UNITED
STATES
SECURITIES
AND EXCHANGE COMMISSION
Washington,
D.C. 20549
FORM
10-K
(Mark
One)
☒ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
For
the fiscal year ended December 31, 2023
OR
☐TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
For
the transition period from ______________ to ______________
Commission
File Number: 001-39138
JASPER
THERAPEUTICS, INC.
(Exact
name of registrant as specified in its charter)
(Address of principal executive offices) (Zip Code)
(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
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. ☐
If
securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant
included in the filing reflect the correction of an error to previously issued financial statements. ☐
Indicate
by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based
compensation received by any of the registrant’s executive officers during the relevant recovery period pursuant to
§240.10D-1(b). ☐
Indicate
by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Act). Yes ☐ No ☒
The
aggregate market value of the voting and non-voting common equity held by non-affiliates of the registrant as of June 30, 2023 (the last
business day of the registrant’s most recently completed second fiscal quarter) was approximately $110.5 million based on the closing
price of the registrant’s common stock on June 30, 2023 of $13.70 (after giving effect to the 1-for-10 reverse stock split effected
on January 4, 2024) per share, as reported by the Nasdaq Capital Market.
As of February 26, 2024, the number of shares
of the registrant’s common stock outstanding was 15,063,896 shares of voting common stock, $0.0001 par value per share, and no shares
of non-voting common stock, $0.0001 par value per share.
DOCUMENTS
INCORPORATED BY REFERENCE
Portions of the registrant’s Definitive Proxy
Statement relating to the 2024 Annual Meeting of Stockholders, which will be filed with the Securities and Exchange Commission within
120 days after the end of the registrant’s fiscal year ended December 31, 2023, are incorporated by reference into
Part III of this Annual Report on Form 10-K.
TABLE
OF CONTENTS
PART I
Item 1. Business 1
Item 1A. Risk Factors 24
Item 1B. Unresolved Staff Comments 81
Item 1C. Cybersecurity 81
Item 2. Properties 81
Item 3. Legal Proceedings 81
Item 4. Mine Safety Disclosures 81
PART II
Item 6. [Reserved] 82
Item 7A. Quantitative and Qualitative Disclosures About Market Risk 95
Item 8. Financial Statements and Supplementary Data F-1
Item 9A. Controls and Procedures 96
Item 9B. Other Information 96
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 96
PART III
Item 10. Directors, Executive Officers and Corporate Governance 97
Item 11. Executive Compensation 97
PART IV
Item 14. Principal Accountant Fees and Services 98
Item 15. Exhibit and Financial Statement Schedules 98
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. In addition, except
as otherwise indicated, all information in this Annual Report on Form 10-K gives effect to the 1-for-10 reverse stock split of the common
stock that was effected on January 4, 2024.
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; and
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. 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 focused on developing therapeutics targeting mast cell driven diseases such as Chronic Spontaneous Urticaria
(“CSU”) and Chronic Inducible Urticaria (“CIndU”). We also have ongoing programs in diseases where
targeting diseased hemopoietic stem cells can provide benefits, such as Lower to Intermediate Risk Myelodysplastic Syndrome
(“LR-MDS”), and stem cell transplant conditioning regimens.
Our lead product candidate, briquilimab,
is a monoclonal antibody designed to block stem cell factor (“SCF”) from binding to and signaling through the CD117 (“c-Kit”)
receptor on mast and stem cells. The SCF/c-Kit pathway is a survival signal for mast cells and we believe that blocking this pathway may
lead to depletion of these cells from skin, which could lead to significant clinical benefit for patients with mast-cell driven diseases
such as chronic urticarias. To that end, we have commenced a Phase 1b/2a clinical study in CSU, are commencing a Phase 1b/2a clinical
study in CIndU and are evaluating the potential for briquilimab in other mast cell driven diseases.
We also believe that utilizing briquilimab to block
SCF binding and signaling can result in the depletion of diseased hematopoietic stem cells (“HSCs”) from the bone marrow in
certain hematologic malignancies such as myelodysplastic syndrome (“MDS”), and as a result, we are currently enrolling a Phase
1 trial evaluating briquilimab as a second-line therapy in patients with LR-MDS. We are also developing briquilimab as a one-time conditioning
therapy for severe combined immunodeficiency (“SCID”) patients undergoing a second stem cell transplant for which we are currently
conducting a Phase 1/2 clinical trial. Briquilimab is also being studied by our academic and institutional partners, Stanford University
and the National Institutes of Health, in other transplant settings, including Fanconi Anemia (“FA”), sickle cell disease
(“SCD”), chronic granulomatous disease and GATA-2 Type MDS.
We intend to become a fully integrated discovery,
development and commercial company in the field of mast cell therapeutics. We are developing our product candidates to be used individually
or, in some cases, in combination with other therapeutics. 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 broaden our pipeline with additional mast cell indications and next-generation products by leveraging our research
organization.
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 diseased stem cells prior to the transplantation of HSCs.
1
Briquilimab
We believe briquilimab is a unique, humanized,
monoclonal antibody that targets the underlying biology of mast cell survival to potentially serve as a therapeutic to prevent mast cell
driven diseases. In addition we believe briquilimab targets a key differentiation pathway for HSCs and may be developed to improve the
efficacy and safety of hematopoietic stem cell transplantation. Briquilimab binds to human c-Kit, the receptor for SCF, which is expressed
on the surface of various cells, including mast cells and hematopoietic stem and progenitor cells. The interaction of SCF and c-Kit is
required for mast cells to survive and for HSCs to remain in the bone marrow. By blocking SCF from binding to c-Kit and disrupting these
critical signals, briquilimab leads to the depletion of mast cells in the skin and the differentiation of stem cells in the bone marrow.
Briquilimab is designed to bind to c-Kit with a greater affinity than SCF.
The monoclonal antibody isotype and other modifications
of briquilimab were chosen carefully to retain high affinity binding to the c-Kit 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, designing
briquilimab as an IgG1 isotype instead of an IgG2 isotype results in more potent inhibition of c-Kit, potentially increasing the effect
on mast cell depletion. Briquilimab was also designed to be aglycosylated in order to eliminate the recruitment of other immune effector
cells that may bring unwanted effects to any cell that expresses c-Kit. This finding and other data demonstrate that not all anti-c-Kit
antibodies behave equally or have the same mechanism of action.
We are focused on advancing Briquilimab in development
as a chronic therapy in mast cell driven diseases such as CSU, CIndU and other mast cell driven indications currently under evaluation.
We also currently have an ongoing study in LR-MDS, as well as a study as a conditioning agent to clear HSCs from the bone marrow prior
to re-transplant in patients with SCID. We partnered with the National Institutes of Health (the “NIH”) and Stanford University
in several investigator sponsored trials for patients with a variety of diseases undergoing hematopoietic stem cell transplant.
Briquilimab as a Primary Therapeutic for Disorders
of Mast Cells
Mast cells are primary cells of the immune system
derived from HSCs 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 a mast cell is triggered, such as by an allergen specific to membrane-bound Immunoglobulin
E (“IgE”) antibodies, the mast cell is activated and releases 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 antihistamines. 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 c-Kit receptor
by inhibiting the binding of SCF, the ligand for the c-Kit receptor. The interaction of SCF/c-Kit on mast cells is critical for development,
proliferation and survival. Without continued signaling through c-Kit, mast cells will undergo apoptosis and die. We have shown that a
single subcutaneous dose of briquilimab leads to depletion of mast cells in the skin of healthy human volunteers for at least 29 days.
We believe that depletion of mast cells in the skin of patients with chronic urticaria or other mast cell driven diseases has the potential
to lead to improved disease control for those patients without adequate response to current therapies.
2
Figure 1 – Healthy volunteers administered single
doses of briquilimab 42 mg to 280 mg subcutaneously received punch skin biopsies to evaluate the decreases in mast cells at 4 weeks after
briquilimab was administered compared to the baseline.
(1) Jasper internal data (Phase 1a, healthy volunteer study).
Figure 2 – Healthy volunteers administered
single doses of briquilimab at the indicated doses and routes received punch skin biopsies to evaluate the number of mast cells present
at the indicated time points.
3
Briquilimab in Chronic Urticaria
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, CIndU, allergic asthma, prurigo nodularis
and eosinophilic esophagitis, the mast cell response is dysregulated and may lead to unwanted responses such as hives, itching, airway
constriction or conjunctivitis. Current therapeutic approaches to controlling mast cell response include antihistamines to counteract
the release of histamine by activated mast cells and anti-IgE antibody therapy to try to eliminate the antibodies responsible for a trigger
of 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.
In late 2023, we commenced a Phase 1b/2a clinical
study in patients with CSU. CSU is a disorder of mast cells in the skin in which patients 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. CSU is thought to affect over five million patients
in the United States, France, Germany, Italy, Spain, and the United Kingdom. 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 is thought to be a trigger of mast cell activation. Based on human healthy volunteer clinical data showing that briquilimab
can deplete mast cells from the skin and from data in a study of CSU patients showing that an anti- c-Kit antibody can control disease
symptoms, we believe that briquilimab could be effective therapy for CSU patients. The Phase 1b/2a study is a monotherapy study being
conducted in CSU patients who are refractory to antihistamine therapy and who have had an inadequate response to omalizumab. The study
design has three parts. The first part is an open-label 3+3 dose escalation with two dose cohorts (10mg and 40mg). The second part consists
of four dose cohorts (80mg Q8W, 120mg Q8W, 120mg Q12W and 180mg Q12W) in a double-blind placebo controlled format. The final part is a
single dose cohort (240 mg single-dose) in a double-blind placebo controlled format.
Figure 3 – Study Design for the Phase 1b/2a CSU Study
We are also commencing a Phase 1b/2a clinical
study in patients with CIndU. Similar to CSU, CIndU is a disorder of mast cells in the skin in which patients experience swelling,
redness and itching of the skin that lasts at least six weeks, but CIndU is induced by specific physical or environmental stimuli,
including cold, heat, exercise, pressure, sunlight and others. CIndU includes physical urticarias, such as symptomatic dermographism
and cold urticaria, as well as non-physical urticarias caused by exposure to specific stimuli, such as cholinergic urticaria and
aquagenic urticaria.
4
The FDA-approved drug therapy for CIndU consists solely of second generation
H1-antihistamines. The biologic rationale for this therapy is based on modulating mast cell response. Antihistamines work to counteract
the effects of histamine that is released from activated mast cells. CIndU is thought to affect over two million patients in the United
States, France, Germany, Italy, Spain and the United Kingdom. Approximately 40% of these patients’ CIndU is not controlled by first
line antihistamines and these patients could be eligible for biologic therapy depending on disease severity. 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 an effective therapeutic for CIndU patients. The Phase 1b/2a study is a monotherapy study being conducted in CIndU patients who are
refractory to antihistamine therapy. The study design contains a single dose in two dosing cohorts (40mg and 120mg) with a provocation
test measured at 12 weeks post-dosing.
Figure 4 – Study Design for the
Phase 1b/2a CIndU Study
Briquilimab in Other Mast Cell Disorders
Mast cells may also be the key cellular target
for a number of other inflammatory or autoimmune diseases outside of the chronic urticarias such as allergic asthma, atopic dermatitis,
eosinophilic esophagitis or prurigo nodularis.
Allergic asthma is a form of asthma triggered by
specific allergens that leads to constriction of smooth muscles in the airways, cellular infiltration of various immune mediators and
excess production of mucus. Patients with allergic asthma may have an increased number of mast cells in the bronchi and may be responsive
to agents that modulate mast cell response, including antihistamines and anti IgE monoclonal antibody therapy.
Atopic dermatitis is a chronic disease that causes
inflammation, redness, and irritation of the skin. It is a common condition that usually begins in childhood; however, anyone can get
the disease at any age. Atopic dermatitis causes the skin to become extremely itchy. In most cases, there are periods of time when the
disease is worse, called flares, followed by periods when the skin improves or clears up entirely, called remissions. Treatments include
moisturizers, topical steroids, immunomodulators (tacrolimus and pimecrolimus) and biologic therapies (dupilumab). Mast cells may
play an important role in the disease and agents that modulate mast cells may provide benefit to patients.
Eosinophilic esophagitis is an immune disorder
leading to build up of eosinophils in the esophagus and causes difficulty in eating, chronic reflux and/or the sensation of heartburn.
Along with the buildup of eosinophils, there is typically buildup of other immune cells in the affected area including mast cells, basophils
and lymphocytes. Patients may be treated with changes to diet, use of proton pump inhibitors, antihistamines and dupilumab.
Prurigo Nodularis is also a disease that manifests
in the skin. Patients develop severe itch and firm bumps on the skin, called nodules, that may lead to loss of sleep and bleeding due
to scratching. Degranulation of mast cells in the skin is thought to trigger peripheral sensory neurons in the skin leading to itch. Various
medications are used to treat Prurigo Nodularis including anti-itch creams and topical steroids. For cases that remain uncontrolled physicians
may prescribe antihistamines or biologics such as dupilumab.
We are currently engaged in pre-clinical evaluation
of briquilimab as a potential therapeutic in these and a number of other mast cell driven diseases and expect to continue to expand our
portfolio of mast cell indications in clinical development moving forward.
Briquilimab as a Primary Therapeutic for Lower Risk Myelodysplastic
Syndrome
A transforming event in HSCs 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 c-Kit and anti-c-Kit antibodies can target and eradicate these pathogenic cells. This is especially
significant in a disease like LR-MDS where available therapies either lack disease-modifying activity or possess off-target toxicity.
Development of anti-c-Kit monoclonal antibodies, which might be safely used to preferentially target MDS clones, would represent a major
step forward for the treatment of this disease.
5
MDS is 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. Approximately 29,000 patients are diagnosed with MDS annually in the major global markets.
Of all newly diagnosed MDS patients, about 70% have low to intermediate risk disease. About half of these patients cannot maintain adequate
hemostasis and become dependent on blood or platelet transfusion and may be eligible for erythropoietin stimulating agents. These patients
may still maintain an adequate number of healthy stem cells to support normal hemostasis; however, because the diseased stem cells have
taken over most of the bone marrow, there is no room for the healthy stem cells to undergo the expansion needed for normal hemostasis.
We believe that treatment with briquilimab has the potential to open adequate space in the bone marrow for healthy stem cells to expand
and restore normal hemostasis.
Briquilimab and other anti-c-Kit monoclonal antibodies
have been shown to deplete normal and diseased MDS human hematopoietic stem cells in clinical and pre-clinical studies. Scientists at
Stanford showed 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-c-Kit+ cells
prior to administration of fludarabine or radiation. In studies in non-human primates and healthy human volunteers, administration of
a single dose of briquilimab resulted in limited depletion of healthy HSCs followed by recovery in approximately six weeks. By depleting
diseased hematopoietic stem cells, we believe that briquilimab may allow for preferential recovery of healthy HSCs and restoration of
normal hematopoiesis.
These preclinical studies of immune deficient mice
engrafted with MDS HSCs from patients with “high-risk and very high-risk disease” per the Revised International Prognostic
Scoring System (“IPSS-R”) criteria demonstrate the utility of anti-c-Kit antibodies in the treatment of MDS. Mice xenografted
with higher-risk MDS HSCs were treated with anti-human c-Kit 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 5).
Given the transient depletion of higher-risk MDS cells, studies were conducted to determine whether an anti-c-Kit 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 5).
Figure 5: (A) c-Kit 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.
We are evaluating briquilimab as a therapeutic
for certain MDS patients. 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 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. We are currently enrolling a Phase 1 clinical study of briquilimab monotherapy in lower-risk MDS patients.
The study is a standard 3+3 dose escalation study dosing patients every 8 weeks, commencing at 0.3mg/kg and potentially proceeding to
doses of 0.6 mg/kg, 0.9mg/kg and 1.2mg/kg. Initial data in this study is expected to be presented in 2024.
6
Briquilimab as a Conditioning Agent for SCID Patients Undergoing
Re-Transplantation
We are also developing briquilimab as a conditioning agent for SCID
patients undergoing a stem cell re-transplantation. 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.
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 HCT. The incidence of SCID is estimated at one in 80,000 live births across all
ethnic groups. Due to the toxicities associated with the current 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 conditioning
(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 typically 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 Re-Transplantation
The ability of briquilimab to open a human hematopoietic
stem cell niche was evaluated in humanized immune deficient mice that were stably engrafted with human hematopoietic grafts at Stanford.
Two weeks after a single treatment with 0.3 mg/kg or 1.0 mg/kg of briquilimab, mice showed depletion of human HSCs and progenitor cells
(CD45+CD34+c-Kit+) in the bone marrow.
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. The second human HSC graft was transduced with a lentiviral vector expressing fluorescent
mCitrine to allow assessment of its engraftment. mCitrine-marked second human donor cells were observed in all mice treated with briquilimab,
whereas no evidence of second human donor cells were found in unconditioned mice, demonstrating that briquilimab conditioning permitted
second donor HSC engraftment.
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Clinical Data for Briquilimab for Severe Combined
Immunodeficiency Re-Transplantation
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 SCID patients undergoing stem cell re-transplantation. 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 defined in the Phase 2 studyare
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 have shown that 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, 2023 in this open label clinical trial,eleven T-B-
SCID re-transplant patients have been treated in the ongoing SCID Phase 1/2 study. Seven of the eleven transplanted patientswith
1 - 5 years of follow-up have shown engraftment of donor cells and production of functional immune cells. No briquilimab treatment-related
serious adverse events (“SAEs”) have been reported through December 31, 2023 in this clinical trial.
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.
Briquilimab in Other Stem Cell Transplant Regimens
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.
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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 can lead to less effective
transplants. These toxicities include a range of acute and chronic effects to the gastrointestinal tract, kidneys, liver, lung and 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 transplants in multiple diseases.
Briquilimab for Fanconi Anemia Patients Undergoing Stem Cell Transplantation
FA is a rare but serious blood disorder that prevents bone marrow from
making sufficient new red blood cells. It can also cause the bone marrow to make abnormal blood cells. FA typically presents at birth
or early in childhood between five and ten years of age. Ultimately, it can lead to serious complications, including bone marrow failure,
severe aplastic anemia and cancers such as AML and MDS. Treatment may include blood transfusions or medicine to create more red blood
cells, but HCT is the only cure. Briquilimab as a conditioning agent for FA patients undergoing stem cell transplantation is being evaluated
in a clinical trial collaboration with Stanford. Stanford has reported data for the first five patients, showing 100% donor myeloid chimerism
in the first four patients with available bone marrow chimerism data. Additional enrollment is ongoing.
Briquilimab for Sickle Cell Disease Patients Undergoing Stem Cell Transplantation
SCD is an inherited blood disorder that affects the hemoglobin protein
in red blood cells that delivers oxygen to tissues and organs. Approximately 300,000 infants are born with SCD annually worldwide, and
the number of cases is expected to significantly increase. Currently, HCT is the only cure available for SCD. Allogeneic transplants as
well as new autologous gene-edited transplants both currently rely on myeloablative conditioning with either busulfan or melphalan. We
believe briquilimab could be a significant advance for patients, replacing these current agents which are known to be genotoxic and associated
with limited efficacy and serious adverse effects, including veno-occlusive disease, infertility and secondary malignancies. Briquilimab
as a conditioning agent for SCD patients undergoing stem cell transplantation is currently being evaluated in a clinical trial collaboration
with the National Heart, Lung, and Blood Institute (“NHLBI”). The NHLBI has reported data for the first three patients in
this study, showing 100% donor myeloid chimerism at 30 days and increased levels of hemoglobin versus pre-transplant baseline. Additional
enrollment is ongoing.
Briquilimab for Chronic Granulomatous Disease Patients Undergoing Stem Cell Transplantation
CGD is a rare, inherited disease of the immune
system that develops in infancy or early childhood and results in severe and sometimes life-threatening infections. Allogeneic hematopoietic
stem cell transplant is a proven cure for CGD. However, its use is limited because of the associated serious adverse effects and limited
efficacy of current conditioning agents used to deplete stem cells in preparation for transplantation. Briquilimab for CGD patients will
be evaluated in a clinical trial in collaboration with the National Institute of Allergy and Infectious Diseases. Enrollment in this study
is ongoing.
Briquilimab for GATA-2 MDS Patients Undergoing Stem Cell Transplantation
GATA-2 MDS is a type of MDS characterized by mutations
in the GATA-2 gene resulting in complex phenotypes including increased risk of infection, deficiencies of immune cells such as B- and
NK-cells and overall poor prognosis. Allogeneic stem cell transplant may be used to cure these patients; however, the use of current conditioning
agents can be difficult due to the fragile health status of these patients. Briquilimab-based conditioning for GATA-2 MDS patients will
be evaluated in a clinical trial in collaboration with the National Cancer Institute (“NCI”). Enrollment in this study is
ongoing.
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Briquilimab for Acute Myeloid Leukemia and Myelodysplastic Syndrome
We have completed an 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 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.
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MDS/AML patients wereenrolled. 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 total body irradiation 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.
No
briquilimab-related SAEs have been reportedin
this trial, including no cases of oral mucositis, and no cases of veno-occlusive disease. Among the 31 patients enrolled, there
have been four cases of grade 2 acute GvHD, one case of late onset grade 3 GvHD, four cases of mild chronic GvHD and four cases of moderate
chronic GvHD. SAEs have been reported in twenty patients, including infections, cardiovascular events, disease progression or relapse
and secondary graft failure, which is loss of a previously functioning graft. None were related to treatment as determined by the investigator.
While promising data has been generated to date
in FA, SCD, CGD, GATA-2 MDS and AML/MDS, we do not currently plan to pursue additional clinical development in these indications without
a partner. We will continue to work with the FDA, the transplant community and potential partners to explore development pathways and
ensure briquilimab remains ready for continued development in these indications.
Our Strategy
Our goal is to develop and commercialize briquilimab as a safe and
efficacious therapeutic to address the significant unmet medical need for patients suffering from mast cell driven diseases such as CSU
and CIndU. As part of our strategy, we aim to:
Build a leading biotechnology company to
enable cures via immune modulation. 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 and commercializing therapeutics with a focus on
mast cell driven diseases.
Advance the development of briquilimab as
a chronic therapeutic targeted primarily at mast cell driven diseases. We are focused on developing briquilimab as a repeat dose
therapy for disorders of mast cells, including CSU, CIndU and additional mast cell driven indications currently under pre-clinical evaluation
utilizing our proprietary Jasper Mouse.
Continue to evaluate briquilimab as a
novel, targeted pre-transplant conditioning agent enabling more efficacious and safer HCT as well as a therapeutics in
LR-MDS. We are continuing ongoing programs evaluating briquilimab in the field of HCT to address effective and safe
pre-transplant conditioning in hematologic monogenic and malignant disorders. We are also continuing our ongoing clinical study of
briquilimab as a treatment for patients with LR-MDS.
Commercialize our product candidates to expand
the use of effective and safe mast 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 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 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 cell therapies.
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Agreements with Amgen
In November 2019, we entered into a worldwide exclusive license agreement
with Amgen for briquilimab (formerly AMG-191 and JSP191) in all indications and territories worldwide, which also includes translational
science and materials from Stanford University. We were assigned and accepted Amgen’s rights and obligations, effective November
21, 2019, for the Investigator Sponsored Research Agreement (“ISRA”), entered into in June 2013, between Amgen and The
Board of Trustees of the Leland Stanford Junior University (“Stanford”) and Quality Agreement between Amgen and Stanford,
effective as of October 7, 2015. Under the ISRA, we received an option to negotiate a definitive license with Stanford for rights to certain
Stanford intellectual property related to the study of briquilimab in exchange for an option exercise fee of $1.0 million, payable over
a two-year period (the “Option”). We exercised the Option to Stanford docket S06-265 “Antibody-based clearance of endogenous
stem cell niches prior to transplantation of bone marrow or HSCs (c-kit)” granted by Stanford under the ISRA on June 2, 2020. As
a result, we have worldwide exclusive rights to develop and commercialize briquilimab in all indications, including stem cell transplants.
The issued U.S. patents would be expected to expire in 2027, absent any applicable patent term extensions.
License Agreement with Stanford
In March 2021, we entered into an exclusive license
agreement with respect to the use of briquilimab from the Stanford Office of Technology Licensing to license U.S. Patent Application Serial
Number 60/856,435, filed Nov. 3, 2006, and U.S. Patent Application Serial Number 12/447,634 (publication number US 2010/0226927 Al) and
know-how for the purpose of depleting endogenous blood stem cells in patients for whom hematopoietic cell transplantation is indicated.
Intellectual Property
Our success depends in part on our ability to obtain and maintain proprietary
protection for our product candidates and other discoveries, inventions, trade secrets and know-how that are critical to our business
operations. It also depends in part on our ability to operate without infringing the proprietary rights of others, and in part, on our
ability to prevent others from infringing our proprietary rights. We have a series of in-licensed patents outlined below with an additional
pending patent application in the United States.
In-licensed Amgen Portfolio
We have exclusively licensed a patent family from
Amgen applicable to our clinical development programs that contain patents and applications directed to humanized c-kit antibody. As of
February 26, 2024, this patent portfolio includes three issued U.S. patents and one European patent, as well as granted patents in Australia,
Canada, Japan, and Mexico, and pending patent applications in Europe and Hong Kong. The issued U.S. and European patents would be expected
to expire in 2027, absent any applicable patent term extensions.
In-licensed Stanford Portfolio
We have an exclusive license in the field of use of briquilimab for
the purpose of depleting endogenous blood stem cells in patients for whom hematopoietic cell transplantation is indicated to a patent
family from Stanford University applicable to targeted conditioning that contains patents and applications directed to immunodepletion
of endogenous stem cell niche prior to hematopoietic stem cell transplantation. As of February 26, 2024, this patent portfolio includes
two issued U.S. patents and two European patents, as well as pending U.S., European, and Hong Kong patent applications. The issued U.S.
and European patents would be expected to expire in 2027, absent any applicable patent term extensions.
Jasper Portfolio
As of February 26, 2024, we own nine patent families directed to compositions
and/or methods for hematopoietic stem cell transplantation, one patent family directed to other methods of treating certain hematopoietic
malignancies, three patent families directed to treating mast cell-driven disease, and one patent family directed to therapeutic efficacy
testing models. These patent families include six pending U.S. provisional applications, two pending U.S. utility applications, eight
PCT applications, and applications pending in Europe, and certain other jurisdictions. Any patents that grant from these applications
would be expected to expire in 2042 to 2044, absent any applicable patent term extensions.
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Additional Intellectual Property
We also rely on trade secrets, including know-how,
confidential information, unpatented technologies and other proprietary information, to strengthen or enhance our competitive position,
and prevent competitors from reverse engineering or copying our technologies. We maintain, as trade secrets, information relating our
product candidates currently in development, as well as information related to our business strategy and business methods. However, trade
secrets and confidential know-how are difficult to protect. To avoid inadvertent and improper disclosure of trade secrets, and to avoid
the risks of former employees using these trade secrets to gain future employment, it is our policy to require employees, consultants
and independent contractors to assign to us all rights to intellectual property they develop in connection with their employment with
or services for us. We also protect our existing and developing intellectual property expressly through confidentiality provisions in