete normal and diseased stem cells. The blocking of SCF by briquilimab
may remove a critical survival signal on stem cells that leads to their depletion in the bone marrow. Furthermore, the mechanism of action
(“MOA”) of briquilimab on stem cells may be synergistic with other disruptors of stem cell survival such as radiation, azacytidine,
and CD47. Our clinical strategy in SCD, AML and Higher Risk MDS aims to exploit this potentially synergistic mechanism to combine briquilimab
and low dose radiation to fully clear both diseased and normal stem cells prior to transplantation of donor cells.
The monoclonal antibody isotype and other modifications of briquilimab
were also chosen carefully to retain high affinity binding to the CD117 receptor and SCF signal blockade without recruiting other immune
cells that could lead to receptor activation, mast cell degranulation or other off-target toxicities. For example, simply changing briquilimab
from an IgG1 isotype to an IgG2 isotype would result in less potent inhibition of CD117, potentially decreasing the effect on mast and
stem cell depletion. This finding and other data demonstrate that not all anti-CD117 antibodies behave equally or have the same MOA.
Other known approaches to target CD117, such as anti-CD117 antibodies
linked to a toxin, may have off-target toxicity. In contrast to briquilimab, which provides a transient SCF signal blockade, a toxin linked
anti-CD117 antibody requires internalization by CD117 expressing cells leading to cell death. Any CD117 expressing cell including stem
cells, mast cells, germ cells and melanocytes may be affected by this mechanism. Furthermore, the complexity of an antibody-drug conjugate
molecule adds to the manufacturing, clinical and regulatory risks of the drug development process, especially for a novel linker/payload
combination that may be subject to different regulatory and Chemistry, Manufacturing and Controls reviews.
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Preclinical Transplant Data for Briquilimab — General
We conducted a preclinical study to determine if NHP HSCs are sufficiently
similar to human HSCs to allow use of the same phenotype assays used in human studies to evaluate the effect of briquilimab on NHP hematopoiesis.
This study tested, by flow cytometry, a technique used to measure physical and chemical characteristics of a population of cells, whether
homologous subsets of NHP bone marrow express the same cellular markers as human HSCs (CD34, CD90, and CD117), and if the human antibody
reagents used to identify these markers could also be used for NHP HSCs. Bone marrow samples (or bone marrow aspirates) of NHPs and humans
were stained with the antibody reagents directed against human CD34, CD90, and CD117. HSCs in both human and NHP bone marrow were phenotypically
identified using the anti-human antibodies against CD34 and CD90. A high percentage of human and NHP cells expressing CD34 and CD90 (also
CD34+ and CD90+) also express CD117. Overall, we believe these data support the use of human antibody reagents for CD34 and CD90 to assess
the effect of briquilimab on hematopoiesis in NHP in vitro and in vivo studies.
Figure 1: Briquilimab binds CD117 on CD34+CD90- and CD34+CD90+
cells in human and NHP bone marrow. Left panel: flow cytometric analysis of HSCs fluorescently labelled for CD34 and CD90. Right panel:
the identified CD34+CD90- and CD34+CD90+ cells are then fluorescently labelled with 104D2 and briquilimab. Briquilimab and 104D2 non-competitively
labeled the same population suggesting these antibodies bind different epitopes of NHP and human CD117.
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Non-clinical studies in NHPs conducted at Stanford by Hye-Sook
Kwon, Ph.D., now our Director, Biology and Translational Research, demonstrated briquilimab’s ability to deplete bone marrow HSCs
in a large animal model (Figure 2). Non-clinical studies in “humanized” mice demonstrated both depletion of human HSCs and
engraftment of allogeneic donor HSCs. These studies supported the potential for briquilimab to deplete human stem cells prior to stem
cell transplant in the IND filings for the ongoing clinical trials designed to assess the safety
and efficacy of briquilimab in HSC transplants.
Figure 2: Representative flow cytometry analysis for cells fluorescently
labeled with CD34 and CD90 on days 0, 10, and 42 post administration of 1.0 mg/kg briquilimab. CD34+ stem cells in the bone marrow of
this NHP are transiently depleted. HSC depletion lasted up to 21 days in most animals and more than 42 days in one NHP receiving the highest
dose.
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Briquilimab for Severe Combined Immunodeficiency
SCID is a genetically heterogeneous group of over
20 monogenic conditions of the immune system characterized by the lack of normal T lymphocyte development, in addition to deficiencies
of B cells, NK cells, or both in some forms which is currently curable only by hematopoietic cell transplant. The incidence of SCID is
estimated at one in 80,000 live births across all ethnic groups. Due to the toxicities associated with the chemotherapy regimens used
in standard allogeneic HCT to deplete endogenous HSC, some centers do not use conditioning regimens. SCID patients who undergo unconditioned
HCT have relatively improved overall survival but often experience incomplete immune reconstitution characterized by inadequate T cell
numbers and/or ongoing deficiency of B cell humoral immunity. This issue occurs more frequently in those patients who do not have a human
leukocyte antigen-matched donor and who therefore receive T cell depleted haploidentical donor grafts.
Patients who receive full or reduced doses of busulfan (a DNA damaging
drug) tend to engraft well and have full lymphocyte reconstitution. However, due to busulfan’s off-target toxic effects, these patients
experience both short- and long-term complications. Since these patients receive busulfan as infants, they experience chronic complications
such as growth retardation, cognitive defects, craniofacial abnormalities, liver toxicity, seizures and endocrine defects, including infertility,
and increased cancer risk.
Pre-clinical Data for Briquilimab for Severe Combined Immunodeficiency
The ability of briquilimab to deplete human hematopoiesis was evaluated
in humanized immune deficient mice that were stably engrafted with human hematopoietic grafts at Stanford by Aaron Logan, M.D., Ph.D.,
et al. The mice were treated with a single dose of either 0.5 or 3.0 mg/kg briquilimab. No significant differences in depletion of human
cells and HSCs after six weeks of treatment were noted between the two dose levels of briquilimab. After a single treatment with briquilimab,
mice were depleted of human cells in peripheral blood and bone marrow. Human HSCs and progenitor cells (CD45+CD34+CD117+) in the bone
marrow were substantially decreased for six weeks after treatment with briquilimab.
To model human transplantation with a briquilimab-based conditioning
regimen, humanized immune deficient mice that had been stably engrafted with human hematopoietic cells underwent a second transplant using
conditioning with briquilimab with or without the addition of an anti-CD52 antibody (alemtuzumab) that depletes human lymphocytes. The
second human HSC graft was from a different donor and hence, was allogeneic to the first human graft. This second donor graft was transduced
with a lentiviral vector to express the marker green fluorescence protein (“GFP”) to allow assessment of its engraftment.
CD34+ GFP marked cells were injected into untreated control mice or mice that had been treated 23 – 25 days previously with briquilimab
with or without anti-CD52. After six weeks, the blood of these secondarily transplanted mice was evaluated for evidence of GFP-marked
second donor cells.
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Figure 3: Briquilimab in addition to an anti-CD52 antibody demonstrated
the highest level of engraftment. Engraftment was demonstrated by human CD45+ cells marked to express GFP.
Mice pre-treated with briquilimab and anti-CD52
demonstrated the highest level of engraftment, with 67% (six of nine) of human CD45+ cells also expressing GFP. In mice treated only with
briquilimab, 43% (three of seven) were GFP positive. In control mice pre-treated with anti-CD52 alone, no mice (zero of seven) showed
GFP expression, while 10% (one of ten) of the control mice not given any pre-treatment showed GFP expression (Figure 3).
We believe that this study can serve as a preclinical
proof of concept of briquilimab conditioning enhanced engraftment with CD34+ progenitor cells in mice, suggesting it may be efficacious
in an analogous clinical setting. Briquilimab appeared to be particularly effective in this setting when used along with an anti-CD52
antibody, which used a separate lymphodepleting agent to suppress rejection by the immune competent first allograft.
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Clinical Data for Briquilimab for Severe Combined Immunodeficiency
We have an ongoing Phase 1/2 dose escalation open
label clinical trial to evaluate briquilimab as the sole conditioning agent to achieve HSC engraftment in patients undergoing transplant
for SCID. The primary endpoint in Phase 1 is to assess the safety and tolerability of briquilimab as a conditioning agent in SCID patients.
The two primary efficacy endpoints in Phase 2 are the proportion of patients achieving adequate donor HSC engraftment and the proportion
of patients achieving naïve CD4+ T cell production greater than or equal to 85 cells/uL, a level expected to provide immune reconstitution,
during weeks 36 to 104 post-transplant. Secondary endpoints include durability of naïve T cell production, incidence and severity
of GvHD, hematopoietic recovery and pharmacokinetic properties of briquilimab. Patients receive a single intravenous infusion of briquilimab
on study day 0 in one of four dose cohorts: 0.1 mg/kg, 0.3 mg/kg, 0.6mg/kg or 1.0 mg/kg. Patients will be followed for five years following
transplant. This trial is currently open for enrollment at multiple clinical trial sites in the United States.
Other studies of SCID patients have shown functional
T and B cell reconstitution in patients achieving long-term myeloid donor chimerism of at least 3%. SCID patients who fail to achieve
durable donor cell engraftment from a first transplant may not be candidates for a second transplant using current conditioning agents
due to the toxicity of the conditioning regimen and fragile nature of most SCID patients. These patients may remain on medically supportive
immune therapies such as intravenous immunoglobulin (“IVIG”) or receive an unconditioned “boost” transplant of
donor cells which does not lead to sustained production of new immune cells.
We believe briquilimab has enabled immune reconstitution
for patients based on naïve CD4+ T-cell levels and has shown clinical benefit in T-B- SCID patients in a re-transplant setting. Patients
have shown resolution of chronic infections, independence from or reduction of IVIG therapy and antibody response to vaccine challenge.
Through December 31, 2022 in this open label clinical trial, ten T-B- SCID re-transplant patients have been treated in the ongoing SCID
Phase 1/2 study. Seven of the ten transplanted patients have shown engraftment of donor cells and production of functional immune cells
with up to three years of follow up. No briquilimab treatment-related SAEs have been reported through December 31, 2022 in this clinical
trial.
We expect to complete enrollment in the Phase 1/2 clinical trial
in 2023.
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Briquilimab for Stem Cell Transplant in Acute Myeloid Leukemia and
Myelodysplastic Syndrome
AML is a cancer of the blood and bone marrow, diagnosed
in about 42,000 patients annually within the major global markets. It is primarily a disease of the elderly and is the most common type
of acute leukemia diagnosed in adults. Patients with AML are deemed eligible for stem cell transplantation based on criteria which includes
patient fitness (age and comorbidities) and response to initial treatment, comprising of about 40% of newly diagnosed AML patients. However,
stem cell transplants are administered to approximately 40% of the eligible patient population due to current challenges with highly toxic
conditioning regimens. Currently, approximately 8,000 patients with AML receive a stem cell transplant annually in the major global markets.
MDS is a group of disorders of the bone marrow
where hematopoietic stem cells fail to properly differentiate into mature blood cells, leading to low blood cell count. Approximately
29,000 patients are diagnosed with MDS annually in the major global markets. Of all newly diagnosed MDS patients, about 35% have intermediate
to higher-risk disease and about 30% of those are eligible for HCT based on age, comorbidities and blast count. However, about 60% of
MDS patients do not receive transplants, even though they are otherwise eligible, due to the current challenges with highly toxic conditioning
regimens. Currently, approximately 2,500 patients with MDS receive HCT each year.
HCT offers the only known potentially curative
therapy for many forms of AML and for MDS. Standard of care conditioning regimens can be divided into three groups: myeloablative conditioning,
reduced intensity conditioning and non-myeloablative conditioning. Myeloablative conditioning with high dose busulfan, high dose melphalan
or high dose radiation is the most aggressive approach and is associated with the lowest rates of disease relapse. However, due to significant
toxicities, including treatment-related mortality, this approach is reserved for the most fit and younger patients. Reduced intensity
conditioning with lower dose busulfan or lower dose melphalan can be used for a wider group of patients, but due to substantial toxicities,
many patients remain ineligible. Non-myeloablative conditioning with low dose radiation (200 – 450 cGy, or centigray, a unit of
radiation of exposure) is well tolerated but is associated with lower rates of successful donor chimerism and increased relapse rates
compared to myeloablative or reduced-intensity conditioning.
Due to their age and co-morbidities, older (60
years and older) and less fit MDS and AML patients are typically unable to tolerate more intensive therapy and the toxicities associated
with such treatments, and thus, have a worse prognosis than younger, fitter patients. Thus, safe and effective conditioning prior to HCT
represents an unmet medical need for MDS and AML patients.
Preclinical Data for Briquilimab for Myelodysplastic Syndrome
Preclinical studies of immune deficient mice engrafted
with MDS HSCs from patients with “high-risk and very high-risk disease” per IPSS-R criteria conducted at Stanford by Wendy
Pang, M.D., Ph.D., now our Senior Vice President of Research and Translational Medicine, demonstrate the utility of anti-CD117 antibodies
in the treatment of MDS. Mice xenografted with higher-risk MDS HSCs were treated with anti-human CD117 monoclonal antibody (“mAb”),
SR-1 (the parent clone to briquilimab). Initial studies showed administration of either SR-1 or briquilimab resulted in well-tolerated
and sustained depletion of MDS cells obtained from lower-risk MDS patients. Treatment of mice xenografted with higher-risk MDS HSCs cells
resulted in transient depletion (Figure 4). Given the transient depletion of higher-risk MDS cells, studies were conducted to determine
whether an anti-CD117 antibody followed by a normal human HSC allograft would lead to long-term disease amelioration of higher-risk disease.
Results showed greater than 95% cytogenetically normal CD45+ cells 12 weeks after allograft transplant (Figure 4).
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Figure 4: (A) CD117 mAb depletes MDS stem cells
as demonstrated by decreasing HSC chimerism over time. (B) Normal stem cell engraftment occurs after stem cell depletion as shown by greater
than 95% cytogenetically normal CD45+ cells 12 weeks after transplant in four higher-risk MDS-xenografted mice. (C) Normal blood formation
results after stem cell engraftment with human cell lineages for T cells (CD3+), B cells (CD19+) and myeloid cells (CD13/33+) in the bone
marrow of the four high-risk mice.
Mice xenografted with MDS HSCs from lower-risk or higher-risk patients
were treated with SR-1 concurrently with an anti-mouse CD117 mAb, ACK2, to suppress endogenous mouse HSCs, and then transplanted with
normal human UCB. Twelve weeks after this UCB HSC transplantation, both human myeloid and lymphoid cells like T cells and B cells were
observed in the bone marrow (Figure 4), indicative of successful engraftment and sustained hematopoiesis by healthy UCB HSCs for both
risk categories. Fluorescence in situ hybridization studies assessing clonal cytogenetic abnormalities confirmed that human CD45+ cells
in both groups were predominantly (greater than 95%) cytogenetically normal in all SR-1 treated and UCB HSC engrafted mice. In contrast,
MDS xenografted mice treated with the control antibody showed a persistence of high levels of MDS cells (greater than 95%) and were without
second donor HSC engraftment.
Clinical Data for Briquilimab for Acute Myeloid Leukemia and Myelodysplastic
Syndrome
We have an ongoing open label Phase 1 clinical trial
to evaluate the safety and tolerability of briquilimab conditioning, in combination with low dose radiation (200-300 cGy) and fludarabine,
in patients with AML or MDS undergoing blood stem cell transplantation. At clinical trial entry for the dose finding portion, all patients
were transplant eligible but most still had evidence of measurable residual disease (MRD positive) as detected by cytogenetics, flow cytometry
or next-generation sequencing. The dose of briquilimab is 0.6 mg/kg, fludarabine is administered at 30 mg/m2/day on transplant days -4,
-3, and -2, and total body irradiation (“TBI”) is delivered at 200 or 300 cGy on the day of transplant. The primary endpoints
are to evaluate the safety, tolerability and pharmacokinetic parameters of briquilimab. Secondary endpoints include depletion of host
HSCs, donor engraftment, donor chimerism, MRD clearance, non-relapse mortality, event-free survival and overall survival. Enrolled patients
will be followed for one year. The overall study duration is anticipated to be approximately two years.
We have completed enrollment in this Phase 1 study.
31 MDS/AML patients have been enrolled. There were no briquilimab-related SAEs. All patients demonstrated a
reduction of neutrophil counts (“ANC”) below 500/uL following a single infusion of briquilimab (0.6 mg/kg) in combination
with 200-300 cGy TBI and three days of 30 mg /m2/day fludarabine. Neutrophils are the most
common type of white blood cell and are the first cells to engraft. Following transplant, all patients showed successful donor engraftment
as evidenced by a recovery of neutrophil counts exceeding 500/uL in 13-24 days (Figure 5).
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Figure 5: Neutrophil depletion and recovery in
patients of the Phase 1 MDS/AML clinical trial. All patients demonstrated ANC greater than 500/uL within 13-24 days after transplant.
Subanalysis
of the first twelve AML patients, median age of 70 years and all of whom were at least one year post-transplant, showed 67% relapse free
survival, 75% overall survival and 8% non-relapse mortality at one year post-transplant. Nine of the twelve AML patients entered the trial
with MRD, detected by either flow cytometry or next generation sequencing, and six of these patients no longer had evidence of MRD at
one year post-transplant, with median time to MRD clearance of 90 days post-transplant (Figure 6). 67% of the AML patients are alive and