CELCUITY INC. You should read the following discussion and analysis of our financial condition
and results of operations together with our unaudited condensed financial
statements and the related notes appearing under Item 1 of Part I of this
Quarterly Report on Form 10-Q (this "Quarterly Report"). Some of the information
contained in this discussion and analysis or set forth elsewhere in this
Quarterly Report, including information with respect to our plans and strategy
for our business and expected financial results, includes forward-looking
statements that involve risks and uncertainties. You should review the "Risk
Factors" discussed in our Annual Report on Form 10-K for the year ended
Overview
We are a clinical-stage biotechnology company seeking to extend the lives of cancer patients by pursing an integrated companion diagnostic (CDx) and therapeutic (Rx) strategy that leverages our CELsignia CDx platform. CELsignia is uniquely able to analyze live patient tumor cells to identify new groups of cancer patients likely to benefit from targeted therapies. This enables a CELsignia CDx to support advancement of new indications for already approved targeted therapies. Our therapeutic strategy aims to utilize CELsignia's unique insights into tumor cell biology to identify, in-license, and develop potential first-in-class or best-in-class targeted therapies that treat the same cancer driver a CELsignia CDx can identify. We believe this integrated CDx and Rx strategy will maximize the impact our CELsignia platform has on the treatment landscape for cancer patients.
Our 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 it. 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, 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.
Our 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.
We are supporting the advancement of new potential indications for six different targeted therapies, controlled by other pharmaceutical companies, that would rely on a CELsignia CDx to select patients. Five Phase 2 trials are underway to evaluate the efficacy and safety of these therapies in CELsignia selected patients. These patients are not currently eligible to receive these drugs and are not identifiable with a molecular test.
The first drug candidate we are developing internally is gedatolisib, a potent,
well-tolerated, small molecule dual inhibitor, administered intravenously, that
selectively targets all Class 1 isoforms of PI3K and mammalian target of
rapamycin (mTOR). In
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Supporting 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. By 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 patients. 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. With each program, we are:
· Leveraging the proprietary insights CELsignia provides into live patient
tumor cell function
· Using a CELsignia CDx to identify new patients likely to respond to the
paired targeted therapy
· Developing a new targeted therapeutic option for breast cancer patients
· Maximizing the probability of getting regulatory approval to market the
targeted therapy indication
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.
Our second CELsignia test for breast cancer evaluates independent c-Met signaling activity and its involvement with HER family signaling in HER2-negative breast cancer tumor cells. Our internal studies show that approximately 20%-25% of HER2-negative breast cancer patients have abnormal c-Met signaling activity that is co-activated with abnormal HER family signaling. These studies suggest that this sub-group of HER2-negative breast cancer patients may best respond to treatment with a combination of HER family and c-Met inhibitors.
Our 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 create the CELsignia Multi-Pathway Activity Test, or CELsignia MP Test. 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.
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 15,000 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. There is 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. We initiated discussions with pharmaceutical companies about collaborating on clinical trials in late 2020.
We also made significant progress in 2020 developing a new CELsignia test intended to diagnose cancers driven by dysregulated RAS signaling.
Dysregulation of RAS signaling, which includes the RAF/MEK/ERK and PI3K/AKT/mTOR pathways, is estimated to drive 30%-40% of all cancers. Pharmaceutical companies have developed numerous drugs that target RAS-involved pathways. However, the number of interactions amongst RAS-regulated pathways has made it extremely difficult to use molecular tests to identify patients with dysregulated RAS signaling tumors. The challenge of diagnosing a cancer driven by a dysregulated RAS signaling network is magnified because two or more different pathways are typically involved. Recent research has also found that RAS mutations play a much less important role in dysregulated RAS signaling than previously thought. Our CELsignia platform is uniquely suited to untangle the complexity of dysregulated RAS signaling tumors and identify the targeted therapy combination capable of treating it.
Once development of the new RAS test is completed, we intend to add it to our current CELsignia MP Test for breast and ovarian cancer. This next generation CELsignia test would provide an analysis of EGFR/HER1, HER2, HER3, c-MET, PI3K, and RAS-involved signaling activity for each patient tumor specimen received.
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In addition to our CELsignia tests for HER2-negative breast cancer and ovarian
cancer, we expect to develop CELsignia tests to diagnose eight new potential
cancer sub-types we have discovered in lung, ovarian, kidney, and bladder
cancers. Approved or investigational drugs are currently available to treat
these new potential cancer sub-types. We expect to launch these additional tests
on a staggered basis over the next few years while continuing our research to
identify additional new cancer sub-types. Our overall commercialization
strategy is to develop diagnostics that expand the patient population eligible
for targeted therapies. We are collaborating with
Our current programs include:
· Herceptin® and Perjeta® for HER2-negative early-stage breast cancer
patients. Each drug targets the HER2 receptor and is owned by Genentech,
Inc. These drugs are only currently approved to treat cancer patients who
are HER2+.
· Vizimpro® and Xalkori® for HER2-negative late-stage breast cancer
patients. Vizimpro, a pan-HER inhibitor, and Xalkori, a c-Met inhibitor,
are owned by Pfizer, Inc. These drugs are currently only approved to treat
patients with non-small cell lung cancer who have specific molecular
mutations.
· Tabrecta® and Nerlynx® for HER2-negative late-stage breast cancer
patients. Tabrecta, a c-Met inhibitor, is owned by Novartis AG and Nerlynx
is owned by Puma Biotechnology, Inc. Tabrecta is currently only approved
to treat patients with non-small cell lung cancer who have specific
molecular mutations. Nerlynx is currently only approved to treat HER2+
breast cancer patients.
· Nerlynx and Faslodex for ER+/HER2-negative late-stage breast cancer
patients. Faslodex, a selective estrogen receptor degrader, is owned by
AstraZeneca.
· Nerlynx for ER-/HER2- early-stage breast cancer patients.
Interventional Clinical Trials in Process using a CELsignia Test to Select Patients for Treatment
FACT-1 Clinical Trial to Evaluate Efficacy of
We are collaborating with NSABP and
A synopsis of the trial protocol is provided below.
FACT-1 Clinical Trial Synopsis
Primary Objective To evaluate the efficacy of neoadjuvant HER2
drug treatment in early-stage HER2-negative
breast cancer patients with abnormal HER2
signaling
Sites/Sponsor Multi-center in collaboration with NSABP and
Subjects Genentech
Endpoint 54 HER2-negative early-stage breast cancerInvestigational Arm (26 ER+/28ER-)
Pathological complete response (ypT0/Tis
ypN0)
AC-T + Trastuzumab + Pertuzumab
FACT-2 Clinical Trial to Evaluate Efficacy of Puma's HER2 Targeted Therapy
We are collaborating with Puma and
A synopsis of the trial protocol is provided below.
FACT-2 Clinical Trial Synopsis
Primary Objective To evaluate the efficacy of neoadjuvant HER2
drug treatment in early-stage
triple-negative breast cancer patients with
abnormal HER2 signaling
Sites/Sponsor Multi-center in collaboration with West
Subjects Cancer Center and Puma
Endpoint 27 early-stage triple-negative breast cancerInvestigational Arm with abnormal HER2 signaling
Pathological complete response (ypT0/Tis
ypN0)
Neratinib then Paclitaxel + Carboplatin +
Neratinib
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FACT-3 Clinical Trial to Evaluate Efficacy of Pfizer's pan-HER and c-Met Targeted Therapies
In
A synopsis of the trial protocol is provided below.
FACT-3 Clinical Trial Synopsis
Primary Objective To assess the efficacy of combined Vizimpro
plus Xalkori in previously treated
HER2-negative metastatic breast cancer
subjects with hyperactive HER2 and c-Met
signaling tumors
Sites/Sponsor Multi-center in collaboration with Sarah
Subjects Cannon Research Institute and Pfizer
Endpoint 23 late-stage HER2-negative breast cancerInvestigational Arm with abnormal HER2/c-Met signaling
Objective response using RECIST 1.1 criteria
Vizimpro and Xalkori
FACT-4 Clinical Trial to Evaluate Efficacy of Puma's HER2 Targeted Therapy
In
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The goal of the trial is to demonstrate that previously treated HR+, HER2-negative metastatic breast cancer patients who have hyperactive HER2 signaling tumors, as identified by the CELsignia test, respond to treatment with Nerlynx in combination with Faslodex, a hormonal therapy that targets the estrogen receptor. We believe there is significant clinical interest in finding new diagnostic tests and targeted therapies for metastatic HR+, HER2-negative breast cancer patients whose disease progressed on prior therapies. Of particular interest are new therapeutic combinations that can overcome resistance to anti-estrogen therapies like Faslodex. The blockade of estrogen receptor and HER2 pathways when the HER2 pathway is hyperactive using a combination of Neratinib and Faslodex has been demonstrated in animal models.
A synopsis of the trial protocol is provided below.
FACT-4 Clinical Trial Synopsis
Primary Objective To assess the efficacy of combining Nerlynx
plus Faslodex in previously treated
metastatic HR-positive, HER2-negative
patients with hyperactive HER2 signaling
tumors
Sites/Sponsor Multi-center in collaboration with Mass
Subjects General and Puma
Endpoint 23 late-stage HR+/HER2-negative breastInvestigational Arm cancer with abnormal HER2 signaling
Objective response using RECIST 1.1 criteria
Nerlynx and Faslodex
FACT-6 Clinical Trial to Evaluate Efficacy of Novartis's c-Met Inhibitor and Puma's pan-HER inhibitor
In
A synopsis of the trial protocol is provided below.
FACT-6 Clinical Trial Synopsis
Primary Objective To assess the efficacy of combined Tabrecta
plus Nerlynx in previously treated
HER2-negative metastatic breast cancer
subjects with hyperactive HER2 and c-Met
signaling tumors
Sites/Sponsor Multi-center in collaboration with MD
Subjects Anderson, Novartis, and Puma
Endpoint Up to 48 late-stage HER2-negative breastInvestigational Arm cancer with abnormal HER2/c-Met signaling
Objective response using RECIST 1.1 criteria
Tabrecta and Nerlynx
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In conjunction with the development of our CELsignia tests, we will seek
collaborations with pharmaceutical companies to field clinical trials to advance
the clinical development of their targeted therapies with the eventual goal of
obtaining
Gedatolisib - An Internal Drug Candidate
Overview
Gedatolisib (PF-05212384) 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
Background on Breast Cancer and Current Treatments
Breast cancer is the most prevalent cancer in women, accounting for 30% of all
female cancers and 13% of cancer-related deaths in
Four different breast cancer subtypes are currently identified using molecular tests that determine the level of ER and HER2 expression. About 70% of breast cancers are ER+/HER2-, which is indicative of hormone dependency. Despite progress in treatment strategies, metastatic ER+/HER2- breast cancer (mBC) remains an incurable disease, with a median overall survival (OS) of three years and a five-year survival rate of 25%.
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Four different classes of targeted therapies are currently used to treat
ER+/HER2- tumors. These drugs generated revenues of nearly
Endocrine-based therapies. Selective ER modulators (tamoxifen), selective ER degrader (fulvestrant), and aromatase inhibitors (AIs) are established standards of care in women with HR+/HER2- mBC. The choice between these regimens when treating mBC depends on the type and duration of prior endocrine therapy treatment as well as the time elapsed from the end of prior endocrine therapy. Besides the well-known efficacy of these treatments as first-line therapies in women without visceral crisis, most patients develop endocrine resistance leading to therapeutic failure. Primary endocrine resistance is defined as relapse during the first two years of prior endocrine therapy or progressive disease within the first six months of first-line endocrine therapy for mBC. Secondary resistance is present (1) when a relapse occurs after the first two years of adjuvant endocrine therapy; (2) when a relapse occurs within 12 months of completing adjuvant endocrine therapy; or (3) when a progressive disease occurs after more than six months from the beginning of endocrine therapy for mBC.
Several mechanisms are responsible for endocrine resistance, including the dysregulation of multiple components of the ER pathway (aberration in ER expression, over-expression of ER co-activators, and down-regulation of co-repressors), altered regulation of signaling molecules involved in cell cycle or cell survival, and the activation of escape pathways that can provide cell replication.
CDK4/6 inhibitors. One common mechanism of resistance to endocrine therapies is the activation of the cyclin-dependent kinases 4 and 6 (CDK4/6) pathway. These kinases drive cell cycle progression and division. Inhibiting activation of the CDK4/6 prevents estrogen from activating the cyclin D1-CDK4/6-Rb complex, thus blockading an important mechanism of resistance to endocrine therapies. The resulting cell cycle arrest induces a significant delay in tumor progression.
CDK 4/6 inhibitors were first introduced in 2015. Endocrine therapies
administered in combination with oral CDK4/6 inhibitors lead to improved
clinical efficacy when compared with endocrine therapies as monotherapy. In two
randomized, double-blind clinical trials, treatment of HR+/HER2- advanced breast
cancer patients with a combination of palbociclib and either letrozole or
fulvestrant demonstrated a significant increase in the median progression free
survival (PFS) period for patients who received palbociclib in combination with
either letrozole or fulvestrant compared to patients who received letrozole or
fulvestrant as single agents. These patients had previously progressed on or
after prior endocrine therapy. Worldwide sales of currently marketed CDK4/6
inhibitors, which are indicated for the treatment of breast cancer, were
PI3K inhibitors. Another common mechanism of resistance to endocrine inhibitors
is the activation of the PI3K pathway, an important intracellular pathway that
regulates cell growth and metabolism. Approximately one third of HR+ breast
cancer tumors resistant to endocrine therapy harbor activating mutations of the
catalytic subunit of PI3K, referred to as PIK3CA. Fulvestrant used in
combination with alpelisib, an oral PI3K-? inhibitor marketed as Piqray® by
Novartis approved by the FDA in
mTOR inhibitors. Similar to CDK4/6 and PI3K, the mTOR pathway has also been
identified as a mechanism of resistance to endocrine therapy. Everolimus is an
mTOR inhibitor that is currently approved by the FDA for the treatment of
HR+/HER2- advanced breast cancer in combination with exemestane, an AI.
Everolimus has also shown clinical benefit in combination with fulvestrant.
These patients had previously progressed on or after prior AI therapy. Worldwide
sales in breast cancer of everolimus, marketed as Afinitor® by Novartis and a
leading mTOR inhibitor, were approximately
The Importance of Targeting PI3K and mTOR in Cancer
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.
PI3K constitutes a lipid kinase family involved in the regulation of diverse cellular processes, including cell proliferation, survival, cytoskeletal organization, and glucose transport. Class I PI3Ks are of particular therapeutic interest. They are heterodimers, comprising a catalytic (p110?, p110?, p110?, or p110?) and a regulatory (p85?, p55?, p50?, p85?, p55?, or p101) subunit. Oncogenic PI3K signaling is activated by cell-surface receptors such as receptor tyrosine kinases, G-protein-coupled receptors, and also by well-known oncogenic proteins such as Ras.
Activities 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. Each of the 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. For example, studies have demonstrated the p110? catalytic isoform is necessary for the growth of tumors driven by PIK3CA mutations and/or oncogenic RAS and receptor tyrosine kinases; the p110? catalytic isoform mediates tumorigenesis arising from the loss of the dephosphorylase activity of PTEN; and the p110? catalytic isoform is highly expressed in leukocytes, making it a desirable target for inhibition in the treatment of hematologic malignancies. 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.
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mTOR is as 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. mTOR 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: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 belongs to a complex network of regulatory feedback loops, and once certain levels of activation are reached, is normally responsible for limiting the proliferative signals transmitted by upstream effectors such as PI3K/AKT activity. Equally complex mTORC2 regulates AKT phosphorylation, GSK3?, and control over glycolysis, and participates in organizing the cellular actin cytoskeleton. In addition, mTORC1 activation leads to the direct reduction of mTORC2 activity and mTOR can activate the functional domain of the ER, leading to ligand-independent hormone receptor activation. In cancer, dysfunctional signaling leads to various constitutive activities of mTOR complexes, making mTOR a good therapeutic target.
The illustration below depicts the PI3K/AKT/mTOR pathway and various pathway activation mechanisms.
[[Image Removed: celc_10qimg7.jpg]]
PI3K/mTOR as Resistance Mechanism to Endocrine and CDK4/6 Inhibitors
The upregulation of the PI3K/AKT/mTOR pathway promotes hormone dependent and independent ER transcriptional activity, which contributes to endocrine resistance, leading to tumor cell growth, survival, motility, and metabolism. It has also been demonstrated in vivo that PI3K and mTOR inhibition can restore sensitivity to endocrine therapy, providing a strong rationale for the combination of the two therapies.
In addition, the PI3K/AKT/mTOR pathway, like other mitogenic pathways, can also promote the activities of cyclin D and CDK4/6 to drive proliferative cell cycling. Internal preclinical studies conducted by Pfizer provided evidence in cell-line xenograft models that the combination of PI3K and CDK4/6 inhibitors may overcome both intrinsic and adaptive resistance to endocrine therapy, leading to tumor regressions. In an MCF7 xenograft model (ER+/HER2-/PIK3CA mutant) the combination of gedatolisib with palbociclib and fulvestrant led to durable tumor regressions. Importantly, tumors regressed to minimal volumes within 20 days of triplet therapy, and continued to remain dormant, without further therapy, for up to 90 days.
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[[Image Removed: celc_10qimg8.jpg]]
Advantages of Gedatolisib over other PI3K and mTOR inhibitors
The important role the PI3K/AKT/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. These challenges may explain why PI3K and mTOR inhibitors have not yielded the outstanding clinical activity many researchers expected.
We 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/AKT/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.
As a result, we believe gedatolisib's unique mechanism of action and intravenous formulation offer distinct advantages over currently approved and investigational therapies that target PI3K or mTOR alone or together.
· Overcomes drug resistance that can occur with isoform-specific PI3K
inhibitors.
Gedatolisib is a pan-class I isoform PI3K inhibitor with low nanomolar potency
for the p110?, p110?, p110?, and p110? isoforms. Each isoform is known to
preferentially affect different signal transduction events that involve tumor
cell survival, depending upon the aberrations associated with the linked
pathway. A pan-PI3K inhibitor can thus treat tumors harboring abnormalities
that signal through different PI3K isoforms, which would potentially induce
anti-tumor activity in a broader population of patients than an
isoform-specific PI3K inhibitor. In addition, it has been reported that
inhibition of one PI3K isoform may be offset by the increased activity of the
other isoforms through different adaptive mechanisms. Inhibiting all four PI3K
isoforms, as gedatolisib does, can thus prevent the confounding effect of
isoform interaction that may occur with isoform-specific PI3K inhibitors.
· Overcomes paradoxical activation of PI3K induced by mTOR inhibition.
As a potent inhibitor of mTOR, in addition to PI3K, gedatolisib, inhibits the
PI3K/AKT/mTOR pathway both upstream and downstream of AKT. Furthermore, it has
been demonstrated that the PI3K pathway is activated following selective mTOR
inhibition by relief of normal feedback regulatory mechanisms, thus providing
a compelling rationale for simultaneous inhibition of PI3K and mTOR.
· Better tolerated by patients than oral PI3K and mTOR drugs.
Gedatolisib is administered intravenously (IV) once weekly or 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. The challenging toxicity profile of these drug
candidates ultimately played a significant role in the decisions to halt their
development, 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/AKT/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-?
specific inhibitor, Piqray, illustrates the challenge. In its Phase 3 pivotal
trial Piqray was found to induce a Grade 3 or 4 adverse event related to
hyperglycemia in 39% of patients evaluated. In addition, 26% of patients
discontinued treatment. 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.
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Clinical Experience with Gedatolisib
As of
Phase 1 First-in-Human Study
Pfizer conducted 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). Subsequent analysis determined that the recommended Phase 2 dose could be increased to 180 mg IV once weekly.
At the MTD, the majority of patients enrolled in the MTD group experienced only grade 1 treatment-related adverse events (AEs). Grade 3 treatment-related adverse events were noted in 23.8% of patients, and the most frequently reported included mucosal inflammation and stomatitis (7.1%), increased ALT (7.1%), and increased AST (4.8%). No treatment-related AEs of grade 4 or 5 severity were reported at any dose level.
Phase 1b ER+/HER2- mBC Clinical Trial Results (preliminary)
In 2016, Pfizer initiated a Phase 1b trial 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 ER+/HER2- metastatic breast cancer. PI3K mutation status was not used as an eligibility criterion. Patient enrollment for the trial is complete.
The illustration below depicts how the combination of gedatolisib, palbociclib, and fulvestrant is intended to simultaneously block interdependent ER, PI3K, mTOR & CDK signaling pathways in ER+ breast cancer to address ER and CDKi resistance mechanisms.
[[Image Removed: celc_10qimg9.jpg]]
A total of 138 patients with ER+/HER2- metastatic breast cancer were dosed in the clinical trial.
· 35 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.
· 103 patients were enrolled in one of four expansion arms (A, B, C, D) to
determine if the triplet combination of gedatolisib plus palbociclib and
letrozole or gedatolisib plus palbociclib and fulvestrant produced a superior
objective response (OR), compared to historical control data of the doublet
combination (palbociclib plus endocrine therapy). All patients received
gedatolisib in combination with standard doses of palbociclib and endocrine
therapy (either letrozole or fulvestrant). In Arms A, B, and C, patients
received an intravenous dose of 180 mg of gedatolisib once weekly. In Arm D,
patients received an intravenous dose of 180 mg of gedatolisib on a four-week
cycle of three weeks-on, one week-off. Objective response was determined using
Response Evaluation Criteria in Solid Tumors v1.0, or RECIST v1.0.
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? Arm A: mBC with progression and no prior endocrine-based systemic therapy
or a CDK4/6 inhibitor in the metastatic setting. First-line
endocrine-based therapy for metastatic disease (CDK4/6 treatment naive).
? Arm B: mBC with progression during one or two prior endocrine-based
systemic therapy in the metastatic setting, with no prior therapy with
any CDK inhibitor. Second- or third-line endocrine-based therapy for
metastatic disease.
? Arm C: mBC with progression during one or two prior endocrine-based
systemic therapies in the metastatic setting and following prior therapy
with a CDK inhibitor. Second- or third-line endocrine-based therapy for
metastatic disease.
? Arm D: mBC having progressed on a CDK inhibitor in combination with
endocrine therapy as the most recent regimen for metastatic disease.
Second- or third-line endocrine-based therapy for metastatic disease.
A preliminary analysis for the 103 patients enrolled in the expansion portion of
the Phase 1b clinical trial, as of the database cutoff date of
· Efficacy analysis for all arms in aggregate:
? 60% objective response rate (ORR): 53 of the 88 evaluable patients had
either a confirmed or unconfirmed partial response, or PR (48 confirmed,
5 unconfirmed).
? 75% clinical benefit rate (CBR): 66 of the 88 evaluable patients had
either a confirmed PR or had stable disease for 24 weeks.
· Best responses, as measured by RECIST v1.0, are shown in the following chart.
The dotted line represents the cutoff for PR (defined as a 30% reduction from
baseline).
[[Image Removed: celc_10qimg10.jpg]]
· Preliminary safety analysis:
? For all arms in aggregate, all patients experienced at least one Grade 1
or Grade 2 treatment-emergent adverse event. The most commonly reported
adverse events regardless of grade and occurring in at least 30% of
patients included stomatitis (81%), neutropenia (80%), nausea (75%),
fatigue (68%), dysegeusia (46%), vomiting (45%), anemia (40%), diarrhea
(34%), decreased appetite (32%), leukopenia (32%).
? For all arms in aggregate, the Grade 3 and 4 treatment-emergent adverse
events occurring in at least 20% of patients were neutropenia (67%),
stomatitis (27%) and rash (20%). Neutropenia is a known class effect of
CDK4/6 inhibitors. 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; Grade 3 or 4
hyperglycemia was reported in 7% of patients. Gedatolisib was
discontinued in 10% of patients.
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? For the patients in Arm D, who received the recommended phase two dose,
Grade 3 and 4 treatment-emergent adverse events occurring in at least 20%
of patients were neutropenia (67%) stomatitis and (22%). All grades of
treatment-related adverse events related to hyperglycemia was reported in
22% of patients; Grade 3 or 4 hyperglycemia was reported in 7% of
patients.
? Gedatolisib was discontinued in 7% of patients.
? 22 patients were continuing to receive gedatolisib in combination with
the other study drugs, 17 of whom have been on study treatment for more
than two years.
· Preliminary best overall response data for each arm is presented in the table
below:
Arm A B C D
(evaluable patients) (N=24) (N=12) (N=27) (N=25)
1L: 2L+: 2L/3L: 2L/3L:
Patients CDKi-Naïve CDKi-naïve CDKi-pretreated Immediately
prior CDKi
Overall Response Rate 84% 75%1 33%2 60%3
(evaluable patients)
Clinical Benefit Rate 92% 92% 48% 76%
(evaluable patients)
1. Arm A: 20 of the 24 evaluable patients had a confirmed PR. 2. Arm B: 9 of the 12 evaluable patients had either a confirmed PR or unconfirmed PR (7 confirmed PR, 2 unconfirmed PR). 3. Arm C: 9 of the 27 evaluable patients had either a confirmed PR or unconfirmed PR (7 confirmed PR, 2 unconfirmed PR). 4. Arm D: 15 of the 25 evaluable patients had either a confirmed PR or unconfirmed PR (14 confirmed PR, 1 unconfirmed PR).
· Preliminary progression free survival (PFS) data for each arm is presented in
the table below:
Arm A B C D
(enrolled patients) (N=31) (N=13) (N=32) (N=27)
Median PFS >29 11.9 5.1 13.2
(months) (95% CI) (Not Yet Reached) (3.7, NR) (3.4, 7.5) (9.0, 16.7)
In light of the preliminary results reported to date from the Phase 1b trial, we intend to initiate, subject to feedback from the FDA, a Phase 2/3 clinical trial evaluating gedatolisib in combination with palbociclib and an endocrine therapy in patients with ER+/HER2- advanced or metastatic breast cancer in the first half of 2022.
We expect to use the CELsignia PI3K activity test to help support development of gedatolisib for breast cancer indications. Our internal 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.
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Phase 2 Pilot Clinical Trial for HER2+/PIK3CA+ Patients
As of a data cutoff date of
Best Response
[[Image Removed: celc_10qimg11.jpg]]
* Patient whose target lesion decreased by 63% but a new leptomeningeal seeding occurred.
The duration of treatment for the 16 patients evaluated is shown in the chart
below. As of the
Duration of Treatment
[[Image Removed: celc_10qimg12.jpg]]
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Impact of COVID-19 on our Business
Health and Safety
To help protect the health and safety of our employees, suppliers and collaborators, we took proactive, aggressive action from the earliest signs of the outbreak. We enacted rigorous safety measures in our laboratory and administrative offices, including implementing social distancing protocols, allowing working from home for those employees that do not need to be physically present in a lab to perform their work, suspending travel, implementing temperature checks at the entrances to our facilities, extensively and frequently disinfecting our workspaces and providing masks to those employees who must be physically present. We expect to continue with these measures until the COVID-19 pandemic is contained and we may take further actions as government authorities require or recommend or as we determine to be in the best interests of our employees, suppliers, and collaborators.
Clinical Trials and Collaborations
As a result of the COVID-19 pandemic, governmental authorities implemented numerous and constantly evolving measures to try to contain the virus, such as travel bans and restrictions, limits on gatherings, quarantines, shelter-in-place orders, and business shutdowns. As we continue to advance our clinical trial collaborations, we are in close contact with our current clinical sponsors, and principal investigators, as well as prospective pharmaceutical company and clinical collaborators, to assess the impact of COVID-19 on our trial enrollment timelines and collaboration discussions. Based on delays in the enrollment of patients in our ongoing clinical trials due to the pandemic, we now expect interim results from the FACT-1 and FACT-2 trials to be delayed until late 2021 or early 2022 and final results approximately nine months later. As the impact of COVID-19 on our industry becomes clearer, we may need to reassess the timing of our anticipated clinical milestones. Prospective clinical trial collaborations with pharmaceutical companies and sponsors may also be delayed but the impact on the timing of finalizing agreements is not yet known.
Research and Development
While our facility currently remains operational, the evolving measures to try
to contain the virus have impacted and may further impact our workforce and
operations, as well as those of our vendors and suppliers. Our laboratory
remains operational as of this date, but, in response to the COVID-19 pandemic,
we have implemented protective policies that reduce the number of research and
development staff operating in our laboratory at any one time. However, in light
of the focus of healthcare providers and hospitals on fighting the virus,
several of the clinical sites that provide us tumor tissue for research have
halted this service, reducing the number of new tumor tissue specimens we would
typically expect to receive. These various constraints may slow or diminish our
research and development activities. In addition, cancer research-related
industry meetings, such as the
Liquidity
Although there is uncertainty related to the anticipated impact of the recent COVID-19 outbreak on our future results, we believe our existing balance of cash and cash equivalents will be sufficient to meet our cash needs arising in the ordinary course of business for at least the next twelve months.
Results of Operations
We have not generated any revenue from sales to date, and we continue to incur
significant research and development and other expenses related to our ongoing
operations. As a result, we are not and have never been profitable and have
incurred losses in each period since our inception in 2012. For the three months
ended
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Components of Operating Results
Revenue
To date, we have not generated any revenue. Initially, our ability to generate
revenue will depend primarily upon our ability to obtain partnership agreements
with pharmaceutical companies to provide companion diagnostics for such
pharmaceutical partners' existing or investigational targeted therapies. We
expect these partnerships to generate significant revenue from the sale of tests
to identify patients eligible for clinical trials, from milestone payments, and,
potentially, from royalties on the incremental drug revenues our tests enable.
Once a new drug indication is received that requires use of our companion
diagnostic to identify eligible patients, we expect to generate revenues from
sales of tests to treating physicians. With the execution of the Pfizer license
agreement in
Research and Development
Since our inception, we have primarily focused on research and development of
our CELsignia platform, development and validation of our CELsignia tests, and
research related to the discovery of new cancer sub-types. Beginning in
· employee-related expenses related to our research and development
activities, including salaries, benefits, recruiting, travel and
stock-based compensation expenses;
· laboratory supplies;
· consulting fees paid to third parties;
· clinical trial costs;
· facilities expenses; and
· legal costs associated with patent applications.
Internal and external research and development costs are expensed as they are incurred. As we initiate clinical trials to evaluate efficacy of targeted therapies in cancer patients selected with one of our CELsignia tests and to develop gedatolisib, the proportion of research and development expenses allocated to external spending will grow at a faster rate than expenses allocated to internal expenses.
General and Administrative
General and administrative expenses consist primarily of salaries, benefits and stock-based compensation related to our executive, finance and support functions. Other general and administrative expenses include professional fees for auditing, tax, and legal services associated with being a public company, director and officer insurance and travel expenses for our general and administrative personnel.
Sales and Marketing
Sales and marketing expenses consist primarily of professional and consulting fees related to these functions. To date, we have incurred immaterial sales and marketing expenses as we continue to focus primarily on the development of our CELsignia platform and corresponding CELsignia tests. We would expect to begin to incur increased sales and marketing expenses in anticipation of the commercialization of our first CELsignia tests and the commercialization of our first drug, gedatolisib. These increased expenses are expected to include payroll-related costs as we add employees in the commercial departments, costs related to the initiation and operation of our sales and distribution network and marketing related costs.
Interest Expense
Interest expense is the result of finance lease obligations.
Interest Income
Interest income consists of interest income earned on our cash, cash equivalents, and investment balances.
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Results of Operations
Three Months Ended
March 31, Increase (Decrease)
2021 2020 $ Percent Change
Statements of
Operations Data:
Operating expenses:
Research and
development $ 2,236,342 $ 1,847,414 $ 388,928 21 %
General and
administrative 555,428 463,399 92,029 20
Total operating
expenses 2,791,770 2,310,813 480,957 21
Loss from operations (2,791,770 ) (2,310,813 ) (480,957 ) 21
Other income (expense)
Interest expense (24 ) (33 ) 10 n/a
Interest income 388 63,851 (63,463 ) (99 )
Loss on sale of fixed
assets (263 ) - (263 ) n/a
Other income, net 101 63,818 (63,716 ) (100 )
Net loss before income
taxes (2,791,668 ) (2,246,995 ) (544,673 ) 24
Income tax benefits - - - -
Net loss $ (2,791,668 ) $ (2,246,995 ) $ (544,673 ) 24 %
Research and Development
Our research and development expenses for the three months ended
Conducting a significant amount of research and development is central to our business model. We plan to increase our research and development expenses for the foreseeable future as we seek to discover new cancer sub-types, develop and validate additional CELsignia tests to diagnose such sub-types and develop gedatolisib. We also expect to incur increased expenses to support companion diagnostic business development activities with pharmaceutical companies as we develop additional CELsignia tests.
General and Administrative
Our general and administrative expenses for the three months ended
We anticipate that our general and administrative expenses will increase in future periods, reflecting both increased costs in connection with the potential future commercialization of CELsignia tests, an expanding infrastructure, and increased professional fees associated with being a public company.
Interest Expense
Interest expense for the three months ended
Interest Income
Interest income for the three months ended
Liquidity and Capital Resources
Since our inception, we have incurred losses and cumulative negative cash flows
from operations. Through
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Cash from these capital raising activities has been our primary source of funds
for our operations since inception. As of
We expect that our research and development and general and administrative expenses will increase as we continue to develop our CELsignia platform and additional CELsignia tests, conduct research related to the discovery of new cancer sub-types, conduct clinical trials, develop gedatolisib and pursue other business development activities. We would also expect to incur sales and marketing expenses as we commercialize our CELsignia tests and gedatolisib. We expect to use cash on hand to fund our research and development expenses, capital expenditures, working capital, sales and marketing expenses, and general corporate expenses, as well as for the increased costs associated with being a public company.
Based on our current business plan, we believe that our current cash on hand will provide sufficient cash to finance operations and pay obligations when due for at least the next twelve months.
We may seek to raise additional capital to expand our business, pursue strategic investments, and take advantage of financing or other opportunities that we believe to be in the best interests of the Company and our stockholders. Additional capital may be raised through the sale of common or preferred equity or convertible debt securities, entry into debt facilities or other third-party funding arrangements. The sale of equity and convertible debt securities may result in dilution to our stockholders and those securities may have rights senior to those of our common shares. Agreements entered into in connection with such capital raising activities could contain covenants that would restrict our operations or require us to relinquish certain rights. Additional capital may not be available on reasonable terms, or at all.
Cash Flows
Three Months Ended
March 31,
2021 2020
(unaudited)
Net cash provided by (used in):
Operating activities $ (2,521,505 ) $ (1,833,601 )
Investing activities (30,425 ) (45,604 )
Financing activities 25,850,921 (1,438 )
Net increase (decrease) in cash and cash equivalents
Operating Activities
Net cash used in operating activities was approximately
Investing Activities
Net cash used in investing activities for the three months ended
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Financing Activities
Net cash provided by financing activities for the three months ended
Off-Balance Sheet Arrangements
We do not currently have any off-balance sheet arrangements as defined in Item 303(a)(4) of Regulation S-K.
Recent Accounting Pronouncements
From time to time new accounting pronouncements are issued by the
Critical Accounting Policies and Use of Estimates
Our management's discussion and analysis of financial condition and results of
operations is based on our unaudited condensed financial statements, which have
been prepared in accordance with
Our significant accounting policies are more fully described in Note 2 to our unaudited condensed financial statements included in Item 1 of Part I of this Quarterly Report.
Private Securities Litigation Reform Act
The Private Securities Litigation Reform Act of 1995 provides a "safe harbor"
for forward-looking statements. Such forward-looking information is included in
this Quarterly Report and in other materials filed or to be filed by us with the
In some cases, you can identify forward-looking statements by the following words: "anticipate," "believe," "continue," "could," "estimate," "expect," "intend," "may," "ongoing," "plan," "potential," "predict," "project," "should," "will," "would," or the negative of these terms or other comparable terminology, although not all forward-looking statements contain these words. Forward-looking statements are only predictions and are not guarantees of performance. These statements are based on our management's beliefs and assumptions, which in turn are based on their interpretation of currently available information.
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These statements involve known and unknown risks, uncertainties and other factors that may cause our results or our industry's actual results, levels of activity, performance or achievements to be materially different from the information expressed or implied by these forward-looking statements. Certain risks, uncertainties and other factors include, but are not limited to, our limited operating history; the unknown impact of the COVID-19 pandemic on our business; our initial success being heavily dependent on the success of our CELsignia HER2 Pathway Activity Test; our inability to develop and commercialize gedatolisib; our inability to determine whether our CELsignia tests are currently commercially viable; challenges we may face in developing and maintaining relationships with pharmaceutical company partners; the complexity and timeline for development of CELsignia tests and gedatolisib; the uncertainty and costs associated with clinical trials; the uncertainty regarding market acceptance by physicians, patients, third-party payors and others in the medical community, and with the size of market opportunities available to us; the pricing of molecular and other diagnostic products and services that compete with us; uncertainty with insurance coverage and reimbursement for our
CELsignia tests; difficulties we may face in managing growth, such as hiring
and retaining a qualified sales force and attracting and retaining key
personnel; changes in government regulations; and obtaining and maintaining
intellectual property protection for our technology and time and expense
associated with defending third-party claims of intellectual property
infringement, investigations or litigation threatened or initiated against us.
These and additional risks, uncertainties and other factors are described more
fully in our Annual Report on Form 10-K for the year ended
You should read the cautionary statements made in this Quarterly Report as being applicable to all related forward-looking statements wherever they appear in this Quarterly Report. We cannot assure you that the forward-looking statements in this Quarterly Report will prove to be accurate. Furthermore, if our forward-looking statements prove to be inaccurate, the inaccuracy may be material. You should read this Quarterly Report completely. Other than as required by law, we undertake no obligation to update these forward-looking statements, even though our situation may change in the future.
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