10-K
1
tm211142d1_10k.htm
FORM 10-K
UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 10-K
(Mark One)
For the fiscal year ended December 31,
2020
OR
For the transition period from __ to __
Commission file number 001-36333
BIO-PATH HOLDINGS, INC.
(Exact name of registrant as specified in
its charter)
or organization)
(Address of principal executive offices) (Zip Code)
Registrant’s telephone number,
including area code: (832) 742-1357
Securities registered pursuant to Section 12(b) of
the Act:
Title of each class Trading Symbol Name of each exchange on which registered
Common Stock, par value $0.001 per share BPTH The Nasdaq Capital Market
Securities registered pursuant to Section 12(g) of
the Act: None
Indicate
by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ̈No x
Indicate
by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act.
Yes ̈No x
Indicate
by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the
Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to
file such reports), and (2) has been subject to such filing requirements for the past 90 days. Yes xNo ̈
Indicate
by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant
to Rule 405 of Regulation S-T (§ 232.405 of this chapter) during the preceding 12 months (or for such shorter period
that the registrant was required to submit such files). Yes xNo
̈
Indicate by check mark whether the registrant is a large accelerated
filer, an accelerated filer, a non-accelerated filer, a smaller reporting company, or an emerging growth company. See the definitions
of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and “emerging
growth company” in Rule 12b-2 of the Exchange Act.
Large accelerated filer ̈ Accelerated filer ̈
Non-accelerated filer x Smaller reporting company x
Emerging growth company ̈
If
an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for
complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange
Act. ̈
Indicate
by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness
of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by
the registered public accounting firm that prepared or issued its audit report. ̈
Indicate
by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Act). Yes ̈No x
As of March 1, 2021, there were 6,947,912 shares of the
registrant’s common stock issued and outstanding. The aggregate market value of the voting stock held by non-affiliates
of the registrant was approximately $18,472,208.15 as of June 30, 2020, the last business day of the registrant’s most
recently completed second fiscal quarter, based on the last sales price of the registrant’s common stock as reported on
The Nasdaq Capital Market on such date. For purposes of the preceding sentence only, all directors, executive officers and beneficial
owners of 10% or more of the shares of the registrant’s common stock are assumed to be affiliates.
DOCUMENTS INCORPORATED BY REFERENCE: NONE
TABLE OF CONTENTS
Page
PART I 2
Item 1. Business 2
Item 1A. Risk Factors 25
Item 1B. Unresolved Staff Comments 51
Item 2. Properties 51
Item 3. Legal Proceedings 51
Item 4. Mine Safety Disclosures 51
Item 6. [Reserved] 52
Item 7A. Quantitative and Qualitative Disclosures About Market Risk 60
Item 8. Financial Statements and Supplementary Data 60
Item 9A. Controls and Procedures 60
Item 9B. Other Information 61
PART III 62
Item 10. Directors, Executive Officers and Corporate Governance 62
Item 11. Executive Compensation 67
Item 14. Principal Accounting Fees and Services 78
Item 15. Exhibits and Financial Statement Schedules 80
Unless the context requires otherwise,
references in this Annual Report on Form 10-K to “we,” “our,” “us,” “the Company”
and “Bio-Path” refer to Bio-Path Holdings, Inc. and its subsidiary. Bio-Path Holdings, Inc.’s wholly-owned
subsidiary, Bio-Path, Inc., is sometimes referred to herein as “Bio-Path Subsidiary.”
CAUTIONARY NOTE REGARDING FORWARD-LOOKING
STATEMENTS
This Annual Report on Form 10-K contains
“forward-looking statements” within the meaning of Section 27A of the Securities Act of 1933, as amended (the
“Securities Act”), and Section 21E of the Securities Exchange Act of 1934, as amended (the “Exchange Act”).
Forward-looking statements can be identified by words such as “anticipate,” “expect,” “intend,”
“plan,” “believe,” “seek,” “estimate,” “project,” “goal,”
“strategy,” “future,” “likely,” “may,” “should,” “will”
and variations of these words and similar references to future periods, although not all forward-looking statements contain these
identifying words. Forward-looking statements are neither historical facts nor assurances of future performance. Instead, they
are based on our current beliefs, expectations and assumptions regarding the future of our business, future plans and strategies,
projections, anticipated events and trends, the economy and other future conditions. Because forward-looking statements relate
to the future, they are subject to inherent risks, uncertainties and changes in circumstances, including those discussed in “Item
1A. Risk Factors” of this Annual Report on Form 10-K and in other reports or documents we file with the U.S. Securities
and Exchange Commission (“SEC”). As a result, our actual results and financial condition may differ materially from
those expressed or forecasted in the forward-looking statements, and you should not rely on such forward-looking statements. We
can give no assurances that any of the events anticipated by the forward-looking statements will occur or, if any of them do,
what impact they will have on our results of operations and financial condition. Important factors that could cause our actual
results and financial condition to differ materially from those indicated in the forward-looking statements include, among others,
the following:
· our ability to retain and attract key personnel;
· disruptions to our operations due to expansions of our operations;
· risks associated with product liability claims;
· our ability to use net operating loss carryforwards;
· risks that that our clinical trials may be delayed or terminated;
· changes in existing laws and regulations affecting the healthcare industry;
· our ability to maintain orphan drug exclusivity for our drug candidates;
· our reliance on third parties for manufacturing our clinical drug supplies;
· risks associated with the manufacture of our drug candidates;
· market acceptance of our drug candidates;
· third-party payor reimbursement practices;
· infringement on the intellectual property rights of third parties;
· costs and time relating to litigation regarding intellectual property rights;
· our need to raise additional capital;
· the volatility of the trading price of our common stock;
· our common stock being thinly traded;
· our ability to pay cash dividends;
· costs and expenses associated with being a public company; and
Please also refer to “Item 1A. Risk
Factors” of this Annual Report on Form 10-K and other reports or documents we file with the SEC for a discussion of
risks and factors that could cause our actual results and financial condition to differ materially from those expressed or forecasted
in this Annual Report on Form 10-K.
Any forward-looking statement made by us
in this Annual Report on Form 10-K is based only on information currently available to us and speaks only as of the date
on which it is made. We undertake no obligation to publicly update any forward-looking statement, whether as a result of new information,
future developments or otherwise. However, you should carefully review the risk factors set forth in other reports or documents
we file from time to time with the SEC.
PART I
ITEM 1. BUSINESS
Overview
We are a clinical and preclinical stage
oncology focused RNAi nanoparticle drug development company utilizing a novel technology that achieves systemic delivery for target
specific protein inhibition for any gene product that is over-expressed in disease. Our drug delivery and antisense technology,
called DNAbilize®, is a platform that uses P-ethoxy, which is a deoxyribonucleic acid (DNA) backbone modification that is intended
to protect the DNA from destruction by the body’s enzymes when circulating in vivo, incorporated inside of a lipid bilayer
having neutral charge. We believe this combination allows for high efficiency loading of antisense DNA into non-toxic, cell-membrane-like
structures for delivery of the antisense drug substance into cells. In vivo, the DNAbilize® delivered antisense drug substances
are systemically distributed throughout the body to allow for reduction or elimination of target proteins in blood diseases and
solid tumors. Through testing in numerous animal studies and treatment in over 80 patients, the Company’s DNAbilize®
drug candidates have demonstrated an excellent safety profile. DNAbilize® is a registered trademark of the Company.
Using DNAbilize® as a platform for
drug development and manufacturing, we currently have four drug candidates in development to treat at least five different cancer
disease indications. Our lead drug candidate, prexigebersen (pronounced prex” i je ber’ sen), which targets growth
factor receptor-bound protein 2 (Grb2), initially started the efficacy portion of a Phase 2 clinical trial for untreated acute
myeloid leukemia (“AML”) patients in combination with low-dose cytarabine (“LDAC”). The interim data we
released on March 6, 2019 showed that 11 (65%) of the 17 evaluable patients had a response, including five (29%) who achieved
complete remission (“CR’), including one CR with incomplete hematologic recovery (“CRi“) and
one morphologic leukemia free state, and six (35%) stable disease responses, including two patients who had greater than a 50%
reduction in bone marrow blasts. However, DNA hypomethylating agents are now the most frequently used agents in the treatment
of elderly AML patients in the U.S. and Europe. As a result, Stage 2 of the Phase 2 trial in AML was amended to, among other things,
remove the combination treatment of prexigebersen and LDAC and replace it with the combination treatment of prexigebersen and
decitabine, a DNA hypomethylating agent, for treatment of a second cohort of untreated AML patients. Since decitabine is also
used as a treatment for relapsed/refractory AML patients, a cohort of relapsed/refractory AML patients was also added to the study.
The U.S. Food and Drug Administration (“FDA”)
recently granted approval of venetoclax in combination with LDAC, decitabine, or azacytidine (the latter two drugs are DNA hypomethylating
agents) as frontline therapy for newly diagnosed AML in adults who are 75 years or older, or who have comorbidities precluding
intensive induction chemotherapy. We believe this recent frontline therapy approval provides an opportunity to include prexigebersen
with the combination therapy for the treatment of de novo AML patients. Preclinical efficacy studies for the triple combination
treatment of prexigebersen, decitabine and venetoclax in AML have been successfully completed. In the preclinical efficacy studies,
four AML cancer cell lines were treated with three different combinations of decitabine, venetoclax and prexigebersen. Decrease
in AML cell viability was the primary measure of efficacy. The triple combination of decitabine, venetoclax and prexigebersen showed
significant improvement in efficacy in three of the four AML cell lines. Based on these results, the Company believes that adding
prexigebersen to the treatment combination of decitabine and venetoclax could lead to improved efficacy in AML patients. Accordingly,
the Company further amended Stage 2 of this Phase 2 clinical trial to add the triple combination treatment comprised of prexigebersen,
decitabine and venetoclax, which amendment has been approved by the FDA.
Bio-Path’s approved amended Stage
2 for this Phase 2 clinical trial currently has three cohorts of patients. The first two cohorts will treat patients with the triple
combination of prexigebersen, decitabine and venetoclax. The first cohort will include untreated AML patients, and the second cohort
will include relapsed/refractory AML patients. Finally, the third cohort will treat relapsed/refractory AML patients, who are venetoclax-resistant
or -intolerant, with the two-drug combination of prexigebersen and decitabine. The full trial design plans have approximately 98
evaluable patients for the first cohort having untreated AML patients with a preliminary review performed after 19 evaluable patients
and a formal interim analysis after 38 evaluable patients. The full trial design plans have approximately 54 evaluable patients
for each of the second cohort, having relapsed/refractory AML patients, and the third cohort, having AML patients who are venetoclax-resistant
or -intolerant, in each case with a review performed after 19 evaluable patients. The study is anticipated to be conducted at ten
clinical sites in the U.S., and Gail J. Roboz, MD will be the national coordinating Principal Investigator for the Phase 2 trial.
Dr. Roboz is a professor of medicine and director of the Clinical and Translational Leukemia Program at the Weill Medical
College of Cornell University and the New York-Presbyterian Hospital in New York City. On August 13, 2020, we announced the
enrollment and dosing of the first patient in this approved amended Stage 2 of the Phase 2 clinical study.
Our second drug candidate, Liposomal Bcl-2
(“BP1002”), targets the protein Bcl-2, which is responsible for driving cell survival in up to 60% of all cancers.
On November 21, 2019, we announced that the FDA cleared an Investigational New Drug (“IND”) application for BP1002.
An initial Phase 1 clinical trial will evaluate the safety of BP1002 in refractory/relapsed lymphoma and chronic lymphocytic leukemia
(“CLL”) patients. Initially, a total of six evaluable patients are scheduled to be treated with BP1002 monotherapy
in a standard 3+3 design. The Phase 1 clinical trial is being conducted at several leading cancer centers, including The University
of Texas MD Anderson Cancer Center (“MD Anderson”), the Georgia Cancer Center and the Sarah Cannon Research Institute,
and is now open for enrollment. Ian W. Flynn, MD is the national coordinating Principal Investigator for the Phase 1 trial. Dr. Flynn
serves as the director of lymphoma research at the Sarah Cannon Research Institute.
Our third drug candidate, Liposomal STAT3
(“BP1003”), targets the STAT3 protein and is currently in IND enabling studies as a potential treatment of pancreatic
cancer, non-small cell lung cancer (“NSCLC”) and AML. Preclinical models have shown BP1003 to inhibit cell viability
and STAT3 protein expression in NSCLC and AML cell lines. Further, BP1003 successfully penetrated pancreatic tumors and significantly
enhanced the efficacy of gemcitabine, a treatment for patients with advanced pancreatic cancer, in a pancreatic cancer patient
derived tumor model. Our lead indication for BP1003 is pancreatic cancer due to the severity of this disease and the lack of effective,
life-extending treatments. For example, pancreatic adenocarcinoma is projected to be the second most lethal cancer behind lung
cancer by 2030. Typical survival for a metastatic pancreatic cancer patient is about three to six months from diagnosis. We expect
to complete several IND enabling studies of BP1003 in 2021. If those studies are successful, our goal is to file an IND in late
2021 for the first-in-humans Phase 1 study of BP1003 in patients with refractory, metastatic solid tumors, including pancreatic
cancer and NSCLC.
In addition, a modified product named prexigebersen-A,
Bio-Path’s fourth drug candidate, has shown to enhance chemotherapy efficacy in preclinical solid tumor models. Prexigebersen-A
incorporates the same drug substance as prexigebersen but has a slightly modified formulation designed to enhance nanoparticle
properties. In late 2019, we filed an IND application to initiate a Phase 1 clinical trial of prexigebersen-A in patients with
solid tumors, including ovarian, endometrial, pancreatic and breast cancer. Ovarian cancer is one of the most common type of gynecologic
malignancies, with approximately 50% of all cases occurring in women older than 63 years. This trial is expected to commence after
the IND has been cleared by the FDA, which we currently anticipate being in 2021.
Our DNAbilize® technology-based products are available
for out-licensing or partnering. We intend to apply our drug delivery technology template to new disease-causing protein targets
to develop new nanoparticle antisense RNAi drug candidates. We have a new product identification template in place to define a
process of scientific, preclinical, commercial and intellectual property evaluation of potential new drug candidates for inclusion
into our drug product development pipeline. As we expand, we will look at indications where a systemic delivery is needed and
antisense RNAi nanoparticles can be used to slow, reverse or cure a disease, either alone or in combination with another drug.
On September 25, 2019, we announced that the United States Patent and Trademark Office (“USPTO”) issued a patent
for claims related to DNAbilize®, including its use in the treatment of cancers, autoimmune diseases and infectious diseases.
On October 22, 2020 we announced that the USPTO issued a Notice of Allowance for U.S. Patent Application No. 16/333,221
entitled “Combination Therapy with Liposomal Antisense Oligonucleotides.” On February 10, 2021, we announced
that the USPTO granted U.S. Patent No. 10,898,506 titled, “P-ethoxy nucleic acids for liposomal formulation.”
The new patent builds on earlier patents granted that protect the platform technology for DNAbilize®, the Company’s
novel RNAi nanoparticle drugs. The new patent is the third patent in our family of platform intellectual property and offers expanded
defense of our DNAbilize® platform technology. In addition, the USPTO has mailed an Issue Notification for a patent
related to the Company’s lead product candidate, prexigebersen, in combination with either a cytidine analogue, such as
decitabine, or the Bcr-Abl tyrosine kinase inhibitors dasatinib and nilotinib. This patent was issued as U.S. Patent No. 10,927,379
on February 23, 2021. The patent will offer target-specific protection for on-going clinical trials using prexigebersen in
combination with decitabine as a treatment for AML. We continue our efforts to build protection around our technology as it safeguards
our platform technology and target-specific technology, is a deterrent to would-be competitors and creates value around our core
competencies.
We have certain intellectual property as
the basis for our current drug products in clinical development, prexigebersen, prexigebersen-A, BP1002 and BP1003. We are developing
RNAi antisense nanoparticle drug candidates based on our own patented technology to treat cancer and autoimmune disorders where
targeting a single protein may be advantageous and result in reduced patient adverse effects as compared to small molecule inhibitors
with off-target and non-specific effects. We have composition of matter and method of use intellectual property for the design
and manufacture of antisense RNAi nanoparticle drug products.
Our pipeline for development of antisense
therapeutics is set forth in Figure 1 below:
Figure 1. Bio-Path Pipeline for Development
of Therapeutics
* Received orphan drug designation
from the U.S. FDA and from the European Medicines Agency (EMA) for AML
Our basic drug development concept is to
block expression of proteins associated with disease. Messenger RNA (mRNA) is essential in the process of creating proteins. We
have developed DNAbilize® nanoparticle drug delivery systems to deliver short strands of antisense DNA drugs to
cells and block the production of proteins associated with disease progression (Figure 2).
Figure 2.
Antisense DNA therapeutics is the field
of designing short DNA sequences that are complementary to a mRNA for a protein of interest with the intention of inhibiting the
production of the targeted protein. The DNA will find the matching RNA and form a complex. The complexed RNA will not have access
to the protein-making machinery, which prevents the cell from translating it into a protein. Thus, protein production is turned
off and levels of the targeted protein are reduced in the cell. This gene-specific process of controlling protein expression has
led to great interest in using antisense DNA to shut off the production of proteins involved in disease. Antisense therapeutics
have been in development for over 20 years. However, challenges to antisense therapeutics, such as instability of antisense drugs
inside of the body and inefficient delivery of antisense to disease cells, have thawed antisense therapeutic potential.
We believe our DNAbilize®
technology, which is the combination of the protected P-ethoxy antisense DNA backbone with the neutral liposome nanoparticle, is
the ideal approach for antisense DNA therapeutics because it overcomes the challenges associated with both antisense stability
and intracellular delivery. The P-ethoxy modification used in our DNAbilize® technology is completely sulfur free.
We avoid using sulfur-containing antisense because it has been associated with causing liver toxicity and life-threatening bleeding
and clotting complications. We prefer neutral lipids to cationic lipids for intracellular delivery because encapsulating the antisense
DNA inside a neutral charged lipid bilayer facilitates the delivery and transfer of DNA into the cell to be fluid and gentle. While
many companies have focused research on either the DNA stabilization problem or the lipid delivery problem, we are not aware of
any company that has developed improvements in both areas. DNAbilize® is truly a stand-alone platform because, as
demonstrated by our published preclinical studies, it allows for high doses of drug products to be delivered throughout the entire
body while minimizing toxicity. This allows our research and development efforts to focus on drug targets rather than on indications
because the DNAbilize® system should not be limited in what types of indications it can treat. As such, we believe
that DNAbilize® represents the first ever antisense therapeutic approach that can successfully treat hematological
and systemic diseases.
Because of our unique ability to address
unmet needs in hematological malignancies, our lead drug candidates focus on cancers of the blood and lymph. Our lead drug candidate,
prexigebersen, targets the protein Grb2, a bridging protein between activated and mutated cellular kinases and the proteins involved
in cell propagation, and in particular, the Ras protein. When mutations occur that activate these kinases, the cell propagates
uncontrollably, via Grb2, and this results in disease progression. Inhibition of Grb2 interrupts this pathway and shuts off propagation
signals.
The efficacy of prexigebersen in combination
with standard of care therapies is being evaluated in a Phase 2 clinical trial for AML patients. The multi-site trial is being
conducted at leading cancer centers, including Weill Medical College of Cornell University, Baylor Scott &White Health,
The University of Kansas, New Jersey Hematology Oncology Associates, West Virginia University/Mary Babb Randolph Cancer Center
and MD Anderson.
Our second drug candidate, BP1002, targets
the protein Bcl-2. Bcl-2 is an anti-apoptotic member of the Bcl-2 family of proteins that regulate cell death. Overexpression
of Bcl-2 results in deregulated cell survival in cancer cells, thus reducing their sensitivity to many of the drugs currently
used in the clinic, which mediate their therapeutic effects (at least in part) through the activation of the Bcl-2-regulated apoptotic
pathway. The Phase 1 clinical trial will evaluate the safety of BP1002 in refractory/relapsed lymphoma and CLL patients. The Phase
1 clinical trial is being conducted at several leading cancer centers, including MD Anderson, the Georgia Cancer Center and the
Sarah Cannon Research Institute.
The intended indications of our two other
drug candidates, prexigebersen-A and BP1003, are in solid tumors. Safety and efficacy of prexigebersen-A in combination with paclitaxel
will be investigated in patients with recurrent ovarian or endometrial cancer. Safety and efficacy of BP1003 in combination with
gemcitabine will be investigated in patients with refractory, metastatic pancreatic cancer.
Strategy
Our strategy is to develop our lead candidates,
prexigebersen, prexigebersen-A, BP1002 and BP1003, for multiple indications where the pathways involving Grb2, Bcl-2 and STAT3,
respectively, are utilized to promote cancer growth, survival, angiogenesis and tumor surveillance evasion. Using DNAbilize®
technology, we plan to develop therapeutics to a wide range of diseases and disorders independently and in partnership with others.
The key elements of our strategy include:
Overview of Drug Candidates
The historical perspective of cancer treatments
has been the use of drugs that affect the entire body. Advances in the past decade have shifted to treating the tumor tissue itself.
One of the main strategies in these developments has been targeted therapy, involving drugs that are targeted to block the expression
of specific disease-causing proteins while having little or no effect on other healthy tissue. We believe that nucleic acid drug
products, specifically antisense, are a promising field of targeted therapy. Development of antisense as cancer drugs, however,
has been limited by the lack of a suitable method to deliver antisense drugs to cancer cells with high uptake into the cancer cells
without causing toxicity to non-cancer cells. Our currently licensed DNAbilize® neutral-lipid based liposome technology
is designed to overcome these limitations. We have published preclinical studies demonstrating that our DNAbilize®
technology could efficiently deliver antisense therapeutics to mouse models of hematological malignancies and solid tumors, decrease
target proteins production and suppress tumor progression. In addition, to date, no adverse effects attributed to the study drugs
have been observed in our leukemia and lymphoma clinical trials.
PREXIGEBERSEN
Prexigebersen is targeted at the protein
Grb2. Antisense inhibition of Grb2 interrupts the signals between mutated and activated receptors that connect to a well-known
cancer associated switch called Ras protein. Inhibition of Grb2 suppresses cancer cells propagation and does not result in adverse
events typically observed with receptor inhibitors or Ras pathway inhibitors. We believe that prexigebersen has the potential
to be an ideal combination for any number of cancer therapeutics where the Ras pathway is aberrantly activated and patient fitness
is a major concern, such as in AML.
Indications for Acute Myeloid Leukemia (AML),
Myelodysplastic Syndrome (MDS)
AML - Background and Common Treatments.
AML is the rapid accumulation of immature myeloid cells in the blood, resulting in a drop of the other cell types such as red
blood cells and platelets. The expansion of immature monocytes leaves the patient unable to fight infection. If AML is left untreated,
it usually results in death within three months. AML incidence increases with age, with more than 50% of the cases in people age
60 or older. AML is the most common acute leukemia in adults, and the National Cancer Institute estimates that approximately 20,000
new cases occur each year (Figure 3). The cure rate is between 5 to 15% in older adults, and those who cannot receive the standard
course of chemotherapy have an average survival rate of five to ten months. Prior to venetoclax approval, the frontline low-intensity
therapies for elderly AML patients were LDAC, decitabine or azacytidine (the latter two drugs are DNA hypomethylating agents).
The FDA recently granted approval of venetoclax (a Bcl-2 inhibitor) for the newly diagnosed AML patients aged 75 years and older
or adults who cannot be treated with intensive induction chemotherapy. Venetoclax is used in combination with LDAC, decitabine
or azacytidine. Mutation in the Bcl-2 binding domain, which reduces venetoclax’s ability to bind to Bcl-2, has been linked
with venetoclax resistance in CLL patients. Such venetoclax resistance may also occur in AML patients. AML remains an area of
high unmet need for both the relapsed and the de novo elderly population who are typically ineligible for induction therapy.
Figure 3. Basic Statistics for AML
MDS - Background and Common Treatments.
MDS is a bone marrow disease, characterized by a reduced number of mature blood cells. MDS is diagnosed in about 15,000 people
in the United States (“U.S.”) yearly. MDS patients are stratified into different risk groups. Higher risk MDS patients
have a survival of less than two years and, if untreated, can evolve into secondary AML. Secondary AML patients are often older
and treated with DNA hypomethylating agents. Higher risk MDS and secondary AML patients who have progressed from DNA hypomethylating
agents have very poor prognosis. Novel treatment strategies for these patients are needed. The Company expects to design a clinical
trial in the future evaluating MDS patients with prexigebersen.
Prexigebersen Development and Treatment
for Leukemia. The safety, pharmacokinetics, and efficacy of our lead DNAbilize® antisense drug candidate, prexigebersen,
was assessed in patients having AML, CML, MDS or ALL in a Phase 1 trial. The Phase 1 clinical trial was a dose-escalating study
to determine the safety and tolerability of escalating doses of prexigebersen. Additionally, the pharmacokinetics and anti-leukemic
effects, including down-regulation of the target Grb2 protein in patient samples, of the drug candidate were determined. Results
of the clinical study were published in the scientific journal Lancet Haematology in 2018.
Phase 1 Clinical Trial
Two new assays to provide scientific proof
of concept of the delivery technology were developed in the Phase 1 clinical trial. The first assay involved a method to measure
down-regulation of the target protein in a patient blood sample that was achieved. The measurement provided critical proof that
DNAbilize® neutral liposome delivery technology delivered the drug substance to the cell and was able to transport it across
the cell membrane into the interior to block cellular production of the Grb2 protein. The second assay involved a novel detection
method for the drug substance in blood samples to assess the pharmacokinetics of the drug.
In August 2013, we announced that
our DNAbilize® liposomal delivery technology achieved a major milestone in the development of antisense therapeutics based
on a scientific assay confirming that treating patients with our drug candidate prexigebersen inhibits the Grb2 disease-causing
target protein in patients with blood cancers (Figure 4). Inhibition of the disease-causing protein has the effect of down regulating
the disease. This will allow for prexigebersen to be used potentially in combination with current frontline treatments. This discovery
also points to the potential use of a liposomal antisense treatment as a standalone treatment to transform and manage a disease
that has a disease-causing protein as a chronic disorder. This accomplishment is a potentially significant breakthrough for antisense
therapeutics, whose development, to date, as a class of therapeutics has been severely limited by a lack of a systemic delivery
mechanism that can safely distribute the drug throughout the body and deliver the antisense drug substance across the cell membrane
into the interior of the cell. Further, we expect that scientific proof of principle for DNAbilize® may lead to licensing
and business development opportunities, supporting our business model.
Inhibition of Target Grb2 Protein
· Grb2 levels were compared to baseline prior to treatment.
Figure 4. Grb2 Protein and Downstream
pERK are
Downregulated in Prexigebersen Treated
Patient’s Cells
Grb2 levels decreased in 10 out of 12
patient samples by end of treatment (EOT)
pErk levels decreased in 7 of 12 patient
samples by EOT
Subject Prexigebersen (mg/m2) Cohort Grb2 Decrease (EOT) pERK Decrease (EOT)
A Phase 1 clinical trial is typically ended
when a maximum tolerated dose (“MTD”) is encountered. However, due to the lack of toxicity of prexigebersen, a MTD
was not observed. Lack of toxicity is a major advantage for the drug candidate prexigebersen since it allows higher levels of drug
to be administered to the patient, increasing the potential therapeutic benefit. During the Phase 1 trial, 80% of the evaluable
patients had refractory/relapsed AML, having failed at least 6 prior therapies. In our study, 83% of patients showed decreased
circulating blasts and anti-leukemic activity and eight patients stabilized for extended treatments.
Phase 2 Clinical Trials
On February 9, 2015, we announced
that we began enrollment into the combination therapy Phase 1b clinical trial for prexigebersen in patients with AML. The combination
therapy Phase 1b clinical trial consisted of two dosing cohorts of prexigebersen (60 mg/m2 and 90 mg/m2)
to test the safety profile of treating AML patients with prexigebersen in combination with LDAC. Patients ineligible for intensive
induction therapy are currently treated with LDAC.
An important outcome of the Phase 1b clinical
trial was the ability to assess the pharmacokinetics of the drug. On June 6, 2016, we announced that no dose limiting toxicities
were observed in patients treated with the combination therapy of prexigebersen and LDAC. Of the six evaluable patients from the
Phase 1b clinical trial, four patients completed more than two cycles of treatment, three patients achieved CR and two patients
had over 50% decrease in bone marrow blast counts (Figure 5). Pharmacokinetics of prexigebersen demonstrated a half-life at 60
mg/m2 of 30 hours, significantly better than the 90 mg/m2 dose. The final analysis of these data, along
with the demonstrated reductions in bone marrow blasts, suggested that 60 mg/m2 is the appropriate dose for use in
the Phase 2 trial.
Figure 5. Five out of six patients in
cohorts 7 and 8 receiving the combination
prexigebersen + LDAC have greater than 50% decrease in bone marrow blasts
A summary of the clinical trial results
for the Phase 1 monotherapy for indications of AML, CML, MDS and ALL, and Phase 1b combination therapy for prexigebersen for indications
of AML is shown in Figure 6 below. The first six cohorts, patients 001 to 034, were treated in the Phase 1 clinical trial using
prexigebersen as a monotherapy. The seventh cohort, patients 035, 037 and 038, were treated in our Phase 1b clinical trial evaluating
the combination therapy of 60 mg/m2 prexigebersen. The eighth cohort, patients 039, 040 and 041, were treated with
combination therapy of 90 mg/m2.
Figure 6. Summary Cohorts 1-8 Prexigebersen
Clinical Trial Phase 1 and 1B
Peripheral or bone marrow blast %
Patients Diagnosis Baseline Nadir Off- Tx Reason Discontinued Cycles Completed
23 MDS NE NE NE PD 1
Nadir: the lowest point, Off-TX: off treatment, No: no reduction
in blasts, DLT: dose limiting toxicity, PD: progressive disease, NE: not enough sample to evaluate, ND: not done, CR: complete
remission with incomplete hematologic recovery, CR: complete remission, SD: stable disease
Results from the Phase 1b clinical trial
demonstrated it is safe to add prexigebersen to LDAC, which appears to yield better response rates in this AML patient population.
On November 2, 2016, we announced that the first patient in the efficacy portion of the Phase 2 trial was dosed. The full
trial design includes approximately 54 evaluable patients with an interim analysis to be performed after 19 patients are treated
with the combination. The multi-site trial was conducted at leading cancer centers, among them are Weill Medical College of Cornell
University, Baylor Scott & White Health, The University of Kansas, New Jersey Hematology Oncology Associates, West Virginia
University/Mary Babb Randolph Cancer Center, and MD Anderson.
Thirty-three patients were pre-screened
for the efficacy portion of the Phase 2 prexigebersen + LDAC combination study. Thirty patients were enrolled and 17 patients
were deemed evaluable. The interim data that we released on March 6, 2019 showed that 11 (65%) of the 17 evaluable patients
had a response, including five (29%) who achieved CR, including one CRi and one morphologic leukemia free state, and
six (35%) stable disease responses, including two patients who had greater than a 50% reduction in bone marrow blasts. The efficacy
data from the 17 evaluable patients was very favorable compared to the reported CR, CRp and CRi rates of 7 to 13% with LDAC treatment
alone. Importantly, through investigation by the principal investigators, it was observed that 68% of patients were secondary
AML patients, a difficult class to treat.
Results to date have shown prexigebersen,
with its efficacy and excellent safety profile, to be an effective combination candidate with frontline therapy. However, DNA
hypomethylating agents are now the most frequently used agents in the treatment of elderly AML patients in the U.S. and Europe.
As a result, we amended Stage 2 of the Phase 2 trial in AML to remove the combination treatment of prexigebersen and LDAC and
replace it with the combination treatment of prexigebersen and decitabine. Since decitabine is also used as a treatment for relapsed/refractory
AML patients, a cohort of relapsed/refractory AML patients was also added to the study.
We believe the recent approval of the frontline
venetoclax and decitabine combination therapy provides an opportunity for combining prexigebersen with the combination therapy
for the treatment of de novo AML patients. Preclinical testing of prexigebersen with venetoclax and decitabine demonstrated
the potential to enhance efficacy of the frontline treatment combination. The triple combination of prexigebersen, venetoclax and
decitabine showed significant improvement in decreasing the viability of three of the four AML cell lines tested. Bio-Path’s
approved amended Stage 2 for this Phase 2 clinical trial has three cohorts of patients. The first two cohorts will treat patients
with the triple combination of prexigebersen, decitabine and venetoclax with the first cohort including untreated AML patients
and the second cohort including relapsed/refractory AML patients. Finally, the third cohort will treat relapsed/refractory AML
patients who are venetoclax-resistant or -intolerant with the two-drug combination of prexigebersen and decitabine.
The first step in establishing the amended
Stage 2 of the Phase 2 trial in AML was demonstrating the safety of treating patients with the two-drug combination of prexigebersen
and decitabine, which was reported in November 2019. The safety segment of Stage 2 of the Phase 2 clinical trial comprised
six evaluable patients who were treated with the combination of prexigebersen and decitabine. Although the treatment combination
of prexigebersen and decitabine is not the treatment planned for the efficacy evaluation of Stage 2 of the Phase 2 clinical trial,
the efficacy profile in this safety segment of the study was encouraging with 50% of patients having a response, including two
complete responses (33%) with incomplete hematologic recovery and one patient (17%) showing partial response. For reference, in
this class of AML patients, the complete response rate to treatment with decitabine alone is approximately 20%.
Importantly, results from patients who
were previously treated with the two-drug combination of prexigebersen and decitabine prior to the amendment to Stage 2 of the
Phase 2 trial in AML and who meet the criteria for enrollment in the third cohort of the amended Stage 2 of the Phase 2 trial
in AML can be included in the third cohort results. This represents a beneficial head-start in the third cohort enrollment. This
third cohort represents a significant, unmet opportunity in clinical treatment, as options are limited for AML patients who fail
frontline therapy.
On August 13, 2020, we announced the
enrollment and dosing of the first patient in the amended Stage 2 of the Phase 2 clinical study. This patient was in the relapsed/refractory
cohort and treated with the triple combination of prexigebersen, decitabine and venetoclax. Additionally, the first six evaluable
patients in the amended Stage 2 of the Phase 2 trial in AML have now been treated with the triple combination of prexigebersen,
decitabine and venetoclax to test the safety of this treatment combination. Pending safety review, the dosing of the triplet combination
will continue as planned.
Development of new therapeutics for AML
can meet currently unmet needs for patients who have very few treatment options due to age, fitness or treatment-resistance of
advanced genetically unstable cells. Elderly patients unfit to receive a stem cell transplant or induction therapy face a likelihood
of relapse to a more resistant leukemia. Prexigebersen and DNAbilize® technology offer new hope for achieving remission
for fragile populations. We believe that the combination of prexigebersen with frontline chemotherapy can provide a way to treat
cancer without added toxicity so that the patient can remain under treatment long enough to reach complete remission.
PREXIGEBERSEN-A
Data supports a prominent role of Grb2
in the progression of solid tumors, and overexpression of Grb2 has been associated with chemosensitivity, poor prognosis and advanced
disease in several malignancies including gynecologic malignancies.
Indications for Solid Tumors (e.g.,
Ovary, Endometrium)
Ovarian cancer is one of the most common
type of gynecologic malignancies, with 50% of all cases occurring in women older than 63 years. It is the fifth most frequent
cause of cancer death in women. In the U.S., 21,750 new cases of and 13,940 deaths from ovarian cancer were expected in 2020.
Around 70% of patients diagnosed with ovarian cancer will have a recurrence. Recurrent ovarian cancer is treatable but rarely
curable. The average duration of survival after recurrence of ovarian cancer is less than 2 years. The 5-year survival rate for
patients with recurrent ovarian cancer following standard salvage chemotherapy treatment is less than 10%. Given the poor outcomes
of treatment for ovarian cancer, novel drug treatments are urgently needed.
Endometrial cancer is the most common gynecologic
malignancy in the U.S. In the U.S., 65,620 new cases of and 12,590 deaths from endometrial cancer were expected in 2020. The majority
of cases are diagnosed at an early stage and are amenable to treatment with surgery alone. However, approximately 50% of advanced
stage endometrial cancers will recur. Recurrent endometrial cancer is incurable with currently available standard therapies. The
median survival for patients with recurrent endometrial carcinoma hardly exceeds 12 months. Novel drug treatments for recurrent
endometrial carcinoma are urgently needed.
Development and Treatment for ovarian
and endometrial cancer
Grb2 may be a novel potential therapeutic
target for ovarian and endometrial cancer, and prexigebersen-A may provide clinical benefit against these gynecologic malignancies.
Preclinical experiments were conducted in collaboration with leaders in the field of ovarian cancer at MD Anderson. Results of
the preclinical study were published in the scientific journal Oncotarget in July 2020. Prexigebersen-A effectively penetrated
ovarian tumors and decreased target Grb2 protein level in preclinical ovarian tumor models. Prexigebersen-A was demonstrated to
reduce tumor burden both as a monotherapy and in combination with paclitaxel, a therapy commonly used to treat patients with advanced
ovarian or endometrial cancer. In late 2019, we filed an IND application to initiate a Phase 1 clinical trial of prexigebersen-A
in patients with advanced or recurrent solid tumors. This trial is expected to commence after the IND has been cleared by the
FDA, which we currently anticipate being in 2021, at several leading cancer centers and will evaluate the safety of prexigebersen-A
in these patients. Assuming positive Phase 1 results, we expect that we would advance to a Phase 1b clinical trial of prexigebersen-A
in combination with paclitaxel in patients with recurrent ovarian or endometrial tumors.
Indications for Triple Negative Breast
Cancer (TNBC) and Inflammatory Breast Cancer (IBC)
TNBC and IBC - Background and Common
Treatments. Approximately 15 to 20% of breast cancers fall into the category of triple-negative. TNBC tumors do not express
estrogen receptors, progesterone receptors, and low human epidermal growth factor receptor 2 (HER2). These negative indicators
mean that the growth of the cancer is not supported by the hormones estrogen and progesterone, or by the presence of HER2 receptors.
Therefore, TNBC does not respond to hormonal therapy or therapies that target HER2 receptors. In addition, TNBC tumors are very
aggressive. IBC is a rare and very aggressive type of breast cancer that accounts for 2 to 5% of all breast cancers. A lack of
targeted treatments for these types of breast cancer has led to development of new therapeutics currently in clinical trials.
Overexpression of receptor tyrosine kinases has been reported for TNBC and IBC. Since Grb2 is vital in the cancer signaling of
receptor tyrosine kinases, the Company and collaborators at MD Anderson are interested in developing prexigebersen-A as a potential
treatment for TNBC and IBC.
BP1002
BP1002, also known by its scientific name
as Liposomal Bcl-2, is our second liposome delivered antisense drug candidate. BP1002 is intended to target the lymphoma, CLL
and certain solid tumor markets. We believe that BP1002 has the potential to treat 40 to 60% of solid tumors.
Bcl-2 is a protein that is involved in
regulating apoptosis, or programmed cell death. Apoptosis is a physiologic mechanism of cell turnover by which cells actively
commit suicide in response to aberrant external signals. Over-expression of Bcl-2 prevents the induction of apoptosis in response
to cellular insults such as treatment with chemotherapeutic agents. Bcl-2 is over-expressed in more than 90% of follicular lymphoma
(FL) due to a chromosomal rearrangement and is the key factor in the initiation of this malignancy. Bcl-2 was also found to contribute
to the pathophysiology of other lymphomas, such as CLL, mantle cell lymphoma, Waldenströms macroglobulinemia and double-hit
diffused large B-cell lymphoma, all of which are subtypes of non-Hodgkin’s lymphoma (NHL).
Non-Hodgkin’s Lymphoma - Background
and Common Treatments. Lymphoma can start anywhere in the body where lymph tissue is found. The major sites of lymph tissue
are lymph nodes, bone marrow, spleen, thymus, adenoids and tonsils and the digestive tract. NHL is a term used for many different
types of lymphoma that share some common characteristics. In the U.S., approximately 77,240 new cases of and 19,940 deaths from
NHL were expected in 2020 (Figure 7). Approximately 40% of NHLs are indolent lymphomas and approximately 60% are more aggressive
lymphomas. Indolent lymphomas grow and spread slowly. Some indolent lymphomas might not need to be treated right away but can
be monitored closely instead. On the other hand, aggressive lymphomas usually need to be treated right away, as they grow and
can spread quickly to other parts of the lymph system or to other parts of the body, such as the liver, brain or bone marrow.
Figure 7. Basic statistics of Non-Hodgkin’s
Lymphoma
BP1002 - Development and Treatment for
lymphoma. On December 22, 2014, we announced that we initiated development of BP1002 as a treatment for refractory/relapsed
patients with NHL (including CLL, mantle cell lymphoma, Waldenströms macroglobulinemia, diffused large B-cell lymphoma, peripheral
T-cell lymphoma, cutaneous T-cell lymphoma, and marginal zone lymphoma) and Hodgkin’s lymphoma.
Therapies that directly and specifically
block or inhibit protein synthesis of Bcl-2 could be transformative for NHL. Previous attempts at a Bcl-2 antisense by Genta Inc.
and ProNAi failed to show an improvement in remission or overall survival rates. The Genta antisense was a phosphorothioate DNA
with dose-limiting toxicity and it also did not have a lipid delivery mechanism to aid in prevention of clearance by the liver,
reducing the levels of antisense reaching diseased cells. The ProNAi antisense was administered with an anionic, pH-tunable liposome.
The drug was tolerable but its low response rate in DLBCL patients in a Phase 2 study prompted the company to discontinue further
clinical development. We believe that BP1002 overcomes the failures of previous antisense attempts at inhibiting Bcl-2. With BP1002,
more drug substance can reach the lymphoma cells so that the cancer cells can be treated with a safe and therapeutically relevant
dose. The small molecule Bcl-2 inhibitor venetoclax was approved by the FDA in June 2018 for the treatment of patients with
CLL and SLL who have received at least one prior therapy. In May 2019, the FDA approved venetoclax in combination with obinutuzumab
for the treatment of adult CLL and SLL patients with previously untreated disease. However, treatment with venetoclax can lead
to the development of drug resistance, resulting in disease recurrence. One of the proposed mechanisms of venetoclax resistance
is an acquired mutation in Bcl-2, which reduces venetoclax’s ability to bind and inhibit Bcl-2. Because BP1002 activity
is based on blocking the Bcl-2 messenger RNA and BP1002 targets Bcl-2 at a site different from venetoclax, we expect BP1002 to
overcome such venetoclax resistance mechanism and be an effective approach for patients who have relapsed from venetoclax. We
believe BP1002 provides a new tool for cancer treatment for not just lymphomas, but also many cancers for which Bcl-2 expression
is driving cell survival. The introduction of a new, non-toxic, and specific Bcl-2 inhibitor could be a major advance in cancer
therapeutics.
On November 21, 2019 we announced
that the FDA cleared an IND application for BP1002. An initial Phase 1 clinical trial will evaluate the ability of BP1002 to treat
refractory/relapsed lymphoma and CLL patients. The Phase 1 clinical trial is being conducted at several leading cancer centers,
including MD Anderson, the Georgia Cancer Center and the Sarah Cannon Research Institute and is now open for enrollment. Initially,
a total of six evaluable patients are scheduled to be treated with BP1002 monotherapy in a standard 3+3 design, with a starting
dose of 20 mg/m2. The approved treatment cycle is two doses per week over four weeks, resulting in eight doses administered
over twenty-eight days.
BP1003
BP1003 is our third
liposome delivered antisense drug candidate. BP1003 is a DNAbilize® RNAi nanoparticle containing antisense DNA
targeting STAT3, whose elevated expression/activity is associated with a poorer survival outcome for patients with solid tumors,
including those of gastric cancer, lung cancer, hepatic cancer, osteosarcoma, prostate cancer and pancreatic adenocarcinoma (PDAC).
We believe that a therapeutic that shuts down the STAT3 protein can have significant clinical impact for solid tumors that have
elevated expression/activity of STAT3.
Our lead indication for BP1003 is pancreatic
cancer due to the severity of this disease and the lack of effective, life-extending treatments. PDAC is a cancer of the exocrine
cells of the pancreas. In the U.S. in 2020, approximately 57,600 people were diagnosed with PDAC, and approximately 47,050 (82%)
died from the disease. It is estimated that less than 10% of PDAC patients survive beyond 5 years, and it is projected that by
2030, PDAC will become the second most lethal cancer behind lung cancer. Treatment of the disease is hampered by the location
of the pancreas, which is difficult to reach with conventional therapies and the fibrotic nature of the tumors, which protects
them from penetration by chemotherapeutics. We believe a novel and unconventional therapeutic is needed to overcome these barriers
to treatment.
While competition for therapeutics that
target the STAT3 pathway exist, the competition for specific STAT3 inhibitors is very small. Many peptides designed to bind to
STAT3 suffered from poor intrinsic pharmacokinetic properties, including poor cellular permeability and lack of stability in vivo,
which curtailed their further development. Even second-generation peptidomimetics have failed to overcome these limitations. Most
compounds under development target the pathway upstream of STAT3, such as the JAK2 kinase. However, lack of efficacy of the JAK2
kinase inhibitors was observed in PDAC clinical studies. Ionis Pharmaceuticals, Inc. has developed an antisense DNA-based
STAT3 inhibitor called IONIS-STAT3-2.5Rx. It is being evaluated in clinical trials by AstraZeneca under the name AZD9150 for solid
tumors and NHL. However, due to the toxicity of the DNA chemistry, thrombocytopenia continues to limit the systemic delivery and
efficacy of such compounds for the treatment of cancer. We believe BP1003 avoids these complications.
We hypothesized that the natural lipid
delivery vesicle would have unique characteristics that would allow for penetration of the fibrotic stroma to reach the PDAC cells.
An abstract of the preclinical study was presented in the 2019 American Association for Cancer Research Annual Meeting. Our preclinical
work demonstrated that BP1003 was successful in crossing the scar tissue matrix and delivering antisense drug into the tumor tissue.
Subsequent studies evaluating the combination of BP1003 with gemcitabine, a standard of care for PDAC patients with metastatic
disease, suggest that the regimen has synergistic anti-tumor effects. We expect to complete several IND enabling studies of BP1003
in 2021. If those studies are successful, our goal is to file an IND in late 2021 for the first-in-humans Phase 1 study of BP1003
in patients with refractory, metastatic solid tumors. Assuming positive Phase 1 results, we expect that we would advance to a
Phase 1b clinical trial of BP1003 in combination with gemcitabine in patients with refractory metastatic pancreatic cancer.
We believe that the excellent safety profile
of the DNAbilize® chemistry, the novel lipid formula that allows for penetration of the tumor stroma, and the ability
to target a single protein with precision, makes BP1003 an ideal candidate for combination with approved treatments to extend