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Item 1. Business

2024-03-27 compared with 2023-03-23 · 462 added, 834 removed, 676 unchanged (66% of the section changed)

9 unchanged sentences

imply an endorsement or sponsorship of us by any other companies.

are a clinical-stage biotechnology company focused on development of targeted therapies for treatment of multiple solid tumor indications.

Our lead therapeutic candidate is gedatolisib, a pan-PI3K/mTOR inhibitor.

Its mechanism of action and pharmacokinetic properties are

highly differentiated from other currently approved and investigational therapies that target PI3K or mTOR alone or together.

to our CDx development activities, our CELsignia diagnostic platform is uniquely able to analyze live patient tumor cells to identify

new groups of cancer patients likely to benefit from targeted therapies.

therapeutic candidate, gedatolisib, is a potent, well-tolerated, small molecule dual inhibitor, administered intravenously, that selectively

targets all Class I isoforms of PI3K and mammalian target of rapamycin (mTOR).

In April 2021, we obtained exclusive global development

and commercialization rights to gedatolisib under a license agreement with Pfizer, Inc.

Our initial clinical development program for

gedatolisib will focus on the treatment of patients with hormone receptor positive (HR+), HER2-negative, advanced or metastatic breast

In 2022, we dosed our first patient in our Phase 3 clinical trial, VIKTORIA-1, evaluating gedatolisib in combination with fulvestrant

with or without palbociclib in patients with HR+/HER2- advanced breast cancer (ABC).

the development of a potential first-in-class targeted therapy for breast cancer, like gedatolisib, with our CELsignia platform is a

natural extension of our strategy to use our CELsignia CDx to enable new indications for other companies’ targeted therapies.

combining companion diagnostics designed to enable proprietary new drug indications with targeted therapies that treat signaling dysregulation

our CDx identifies, we believe we are uniquely positioned to improve the standard-of-care for many early and late-stage breast cancer

Our goal is to play a key role in the multiple treatment approaches required to treat breast cancer patients at various stages

of their disease.

(Rx) Product Development

is a potent, reversible dual inhibitor that selectively targets PI3K and mTOR.

Gedatolisib was originally developed by Wyeth and clinical

development was continued by Pfizer after it acquired Wyeth.

We exclusively licensed global rights to gedatolisib from Pfizer in April

A Phase 1b trial evaluating patients with ER+/HER2- metastatic breast cancer was initiated in 2016 and subsequently enrolled 138

January 13, 2022, gedatolisib was granted Fast Track designation for the treatment of patients with HR+/HER2- metastatic breast cancer

after progression on CDK4/6 therapy.

Fast Track designation is granted by the FDA for products that are intended for the treatment of

serious or life-threatening disease or conditions and which demonstrate the potential to address an unmet medical need.

are a clinical-stage biotechnology company focused on the development of targeted therapies for the treatment of multiple solid tumor

Our lead therapeutic candidate is gedatolisib, a potent, well-tolerated, small molecule reversible inhibitor, administered

intravenously, that selectively targets all Class I isoforms of phosphatidylinositol-3-kinase (PI3K) and the two mechanistic target of

rapamycin (mTOR) sub-complexes, mTORC1 and mTORC2.

Gedatolisib’s mechanism of action and pharmacokinetic properties are highly

differentiated from other currently approved and investigational therapies that target PI3K or mTOR alone or together.

We believe there

is significant potential for gedatolisib to address breast and prostate cancer tumors, and it has the potential to be used in other tumor

types where the PAM pathway is either:

i) driving tumorigenesis directly;

ii) cooperating with other dysregulated signaling pathways;

or iii) a mechanism of resistance to other drug therapies.

obtained exclusive global development and commercialization rights to gedatolisib in April 2021 under a license agreement with Pfizer,

As of December 31, 2023, 492 patients with solid tumors have received gedatolisib in eight completed clinical trials.

Gedatolisib’s

safety, tolerability and pharmacokinetic profile were determined in a Phase 1 First-in-Human study.

Of the 492 patients, 129 were treated

with gedatolisib as a single agent in three clinical trials.

The remaining 363 patients received gedatolisib in combination with other

anti-cancer agents in five clinical trials.

Additional patients received gedatolisib in combination with other anti-cancer agents in

nine investigator sponsored clinical trials.

initial clinical development programs for gedatolisib are focusing on the treatment of patients with hormone receptor positive (HR+),

human epidermal growth factor receptor 2 negative (HER2-), or HR+/HER2-, advanced or metastatic breast cancer and patients with metastatic

castration resistant prostate cancer (mCRPC).

January 2022, gedatolisib was granted Fast Track designation for the treatment of patients with HR+/HER2- metastatic breast cancer after

progression on CDK4/6 therapy.

Fast Track designation is granted by the FDA for products that are intended for the treatment of serious

or life-threatening disease or conditions and which demonstrate the potential to address an unmet medical need.

July 2022, gedatolisib was granted Breakthrough Therapy Designation for HR+/HER2- advanced breast cancer after progression on CDK4/6

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medicine that is intended to treat a serious or life-threatening condition.

The criteria for Breakthrough Therapy designation require

The criteria for Breakthrough Therapy designation requires

preliminary clinical evidence that demonstrates the drug may have substantial improvement on one or more clinically significant endpoints

over available therapy.

2022, we activated VIKTORIA-1, a Phase 3, open-label, randomized clinical trial to evaluate the efficacy and safety of two regimens in

adults with HR+/HER2- advanced breast cancer whose disease has progressed after prior CDK4/6 therapy in combination with an aromatase

December 2022, we dosed the first patient in our Phase 3, open-label, randomized clinical trial, VIKTORIA-1.

This trial is evaluating

the efficacy and safety of two regimens in adults with HR+/HER2- advanced breast cancer whose disease has progressed after prior CDK4/6

therapy in combination with an aromatase inhibitor:

1) gedatolisib in combination with palbociclib and fulvestrant;

and 2) gedatolisib in combination with fulvestrant.

clinical sites in North America, Europe, South America, Asia, and Australia have been selected to participate in the study.

clinical site was activated in the third quarter of 2022.

The first dosage of a patient in the trial occurred in December 2022.

and 2) gedatolisib

in combination with fulvestrant.

Over two hundred clinical sites in North America, Europe, South America, Asia, and Australia are participating

in the study.

February 2024, we dosed our first patient in our Phase 1b/2 clinical trial, CELC-G-201, evaluating gedatolisib in combination with darolutamide

in patients with mCRPC.

PI3K/AKT/mTOR Pathway

Dysregulation

of the PI3K/protein kinase B (AKT)/mTOR, or PAM, signaling pathway is observed in many types of cancer, including breast and prostate

The important role the PAM pathway plays in cancer has led to significant investment in the development of many different PI3K

and mTOR inhibitors for solid tumors.

associated with PI3K involve complex essential cell regulatory mechanisms including feedforward and feedback signaling loops.

Overactivation

of the pathway is frequently present in human malignancies and plays a key role in cancer progression.

Four catalytic isoforms of Class

I PI3K preferentially mediate signal transduction and tumor cell survival based on the type of malignancy and the genetic or epigenetic

alterations an individual patient harbors.

Due to the multiple subcellular locations, activities, and importance of the different PI3K

complexes in regulating many types of cancer cell proliferation, control of PI3K activity is an important target in cancer therapy.

is a critical effector in cell-signaling pathways commonly dysregulated in human cancers.

The mTOR signaling pathway integrates both

intracellular and extracellular signals and serves as a central regulator of cell metabolism, growth, proliferation, and survival.

is a serine/threonine protein kinase, a downstream effector of PI3K, and regulated by hormones, growth factors, and nutrients, that are

contained in two functionally distinct protein assemblies – mTORC1 and mTORC2.

In cancer, dysfunctional signaling leads to various

constitutive activities of the mTOR complexes, making mTOR a good therapeutic target.

efficacious and well-tolerated therapies that target this pathway has been challenging.

This reflects the inherent adaptability and complexity

of the PI3K pathway, where numerous feedforward and feedback loops, crosstalk with other pathways, and compensatory pathways enable resistance

to PI3K inhibition.

Another major hurdle for the development of PI3K pathway inhibitors has been the inability to achieve optimal drug-target

blockade in tumors while avoiding undue toxicities in patients.

targeting multiple nodes of the PAM pathway, gedatolisib can overcome adaptive resistance mechanisms that inhibitors targeting single

PI3K/mTOR nodes do not address.

As a result, we believe gedatolisib offers distinct advantages over currently approved and investigational

therapies that target PI3K or mTOR alone or together.

limitations of therapies that only inhibit a single Class I PI3K isoform or only one mTOR kinase complex.

is a pan-class I isoform PI3K inhibitor with low nanomolar potency for the p110α, p110β, p110γ, and p110δ isoforms.

Because gedatolisib inhibits all four PI3K isoforms and both mTOR complexes, it prevents the confounding effect of isoform interaction

that may occur with isoform specific PI3K inhibitors and the confounding interaction between PI3K isoforms, AKT, and mTOR.

node-specific inhibitors cross-activate uninhibited sub-units due to numerous feedforward and feedback loops between the PI3K isoforms,

AKT, and mTOR, which in turn induces compensatory resistance that reduces the efficacy of isoform specific PI3K, pan-AKT, or single mTOR

kinase complex inhibitors.

compare the functional effect of inhibiting single versus multiple PAM pathway nodes, we evaluated gedatolisib, and node-selective inhibitors

for PI3Kα (alpelisib), AKT (capivasertib) and mTORC1 (everolimus) in a panel of breast cancer cell lines using a live cell proliferation

rate dose response analysis.

The results of this analysis are presented in the table below.

Cancer Cell Line Proliferation Rate Dose Response Analysis

values for 14 PIK3CA MT and 14 PIK3CA WT breast cancer cell lines

Growth rate (GR) was assessed using 28 cell lines by measuring live cells reducing potential with Real Time-Glo MT luciferase assay before

and after 72-hour drug treatment.

GR50 (concentration required to inhibit growth rate by 50%) is a measure of potency.

Max cell growth

inhibition (GR at highest drug concentration tested ) is a measure of efficacy.

Rossetti SABCS 2023

average, gedatolisib was 300-fold more potent than the single node PAM inhibitors analyzed and only gedatolisib induced a significant

cytotoxic effect.

In addition, gedatolisib’s potency and efficacy was comparable in cell lines with and without PIK3CA mutations,

in contrast to the single node PAM inhibitors.

tolerated by patients than oral PI3K and mTOR drugs.

is administered intravenously (IV) on a four-week cycle of three weeks-on, one week-off, in contrast to the orally administered pan-PI3K

or dual PI3K/mTOR inhibitors that are no longer being clinically developed.

Oral pan-PI3K or PI3K/mTOR inhibitors have repeatably been

found to induce significant side effects that were not well tolerated by patients.

This typically leads to a high proportion of patients

requiring dose reductions or treatment discontinuation, despite showing promising efficacy.

By contrast, gedatolisib stabilizes at lower

concentration levels in plasma compared to orally administered PI3K inhibitors, resulting in less toxicity, while maintaining concentrations

sufficient to inhibit PI3K/mTOR signaling.

Isoform-specific

PI3K inhibitors administered orally were developed to reduce toxicities in patients.

While the range of toxicities associated with isoform-specific

inhibitors is narrower than oral pan-PI3K or PI3K/mTOR inhibitors, administering them orally on a continuous basis still leads to challenging

The experience with an FDA approved oral p110-α specific inhibitor, Piqray, illustrates the challenge.

3 pivotal trial, Piqray was found to induce a Grade 3 or 4 adverse event (AE) related to hyperglycemia in 39% of patients evaluated.

In addition, 26% of patients discontinued alpelisib due to treatment related adverse events.

By contrast, in the 103-patient dose expansion

portion of the Phase 1b clinical trial with gedatolisib, only 7% of patients experienced Grade 3 or 4 hyperglycemia and less than 10%

discontinued treatment.

of December 31, 2023, 492 patients with solid tumors have received gedatolisib in eight completed clinical trials.

Gedatolisib’s

safety, tolerability and pharmacokinetic profile were determined in a Phase 1 First-in-Human study.

Of the 492 patients, 129 were treated

with gedatolisib as a single agent in three clinical trials.

The remaining 363 patients received gedatolisib in combination with other

anti-cancer agents in five clinical trials.

Additional patients received gedatolisib in combination with other anti-cancer agents in

nine investigator sponsored clinical trials.

Cancer Program

cancer is the most prevalent cancer in women, accounting for 30% of all female cancers and 13% of cancer-related deaths in the United

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States in 2023, and approximately 43,200 breast cancer patients would die of the disease.

Approximately 190,000, or 70%, of these new

cases are for HR+/HER2- breast cancer.

different breast cancer subtypes are currently identified using molecular tests that determine the level of HR and HER2 expression.

70% of breast cancers are HR+/HER2-, which is indicative of hormone dependency.

Despite progress in treatment strategies, metastatic

HR+/HER2- breast cancer (MBC) remains an incurable disease, with a median overall survival (OS) of three years and a five-year survival

most common subtype of advanced breast cancer (ABC) is HR+/HER2-.

Approximately 70% of all breast cancer tumors express the estrogen

receptor (ER), which, upon activation, regulates the expression of various genes involved in tumor proliferation.

Despite progress in

treatment strategies, metastatic HR+/HER2- breast cancer (MBC) remains an incurable disease, with a median overall survival (OS) of three

years and a five-year survival rate of 34%.

different classes of targeted therapies are currently used to treat HR+/HER2- tumors:

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related mechanisms of resistance to endocrine therapy, namely, activation of the CDK4/6, PI3K and mTOR pathways.

specifically relates to gedatolisib, activation of the PI3K/mTOR pathway has been implicated in a wide variety of human cancers, involving

either activating mutations, or other unknown drivers of pathway amplification.

These include cancers of the breast, prostate, endometrial,

colon, rectum, and lung, among others.

associated with PI3K involve complex essential cell regulatory mechanisms including feedforward and feedback signaling loops.

Overactivation of the pathway is frequently present in human malignancies and plays a key role in cancer progression.

Four catalytic

isoforms of Class I PI3K preferentially mediate signal transduction and tumor cell survival based on the type of malignancy and

the genetic or epigenetic alterations an individual patient harbors.

Due to the multiple subcellular locations, activities, and

importance of the different PI3K complexes in regulating many types of cancer cell proliferation, control of PI3K activity is an

important target in cancer therapy.

is a critical effector in cell-signaling pathways commonly dysregulated in human cancers.

The mTOR signaling pathway integrates both

intracellular and extracellular signals and serves as a central regulator of cell metabolism, growth, proliferation, and survival.

is a serine/threonine protein kinase, a downstream effector of PI3K, and regulated by hormones, growth factors, and nutrients, that is

contained in two functionally distinct protein assemblies – mTORC1 and mTORC2.

In cancer, dysfunctional signaling leads to various

constitutive activities of the mTOR complexes, making mTOR a good therapeutic target.

addition, the PI3K/mTOR pathway, like other mitogenic pathways, can also promote the activities of cyclin D and CDK4/6 to drive proliferative

cell cycling.

The available evidence indicates that resistance to CDK4/6 inhibition in patients with HR+/HER2- advanced breast cancer

is a transient adaptive mechanism, most likely involving the PI3K/mTOR pathway.

This data indicates that CDK4/6 signaling is restored

in CDK4/6 resistant tumors when PI3K/mTOR inhibitors are applied.

Thus, continuing CDK4/6 inhibitor treatment in combination with a PI3K/mTOR

inhibitor in patients who progressed on their prior CDK4/6 inhibitor, would both blockade the reactivated CDK4/6 pathway and prevent

adaptive activation of the PI3K/mTOR pathway.

This suggests the limited efficacy induced by current standard-of-care (SOC) therapies

in patients who have progressed on a CDK4/6 therapy reflects the mechanistic inadequacy of relying on partial PI3K/mTOR inhibition (e.g.,

alpelisib or everolimus) and no CDK4/6 inhibition to address this complex disease mechanism.

70% of breast cancers have direct or indirect activation of the PAM pathway.

The upregulation of the PAM pathway promotes hormone-dependent

and independent ER transcriptional activity, which contributes to endocrine resistance, leading to tumor cell growth, survival, motility,

and metabolism.

Clinical studies have demonstrated that PI3K and mTOR inhibition can restore sensitivity to estrogen therapy (ET).

Additionally,

the PAM pathway, like other mitogenic pathways, can also promote the activities of cyclin D and CDK4/6 to drive proliferative cell cycling.

The available evidence indicates that resistance to CDK4/6 inhibition in patients with HR+/HER2- advanced breast cancer is a transient

adaptive mechanism, most likely involving the PI3K/mTOR pathway.

This data indicates that CDK4/6 signaling is restored in CDK4/6 resistant

tumors when PI3K/mTOR inhibitors are applied.

Thus, continuing CDK4/6 inhibitor treatment in combination with a PI3K/mTOR inhibitor in

patients who progressed on their prior CDK4/6 inhibitor, would both blockade the reactivated CDK4/6 pathway and prevent adaptive activation

of the PI3K/mTOR pathway.

This suggests the limited efficacy induced by current standard-of-care (SOC) therapies in patients who have

progressed on a CDK4/6 therapy reflects the mechanistic inadequacy of relying on partial PI3K/mTOR inhibition (e.g., alpelisib or everolimus)

and no CDK4/6 inhibition to address this complex disease mechanism.

believe the complex connection between the PI3K/mTOR and CDK4/6 pathways can enable gedatolisib to adaptively reactivate CDK4/6 signaling

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gedatolisib initiates.

of gedatolisib anti-tumor in vivo activity was provided in a study evaluating the combination of gedatolisib and a CDK4/6 inhibitor in

cell-line xenograft model where response to endocrine therapy was improved and tumor regressions were induced.

In a study evaluating

the MCF7 xenograft model (ER+/HER2-/PIK3CA mutant), the combination of gedatolisib with palbociclib and fulvestrant caused 90% tumor

regression with no tumor regrowth observed for more than 60 days after the final dose.

of Gedatolisib over other PI3K and mTOR inhibitors

important role the PI3K/mTOR pathway plays in cancer has led to significant investment in the development of many different PI3K and

mTOR inhibitors for solid tumors.

However, developing efficacious and well-tolerated therapies that target this pathway has been challenging.

This reflects the inherent adaptability and complexity of the PI3K pathway, where numerous feedforward and feedback loops, crosstalk

with other pathways, and compensatory pathways enable resistance to PI3K inhibition.

Another major hurdle for the development of PI3K

pathway inhibitors has been the inability to achieve optimal drug-target blockade in tumors while avoiding undue toxicities in patients.

believe there is significant potential for gedatolisib to address previously treated breast cancer tumors and has the potential to be

used in other tumor types where the PI3K/mTOR pathway is either:

i) driving tumorigenesis directly;

ii) cooperating with other dysregulated

signaling pathways;

or iii) a mechanism of resistance to other drug therapies.

a result, we believe gedatolisib’s unique mechanism of action, favorable pharmacokinetic properties, and intravenous formulation

offer distinct advantages over currently approved and investigational therapies that target PI3K or mTOR alone or together.

limitations of therapies that only inhibit a single Class I PI3K isoform or only one mTOR kinase complex.

is a pan-class I isoform PI3K inhibitor with low nanomolar potency for the p110α, p110β, p110γ, and p110δ

Because gedatolisib inhibits all four PI3K isoforms and both mTOR complexes, it prevents the confounding effect of isoform

interaction that may occur with isoform-specific PI3K inhibitors and the confounding interaction between PI3K isoforms and mTOR.

This compares to therapies that only inhibit a single Class I isoforms (e.g., alpelisib, a PI3K-α inhibitor) or only one mTOR

kinase complex (e.g., everolimus, an mTORC1 inhibitor), which cross-activate uninhibited sub-units due to numerous feedforward and

feedback loops between the PI3K isoforms and mTOR, which in turn induces compensatory resistance that reduces the efficacy of isoform

specific PI3K or single mTOR kinase complex inhibitors.

tolerated by patients than oral PI3K and mTOR drugs.

is administered intravenously (IV) on a four-week cycle of three weeks-on, one week-off, in contrast to the orally administered pan-PI3K

or dual PI3K/mTOR inhibitors that are no longer being clinically developed.

Oral pan-PI3K or PI3K/mTOR inhibitors have repeatably

been found to induce significant side effects that were not well tolerated by patients.

This typically leads to a high proportion

of patients requiring dose reductions or treatment discontinuation, despite showing promising efficacy.

By contrast, gedatolisib

stabilizes at lower concentration levels in plasma compared to orally administered PI3K inhibitors, resulting in less toxicity, while

maintaining concentrations sufficient to inhibit PI3K/mTOR signaling.

Isoform-specific

PI3K inhibitors administered orally were developed to reduce toxicities in patients.

While the range of toxicities associated with

isoform-specific inhibitors is narrower than oral pan-PI3K or PI3K/mTOR inhibitors, administering them orally on a continuous basis

still leads to challenging toxicities.

The experience with an FDA approved oral p110-α specific inhibitor, Piqray, illustrates

the challenge.

In its Phase 3 pivotal trial, Piqray was found to induce a Grade 3 or 4 adverse event (AE) related to hyperglycemia

in 39% of patients evaluated.

In addition, 26% of patients discontinued alpelisib due to treatment related adverse events.

in the 103-patient dose expansion portion of the Phase 1b clinical trial with gedatolisib, only 7% of patients experienced Grade

3 or 4 hyperglycemia and less than 10% discontinued treatment.

Experience with Gedatolisib

of December 31, 2022, 492 patients with solid tumors have received gedatolisib in eight clinical trials sponsored by Pfizer.

patients, 129 were treated with gedatolisib as a single agent in three clinical trials.

The remaining 363 patients received gedatolisib

in combination with other anti-cancer agents in five clinical trials.

Additional patients received gedatolisib in combination with other

anti-cancer agents in nine investigator sponsored clinical trials.

of gedatolisib’s anti-tumor activity in breast cancer cells was provided in a study evaluating the MCF7 xenograft model (ER+/HER2-/PIK3CA

mutant), where the combination of gedatolisib with palbociclib and fulvestrant caused 90% tumor regression with no tumor regrowth observed

for more than 60 days after the final dose.

Layman SABCS 2021

Experience with Gedatolisib in Breast Cancer

favorability of preliminary results from our most recently completed clinical trial, a Phase 1b study which evaluated 138 patients with

HR+/HER2- advanced breast cancer (ABC), led us to focus on our initial clinical development program on advanced breast cancer.

January 13, 2022, gedatolisib was granted Fast Track designation for the treatment of patients with HR+/HER2- metastatic breast cancer

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breast cancer whose disease progressed during treatment with a CDK4/6 therapy and an aromatase inhibitor.

Gedatolisib’s

safety, tolerability and pharmacokinetic profile were determined in a Phase 1 First-in-Human study.

The favorability of preliminary results

from our most recently completed clinical trial, a Phase 1b study which evaluated 138 patients with HR+/HER2- advanced breast cancer

(ABC), led us to focus on our initial clinical development program on advanced breast cancer.

1 First-in-Human Study

2013, Pfizer completed a Phase 1, open-label, dose-escalation first-in human study of single-agent gedatolisib in patients with advanced

solid tumors.

The primary objective of Part 1 of the study was to determine the safety, tolerability, and maximum tolerated dose (MTD)

of single-agent gedatolisib administered once weekly as an intravenous (IV) infusion.

Seventy-seven patients with advanced solid tumors

received doses of gedatolisib and the MTD was determined to be 154 mg IV once weekly (n = 42).

Based on results and analyses from subsequent

clinical trials, the maximum tolerated dose was determined to be 180 mg IV once weekly.

1b HR+/HER2- ABC Clinical Trial Results

2016, Pfizer initiated a Phase 1b dose-finding trial with an expansion portion for safety and efficacy to evaluate gedatolisib when added

to either the standard doses of palbociclib plus letrozole or palbociclib plus fulvestrant in patients with HR+/HER2- advanced breast

PI3K mutation status was not used as an eligibility criterion.

Phase 1b dose-finding trial with an expansion portion for safety and efficacy evaluated gedatolisib when added to either the standard

doses of palbociclib plus letrozole or palbociclib plus fulvestrant in patients with HR+/HER2- advanced breast cancer.

PI3K mutation

status was not used as an eligibility criterion.

Patient enrollment for the trial is complete.

total of 138 patients with HR+/HER2- advanced breast cancer were dosed in the clinical trial.

Seven patients from this study continue

to receive study treatment, as of December 31, 2022, each of whom have received study treatment for more than four years.

patients were enrolled in two dose escalation arms to evaluate the safety and tolerability and determine the MTD of gedatolisib when

used in combination with the standard doses of palbociclib and endocrine therapies.

The MTD was determined to be 180 mg administered

intravenously once weekly.

Five patients from this study continue

to receive study treatment, as of December 31, 2023, each of whom have received study treatment for more than five years.

patients were enrolled in two dose escalation arms to evaluate the safety and tolerability and determine the maximum tolerable dose

(MTD) of gedatolisib when used in combination with the standard doses of palbociclib and endocrine therapies.

The MTD was determined

to be 180 mg administered intravenously once weekly.

patients were enrolled in one of four expansion arms (A, B, C, D) to determine if the triplet combination of gedatolisib plus palbociclib

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Second- or third-line endocrine-based therapy for advanced disease.

ABC having progressed on a CDK inhibitor in combination with endocrine therapy as the most recent regimen for advanced disease.

ABC with progression during one or two prior endocrine-based systemic therapies in the advanced setting and following prior

therapy with a CDK inhibitor.

Second- or third-line endocrine-based therapy for advanced disease.

for the 103 patients enrolled in the expansion portion of the Phase 1b clinical trial, as of a database cutoff date of June 29, 2022,

analysis for all arms in aggregate:

for the 103 patients enrolled in the expansion portion of the Phase 1b clinical trial showed:

analysis for all arms in aggregate amongst patients with evaluable tumors:

objective response rate (ORR)

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responses, as measured by RECIST v1.0, are shown in the following chart for Arm A (1 st line patients) and Arm D (2 nd /3 rd

line patients who received recommended dosing regimen).

line patients who received Phase 3 dosing regimen).

The dotted line represents the cutoff for partial response (PR), defined

as a 30% reduction from the baseline tumor assessment.

Layman SABCS 2021

all arms in aggregate, all patients experienced at least one Grade 1 or Grade 2 treatment-emergent adverse event.

3 unchanged sentences

Stomatitis was reversible in most patients with a steroidal mouth rinse.

All grades of treatment-related adverse events related to hyperglycemia was reported in 22% of patients;

All grades of treatment-related adverse events related to hyperglycemia were reported in 22% of patients;

Grade 3 or 4 hyperglycemia

4 unchanged sentences

All grades of treatment-related adverse events

related to hyperglycemia was reported in 26% of patients;

related to hyperglycemia were reported in 26% of patients;

Grade 3 or 4 hyperglycemia was reported in 7% of patients.

1 unchanged sentence

overall response data for each arm is presented in the table below:

Total Expansion Arms

(N=103, full analysis set)

Prior Therapy

Expansion Arms

CDKi-pretreated

n (Full, response evaluable)

Study Treatment

Gedatolisib schedule

(Full, response evaluable)

wks on/1 wk off

ORR 1 (evaluable)

mPFS 2 , mos (range)

PFS % at 12 mos 2

% at 12 mos 2

ORR represents PR, except in Arm A, which had 1 CR = Complete response.

Responses per RECIST 1.1;

(2) Includes 2 unconfirmed PR

Abbreviations:

(2) Includes 2 unconfirmed PR Abbreviations:

1L= first line, 2L= second line;

1 unchanged sentence

ORR, objective response rate;

PFS, progression free

PFS, progression free survival

Wesolowski 2022 SABCS

Gedatolisib Clinical Trials

2 Pilot Clinical Trial for HER2+/PIK3CA+ Patients

Korean Cancer Study Group sponsored a Phase 2 pilot clinical trial to evaluate gedatolisib combined with a trastuzumab biosimilar (Herzuma®),

in patients with HER2+/PIK3CA+ metastatic breast cancers whose disease had progressed after treatment with three or more prior HER2 targeted

therapy regimens.

The clinical trial commenced in December 2019 and interim efficacy data from the first 17 patients enrolled was presented

at the San Antonio Breast Cancer Symposium in December 2021.

Patients received a trastuzumab biosimilar (8 mg/kg IV for 1st cycle loading

dose, and then 6 mg/kg IV every 3 weeks) plus gedatolisib (180 mg, weekly IV).

The primary endpoint was objective response, a reduction

of at least 30% in tumor volume by RECIST v1.1.

of a data cutoff date of October 30, 2021, 10 of 17 patients achieved a partial response, an ORR of 59%, and four patients had stable

Fourteen of 17 patients thus received either a partial response or stable disease, resulting in a clinical benefit rate of 82%.

Best responses are shown in the following chart.

The dotted lines represent the cutoff for progressive disease (>20% tumor growth)

and for partial response (>30% tumor regression).

Best Response

Patient whose target lesion decreased by 63% but a new leptomeningeal seeding occurred.

duration of treatment for the 16 patients evaluated is shown in the chart below.

As of the October 30, 2020 data cutoff, 16 patients

(80%) remained on therapy.

Four patients discontinued treatment, one due to disease progression, one due to an adverse event of Grade

1 diarrhea, one participant decision, and one patient being unable to undergo the required MRI imaging due to a titanium rod implant

from non-treatment related worsening of scoliosis.

At the time of data cut-off, the median time on treatment for these 20 patients was

10.1 cycles (approximately 10 months) and all 10 patients who had achieved an objective response remained on therapy assessment.

time of the analysis, nine patients had a continuing response.

The dashed lines show the response at 3 months and 6 months.

1 Clinical Trial in Patients with Solid Tumors

phase 1 study conducted at the Indiana University Simon Cancer Center evaluated the safety, tolerability, pharmacokinetics and preliminary

activity of gedatolisib combined with carboplatin and paclitaxel in patients with advanced solid tumors previously who were treated with

two or more prior chemotherapies.

Seventeen patients were enrolled (10 clear cell ovarian, one low-grade serous ovarian, four endometrial,

and two lung cancers).

The ORR was 65% in all patients (11/17 patients:

eight partial responses and three complete responses) and stable

disease was 17% (3/17).

Among patients with clear cell ovarian cancer, the ORR was 80%, with three patients achieving a complete response.

Gedatolisib Clinical Trials

3 HR+/HER2- ABC Clinical Trial (VIKTORIA-1)

2 unchanged sentences

after prior CDK4/6 therapy in combination with an aromatase inhibitor.

This multi-center, international trial is expected to enroll 701

total subjects at approximately 200 clinical sites across North America, Europe, Latin America, and Asia.

The first clinical site was

activated in the third quarter of 2022.

The first patient was dosed in December 2022.

This multi-center, international trial is expected to enroll approximately

701 total subjects at more than 200 clinical sites across North America, Europe, Latin America, and Asia.

The first patient was dosed

in December 2022.

clinical trial will enable separate evaluation of subjects according to their PIK3CA status.

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assessment by RECIST v1.1, quality of life, and overall survival.

Phase 2 Gedatolisib Clinical Trials

expect to use the CELsignia PI3K Activity Test to help support development of gedatolisib for breast cancer indications.

studies demonstrate how measurement of PI3K-involved signaling may provide a sensitive and specific method of identifying patients most

likely to benefit from PI3K inhibitors.

We believe CELsignia tests uniquely enable us to pursue indications simultaneously for unselected

patient populations and CELsignia selected patient sub-groups.

This approach can greatly reduce the risk of pursing an indication for

a large, but unselected patient population, as we plan to do for the initial gedatolisib indication.

By combining the capabilities of

CELsignia PI3K Activity Test with a potent pan-PI3K/mTOR inhibitor like gedatolisib, we believe we are uniquely suited to maximize the

probability of obtaining regulatory approval to market gedatolisib.

we plan to initiate a Phase 2 clinical trial to evaluate gedatolisib in combination with palbociclib and letrozole in early-stage HR+/HER2-

breast cancer patients.

The tumors from all patients will be evaluated with a CELsignia PI3K Pathway Test.

Cancer Program

the United States, prostate cancer is the second leading cause of cancer death in men.

Current estimates predict that one in eight men

will be diagnosed with prostate cancer in his lifetime.

The American Cancer Society estimates that in 2024 there will be over 299,000

new cases of prostate cancer in the United States and approximately 35,250 deaths from the disease.

Although the majority of patients

are diagnosed with localized prostate cancer, about 6% of patients present with metastatic disease with a 5-year survival rate of 29%.

Androgen deprivation therapy (ADT) via medical or surgical castration has been the mainstay treatment for metastatic prostate cancer.

However, prostate cancer cells develop resistance to ADT and progress to castration resistance, leading to poor prognosis and a median

overall survival of about 3 to 5 years.

with mCRPC have a poor prognosis and a predicted survival rate of fewer than two years from the initial time of progression.

options for prostate cancer depend on many different factors, including the stage of the cancer.

Castration-resistant prostate cancer

is defined by disease progression despite androgen deprivation therapy, or ADT, and is often indicated by rising levels of PSA.

standard of care for men with castration-resistant prostate cancer provides that patients should initially receive a combination of ADT

and either abiraterone, which works by decreasing androgen levels, or enzalutamide, which works by blocking androgen binding to AR.

the disease progresses despite these second-generation hormonal therapies, chemotherapy is considered the next treatment option.

with chemotherapy is generally postponed for as long as possible due to the potential for severe side effects including neuropathies,

nausea, diarrhea, decreased mental capacity and increased risk of infections.

studies have demonstrated a potential association between the PAM pathway and androgen receptor (AR) signaling in prostate cancer cells

developing resistance to ADT.

In these studies, the AR and PAM pathways were shown to cross-regulate each other.

This is similar to the

relationship demonstrated in breast cancer with the estrogen receptor pathway and the PAM pathway.

Additionally, 70% - 100% of mCRPC

tumors have PAM related pathway alterations.

clinical studies have shown promising results by inhibiting the PAM pathway in combination with an AR inhibitor.

In separate Phase 2

and Phase 3 trials, the AKT inhibitor, ipatasertib, showed improvement in radiographic PFS (rPFS) in patients with mCRPC and tumors with

phosphatase and tensin homolog (PTEN) loss when ipatasertib was combined with the AR inhibitor, abiraterone, versus abiraterone alone.

In a Phase 2 trial, the pan-PI3K inhibitor, samotolisib, reported median rPFS of 10.2 when combined with enzalutamide versus 5.5 months

for enzalutamide alone.

of gedatolisib’s in vivo activity in prostate cancer was provided in a study evaluating the 22RV-1, PC3, and C4-2 prostate cancer

xenograft models.

As seen in the figures below, gedatolisib induced greater than 80% tumor growth inhibition, regardless of the xenograft

model’s sensitivity to the AR inhibitor, enzalutamide and the cell lines’ PTEN or AR status.

In addition, gedatolisib combined

with enzalutamide induced significantly greater tumor growth inhibition than enzalutamide alone in the enzalutamide sensitive model (C4-2).

Sen, ASCO-GU, 2023

1b/2 mCRPC Clinical Trial (CELC-G-201)

received approval from the US FDA in mid-2023 to proceed with the clinical development of gedatolisib in combination with Nubeqa®

(darolutamide), an approved androgen receptor inhibitor, for the treatment of patients with mCRPC.

We have since initiated a Phase 1b/2

study (CELC-G-201) that will enroll up to 54 participants with mCRPC who progressed after treatment with an androgen receptor inhibitor.

We dosed our first patient in this trial in February 2024.

the Phase 1b portion of the study, Celcuity expects that 36 participants will be randomly assigned to receive 600 mg darolutamide combined

with either 120 mg gedatolisib in Arm 1 or 180 mg gedatolisib in Arm 2.

An additional 12 participants will then be enrolled in the Phase

2 portion of the study at the recommended phase 2 dose (RP2D) level to enable evaluation of 30 participants treated with the RP2D of

primary objectives of the Phase 1b portion of the trial include assessment of the safety and tolerability of gedatolisib in combination

with darolutamide and determination of the recommended Phase 2 dose of gedatolisib.

The primary objective of the Phase 2 portion of the

trial is to assess the radiographic progression-free survival (rPFS) at six months of patients who received the RP2D.

License Agreement

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either alone or in partnership with others.

Cancer patients are managed by oncologists, medical geneticists and neurologists, and therefore

Cancer patients are managed by oncologists, medical geneticists and urologists, and therefore

we believe can be reached with a targeted sales force.

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approvals and marketing approved products.

are several PI3K and mTOR inhibitors approved by the FDA, including Piqray and Afinitor from Novartis AG, Aliqopa from Bayer Corporation,

are several PI3K, AKT, and mTOR inhibitors approved by the FDA, including Piqray and Afinitor from Novartis AG, Aliqopa from Bayer Corporation,

Copiktra from Verastem, Inc., Zydelig from Gilead Sciences, Inc.

and we are aware that other companies are, or may be, developing products

for this indication, including AstraZeneca plc, BridgeBio Inc., Eli Lilly and Company, F.

Hoffmann-La Roche Ltd, Kazia Therapeutics Limited,

Infinity Pharmaceuticals, Inc., Relay Therapeutics, Revolution Medicines Inc., and Takeda Pharmaceutical Company Limited.

additional companies with programs suitable for addressing these patient populations that could be competitive with our efforts but that

have not yet disclosed specific clinical development plans.

Smaller or early-stage companies, including oncology-focused therapeutics

companies, may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.

These companies may also compete with us in recruiting and retaining qualified scientific and management personnel, establishing clinical

trial sites, enrolling patients in clinical trials and acquiring technologies complementary to, or necessary for, our programs.

The availability

of reimbursement from government and private payors will also significantly impact the pricing and competitiveness of our products.

competitors may obtain FDA or other regulatory approvals for their products more rapidly than we may obtain approvals for our product

candidates, which could result in our competitors establishing a strong market position before we are able to commercialize our product

Development and CDx Programs

proprietary CELsignia diagnostic platform is the only commercially ready technology we are aware of that uses a patient’s living

tumor cells to identify the specific abnormal cellular process driving a patient’s cancer and the targeted therapy that best treats

This enables us to identify patients whose tumors may respond to a targeted therapy, even though they lack a previously associated

molecular mutation.

By identifying cancer patients whose tumors lack an associated genetic mutation but have abnormal cellular activity

a matching targeted therapeutic is designed to inhibit, we believe our CELsignia CDx can expand the markets for a number of already approved

targeted therapies.

Our current CDx identifies breast and ovarian cancer patients whose tumors have cancer drivers potentially responsive

to treatment with human epidermal growth factor receptor 2-negative (HER2), mesenchymal-epithelial transition factor (c-MET), or phosphatidylinositol

3-kinases (PI3K) targeted therapeutics.

CELsignia platform provides an important advantage over traditional molecular diagnostics.

Current molecular diagnostics analyze fragmented

cells to obtain a snapshot of the genetic mutations present in a patient’s tumor.

Using cell fragments prevents molecular diagnostics

from analyzing the dynamic cellular activities, known as cell signaling, that regulate cell proliferation or survival.

Cancer can develop

when critical cell signaling, regulating physiologic activity such as cell proliferation, becomes abnormal or dysregulated.

Since genetic

mutations are often only weakly correlated to the dysregulated cell signaling activity driving a patient’s cancer, a molecular

diagnostic is prone to providing an incomplete diagnosis.

CELsignia tests overcome this limitation by measuring dynamic cell signaling

activity in a cancer patient’s living tumor cells.

When a CELsignia test detects abnormal signaling activity, a more accurate diagnosis

of the patient’s cancer driver is obtained.

are supporting the advancement of new potential indications for four different targeted therapies, controlled by other pharmaceutical

companies, that would rely on a CELsignia CDx to select patients.

Our first analytically validated and commercially ready test using

our CELsignia platform, the CELsignia HER2 Pathway Activity Test for breast cancer, diagnoses two new sub-types of HER2-negative breast

cancer that traditional molecular diagnostics cannot detect.

Our internal studies show that approximately 15-20% of HER2-negative breast

cancer patients have abnormal HER2 signaling activity similar to levels found in HER2-positive breast cancer cells.

As a result, these

HER2-negative patients have undiagnosed HER2-driven breast cancer and would be likely to respond to the same anti-HER2 targeted therapies

only HER2-positive patients receive today.

We have three interventional clinical trials underway to evaluate the efficacy of HER2 targeted

therapies in breast cancer patients selected with our CELsignia HER2 Pathway Activity Test.

and Trucap from AstraZeneca plc.

We are aware that other companies are,

or may be, developing products for this indication, including BridgeBio Inc., Eli Lilly and Company, F.

Hoffmann-La Roche Ltd, Kazia

Therapeutics Limited, Infinity Pharmaceuticals, Inc., Relay Therapeutics, Revolution Medicines Inc., Scorpion Therapeutics, Inc., and

Takeda Pharmaceutical Company Limited.

There may be additional companies with programs suitable for addressing these patient populations

that could be competitive with our efforts but that have not yet disclosed specific clinical development plans.

Smaller or early-stage

companies, including oncology-focused therapeutics companies, may also prove to be significant competitors, particularly through collaborative

arrangements with large and established companies.

These companies may also compete with us in recruiting and retaining qualified scientific

and management personnel, establishing clinical trial sites, enrolling patients in clinical trials and acquiring technologies complementary

to, or necessary for, our programs.

The availability of reimbursement from government and private payors will also significantly impact

the pricing and competitiveness of our products.

Our competitors may obtain FDA or other regulatory approvals for their products more

rapidly than we may obtain approvals for our product candidates, which could result in our competitors establishing a strong market position

before we are able to commercialize our product candidates.

founded our company to develop our proprietary CELsignia diagnostic platform and relied on the capability of this technology to identify

our lead drug candidate, gedatolisib.

CELsignia characterizes the specific activity of various oncogenic signaling pathways, including

the PAM pathway, in living patient tumor cells.

are supporting the advancement of new potential indications for three different targeted therapies, controlled by other pharmaceutical

companies, that would rely on a CELsignia companion diagnostic test to select patients.

Our first analytically validated and commercially

ready test using our CELsignia platform, the CELsignia HER2 Pathway Activity Test for breast cancer, diagnoses two new sub-types of HER2-negative

breast cancer that traditional molecular diagnostics cannot detect.

Our internal studies show that approximately 15-20% of HER2-negative

breast cancer patients have abnormal HER2 signaling activity similar to levels found in HER2-positive breast cancer cells.

these HER2-negative patients have undiagnosed HER2-driven breast cancer and would be likely to respond to the same anti-HER2 targeted

therapies only HER2-positive patients receive today.

We have two interventional clinical trials underway to evaluate the efficacy of

HER2 targeted therapies in breast cancer patients selected with our CELsignia HER2 Pathway Activity Test.

second CELsignia test for breast cancer evaluates independent c-Met signaling activity and its involvement with HER family signaling

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third CELsignia test for breast cancer evaluates PI3K signaling in HER2-negative breast cancer tumor cells.

Our internal studies demonstrate

how measurement of PI3K-involved signaling may provide a more sensitive and specific method of identifying patients most likely to benefit

from PI3K inhibitors than current genetic tests that measure PI3K mutations.

We intend to combine these three tests to expand the CELsignia

With this next generation CELsignia test, we plan to provide an analysis of EGFR/HER1, HER2, HER3, c-MET, and PI3K-node involved

signaling activity for each patient tumor specimen received.

addition, we completed development of our first CELsignia test for ovarian cancer in 2020.

This test identifies a new sub-group of ovarian

cancer patients with tumors that have abnormal c-Met and HER2 signaling activity.

These findings suggest that a significant sub-group

of ovarian cancer patients may respond to treatment with a combination of ErbB and c-Met inhibitors.

Nearly 14,000 women a year die from

ovarian cancer, a disease that has less than a 50% five-year survival rate and a limited range of targeted therapy options.

thus a significant unmet need for additional therapeutic options for ovarian cancer patients.

As a companion diagnostic, our CELsignia

test for ovarian cancer will be intended to help pharmaceutical companies obtain new drug indications and expand treatment options for

this challenging tumor type.

overall commercialization strategy is to develop diagnostics that expand the patient population eligible for targeted therapies.

In furtherance

of this strategy, we have been and will continue to seek collaborations with pharmaceutical companies to field clinical trials to advance

the clinical development of their targeted therapies with the eventual goal of obtaining FDA approval of a new drug indication.

Clinical Trials

are currently collaborating on four Phase 2 clinical trials to evaluate the efficacy of our collaboration partners’ targeted

therapies in patients selected with one of our CELsignia tests.

The goal of these trials is to support the development of four

potential new drug indications to treat patient groups found responsive by our CELsignia test to their approved targeted therapies.

These clinical trials include:

are currently collaborating on three Phase 2 clinical trials to evaluate the efficacy of our collaboration partners’ targeted therapies

in patients selected with one of our CELsignia tests.

The goal of these trials is to support the development of three potential new drug

indications to treat patient groups found responsive by our CELsignia test to their approved targeted therapies.

These clinical trials

Clinical Trial to Evaluate Efficacy of Genentech’s HER2 Targeted Therapies.

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treatment with a matching targeted therapy.

Clinical Trial to Evaluate Efficacy of Puma’s HER2 Targeted Therapy.

We are collaborating with Puma Biotechnology, Inc.

and West Cancer Center to conduct a Phase 2 single-arm interventional trial to evaluate the efficacy and safety of Puma’s

drug, Nerlynx (neratinib), and chemotherapy in breast cancer patients selected with our CELsignia test.

The goal of the trial is

to demonstrate that triple-negative breast cancer patients who have a hyperactive HER2 signaling tumor, as identified by the CELsignia

test, respond to treatment with Nerlynx, a matching HER2 therapy.

Clinical Trial to Evaluate Efficacy of Puma’s pan-HER Inhibitor and chemotherapy.

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and c-Met signaling tumors, as identified by the CELsignia test, respond to treatment with Tabrecta in combination with Nerlynx.

Diagnostics Industry

to the Centers for Disease Control and Prevention, cancer was the second-leading cause of death in the United States in 2020, responsible

for nearly one of every four deaths.

There are many types of cancer treatment options, including surgery, radiation therapy, chemotherapy,

immunotherapy, hormone therapy, stem cell transplant, and targeted therapy.

Targeted therapies are drugs or other substances that block

the growth and spread of cancer by interfering with specific molecular targets involved in the progression of cancer.

Targeted therapies

differ from standard chemotherapy drugs in that they are often cytostatic (block tumor cell proliferation) rather than cytotoxic (kill

tumor cells).

According to the National Cancer Institute, there are currently more than 90 approved targeted oncology therapies, some

of which cost more than $100,000 per treatment course.

tests to detect single biomarkers are now widely used by pathologists to determine the molecular sub-type of a cancer.

When a molecular

biomarker test is used to support the choice of therapy to prescribe, it is often referred to as a “companion diagnostic.”

Increasing numbers of targeted therapeutics are prescribed based on the results from a companion diagnostic test to detect the presence

of a molecular biomarker.

Only patients testing positive for the biomarker are eligible to receive the associated therapy.

diagnostics are becoming increasingly important to the pharmaceutical industry.

The use of companion diagnostics to better match patients

to effective treatments positively impacts clinical outcomes and lowers expenditures on drugs that do not benefit patients.

the eligible patient population to include only likely responders is particularly important when the percentage of likely responders

is only a fraction of the total cancer population.

In these circumstances, narrowing the eligible patient population is often necessary

to meet the clinical endpoint targets required to receive FDA drug approval.

Testing Opportunities

expect to generate recurring companion diagnostic testing revenues once a CELsignia companion diagnostic-linked drug therapy is approved

for patient use.

On average, we believe that the lifetime value of providing the companion diagnostic test will significantly exceed

the revenue generated from the companion diagnostic development program.

We expect to offer each CELsignia test to patients at prices

ranging from $4,000–$7,000, depending on the number of pathways evaluated.

No tests directly comparable to the CELsignia tests

are available today to offer reference points for pricing purposes.

Pricing for several proprietary complex genomic tests, however, fall

within this range and we believe this provides guidance on the amount insurance companies are willing to pay for highly informative tests

that guide patient care.

CELsignia Platform

have made significant investments in research and development of our CELsignia platform.

To measure dynamic cellular activity, we internally

developed two distinct but complementary technologies, which now comprise our CELsignia platform:

proprietary cell microenvironment;

method to quantify dynamic patient cell signaling dysfunction.

utilize our CELsignia platform to create CELsignia tests that measure specific signaling pathway activity in various tumor types.

microenvironment .

Previous research has shown that cancer cells extracted from a patient’s tumor share the molecular features

of the primary cancers from which they were derived and could provide an ex vivo (outside the patient) model of a patient’s

The technology around tumor cell extraction from individual patients and culturing techniques, however, has largely remained undeveloped.

For instance, we are not aware of any competing diagnostic tests that use live patient tumor cells to measure dynamic cell signaling

Studies on the topic have historically highlighted the challenges of deriving a viable patient tumor cell sample from an individual

patient tumor specimen.

have developed a cell microenvironment to extract and expand viable tumor cells from fresh human tumor tissue, which meets the three

critical clinical parameters a patient-derived tumor cell sample would need to satisfy in order to meet the regulatory and clinical requirements

for a diagnostic test measuring signaling activity:

patient cell sample tested must reflect the starting tumor’s composition.

If samples do not reflect the original tumor’s

composition, test results derived from that sample may not be representative of the patient’s tumor.

sample must be available for testing in less than 21 days.

Clinicians generally require test results in cases of complex diseases

such as cancer within two to three weeks so they can begin treatment of their patient as soon as the initial symptoms are evaluated

or a preliminary diagnosis is made.

least 90% of the tumor specimens obtained from a patient must yield testable samples.

Clinicians will only order tests that require

a patient specimen when they are highly likely to receive a test result.

patient cell signaling quantification .

The second component of our CELsignia platform involves methods to quantify specific dynamic

signal transduction events in patient derived tumor cells.

The complexity of signal transduction processes is immense, and the permutations

of the pathway variables are practically unquantifiable.

Current analytical methods to assess these variables use cell fragments.

Point-in-time

measurements are limited to assessment of the compositional status (e.g., mutation), concentration level (e.g., protein amount), or activation

status (e.g., phosphorylation) of a finite number of signaling pathway components.

A key insight underlying our technology was our observation

that, no matter how sophisticated or detailed, a point-in-time molecular profile would only provide a snapshot.

These methods could not

provide a complete, dynamic assessment of the signaling activity driving a patient’s cancer.

These point-in-time molecular analyses

would, in many cases, only provide a weak correlation to the presence of the signaling pathway dysfunction driving a patient’s

Instead, we concluded that a complete diagnosis of cancer and an assessment of a patient’s response to treating their disease

requires measurement of the underlying activity of signaling pathways in live patient tumor cells.

measure live real-time dynamic cell signaling activity, we utilize an impedance biosensor instrument.

An impedance biosensor is an analytical

platform that converts changes in cellular activity to a measurable electrical signal.

When cells are stimulated and change their function,

the accompanying changes alter the electrical signal that is measured.

The output value is quantified over time and used to determine

a Signaling Function Score.

To determine the activity of a specific signaling pathway, an activating agent specific to a pathway receptor

is used to turn on the pathway and a corresponding inhibitory agent specific to the pathway receptor is used to turn signaling off.

signaling pathways are stimulated in this manner, a change in the electrical signal occurs and Signaling Function Score recorded.

relying on the principle of detecting signaling pathway activity, we believe we can develop tests for a range of disease types and targeted

therapies that affect various cellular pathways.

Multi-Pathway Activity Test

CELsignia MP Test is a qualitative laboratory developed test or LDT that measures HER2, c-Met, and PI3K signaling activity in breast

and ovarian tumor cells obtained from patients previously diagnosed with cancer to determine whether or not the patients have one of

the following cancer sub-types:

HER2 signaling driven cancer.

c-Met and HER2 signaling driven cancer.

PI3K-involved signaling driven cancer.

Commercialization Strategy

commercial activities will target three complementary groups at various phases of the development of our CELsignia tests.

Pharmaceutical

For each CELsignia test we develop to diagnose a new cancer sub-type, we intend to identify the matching targeted

therapies, either currently approved or in the investigational phase, and the manufacturer of those therapies.

We intend to initiate

discussions and seek to reach development agreements with each of these pharmaceutical companies when we have verified the prevalence

of the cancer sub-type and completed successful animal studies.

and surgical oncologists.

We plan to initially target key opinion leaders (KOLs) in each cancer type once we have completed the

analytical validation of a CELsignia test.

This will allow us to build awareness and credibility for the CELsignia test as we are

generating clinical validation data.

When a new drug indication is received that requires use of a CELsignia companion diagnostic

to identify eligible patients, we will coordinate the pharmaceutical company’s go-to-market activities with our own.

This coordination

will allow us to significantly leverage the pharmaceutical company’s sales, marketing, and reimbursement activities, unlike

traditional molecular diagnostic companies.

When a new drug indication is received that requires use of a CELsignia companion diagnostic to identify eligible patients, we

expect to coordinate the pharmaceutical company’s reimbursement activities with our own.

CELsignia tests are laboratory developed tests, or LDTs, and subject to regulation under the Clinical Laboratory Improvement Amendments,

We completed the analytical validation of our first CELsignia test and received CLIA certification in 2016.

Our current focus

is to field clinical trials with leading cancer centers in collaboration with pharmaceutical companies to demonstrate that cancer patients

diagnosed with an abnormal signaling pathway by a CELsignia test respond efficaciously to treatment with a matching targeted therapy.

Once favorable efficacy data is available, we expect to generate revenues from CELsignia tests performed in conjunction with the clinical

trials a pharmaceutical company will field during the registrational phase of our partners’ drug approval process.

We also expect

that the agreements we enter into with the pharmaceutical companies partnering with us on these registrational trials will include milestone

payments at initiation and completion of trials and perhaps at various other negotiated points during the trials.

We expect to generate

revenue from the sale of CELsignia tests ordered by physicians upon the approval of our pharmaceutical company’s matching drug,

as a companion diagnostic.

A key requirement for success of these partnerships will be clinical trial results that demonstrate the advantages

of using a CELsignia test as a companion diagnostic.

CELsignia test would be launched upon the approval of a pharmaceutical company’s matching drug as a companion diagnostic.

expect physicians, typically a medical or surgical oncologist, to order our tests in conjunction with the roll-out of the pharmaceutical

company’s matching drug.

The physician will prescribe a CELsignia test and coordinate provision of a patient specimen from a biopsy

or surgical procedure.

The fresh tissue would then be shipped overnight directly to our laboratory where we would use our proprietary

methods to extract diseased cell samples from the patient’s tissue and perform the CELsignia tests ordered.

Test results would

typically be available in 10 to 14 days after receipt of the patient specimen.

For each patient sample analyzed, a Signaling Function

Score would be calculated quantitatively and converted into a final qualitative result:

abnormal or normal.

For patients found to have

an abnormal signaling pathway, clinicians would use the results of the CELsignia test as a guide to select a targeted drug that inhibits

the abnormal signaling activity identified.

and Reimbursement

principal groups that we expect to pay us in the future for our CELsignia tests include:

third-party payors;

payors, including Medicare and state Medicaid plans;

biopharmaceutical

cancer centers, and other institutions;

reimbursement will be an important factor in achieving broad clinical adoption of our CELsignia tests.

At the same time, we believe

broad clinical adoption will help drive favorable reimbursement decisions.

To achieve broad reimbursement coverage with commercial

third-party payors and government payors, including Medicare and Medicaid, we plan to demonstrate the economic and clinical value of

our CELsignia tests to payors by employing a multi-pronged strategy:

a high bar for analytical validation.

We expect to present data on the characterization of new cancer sub-types by CELsignia

tests at conferences and will seek to publish the results in peer-reviewed journals.

the evidence standards necessary to be consistent with leading clinical guidelines.

We believe inclusion in leading clinical

practice guidelines plays a critical role in payers’ coverage decisions.

We plan to conduct clinical validation and clinical

utility studies that are consistent with the requirements of the widely recognized National Comprehensive Cancer Network clinical

practice guidelines.

an internal managed care policy and claims adjudication function as part of our core business operations.

We plan to make obtaining

adequate and widespread reimbursement a critical component of our business operations.

We expect to hire a team of in-house claims

processing and reimbursement specialists who will work with patients and payors to navigate the claims process and obtain maximum

reimbursement.

a network of KOLs.

KOLs are able to influence clinical practice by publishing research and determining whether new tests should

be integrated into practice guidelines.

We expect to collaborate with KOLs early in the development process to ensure our clinical

studies are designed and executed in a way that clearly demonstrates the benefits of our tests to physicians and payers.

a growing library of peer-reviewed studies that demonstrate the test is effective.

We will seek to publish peer-reviewed articles

and review papers to help support our efforts to obtain widespread adoption and reimbursement of our CELsignia tests.

In each disease

area we pursue, we intend to conduct studies in order to develop similar supporting literature.

expenditures.

We intend to build economic models to measure the financial benefits of using our CELsignia test in guiding patient

treatment and minimizing the use of drugs that will not likely have a positive impact.

We plan to use the data we gather through

the use of these models as we meet with commercial third-party payors and government payors.

efforts by commercial third-party and government payors to contain healthcare costs.

A major cost reduction opportunity is to

reduce expenditures for drug courses that provide no patient benefit.

Our technology will enable physicians to prescribe therapies

that have significantly higher response rates than has been the case with targeted therapies to date.

Since this will lower the drug

cost per responsive patient, we believe widespread use of our CELsignia tests is consistent with payors goals of delivering health

care more cost effectively.

present, we are not aware of any other companies that offer diagnostic tests that use a patient’s live tumor cells to identify

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continuing technological innovation and potential in-licensing opportunities to develop and maintain our proprietary position.

entered into the Gedatolisib License Agreement with Pfizer in April 2021, pursuant to which we acquired exclusive worldwide rights under

Pfizer patents and know-how to develop, manufacture and commercialize gedatolisib.

We have exclusive licenses under the Gedatolisib License

Agreement to patent rights in the U.S.

entered into the Gedatolisib License Agreement with Pfizer in April 2021, pursuant to which we acquired exclusive worldwide rights

under Pfizer patents and know-how to develop, manufacture and commercialize gedatolisib.

We have exclusive licenses under the

Gedatolisib License Agreement to patent rights in the U.S.

and numerous foreign jurisdictions relating to gedatolisib.

The patent rights in-licensed under

the Gedatolisib License Agreement include 11 granted patents in the U.S.

and more than 290 patents granted in foreign jurisdictions including

Australia, Canada, China, France, Germany, Spain, United Kingdom and Japan.

patent covering gedatolisib as a composition of matter

has a statutory expiration date in December 2029 and a U.S.

composition of matter patent that covers the lactic acid form of gedatolisib

that is currently in clinical development expires in December 2035, in each case, not including patent term adjustment or any patent

term extension, and relevant foreign counterparts.

respect to CELsignia, we have six issued U.S.

patents and 30 issued international patents covering our diagnostic approach using cell

signaling analysis in living patient cells to guide treatment of patients with targeted therapies and cell sample preparation methods.

The earliest expiration date of patents is 2033.

In addition, we have developed significant proprietary know-how and trade secrets for

the various cell sample preparation and cellular analysis methods we have developed.

rights in-licensed under the Gedatolisib License Agreement include 11 granted patents in the U.S.

and more than 290 patents granted

in foreign jurisdictions including Australia, Canada, China, France, Germany, Spain, United Kingdom and Japan.

covering gedatolisib as a composition of matter have a statutory expiration date in May 2029.

composition of matter patent

that covers the lactic acid form of gedatolisib expires in December 2035.

A pending U.S.

application covering the cyclodextrin

formulation of gedatolisib that is currently in clinical development expires in June 2039, in each case, not including patent

term adjustment or any patent term extension, and relevant foreign counterparts.

respect to CELsignia, we have seven issued U.S.

patents and more than 30 issued international patents covering our diagnostic

approach using cell signaling analysis in living patient cells to guide treatment of patients with targeted therapies and cell

sample preparation methods.

The earliest expiration date of the patents is 2032.

In addition, we have developed significant

proprietary know-how and trade secrets for the various cell sample preparation and cellular analysis methods we have

addition to patents, we rely on trade secrets and know-how to develop and maintain our competitive position.

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proprietary information by third parties.

of Gedatolisib and Other Drug Products in the United States

of Gedatolisib and Other Drug Products

authorities in the U.S.

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record-keeping, promotion, advertising, distribution, post-approval monitoring and reporting, marketing and export and import of drug

products, such as gedatolisib.

Generally, before a new drug can be marketed, considerable data demonstrating its quality, safety and

efficacy must be obtained, organized into a format specific for each regulatory authority and submitted for review and approved by the

regulatory authority.

products, such as gedatolisib and other drugs that may be used in combination with or compete with gedatolisib.

Generally, before a new

drug can be marketed, considerable data demonstrating its quality, safety and efficacy must be obtained, organized into a format specific

for each regulatory authority and submitted for review and approved by the regulatory authority.

The regulatory approval process is time-consuming

and requires significant capital expenditures.

Approval Process

of FDA Approval Process

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criminal prosecution.

Pharmaceutical

product development for a new product or certain changes to an approved product in the U.S.

typically involves preclinical laboratory

and animal tests, the submission to the FDA of an investigational new drug applicable, or IND, which must become effective before clinical

testing may commence, and adequate and well-controlled clinical trials to establish the safety and effectiveness of the drug for each

indication for which FDA approval is sought.

Satisfaction of FDA pre-market approval requirements typically takes many years and the

actual time required may vary substantially based upon the type, complexity and novelty of the product or disease.

The process required by the FDA before a drug may be marketed in the United States generally involves the following:

of nonclinical laboratory tests, animal studies and formulation studies according to good laboratory practices (GLP), or other applicable

to the FDA of an application for an investigational new drug application, or IND, which must become effective before human clinical

trials may begin;

of adequate and well-controlled human clinical trials according to the FDA’s regulations commonly referred to as current good

clinical practices (GCPs), to establish the safety and efficacy of the proposed drug for its intended use;

to the FDA of an NDA for a new drug;

completion of an FDA inspection of the manufacturing facility or facilities where the drug is produced to assess compliance with

the FDA’s current good manufacturing practice standards (cGMP), to assure that the facilities, methods and controls are adequate

to preserve the drug’s identity, strength, quality and purity;

FDA inspection of the nonclinical and clinical trial sites that generated the data in support of the NDA;

and FDA review of the NDA.

lengthy process of seeking required approvals and the continuing need for compliance with applicable statutes and regulations require

the expenditure of substantial resources and approvals are inherently uncertain.

and Clinical Stages

tests include laboratory evaluation of product chemistry, formulation and toxicity, as well as animal trials to assess the characteristics

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under the supervision of qualified investigators, generally physicians not employed by, or under control of, the trial sponsor, in accordance

with Good Clinical Practices, or GCPs, which include the requirement that all research subjects provide their informed consent for their

participation in any clinical trial.

Clinical trials are conducted under protocols detailing, among other things, the objectives of the

clinical trial, dosing procedures, subject selection and exclusion criteria and the parameters to be used to monitor subject safety and

assess efficacy.

with Good Clinical Practices, or GCPs.

Clinical trials are conducted under protocols detailing, among other things, the objectives of

the clinical trial, dosing procedures, subject selection and exclusion criteria and the parameters to be used to monitor subject safety

and assess efficacy.

Each protocol, and any subsequent amendments to the protocol, must be submitted to the FDA as part of an investigational

new drug applicable, or IND.

new drug application, or IND.

Furthermore, each clinical trial must be reviewed and approved by an Institutional Review Board, or IRB,

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trials are minimized and are reasonable in relation to anticipated benefits.

The IRB also approves the informed consent form that must

be provided to each clinical trial subject or his or her legal representative and must monitor the clinical trial until completed.

also are requirements governing the reporting of ongoing clinical trials and completed clinical trial results to public registries.

about most clinical trials must be submitted within specific timeframes for publication on the www.clinicaltrials.gov website.

related to the product, patient population, phase of investigation, trial sites and investigators and other aspects of the clinical trial

is made public as part of the registration of the clinical trial.

Sponsors are also obligated to discuss the results of their clinical

trials after completion.

Disclosure of the results of these trials can be delayed in some cases for up to two years after the date of

completion of the trial.

Competitors may use this publicly available information to gain knowledge regarding the progress of development

The IRB also monitors the clinical trial until completed.

Human clinical trials are typically conducted in three sequential phases, which may overlap or be combined:

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the requirements of the IRB or if the drug has been associated with unexpected serious harm to patients.

There are also requirements

related to registration and reporting of certain clinical trials and completed clinical trial results to public registries.

also are requirements governing the reporting of ongoing clinical trials and completed clinical trial results to public registries.

about most clinical trials must be submitted within specific timeframes for publication on the www.clinicaltrials.gov website.

related to the product, patient population, phase of investigation, trial sites and investigators and other aspects of the clinical trial

is made public as part of the registration of the clinical trial.

Sponsors are also obligated to discuss the results of their clinical

trials after completion.

Disclosure of the results of these trials can be delayed in some cases for up to two years after the date of

completion of the trial.

Competitors may use this publicly available information to gain knowledge regarding the progress of development

Review and Approval Process

completion of the required clinical testing, an NDA is prepared and submitted to the FDA.

FDA approval of the NDA is required before

marketing of the product may begin in the U.S.

The NDA must include the results of all preclinical, clinical and other testing and a

compilation of data relating to the product’s pharmacology, chemistry, manufacture and controls.

The cost of preparing and submitting

an NDA is substantial.

Prior to granting approval of the NDA, which

is required before marketing of the product may begin in the U.S., the FDA must determine whether to accept the submission and, thereafter,

conduct an in-depth review.

This process may take a year or more.

The NDA must include the results of all preclinical, clinical and other

testing and a compilation of data relating to the product’s pharmacology, chemistry, manufacture and controls.

The cost of preparing

and submitting an NDA is substantial.

The submission of most NDAs is additionally subject to a substantial application user fee, currently

for Fiscal Year 2023, and the manufacturer and/or sponsor under an approved NDA are also subject to annual program fees for eligible

products, which are currently $393,933 for Fiscal Year 2023.

FDA has 60 days from its receipt of an NDA to determine whether the application will be accepted for filing based on the agency’s

threshold determination that it is sufficiently complete to permit substantive review.

Once the submission is accepted for filing, the

FDA begins an in-depth review.

The FDA has agreed to certain performance goals in the review of new drug applications.

Most such applications

for standard review drug products are reviewed within ten to twelve months;

most applications for priority review drugs are reviewed

in six to eight months.

Priority review can be applied to drugs that the FDA determines offer major advances in treatment or provide

a treatment where no adequate therapy exists.

The review process for both standard and priority review may be extended by FDA for three

additional months to consider certain late-submitted information, or information intended to clarify information already provided in

the submission.

$4,048,695 for Fiscal Year 2024, and the manufacturer and/or sponsor under an approved NDA are also subject to annual program fees for

eligible products, which are currently $416,734 for Fiscal Year 2024.

FDA may also refer applications for novel drug products, or drug products that present difficult questions of safety or efficacy, to

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and actions in reviewing NDA supplements as it does in reviewing NDAs.

Marketing Exclusivity

NDA approval of a new chemical entity, or NCE, which is a drug that contains no active moiety that has been approved by the FDA in any

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of development programs.

of Gedatolisib and Other Drug Products in the European Union

the EU, our product candidates also may be subject to extensive regulatory requirements.

Union Approval Process

the EU, our product candidates may also be subject to extensive regulatory requirements.

As in the U.S., medicinal products can be marketed

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preclinical and clinical research in the EU are subject to significant regulatory controls.

Clinical Trials Directive 2001/20/EC, the Directive 2005/28/EC on GCP, and the related national implementing provisions of the

individual EU Member States govern the system for the approval of clinical trials in the EU.

Under this system, an applicant must

obtain prior approval from the competent national authority of the EU Member States in which the clinical trial is to be conducted.

Furthermore, the applicant may only start a clinical trial at a specific trial site after the competent ethics committee has issued

a favorable opinion.

The clinical trial application must be accompanied by, among other documents, an Investigational Medicinal

Product Dossier or IMPD, or the Common Technical Document, with supporting information prescribed by Directive 2001/20/EC, Directive

2005/28/EC, where relevant the implementing national provisions of the individual EU Member States and further detailed in

applicable guidance documents.

All suspected unexpected serious adverse reactions to the investigated drug that occur during the

clinical trial have to be reported to the competent national authority and the Ethics Committee of the Member State where they

Clinical Trials Directive 2001/20/EC, the Directive 2005/28/EC on GCP, and the related national implementing provisions of the individual

EU Member States govern the system for the approval of clinical trials in the EU.

Under this system, an applicant must obtain prior approval

from the competent national authority of the EU Member States in which the clinical trial is to be conducted.

Furthermore, the applicant

may only start a clinical trial at a specific trial site after the competent ethics committee has issued a favorable opinion.

trial application must be accompanied by, among other documents, an Investigational Medicinal Product Dossier or IMPD, or the Common

Technical Document, with supporting information prescribed by Directive 2001/20/EC, Directive 2005/28/EC, where relevant, the implementing

national provisions of the individual EU Member States and further detailed in applicable guidance documents.

All suspected unexpected

serious adverse reactions to the investigated drug that occur during the clinical trial have to be reported to the competent national

authority and the Ethics Committee of the Member State where they occurred.

new Clinical Trials Regulation (EU) No 536/2014 came into effect in 2022.

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The timeframe for the evaluation of an MAA under the accelerated assessment

procedure is of 150 days, excluding stop-clocks.

procedure is 150 days, excluding stop-clocks.

Authorization Procedures

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the above-described procedures, before granting an MAA, the EMA or the competent authorities of the Member States of the European Economic

Area, or EEA, make an assessment of the risk-benefit balance of the product on the basis of scientific criteria concerning its quality,

safety and efficacy.

Area, or EEA, assess the risk-benefit balance of the product on the basis of scientific criteria concerning its quality, safety and efficacy.

Regulatory Exclusivity

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and CMS for Diagnostic

Centers for Medicare & Medicaid Services, or CMS, an agency within the U.S.

Department of Health and Human Services, regulates all

clinical laboratory testing (except research) performed on humans in the United States through CLIA.

All clinical laboratories that perform

clinical lab services on human specimens for the purpose of providing information on the diagnosis, prevention or treatment of disease

must receive CLIA certification.

This covers approximately 175,000 laboratories as of 2017.

Laboratories must obtain CLIA certification

and demonstrate compliance with CLIA requirements as confirmed by an inspection by CMS.

CELsignia tests are laboratory developed tests, or LDTs, and subject to regulation under the Clinical Laboratory Improvement Amendments,

The Centers for Medicare & Medicaid Services, or CMS, an agency within the U.S.

Department of Health and Human Services,

regulates all clinical laboratory testing (except research) performed on humans in the United States through CLIA.

All clinical laboratories

that perform clinical lab services on human specimens for the purpose of providing information on the diagnosis, prevention or treatment

of disease must receive CLIA certification.

We received our CLIA certification in 2016.

also had our laboratory certified by the College of American Pathologies, or CAP, in 2016, an organization recognized by CMS as a third-party

reviewer of clinical laboratories.

Several states, including, among others, New York and California, require licensure of out-of-state

labs that receive specimens from the state and compliance with the state’s individual laboratory regulations.

We also had our laboratory certified by the College

of American Pathologies, or CAP, in 2016, an organization recognized by CMS as a third-party reviewer of clinical laboratories.

states, including, among others, New York and California, require licensure of out-of-state labs that receive specimens from the state

and compliance with the state’s individual laboratory regulations.

our laboratory is out of compliance with CLIA requirements, we may be subject to sanctions such as suspension, limitation or revocation

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registration, device listing, quality systems regulations, premarket clearance or premarket approval, and post-market controls).

the FDA proposed regulations that would apply to LDTs, the FDA decided that, at present, those regulations are not moving forward towards

approval and implementation.

In mid-2014, the FDA published a draft Guidance Document describing a proposed approach for a regulatory

framework for LDTs that would have resulted in most of the high-value LDT tests marketed today eventually being required to obtain 510(k)

clearances or PMAs.

If implemented, this regulatory framework would require most hospital clinical labs to abandon a number of tests

they perform or to pursue regulatory clearances or approvals to perform them.

These proposals met significant resistance from Congress,

the hospital industry, and independent clinical laboratories.

The FDA indicated in late 2016 that it does not intend to finalize the

draft Guidance Document at this time.

However, the FDA continues to discuss potential regulatory approaches to LDTs.

the FDA has discussed potential regulation of LDTs and may regulate LDTs in the future.

and Reimbursement of our Product Candidates

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We continue to evaluate the impact of the IRA on our business, operations and financial

condition and results as the full effect of the IRA on our business and the pharmaceutical industry remains uncertain.

In addition, changes

to the Medicaid program or the federal 340B drug pricing program, which imposes ceilings on prices that drug manufacturers can charge

for medications sold to certain health care facilities, could have a material impact on our business.

condition and results as the full effect of the IRA on our business strategy and the pharmaceutical industry remains uncertain.

changes to the Medicaid program or the federal 340B drug pricing program, which imposes ceilings on prices that drug manufacturers can

charge for medications sold to certain health care facilities, could have a material impact on our business following commercialization.

and reimbursement schemes vary widely from country to country.

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manufacturers on the one hand and prescribers, purchasers, formulary managers and beneficiaries on the other hand.

Although there are

a number of statutory exceptions and regulatory safe harbors protecting some common activities from prosecution, the exceptions and safe

harbors are drawn narrowly.

Failure to meet all of the requirements of a particular applicable statutory exception or regulatory safe

harbor does not make the conduct per se illegal under the AKS.

Instead, the legality of the arrangement will be evaluated on a case-by-case

basis based on a cumulative review of all its facts and circumstances.

Several courts have interpreted the statute’s intent requirement

to mean that if any one purpose of an arrangement involving remuneration is to induce referrals of federal healthcare covered business,

the statute has been violated.

In addition, a person or entity does not need to have actual knowledge of the statute or specific intent

to violate it in order to have committed a violation.

Moreover, a claim including items or services resulting from a violation of the

AKS constitutes a false or fraudulent claim for purposes of the federal civil False Claims Act.

On November 20, 2020, the Office of Inspector

General, or OIG finalized further modifications to the AKS.

Under the final rule, OIG added safe harbor protections under the AKS for

certain coordinated care and value-based arrangements among clinicians, providers, and others.

The final rule (with some exceptions)

became effective January 19, 2021.

We continue to evaluate what effect, if any, this rule will have on our business.

A person does not

need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation of the AKS.

a claim including items or services resulting from a violation of the AKS constitutes a false or fraudulent claim for purposes of the

federal civil False Claims Act, which imposes civil penalties, including through civil whistleblower or qui tam actions, against individuals

or entities (including manufacturers) for, among other things, knowingly presenting, or causing to be presented to federal programs (including

Medicare and Medicaid) claims for items or services that are false or fraudulent, claims for items or services not provided as claimed,

or claims for medically unnecessary items or services.

This could apply even if we are not submitting claims directly to payors as would

be the case with drug products.

addition, under a federal law directed at “self-referral,” commonly known as the “Stark Law,” there are prohibitions,

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in violation of the Stark Law.

A person who engages in a scheme to circumvent the Stark Law’s referral prohibition may be fined

up to $100,000 for each such arrangement or scheme.

In addition, any person who presents or causes to be presented a claim to the Medicare

or Medicaid programs in violation of the Stark Law is subject to civil monetary penalties of up to $15,000 per bill submission, an assessment

of up to three times the amount claimed and possible exclusion from participation in federal governmental payor programs.

Bills submitted

in violation of the Stark Law may not be paid by Medicare or Medicaid, and any person collecting any amounts with respect to any such

prohibited bill is obligated to refund such amounts.

Bills submitted in violation of the Stark Law may not be paid by Medicare or Medicaid, and there may be

significant penalties for violations.

Many states have comparable laws that are not limited to Medicare and Medicaid referrals.

we could be held liable under the federal False Claims Act, which imposes civil penalties, including through civil whistleblower or qui

tam actions, against individuals or entities (including manufacturers) for, among other things, knowingly presenting, or causing to be

presented to federal programs (including Medicare and Medicaid) claims for items or services that are false or fraudulent, claims for

items or services not provided as claimed, or claims for medically unnecessary items or services.

This could apply even if we are not

submitting claims directly to payors as would be the case with drug products.

The government may deem manufacturers of such products

to have “caused” the submission of false or fraudulent claims by, for example, providing inaccurate billing or coding information

to customers or promoting a product off-label.

Several biopharmaceutical, medical device and other healthcare companies have been prosecuted

under federal false claims and civil monetary penalty laws for, among other things, allegedly providing free product to customers with

the expectation that the customers would bill federal programs for the product.

Other companies have been prosecuted for causing false

claims to be submitted because of the companies’ marketing of products for unapproved (e.g., or off-label), and thus non-covered,

In addition, the civil monetary penalties statute imposes penalties against any person who is determined to have presented or caused

to be presented a claim to a federal health program that the person knows or should know is for an item or service that was not provided

as claimed or is false or fraudulent.

future marketing and activities relating to the reporting of wholesaler or estimated retail prices for our products, if approved, the

reporting of prices used to calculate Medicaid rebate information and other information affecting federal, state and third-party reimbursement

for our products, and the sale and marketing of our product candidates, are subject to scrutiny under these laws.

regulations present compliance and litigation risks for our business and others in our industry.

We incur compliance-related expenses

and expect to incur additional expenses if and when our products are commercialized.

We may be subject to penalties or limitations on

reimbursement if we are found to have violated these regulations.

federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, created additional federal criminal statutes that prohibit,

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addition, there has been a recent trend of increased federal and state regulation of payments made to physicians and certain other healthcare

The Affordable Care Act, or the ACA, imposed, among other things, new annual reporting requirements through the Physician

Payments Sunshine Act for covered manufacturers for certain payments and “transfers of value” provided to physicians (defined

to include doctors, dentists, optometrists, podiatrists and chiropractors) and teaching hospitals, as well as ownership and investment

interests held by physicians and their immediate family members.

Effective January 1, 2022, these reporting obligations will extend to

include transfers of value made to certain non-physician providers such as physician assistants and nurse practitioners.

Failure to submit

timely, accurately and completely the required information for all payments, transfers of value and ownership or investment interests

may result in civil monetary penalties.

Covered manufacturers must submit reports by the 90 th day of each subsequent calendar

year and the reported information is publicly made available on a searchable website.

providers, and their ownership and investment interests.

The Affordable Care Act, or the ACA, imposed, among other things, new annual

reporting requirements through the Physician Payments Sunshine Act for covered manufacturers for certain payments and “transfers

of value” to these providers.

Failure to submit timely, accurately and completely the required information for all payments, transfers

of value and ownership or investment interests may result in civil monetary penalties.

may also be subject to data privacy and security regulation by both the federal government and the states in which we conduct our business.

HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, or HITECH, and their respective implementing

regulations, including the Final HIPAA Omnibus Rule published on January 25, 2013, impose specified requirements relating to the privacy,

security and transmission of individually identifiable health information held by covered entities and their business associates.

other things, HITECH made HIPAA’s security standards directly applicable to “business associates,” defined as independent

contractors or agents of covered entities that create, receive, maintain or transmit protected health information in connection with

providing a service for or on behalf of a covered entity, although it is unclear that we would be considered a “business associate”

in the normal course of our business.

HITECH also increased the civil and criminal penalties that may be imposed against covered entities,

business associates and possibly other persons, and gave state attorneys general new authority to file civil actions for damages or injunctions

in federal courts to enforce the federal HIPAA laws and seek attorney’s fees and costs associated with pursuing federal civil actions.

In addition, state laws govern the privacy and security of health information in certain circumstances, many of which differ from each

other in significant ways and may not have the same requirements, thus complicating compliance efforts.

See “European Data Collection”

below for a discussion of data privacy and security enactments of the EU.

example, California’s Consumer Privacy Act, or CCPA, went into effect in January 2020, and the California Attorney General has

since promulgated final regulations.

The law provides broad rights to California consumers with respect to the collection and use of

their personal information and imposes data protection obligations on certain businesses.

While the CCPA does not apply to protected

health information that is subject to HIPAA or personal information collected, used or disclosed in research, as defined by federal law,

the CCPA may still affect our business activities.

Moreover, on November 3, 2020, California voters passed the California Privacy Rights

Act, or CPRA, under a ballot initiative.

The CPRA amends the existing CCPA to include new consumer rights and additional data protection

The new data protection requirements under the CPRA apply to information collected on or after January 1, 2022.

promulgation of final regulations, the California State Attorney General has commenced enforcement actions against CCPA violators.

uncertainty surrounding the implementation of CCPA and the amendments under the CPRA exemplifies the vulnerability of our business to

the evolving regulatory environment related to personal data and protected health information.

The California law further expands the

need for privacy and process enhancements and commitment of resources in support of compliance.

Moreover, more than ten states have proposed

bills in the last year with provisions similar to the CCPA and CPRA.

It is likely that other states will pass laws similar to the CCPA

and the CPRA in the near future and a federal data protection law may also be on the horizon.

state and foreign fraud and abuse laws and regulations, such as state anti-kickback and false claims laws, may apply to sales or marketing

arrangements and claims involving healthcare items or services.

Such laws are generally broad and are enforced by various state agencies

and private actions.

Also, many states have similar fraud and abuse statutes or regulations that may be broader in scope and may apply

regardless of payor, in addition to items and services reimbursed under Medicaid and other state programs.

Some state laws require pharmaceutical

regulations, impose specified requirements relating to the privacy, security and transmission of individually identifiable health information

held by covered entities and their business associates.

Among other things, HITECH made HIPAA’s security standards directly applicable

to “business associates,” defined as independent contractors or agents of covered entities that create, receive, maintain

or transmit protected health information in connection with providing a service for or on behalf of a covered entity, although it is

unclear that we would be considered a “business associate” in the normal course of our business.

HITECH also increased the

civil and criminal penalties that may be imposed against covered entities, business associates and possibly other persons, and gave state

attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws

and seek attorney’s fees and costs associated with pursuing federal civil actions.

In addition, state laws govern the privacy and

security of health information in certain circumstances, many of which differ from each other in significant ways and may not have the

same requirements, thus complicating compliance efforts.

See “European Data Collection” below for a discussion of data privacy

and security enactments of the EU.

the state level, California’s Consumer Privacy Act, or CCPA, and the California Privacy Rights Act, or CPRA, impose data

protection obligations on certain businesses.

While we believe that certain limited exceptions under the CCPA for clinical trial

data and other health data would apply to us, these regulations exemplify the vulnerability of our business to the evolving

regulatory environment related to personal data and protected health information, which causes us to incur compliance

and foreign jurisdictions also have fraud and abuse laws and regulations, such as state anti-kickback and false claims laws, which may

apply to sales or marketing arrangements and claims involving healthcare items or services.

Some state laws also require pharmaceutical

companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant federal government compliance

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healthcare providers, marketing expenditures or drug pricing.

order to sell products, we must also comply with state laws, including those that require the registration of manufacturers and wholesale

order to sell products, we will need to comply with state laws, including those that require the registration of manufacturers and wholesale

distributors of drug and biological products.

These include, in certain states, manufacturers and distributors who ship products into

the state even if such manufacturers or distributors have no place of business within the state.

Some states also impose requirements

on manufacturers and distributors to establish the pedigree of product in the chain of distribution, including some states that require

manufacturers and others to adopt new technology capable of tracking and tracing product as it moves through the distribution chain.

Several states have enacted legislation requiring pharmaceutical and biotechnology companies to establish marketing compliance programs,

file periodic reports with the state, make periodic public disclosures on sales, marketing, pricing, clinical trials and other activities,

and/or register their sales representatives, as well as to prohibit pharmacies and other healthcare entities from providing certain physician

prescribing data to pharmaceutical and biotechnology companies for use in sales and marketing, and to prohibit certain other sales and

marketing practices.

All of our activities are potentially subject to federal and state consumer protection and unfair competition laws.

Several states have enacted legislation requiring pharmaceutical and biotechnology companies

to establish marketing compliance programs, file periodic reports with the state, make periodic public disclosures on sales, marketing,

pricing, clinical trials and other activities, and/or register their sales representatives, as well as to prohibit pharmacies and other

healthcare entities from providing certain physician prescribing data to pharmaceutical and biotechnology companies for use in sales

and marketing, and to prohibit certain other sales and marketing practices.

If and when we commercialize our products, all of our activities

are potentially subject to federal and state consumer protection and unfair competition laws.

scope and enforcement of each of these laws is uncertain and subject to rapid change in the current environment of healthcare reform,

especially in light of the lack of applicable precedent and regulations.

Federal and state enforcement bodies have recently increased

their scrutiny of interactions between healthcare companies and healthcare providers, which has led to a number of investigations, prosecutions,

convictions and settlements in the healthcare industry.

It is possible that governmental authorities will conclude that our business

practices may not comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare

laws and regulations.

If our operations are found to be in violation of any of these laws or any other governmental regulations that

may apply to us, we may be subject to significant civil, criminal and administrative penalties, damages, fines, disgorgement, contractual

damages, reputational harm, diminished profits and future earnings, imprisonment, exclusion of drugs from government funded healthcare

programs, such as Medicare and Medicaid, and the curtailment or restructuring of our operations, as well as additional reporting obligations

and oversight if we become subject to a corporate integrity agreement or other agreement to resolve allegations of non-compliance with

these laws, any of which could adversely affect our ability to operate our business and our financial results.

If any of the physicians

or other healthcare providers or entities with whom we expect to do business is found to be not in compliance with applicable laws, they

may be subject to significant criminal, civil or administrative sanctions, including exclusions from government funded healthcare programs.

Ensuring business arrangements comply with applicable healthcare laws, as well as responding to possible investigations by government

authorities, can be time- and resource consuming and can divert a company’s attention from the business.

If our operations are found to be in violation of any of these

laws or any other governmental regulations that may apply to us, we may be subject to significant civil, criminal and administrative

penalties, damages, fines, disgorgement, contractual damages, reputational harm, diminished profits and future earnings, imprisonment,

exclusion of drugs from government funded healthcare programs, such as Medicare and Medicaid, and the curtailment or restructuring of

our business strategy operations, as well as additional reporting obligations and oversight if we become subject to a corporate integrity

agreement or other agreement to resolve allegations of non-compliance with these laws, any of which could adversely affect our ability

to operate our business and our financial results.

If any of the physicians or other healthcare providers or entities with whom we expect

to do business is found to be not in compliance with applicable laws, they may be subject to significant criminal, civil or administrative

sanctions, including exclusions from government funded healthcare programs.

Ensuring business arrangements comply with applicable healthcare

laws, as well as responding to possible investigations by government authorities, can be time- and resource consuming and can divert

a company’s attention from the business.

Data Collection

collection and use of personal health data in or arising from the EU are governed by the provisions of the Data Protection Directive,

and the General Data Protection Regulation, or GDPR.

are subject to the Data Protection Directive, and the General Data Protection Regulation, or GDPR, which govern the collection and use

of personal health data in or arising from the EU.

This directive imposes several requirements relating to the consent of the individuals

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Failure to comply with the requirements of the Data

Protection Directive, the GDPR and the related national data protection laws of the EU Member States may result in fines and other administrative

The GDPR introduces new data protection requirements in the EU and substantial fines for breaches of the data protection rules.

The GDPR regulations may impose additional responsibility and liability in relation to personal data that we process, including in respect

of clinical trials, and we may be required to put in place additional mechanisms ensuring compliance with the new data protection rules.

This may be onerous and adversely affect our business, financial condition, results of operations and prospects.

Protection Directive, the GDPR and the related national data protection laws of the EU Member States may result in substantial fines

and other administrative penalties.

We have incurred, and expect to continue to incur, compliance expenses in connection with the GDPR.

If we are found to be in violation of the GDRP, our product development timeline may be affected, which would affect our ability to generate

revenue and our competitive position.

and Future Legislation

and other jurisdictions, there have been a number of legislative and regulatory changes and proposed changes regarding the healthcare

system that could prevent or delay marketing approval of our product candidates, restrict or regulate post-approval activities and affect

our ability to profitably sell any product candidates.

We expect that current laws, as well as other healthcare reform measures that

may be adopted in the future, may result in more rigorous coverage criteria and additional downward pressure on the price that we, or

any collaborators, may receive.

ACA, for example, revised the methodology by which rebates owed by manufacturers for covered outpatient drugs are calculated under the

Medicaid Drug Rebate Program, extended the Medicaid Drug Rebate Program to utilization of covered drugs dispensed to individuals enrolled

in Medicaid managed care organizations and subjected manufacturers to new annual fees for certain branded prescription drugs.

price of our test may be included in the reimbursement rates for certain drugs, this could significantly impact our pricing.

favorable coverage and reimbursement status is attained for one or more products, less favorable coverage policies and reimbursement

rates may be implemented in the future.

its enactment, there have been numerous judicial, administrative, executive, and legislative challenges to certain aspects of the ACA,

and we expect there will be additional challenges and amendments to the ACA in the future.

For example, various portions of the ACA are

currently undergoing legal and constitutional challenges in the U.S.

Supreme Court, and the Trump Administration issued various Executive

Orders which eliminated cost sharing subsidies and various provisions that would impose a fiscal burden on states or a cost, fee, tax,

penalty or regulatory burden on individuals, healthcare providers, health insurers, or manufacturers of pharmaceuticals or medical devices.

Additionally, Congress has introduced several pieces of legislation aimed at significantly revising or repealing the ACA.

2018, the CMS published a final rule permitting further collections and payments to and from certain ACA qualified health plans and health

insurance issuers under the ACA risk adjustment program in response to the outcome of the federal district court litigation regarding

the method CMS uses to determine this risk adjustment.

Since then, the ACA risk adjustment program payment parameters have been updated

It is unclear whether the ACA will be overturned, repealed, replaced, or further amended.

We cannot predict what affect further

changes to the ACA would have on our business, especially given the new Biden Administration.

Additionally,

other federal health reform measures have been proposed and adopted in the U.S.

since the ACA was enacted:

Budget Control Act of 2011, among other things, created measures for spending reductions by Congress.

A Joint Select Committee on

Deficit Reduction, tasked with recommending a targeted deficit reduction of at least $1.2 trillion for the years 2013 through 2021,

was unable to reach required goals, thereby triggering the legislation’s automatic reduction to several government programs.

These changes included aggregate reductions to Medicare payments to providers of up to 2% per fiscal year, which went into effect

in April 2013 and, due to subsequent legislative amendments to the statute, including the BBA, will remain in effect through 2027,

unless additional Congressional action is taken.

However, pursuant to the Coronavirus Aid, Relief and Economic Security Act, or CARES

Act, and subsequent legislation, these Medicare sequester reductions are suspended from May 1, 2020 through March 31, 2021 due to

the COVID-19 pandemic.

Proposed legislation, if passed, would extend this suspension until the end of the pandemic.

American Taxpayer Relief Act of 2012, among other things, reduced Medicare payments to several providers, and increased the statute

of limitations period for the government to recover overpayments to providers from three to five years.

there has been heightened governmental scrutiny over the manner in which companies set prices for their products, which have resulted

in several recent Congressional inquiries and proposed and enacted bills designed to, among other things, bring more transparency to

product pricing, review the relationship between pricing and patient programs, and reform government program reimbursement methodologies

for products.

In addition, the U.S.

government, state legislatures, and foreign governments have shown significant interest in implementing

cost containment programs, including price-controls, restrictions on reimbursement and requirements for substitution of generic products

for branded prescription drugs to limit the growth of government paid healthcare costs.

states in the U.S.

have also increasingly passed legislation and implemented regulations designed to control pharmaceutical product pricing,

including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure

and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

the Biden administration have each indicated that it will continue to seek new legislative and/or administrative measures to control

and other jurisdictions, continued healthcare reform measures may result in more rigorous coverage criteria and additional downward

pressure on the price that we, or any collaborators, may receive.

Individual states in the U.S.

have also been increasingly passing legislation and implementing regulations designed to control

pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain

product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other

countries and bulk purchasing.

have also been increasingly passing legislation

and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement

constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some

cases, designed to encourage importation from other countries and bulk purchasing.

Regulations may also prevent or delay marketing approval

of our product candidates, restrict or regulate post-approval activities and affect our ability to profitably sell any product candidates.

Regulatory Requirements

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development of new regulations will affect our business operations or the cost of compliance.

of COVID-19 on our Business

a result of the COVID-19 pandemic, we experienced delays in the enrollment of patients in our ongoing FACT-1 and FACT-2 clinical trials.

While the COVID-19 pandemic has significantly subsided, future outbreaks or variants of the virus may cause additional delays in our

clinical trial work.

of Public Health Matters on our Business

a result of the COVID-19 pandemic, we experienced delays in the enrollment of patients in certain CELsignia-related clinical trials.

While the COVID-19 pandemic has significantly subsided, future outbreaks or variants of the virus or other public health disruptions

may cause additional delays in our clinical trial work.

were organized as a Minnesota limited liability company in 2011 and commenced operations in 2012.

8 unchanged sentences

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What changed 10-K

Item 1. Business