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, 2024
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 001-40804
PASITHEA THERAPEUTICS CORP.
(Exact name of registrant as specified in its charter)
State or other jurisdiction of (I.R.S. Employer
incorporation or organization Identification No.)
(Address of principal executive offices) (Zip Code)
Registrant’s telephone number, including
area code: (786)977-3380
Securities registered pursuant to Section 12(b)
of the Act:
Title of each class Trading Symbol(s) Name of each exchange on which registered
Common Stock, par value $0.0001 per share KTTA The Nasdaq Capital Market
Securities registered pursuant to Section 12(g)
of the Act: None
Indicate by check mark if the registrant is a
well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☐ No ☒
Indicate by check mark if the registrant is not
required to file reports pursuant to Section 13 or Section 15(d) of the Act. Yes ☐ No ☒
Indicate by check mark whether the registrant
(1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months
(or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements
for the past 90 days. Yes ☒ No ☐
Indicate by check mark whether the registrant
has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (§ 232.405
of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit such files). Yes
☒ No ☐
Indicate by check mark whether the registrant
is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company, or an emerging growth company.
See the definitions of “large accelerated filer,” “accelerated filer” “smaller reporting company,”
and “emerging growth company” in Rule 12b-2 of the Exchange Act.
Large accelerated filer ☐ Accelerated filer ☐
Non-accelerated filer ☒ Smaller reporting company ☒
Emerging growth company ☒
If an emerging growth company, indicate by checkmark
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 common stock,
par value $0.0001 per share (“Common Stock”), held by non-affiliates of the registrant as of the last business day of the
registrant’s most recently completed second fiscal quarter (June 30, 2024) was $4.1 million.
As of March 20, 2025, there were 2,705,263 shares
of the registrant’s Common Stock outstanding.
DOCUMENTS INCORPORATED BY REFERENCE
None.
PASITHEA THERAPEUTICS CORP.
2024 FORM 10-K ANNUAL REPORT
TABLE OF CONTENTS
Page
PART I
ITEM 1. BUSINESS 1
ITEM 1A. RISK FACTORS 29
ITEM 1B. UNRESOLVED STAFF COMMENTS 54
ITEM 1C. CYBERSECURITY 54
ITEM 2. PROPERTIES 54
ITEM 3. LEGAL PROCEEDINGS 54
ITEM 4. MINE SAFETY DISCLOSURES 54
PART II
ITEM 6. [RESERVED] 55
ITEM 7A. QUANTITATIVE AND QUALITATIVE DISCLOSURES ABOUT MARKET RISK 61
ITEM 8. FINANCIAL STATEMENTS AND SUPPLEMENTARY DATA 61
ITEM 9A. CONTROLS AND PROCEDURES 61
ITEM 9B. OTHER INFORMATION 62
ITEM 9C. DISCLOSURE REGARDING FOREIGN JURISDICTIONS THAT PREVENT INSPECTIONS 62
PART III
ITEM 10. DIRECTORS, EXECUTIVE OFFICERS AND CORPORATE GOVERNANCE 63
ITEM 11. EXECUTIVE COMPENSATION 70
ITEM 14. PRINCIPAL ACCOUNTANT FEES AND SERVICES 82
PART IV
ITEM 15. EXHIBIT AND FINANCIAL STATEMENT SCHEDULES 84
SIGNATURES 86
i
CAUTIONARY NOTE REGARDING FORWARD-LOOKING STATEMENTS
This annual report contains
forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities
Exchange Act of 1934, as amended. These statements are generally identified by the use of such words as “may,” “could,”
“should,” “would,” “believe,” “anticipate,” “forecast,” “estimate,”
“expect,” “intend,” “plan,” “continue,” “outlook,” “will,” “potential”
and similar statements of a future or forward-looking nature. These forward-looking statements speak only as of the date of filing this
annual report with the SEC and include, without limitation, statements about the following:
● our lack of operating history;
● the success of competing therapies that are or may become available;
ii
● our dependence on third parties;
Because forward-looking statements
are inherently subject to risks and uncertainties, some of which cannot be predicted or quantified and some of which are beyond our control,
you should not rely on these forward-looking statements as predictions of future events. The events and circumstances reflected in our
forward-looking statements may not be achieved or occur and actual results could differ materially from those projected in the forward-looking
statements. You should refer to the “Risk Factors” section of this annual report for a discussion of important factors that
may cause our actual results to differ materially from those expressed or implied by our forward-looking statements. We operate in an
evolving environment and new risk factors and uncertainties may emerge from time to time. It is not possible for management to predict
all risk factors and uncertainties. As a result of these factors, we cannot assure you that the forward-looking statements in this annual
report will prove to be accurate. Except as required by applicable law, we do not plan to publicly update or revise any forward-looking
statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise. You should
review the factors and risks and other information we describe in the reports we will file from time to time with the SEC.
iii
EXPLANATORY NOTE
On December 28, 2023, our board of directors (“Board”)
approved a 1:20 reverse stock split (the “Reverse Stock Split”) of our outstanding shares of common stock, par value $0.0001
per share (“Common Stock”), which became effective on January 2, 2024. In connection with the Reverse Stock Split, there was
a corresponding reduction in the number of authorized shares of Common Stock to 100,000,000.
Unless otherwise noted, the
share and per share information in this Annual Report on Form 10-K reflects the Reverse Stock Split.
iv
PART I
ITEM 1. BUSINESS
Overview
We are a clinical-stage biotechnology
company focused on the discovery, research and development of innovative treatments for central nervous system (CNS) disorders and other
diseases, including RASopathies and certain cancers.
During the year ended December
31, 2023, we discontinued our support services to anti-depression clinics in the U.K. and related at-home services in New York, NY. In
addition, we discontinued our clinical operations in Los Angeles, CA and disposed of the related property. Accordingly, as of December
31, 2024, we currently have one reportable segment, “Therapeutics,” related to the research and development of our therapeutic
product candidates.
Our Therapeutic Pipeline
We are advancing a
pipeline of three therapeutic product candidates, with a focus on our lead product candidate, PAS-004, a next-generation macrocyclic
(as defined below) mitogen-activated protein kinase, or MEK inhibitor, that we believe may address the limitations and liabilities
associated with existing drugs with a similar mechanism of action. PAS-004 is a small molecule allosteric inhibitor of MEK 1 and 2
(“MEK 1/2”) for potential use in the treatment of a range of RASopathies, including neurofibromatosis type 1
(“NF1”), a number of MAPK pathway driven tumors, such as BRAFv600 and BRAF fusion tumors, among other indications
including ETS2 driven diseases, such as inflammatory bowel disease (“IBD”), primary sclerosing cholangitis and
ankylosing spondylitis.
MEK 1/2 are two of several
protein kinases involved in a signaling cascade, known as the mitogen-activated protein kinase, or MAPK pathway. The MAPK pathway
is an important pathway in cellular biology which has been a frequent target for drug discovery efforts. The MAPK pathway has been implicated
in a variety of diseases, as it functions to drive cell proliferation, differentiation, survival and a variety of other cellular functions
that, when abnormally upregulated, are critical for the formation and progression of tumors, fibrosis and other diseases. MEK inhibitors
block phosphorylation (activation) of extracellular signal-regulated kinases (“ERK”), which can lead to cell death and inhibition
of tumor growth.
Existing
MEK inhibitors approved by the U.S. Food and Drug Administration (the “FDA”) are marketed for a range of diseases, including
certain cancers and NF1-associated plexiform neurofibromas (“NF1-PN”), including selumitinib (Koselugo) for NF1-PN pediatric
patients and mirdametinib (Gomekli) for adult and pediatric NF1-PN patients. We believe that current MEK inhibitors have certain limitations,
including known toxicities. Unlike FDA-approved MEK inhibitors, PAS-004 features a macrocyclic structure, a characteristic that we believe
enhances potency, metabolic stability, and oral bioavailability. Macrocyclic molecules also provide structural rigidity, enabling stronger
binding with target receptors. PAS-004’s macrocyclic design was specifically developed to improve metabolic stability and optimize
its pharmacokinetic (PK) profile. The structure of PAS-004 is distinct from other earlier generation MEK inhibitors as
it maintains critical protein/ligand contacts but does not possess a primary alcohol or hydroxamate functionality, a known metabolic
liability in earlier generation MEK inhibitors. As described in greater detail below, PAS-004 offers a long half-life, a low peak (Cmax)
to trough (Cmin) drug concentration ratio, and stable steady-state drug levels over time. We believe that sustained suppression of the
MAPK pathway may result in improved efficacy, safety, and a broader therapeutic window compared to current FDA-approved MEK inhibitors
for NF1-PN, which have short half-lives and require twice-daily dosing. However, the ultimate safety and efficacy profile of PAS-004
will require clinical testing to be completed.
In December 2023, the FDA
cleared our Investigational New Drug application (the “IND”) for PAS-004 and we received a study may proceed letter for our
first-in-human Phase 1 multicenter, open-label trial of PAS-004 in patients with MAPK pathway-driven advanced tumors with a documented
RAS, NF1 or RAF mutation or patients who have failed BRAF/MEK inhibition (the “FIH Phase 1 Dose Escalation Study”). We are
currently conducting the FIH Phase 1 Dose Escalation Study at four clinical sites in the U.S. and three sites in Eastern Europe. The primary
objective of the FIH Phase 1 Dose Escalation Study is to assess the safety and tolerability of PAS-004 when administered as a single dose
(day 1) and as multiple doses (28-day treatment cycles). Secondary objectives are (I) to characterize the PK profile of PAS-004 when administered
as a single dose and as multiple doses, (ii) to evaluate the pharmacodynamics (“PD”) effect of PAS-004, (iii) to evaluate
the preliminary anticancer activity (efficacy) of PAS-004 per Response Evaluation Criteria in Solid Tumors (“RECIST”) 1.1
criteria, and (iv) to define the preliminary recommended Phase 2 dose(s) of PAS-004 in adults with MAPK pathway driven advanced solid
tumors.
1
On September 9, 2024, we announced
the successful completion of long-term chronic toxicology studies for PAS-004. On September 26, 2024, we announced safety, tolerability,
pharmacokinetic (PK) and preliminary efficacy data from the first two cohorts of patients in our FIH Phase 1 Dose Escalation Study. To
date, we have completed dosing of a total of 17 patients through cohort 4 (15 mg capsule), including cohort 4b (4 mg tablet) and are currently
dosing four patients in cohort 5 (22 mg capsule). We have observed no dose limiting toxicities (“DLTs”), rash or ocular toxicities
in any of the cohorts assessed to date, and all treatment related adverse events have been either Grade 1 or Grade 2, which support PAS-004’s
potential favorable safety and tolerability profile. Additionally, PAS-004 has demonstrated favorable PK properties, including a long
half-life of approximately 60 hours, a low peak to trough (Cmax to Cmin) ratio as compared to other FDA approved MEK inhibitors, and linear
pharmacokinetics.
PAS-004 has received orphan-drug
designation from the FDA for the treatment of NF1. Our clinical development plan for PAS-004 is to advance PAS-004 into a Phase 1/1b clinical
trial in adult NF1-PN patients followed by pediatric NF1-PN patients and ultimately complete registrational clinical trials in these patient
populations, as they represent the initial indication for which we plan to seek marketing approval for PAS-004.
Our remaining two programs,
PAS-003 and PAS-001, are in the earlier stages of development and are based on novel targets for the treatment of CNS disorders. PAS-003
is being developed for amyotrophic lateral sclerosis (ALS), while PAS-001 is targeted for schizophrenia.
Our
PAS-003 program aims to develop a proprietary humanized monoclonal antibody (“mAb”) with a mechanism-of-action targeting a5b1
integrin for the treatment of ALS and potentially address other CNS disorders, such as Multiple Sclerosis (MS) and stroke. We believe
targeting a5b1
integrin may have a beneficial impact on disease due to modulation of multiple cell types and mechanisms involved in neuroinflammation,
which occurs in ALS. We acquired PAS-003 in connection with our acquisition of Alpha-5 Integrin, LLC, a privately held biotechnology company,
in June 2022.
In November 2023, we announced
that we selected our PAS-003 lead development candidate, a humanized monoclonal antibody with optimal properties that targets α5β1
integrin for the treatment of both sporadic and familial ALS. PAS-003 is now ready for manufacturing and IND-enabling studies.
Our PAS-001 discovery program aims to develop a brain penetrant small
molecule targeting the complement component 4A (“C4A”) for the treatment of schizophrenia. Recent findings implicate C4A in
synaptic loss (fewer connections between nerve cells), which has been shown to occur in schizophrenia. In humans, structural variation
in the complement 4 gene (C4) is an important genetic risk factor for schizophrenia.
During the year ended December
31, 2023, we determined to cease further development of our PAS-002 program for multiple sclerosis (“MS”) due to several factors
including the significant capital, resources and time required to develop the program, and the current and projected availability of effective
treatment options for MS patients, among others.
Our Strategy
Our mission is to develop
innovative therapies to address areas of high unmet medical need, initially in RASopathies and CNS disorders. To achieve our mission,
we are executing a near-term strategy with the following key elements:
2
Overview of Our Lead Program: PAS-004
MAPK Pathway Overview
Signaling pathways describe
a series of biological mechanisms in which a group of molecules work together to control a cell function. A cell receives signals from
its environment when a molecule binds to a specific receptor on or in the cell. This process may be repeated multiple times through the
entire signaling pathway until the last receptor is activated and the cell function is carried out. Abnormal activation of signaling pathways
may lead to diseases.
The MAPK pathway, which
relies upon the Ras/Raf/MEK/ERK signaling cascade, represents a central biological pathway in all human cells that is responsible for
regulating cellular transcription, proliferation and survival. The general structure of the pathway consists of Ras, a small GTPase, and
three downstream protein kinases, Raf, MEK and ERK. ERK 1 and 2 (“ERK 1/2”) are structurally similar protein-serine/threonine
kinases that regulate a variety of cellular processes including adhesion, migration, survival, differentiation, metabolism, proliferation,
transcription, cytoskeletal remodeling and cell cycle progression. MEK 1/2 catalyzes the phosphorylation of ERK 1/2, which is required
for enzyme activation. Phosphorylated ERK 1/2 moves to the nucleus, and in turn activates many transcription factors, regulates gene expression,
and controls various physiological processes, finally inducing cell repair or cell death.
In addition, at the level
of Ras, the pathway is negatively regulated by several proteins, including neurofibromin, the protein encoded by the NF1 gene.
Given its direct regulation of ERK, which directly controls downstream signaling through the MAPK pathway, MEK occupies a pivotal
position in this signaling cascade and represents a rational small-molecule therapeutic target for multiple diseases, including RASopathies
(such as NF1-PN), CNS indications (such as ALS), cardiomyopathies (such as LMNA cardiomyopathy) and oncology indications, where overactivation
of the MAPK pathway contributes to disease onset and/or progression.
Background of MEK Inhibitors
MAPK represents one of the
most highly targeted signaling pathways in drug development. Several allosteric inhibitors of MEK 1/2 are currently in clinical development
with five already approved by the FDA; three for various oncological indications, two for the treatment of children aged two and older
with NF1-PN, and one for the treatment of adults with NF1-PN. A limitation of current FDA approved MEK inhibitors are their high rates
of serious treatment-related adverse events, which may contribute to poor tolerability. These MEK inhibitors often require multiple doses
per day leading to high maximum concentrations (“Cmax”) potentially resulting in a higher rate of adverse events and discontinuations
in real world practice.
Our rationale in developing
PAS-004 is to address these shortcomings to potentially provide patients with better outcomes and improved safety.
3
RASopathies Overview
RASopathies are a clinically
defined group of genetic syndromes caused by germline mutations in genes that encode components or regulators of the MAPK pathway. These
disorders include neurofibromatosis type 1 (NF1), Noonan syndrome, capillary malformation–arteriovenous malformation syndrome, Costello
syndrome, cardio-facio-cutaneous syndrome, and Legius syndrome. Because of the common underlying MAPK pathway dysregulation amongst all
of these syndromes, RASopathies exhibit numerous overlapping phenotypic features, including CNS abnormalities. The MAPK pathway plays
an essential role in regulating various cell cycle functions, which are critical to normal human development. Therefore, we believe there
is a strong scientific rationale for targeting the MAPK pathway with small-molecule therapeutics to treat various RASopathies.
Neurofibromatosis type 1 (NF1) Overview
The initial indication we
plan to seek marketing approval for PAS-004 is the treatment of NF1-PN. NF1 is a RASopathy and part of a group of conditions known as
neurocutaneous disorders, conditions that affect the skin and the CNS. NF1 affects approximately one in 3,000 newborns throughout the
world, with approximately 100,000 patients living in U.S. with NF1.
NF1 arises from mutations
in the NF1 gene which encodes the tumor suppressor neurofibromin. Loss of NF1 function leads to loss of neurofibromin activity, leading
to Ras being locked in its active confirmation, which stimulates MEK, and then ERK activity.
NF1 is characterized by multiple
café au lait (light brown) skin spots and neurofibromas (small benign growths) on or under the skin, and/or freckling in the armpits
or groin. Individuals with NF1 may have other manifestations of the disorder, including cardiac malformations, cardiovascular disease,
vasculopathy, hypertension, vitamin D deficiency, brain malformations, and seizures. About 50% of people with NF1 also have learning disabilities.
Softening and curving of bones, and curvature of the spine (scoliosis) may occur in some patients with NF1. Occasionally, tumors
may develop in the brain, on cranial nerves, or on the spinal cord. NF1 is usually diagnosed during childhood.
Throughout their lifetime,
about 30% to 50% of NF1 patients progress to develop plexiform neurofibromas (“PNs”), which are tumors that grow in an infiltrative
pattern along the peripheral nerve sheath and can cause severe disfigurement, pain and functional impairment. In rare cases NF1-PN may
be fatal. NF1-PN are most often diagnosed within the first twenty years of life. These tumors are characterized by aggressive growth,
which is typically more rapid during childhood. While NF1-PN are initially benign, these tumors can undergo malignant transformation,
leading to malignant peripheral nerve sheath tumors (“MPNST”). NF1 patients have an 8% to 13% lifetime risk of developing
MPNST, a diagnosis that carries a 12-month survival rate of under 50%. In addition to MPNST, NF1 patients are at an increased risk of
developing other malignancies, including breast cancer and gliomas.
Until recently, the only treatment
option for NF1-PN was the surgical removal of the tumors. However, because NF1-PN arise from nerve cells and grow in an infiltrative pattern,
it is challenging to successfully resect tumors and surgery can lead to severe comorbidities, such as permanent nerve damage. Patients
that are ineligible for surgery or those who have had a recurrence post-surgery are often treated with a variety of off-label therapies.
Among these off-label therapies are various systemic treatments, such as chemotherapy and immunotherapy, which have not been shown to
consistently confer a clinical benefit. Given that NF1-PN is driven by dysregulation in the MAPK pathway, MEK inhibitors have emerged
as the only FDA approved therapy for the treatment of inoperable NF1-PNs.
4
Limitations of Current Standard of Care
Koselugo (selumetinib), a
MEK inhibitor, was approved by the FDA in 2020 for NF1 pediatric patients two years of age and older who have symptomatic, inoperable
PNs based on results from the SPRINT trial, a Phase 2 registrational study. In January 2025, results from a Phase 2 study of Koselugo
in adult patients with NF1-PNs was published in Nature Medicine. On February 11, 2025, Gomekli (mirdametinib) was approved by the FDA
for adult and pediatric patients aged 2 and older with NF1 who have symptomatic PNs not amenable to complete resection based on clinical
results from the RenNu Phase 2b clinical trial. In addition to Koselugo and Gomekli, we are aware of other MEK inhibitors in clinical
trials for this indication, as well as the off-label use of other drugs, such as bevacizumab, for the treatment of NF1.
We believe that Koselugo,
Gomekli and other earlier generation MEK inhibitors approved for indications other than NFI suffer from limitations, such as known toxicities,
high rates of drug discontinuation, limited efficacy and a dosing schedule that requires dosing twice a day. We believe that this creates
a significant market opportunity for a next-generation MEK inhibitor that addresses these shortcomings, has a PK and tolerability profile
suitable for long-term once-a-day or less dosing and that can arrest or reverse tumor growth.
Preclinical Profile and Mechanism of Action
of PAS-004
PAS-004 is a next-generation
MEK inhibitor that was rationally designed to have a macrocyclic structure by taking into consideration the metabolic liabilities of earlier
generation MEK inhibitors. The structure of PAS-004 is distinct from other earlier generation MEK inhibitors as
it maintains critical protein/ligand contacts but does not possess a primary alcohol or hydroxamate functionality, a known metabolic
liability in earlier generation MEK inhibitors. It is generally observed that macrocyclic scaffolds improve drug-like properties including
target binding, selectivity, and oral bioavailability.
PAS-004 has displayed promising
PK properties in IND-enabling toxicology studies of both rats and dogs. In these toxicology studies, PAS-004 has demonstrated a half-life
of 11.5 hours in rats and 52 hours in dogs.
Preclinical Studies Overview
In vitro Preclinical Studies of PAS-004
In a screen of 99 protein
kinases, a single high dose of PAS-004 (10 μM) was used to assess kinase inhibition specificity. This assay demonstrated that PAS-004
is a strong inhibitor of only the MEK 1 (~95%) and MEK 2 (>99%) kinases.
In an unpublished preclinical
study, the effects of PAS-004 were compared to selumetinib in tests for the ability to inhibit the growth of three NF1 mutant neurofibroma-derived
Schwann cell lines, the tumorigenic cell of origin for NF1-PN, and two human wild-type Schwann cell lines. Cells were treated for 48 hours
and all PAS-004 treated cell lines showed dose-dependent growth inhibition, with 60-80% growth inhibition in the three neurofibroma-derived
NF1 mutant cell lines and less than 20% inhibition of the wild-type cell lines tested. Growth inhibition with PAS-004 was greater than
the maximal growth inhibition seen with equivalent doses of selumetinib. In addition, the inhibition did not plateau at the highest doses
used in the study, compared to a plateau effect with selumetinib.
Additionally, PAS-004 was
compared to selumetinib in an in vitro potency assay. Western blots from this unpublished preclinical study showed that cells treated
with PAS-004 demonstrated greater reduction in ERK 1/2 phosphorylation as compared to cells treated with selumetinib.
We believe these in vitro
preclinical results support PAS-004’s favorable potency and dose-dependent inhibitory activity against cellular proliferation in
NF1 deficient Schwann cells, demonstrating a profile that appears similar to selumetinib, an FDA approved MEK inhibitor.
5
In vivo Preclinical Studies
In an unpublished preclinical
study, the effects of PAS-004 were assessed in the in vivo Colo-205 xenograft tumor model, a common mouse model used for preclinical
therapies. Results showed that PAS-004 dosed at 5 mg/kg once daily reduced tumor volume. The magnitude of tumor volume reduction was similar
to selumetinib dosed at 25mg/kg, twice daily, as published in Molecular Cancer Therapeutics in 2007.
In an unpublished preclinical
pilot study, PAS-004 was tested for tolerability and preliminary biological efficacy in a genetically engineered mouse model of NF1-PN.
These mice were engineered to develop plexiform neurofibromas that closely phenocopy the human tumors by four months of age with
100% penetrance. In this pilot study, selumetinib was administered in a parallel group, which served as a positive control. Both PAS-004
and selumetinib were administered as single-agents to six mice per group. PAS-004 was administered at 10 mg/kg once daily and selumetinib
was administered at the established maximum tolerated dose of 10 mg/kg, twice daily. Treatment began when the mice reached four months
of age and was continued for 12 weeks or until death. Mice were monitored for signs of toxicity, as well as survival. Results demonstrated
that both PAS-004 and selumetinib showed similar toxicity profiles and both PAS-004 (p=0.0123) and selumetinib (p=0.0048) significantly
reduced the tumor size compared to vehicle-treated mice based on statistical analysis using uncorrected Fisher’s least significant
difference.
We believe the results from
this preclinical pilot study illustrate that PAS-004 may be effective in reducing tumor burden of NF1-associated plexiform neurofibromas.
When administered at 10 mg/kg once daily, PAS-004 and selumetinib, which was dosed at 10mg/kg twice daily, demonstrated similar results.
We believe that the longer half-life of PAS-004, as compared to selumetinib, could potentially enhance efficacy by allowing more sustained
MEK/ERK signaling inhibition. Additionally, it may allow for longer dosing intervals, such as a once-daily regimen, compared to the twice-daily
dosing required for selumetinib.
Mutations in the LMNA gene,
which encodes nuclear lamins A and C, cause diseases affecting various organs, including the heart. Studies have found that the ERK 1/2
kinase branches of the MAPK signaling pathway were abnormally hyperactivated prior to the onset of significant cardiac impairment.
PAS-004 was studied in the
LMNA-cardiomyopathy LmnaH222P/H222P mouse model, a validated model of cardiomyopathy caused by LMNA mutations in humans. In
this study, male mice were orally administered placebo, PAS-004 at 3 mg/kg/day or PAS-004 at 6 mg/kg/day starting at 14 weeks of age when
symptoms of cardiomyopathy were present. Results of this preclinical study were published in Bioorganic & Medicinal Chemistry
in 2017 and are summarized as follows:
6
In unpublished preclinical in vivo studies, PAS-004 was tested
for anti-tumor efficacy in NRAS mutation cancer xenograft models. In the first study, PAS-004 exhibited dose-dependent anti-tumor efficacy
in the lung cancer NCI-H1299 cell-line-derived xenograft model. PAS-004 at dose levels of 10 mg/kg and 5 mg/kg, once daily, significantly
inhibited tumor growth as compared to vehicle control. The anti-tumor efficacy of PAS-004, when taken at equivalent doses, was shown to
be superior to that of binimetinib and selumetinib. In the second study, PAS-004 exhibited dose-dependent anti-tumor efficacy in the liver
cancer xHepG2 cell-line-derived xenograft model. PAS-004 at dose levels of 10 mg/kg and 5 mg/kg, once daily, produced significant antitumor
activities as compared to vehicle control. The anti-tumor efficacy of PAS-004, when taken at equivalent doses was shown to be similar
to that of binimetinib and superior to that of selumetinib.
PAS-004 has demonstrated dose-dependent
response in vivo across several preclinical cancer, LMNA cardiomyopathy and NF1-PN models.
Toxicology Studies
28-day toxicological studies
were performed in both rats and dogs under good laboratory practices (“GLP”) on PAS-004 by Wuxi AppTec (Suzhou) Co., Ltd.
and demonstrated a sufficient safety and toxicology profile of PAS-004 to support our IND with the FDA. Additionally, we have completed
repeat dose toxicity and toxicokinetic studies in Sprague Dawley rats of up to 26 weeks’ duration and in Beagle dogs up to 39 weeks’
duration with 14 or 28-day recovery periods to support chronic dosing of PAS-004.
Additional Indications: ETS2 Driven Diseases
A 2024 Nature publication
titled “A disease-associated gene desert directs macrophage inflammation through ETS2” demonstrated that the ETS2 gene is
a central regulator for multiple inflammatory functions in human macrophages and that ETS2 has a key pathogenic role in IBD. Further,
this publication identified that MEK inhibitors as a class are the strongest known ETS2 inhibitors, providing potent anti-inflammatory
activity and that MEK inhibition reduced inflammatory cytokine release to similar levels as infliximab, an anti-TNF antibody that is widely
used for the treatment of IBD. Blocking ETS2 signaling through MEK 1/2 inhibition was showed to affect multiple cytokines, including TNF
and IL-23, which are targets of existing therapies. Based on this publication, we have begun testing PAS-004 in pre-clinical models of
IBD.
Completion of GMP-Compliant
Manufacturing
In June 2023, we announced
the successful completion of manufacturing the GMP-compliant Phase 1 clinical supplies of the active pharmaceutical ingredient (“API”)
of our lead product candidate PAS-004. Utilizing this drug substance, we have manufactured the drug product in capsule form that we are
utilizing in our ongoing FIH Phase 1 Dose Escalation Study. In 2024, we completed a second batch of API and we have manufactured the drug
product in tablet formulation to support our upcoming Phase 1/1b clinical trial in adult NF1 patients.
Clinical Development Overview
In December 2023 we received
a study may proceed letter from the FDA for our IND and in February 2024 we opened the first clinical site of our first-in-human clinical
trial of PAS-004 in patients with MAPK pathway driven advanced solid tumors with a documented RAS, NF1 and RAF mutation or patients who
have failed BRAF/MEK inhibition. The FIH Phase 1 Dose Escalation Study is a multicenter open-label study designed to evaluate the safety,
tolerability, PK, PD, and preliminary efficacy of PAS-004 in cancer patients with MAPK pathway driven advanced solid tumors. Approximately
30 patients are being enrolled across four clinical sites in the U.S. and three clinical sites in Eastern Europe (Bulgaria and Romania).
Patients are being enrolled into dosing cohorts under a modified 3+3 dose escalation study design. If the first three patients enrolled
into a dosing cohort reach the end of the first 28-day treatment cycle on day 35 without experiencing a DLT, following a review of safety,
PK, and PD data by the safety committee, enrollment into the next highest dosing cohort begins. If two or more of the first three patients
experience a DLT by day 35, dose-escalation will stop and cannot proceed at or above the current dose level. However, if one of the first
three patients enrolled into a dosing cohort experiences a DLT by day 35, an additional three patients will be enrolled into the dosing
cohort (six patients total). If only one of six patients experiences a DLT by day 35, following review of safety, PK and PD by the safety
committee, enrollment into the next highest dose level begin; however, if two or more of the six patients experience a DLT, dose escalation
will stop, and the prior dose level will be declared the maximum tolerated dose (“MTD”). Participants will sequentially receive
one of eight planned dose levels of PAS-004 in capsule formulation (2 mg, 4 mg, 8 mg, 15 mg, 22 mg, 30 mg, 37 mg and 45 mg) to be taken
orally. Additionally, we have completed a dosing cohort using a 4 mg tablet formulation of PAS-004. PAS-004 is administered a single dose
on day 1, followed by a 7-day observation period, before initiating continuous 28-day treatment cycles of PAS-004.
To date, we have dosed 17
patients through cohort 4, including cohort 4b (4 mg tablet). A total of 16 of these patients have completed dosing through the DLT period.
We are currently dosing four patients in cohort 5 (22 mg capsule).
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To date, we have observed
no DLTs, rash or ocular toxicities in any of the cohorts assessed through cohort 4. Additionally, no patients have discontinued treatment
due to AEs. The AE profile of PAS-004 has been characterized by grade 1 and grade 2 treatment-related adverse events (“TRAEs”),
with the most frequently reported of these TRAEs being nausea, vomiting, and diarrhea. This data shows PAS-004 is observed to be well
tolerated and support PAS-004’s favorable safety and tolerability profile.
Interim PK results have demonstrated
a half-life of approximately 60 hours for PAS-004. Following multiple daily dosing, accumulation is consistent and suggests linear PK.
Exposure increases with an increase in dose and dose normalized exposure ranges overlap. At steady-state little fluctuations in drug concentrations
are observed with a ratio of Cmax to Cmin below 2. We believe PAS-004’s PK profile and longer half-life compared to other FDA approved
MEK inhibitors for the treatment of NF1-PN allows durable suppression of ERK phosphorylation, critical for clinical responses.
We plan to provide additional
interim data throughout 2025 and currently expect to complete the FIH Phase 1 Dose Escalation Study in 2026.
Phase 1/1b clinical trial
in adult patients with NF1-PN
Our clinical development plan
for PAS-004 is to initiate to a Phase 1/1b clinical trial in adult patients with NF1-PN followed by pediatric NF1-PN patients and ultimately
complete registrational clinical trials in these patient populations, which are the initial indications that we plan to seek marketing
approval of PAS-004 for.
We are preparing to launch
a Phase 1/1b open label study to assess the safety, tolerability, PK and PD of PAS-004, in adult participants with NF1 with symptomatic
and inoperable, incompletely resected, or recurrent PNs. The study will be conducted at up to five clinical sites in Australia, South
Korea and the U.S. The Company anticipates the first patient will be enrolled in April 2025.
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The primary objective of the
study is to evaluate the safety and tolerability of PAS-004 when administered for one 28-day treatment cycle in adult NF1participants
with at least one and up to two additional target PNs that are symptomatic and inoperable, incompletely resected, or recurrent. Secondary
objectives are (i) to identify the recommended Part B dose (“RPBD”) or MTD of PAS-004, (ii) to characterize the PK and PD
profile of PAS-004, (iii) to evaluate the preliminary efficacy of PAS-004 on target PN volume, (iv) to evaluate the preliminary efficacy
of PAS-004 on the size and appearance, and associated symptoms of cutaneous neurofibromas (CNs), and (v) to evaluate the impact of PAS-004
on quality of life (“QOL”) and any physical symptoms attributed to the target PN. Experimental objectives are (i) to evaluate
the impact of PAS-004 on QOL and any physical symptoms attributed to CNs, (ii) to evaluate the impact of PAS-004 on pain and function
attributed to PNs, and (iii) to investigate PAS-004 effects on CN tumor cellular and molecular biology.
The trial will be conducted
in two parts. In Part A, following a screening period of up to 28 days, up to 24 eligible participants will be enrolled sequentially to
receive one of four planned dose levels of PAS-004 tablets in a modified 3+3 design. Part A will identify the recommended RPBD. During
Part B, up to 24 eligible participants will be enrolled in parallel to receive one of two planned dose levels of PAS-004 tablets. Participants
will be dosed at the RPBD level and at a dose level below the RPBD for up to six continuous 28-day treatment cycles. Part B will identify
the recommended phase 2 dose (RP2D).
Overview of Our Discovery Programs
PAS-003 Program
Amyotrophic Lateral Sclerosis Overview
ALS, or Lou Gehrig’s
disease, is a fatal, progressive motor neuron disease that targets nerve cells in the spinal cord and brain. ALS most commonly affects
people between the ages of 40 and 70, with an average age of 55 at the time of diagnosis. It affects as many as 30,000 patients in the
United States, with 5,000 new cases diagnosed each year.
While approximately 10% of
cases are hereditary, which is known as familial ALS, the large majority of cases (90-95%) are not, which is known as sporadic ALS. While
the pathogenesis of ALS is not fully understood, studies have shown that the disease is multifactorial, with several interlinked mechanisms,
such as neuroinflammation and neurodegeneration.
ALS often begins with muscle
twitching and/or weakness in a limb, however, as the disease progresses, ALS affects control of the muscles needed to move, speak, eat
and breathe. As a result, ALS patients develop extensive muscle wasting and atrophy leading to paralysis and ultimately death. The
life expectancy is low, with patients living on average three to five years after symptom onset, and the patient ́s quality of life
is typically poor.
There are currently four FDA
approved medications to treat ALS and its symptoms. However, they have been shown to only have modest clinical efficacy. Therefore, despite
these therapies, the medical need for new treatments for ALS patients is very high.
Scientific
Background and Rationale for Targeting a5b1
integrin for the treatment of ALS
Integrins are the principal
receptors used by animal cells to bind to the extracellular matrix as well as other cells. Integrins activate intracellular signaling
pathways and can cooperate with other conventional signaling receptors. Integrins are involved in a wide range of biological processes
including cell growth, migration, survival, and proliferation as well as cytokine activation and release. As a result, integrins play
a significant role in many physiological processes, including embryogenesis, organogenesis, and tissue development, but also in pathogenic
ones, including inflammation, infection, and allergic and neoplastic diseases.
Integrins
are composed by two non-covalently linked alpha and beta subunits. a5b1
integrin, also known as the fibronectin receptor, is a heterodimer consisting of the a5
and b1 subunits. Integrins can
be broadly grouped based on ligand specificity. In this classification, integrin a5b1
falls under RGD-recognizing integrins and is known to bind fibronectin, osteopontin, fibrillin, thrombospondin, among others. a5b1
integrin has been shown to play a role in cancer, angiogenesis and in a variety of neurological disorders. a5b1
integrin is a validated drug target supported by the clinical development of anti-a5b1
mAbs by several pharmaceutical companies, including PDL Biopharma, Inc. jointly with Biogen Inc., and Pfizer, Inc., for the treatment
of cancer indications.
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In
a 2018 Nature Neuroscience publication, scientists at the Steinman Laboratory at Stanford University, headed by our Chairman, Prof.
Lawrence Steinman, used mass cytometry to identify an upregulation of a5b1
integrin (CD49e) on brain myeloid cells in the mutant SOD1-G93A mouse model of ALS and demonstrated that a5b1
integrin is upregulated on microglia in the CNS as the disease progresses. Additional preclinical studies have shown that a5b1
integrin is also elevated on macrophages in the periphery and suggest a role for mast cells which also express high level of a5b1
integrin.
In August 2023, we announced
the publication of a study in the peer-reviewed journal Proceedings of the National Academy of Sciences (PNAS) that presented new
findings related to PAS-003 from an interdisciplinary collaboration of scientific teams from the Company, the Mayo Clinic, and Oregon
Health & Science University, combining results from human post-mortem tissues from ALS patients and tissue samples from the SOD1-G93A
mouse model of ALS (“SOD1-G93A”), the most phenotypically relevant preclinical model for ALS.
We have shown an upregulation of a5b1
integrin in the human brain motor regions but not in sensory regions in ALS and that a5b1
expression increases with disease progression in both mouse models of ALS and human ALS patients. Furthermore, we have shown that treatment
with a monoclonal antibody targeting a5b1
leads to increased survival and improved motor function in SOD1-G93A mouse model of ALS.
We
believe these findings suggest that a5b1
integrin in implicated in the pathophysiology of ALS and that targeting a5b1
integrin may provide a treatment for ALS. We have repeated preclinical studies in over 250 animals, using the SOD1-G93A and TDP-43rNLS8
ALS models, and have consistently demonstrated that anti-a5b1
mAb treatment improved motor function on behavioral testing and increased survival in SOD-G93A transgenic mice, as compared to an isotype
control.
We
believe these preclinical results demonstrate that targeting a5b1
integrin has the potential to be a new therapy that could improve outcomes for all ALS patients. In November 2023, we announced that we
selected our PAS-003 lead development candidate, a humanized mAb with optimal properties that targets α5β1 integrin for the
treatment of both sporadic and familial ALS. PAS-003 is now ready for manufacturing and IND enabling studies.
PAS-001
Schizophrenia Overview
Schizophrenia is a chronic
and disabling psychiatric illness characterized by positive psychotic symptoms, such as delusions and hallucinations, negative symptoms,
such as social withdrawal and amotivation, and impairment in cognitive domains, including attention, working memory, verbal learning and
executive function. According to the World Health Organization (“WHO”) schizophrenia affects up to 24 million people in the
world. Schizophrenia has a low lifetime prevalence of about 1%, however the burden of the disease is substantial. Schizophrenia is a leading
cause of adult disease burden and has been ranked 12th in the top global causes of disability for the last decade, leading to substantial
healthcare and societal costs, with annual associated costs in the U.S. estimated to be more than $150 billion.
Current pharmacological treatments
for schizophrenia all act on dopamine D2 receptors. Although they are effective in reducing positive symptoms, they have little effect
on both cognitive and negative symptoms. Furthermore, up to 30% of patients show only partial benefit with antipsychotics and have treatment
resistant schizophrenia. This highlights the need for new therapeutic strategies.
Despite extensive research, the molecular etiology remains unknown.
The current dopamine hypothesis postulates that excessive striatal dopamine transmission and reduced frontal dopamine stimulation underlie
the pathophysiology of positive and negative symptoms, respectively. However, converging lines of genetic, epidemiological and clinical
evidence indicate that inflammatory pathways are also altered in schizophrenia. More recently, a leading hypothesis proposes that synaptic
terminal loss is central to the pathophysiology of schizophrenia, leading to impaired cortical function, and symptoms, including cognitive
impairments.
Scientific Background and Rationale for Targeting
C4A for the treatment of Schizophrenia
The complement system is a
group of proteins found in both the blood and the CNS. In the brain, the complement system plays in almost every aspect of normal brain
development, including neurogenesis, neuronal migration and synaptic refinement, and is now also recognized as a signaling cascade that
facilitate microglial removal of synapses. Microglia are phagocytes residing in the CNS. Unlike other phagocytes, which primarily function
in immunity, microglia are heavily involved in shaping and supporting brain tissue and are key modulators of neuronal development.
There are nine major complement proteins, labeled C1 through C9. Complement protein C4 is the only complement protein that has two different
isotypes encoded by two different genes: C4A and C4B.
According to the synaptic
pruning hypothesis, schizophrenia is thought to arise from a faulty pruning process and excessive synaptic elimination.
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The largest genome-wide association
study (GWAS) in schizophrenia in 2014 identified 128 independent associations spanning 108 conservatively defined loci that meet genome-wide
significance. The most strongly associated GWAS locus is located in the extended Major Histocompatibility Complex (MHC) region on chromosome
6. This locus contains multiple copies of two closely related genes that codes for variants of C4: C4A and C4B. Their analyses revealed
that C4A copy numbers, as well as other structural variance leading to increased C4A mRNA expression, to a large degree explained schizophrenia
risk originating from this locus. This variant remains the strongest polygenic risk factor for schizophrenia identified to date, making
C4A the first gene linked to a specific mechanism underlying the disease. Importantly, schizophrenia risk was not influenced by copy numbers
of the closely related C4B gene.
Animal models of increased
C4A expression show reduced levels of synaptic proteins and increased phagocytosis of synaptic terminals by microglia. Moreover, preclinical
models showed C4A overexpression leads to reduced neurotransmission in prefrontal cortical neurons, reduced social interaction and impaired
memory, which mimic similar abnormalities seen in schizophrenia patients. Finally, excessive microglial synapse elimination has been observed
in schizophrenia patient-derived neural cultures. Post-mortem brain analyses showed that C4A is expressed at significantly higher levels
in people with schizophrenia than controls. C4A levels in cerebro-spinal fluid (“CSF”) have shown to be elevated in patients
with schizophrenia relative to matched controls and correlates with CSF measurements of synapse density. C4A levels have also been found
to be elevated in plasma in schizophrenia, and higher levels predict poorer outcomes in first episode patients.
Several other studies in scientific
journals have also reported increased complement gene expression, protein concentration, and overall activity in the serum or plasma of
schizophrenia cases compared to controls. Further, a 2020 study published in Brain, Behavior and Immunity, found that C4A was overexpressed
in the dorsolateral prefrontal cortex, parietal cortex, superior temporal gyrus and associative striatum of patients with schizophrenia
and that C4A expression was not altered in the peripheral tissues of schizophrenia patients. Further, the study found lifelong C4Aoverexpression
in the brain of schizophrenia patients. Taken together, this evidence has led to the hypothesis that C4A may play an important role in
the pathophysiology of schizophrenia.
We are currently developing
a brain-penetrant small molecule able to down regulate C4A, for the systemic treatment of schizophrenia. To our knowledge, no other company
is exploring this potentially important target. The initial development work and screening is currently being conducted by Evotec, utilizing
Evotec’s integrated research and development expertise and state-of-the-art structure-based drug design techniques. Our goal is
to continue screening and proceeding with early development of PAS-001 while seeking partnerships and/or collaborators to support further
development of the program including preclinical studies.
Acquisitions
Alpha-5 Integrin Therapeutics, LLC
On June 21, 2022, we entered
into a Membership Interest Purchase Agreement (the “Alpha-5 Agreement”) with PD Joint Holdings, LLC Series 2016-A and Prof.
Lawrence Steinman (the “Alpha-5 Sellers”), pursuant to which we purchased from the Alpha-5 Sellers all of the issued and outstanding
equity of Alpha-5 Integrin, LLC, a Delaware limited liability (“Alpha-5”). The Alpha-5 Sellers were the sole title and beneficial
owners of 100% of the equity interests of Alpha-5. In consideration of the equity of Alpha-5, the Alpha-5 Sellers received (i) an aggregate
of 163,044 shares (the “Alpha-5 Shares”) of our Common Stock, (ii) warrants to purchase 50,000 shares of our Common Stock
at an exercise price of $37.60 per share (the “Alpha-5 Warrants”), and (iii) contingent earn-out payments of an aggregate
of 2% to 4% of net sales generated from the sale of a drug currently in development by Alpha-5.
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Prof. Lawrence Steinman, one
of the Alpha-5 Sellers, is our Executive Chairman and Co-Founder, and as such is considered a related party. The terms of the Alpha-5
Agreement were approved by (i) the disinterested members of the audit committee (“Audit Committee”) of our board of directors
(the “Board”) and (ii) the disinterested members the Board, under the Company’s related party transaction
policy.
In connection with the Alpha-5
Agreement, each of the employees of Alpha-5 entered into employment agreements with the Company.