Item 1. Business
Item
1. Business
On December 14, 2020, we entered
into an Agreement and Plan of Merger “(Merger Agreement”) with Chemomab Ltd. (“Chemomab”), an Israeli
limited company and a clinical-stage biotech company focusing on the discovery and development of innovative therapeutics for
fibrosis-related diseases with high unmet need, which included the proposed business combination (“Merger”) of CMB
Acquisition Ltd., a wholly owned subsidiary of ours, with Chemomab as the surviving company, subject to shareholder approval.
As a result, you should not place undue reliance on the plans discussed below relating to the pan-RAS and PDE10/ß-catenin
programs as they are subject to change.
The merger is described in detail in a
proxy statement / prospectus that we filed with the SEC on February 12, 2021 and that is available at this link: https://www.sec.gov/Archives/edgar/data/1534248/000110465921021553/tm211883-6_424b3.htm
Overview
We are a preclinical biotechnology company
committed to discovering and developing new cancer therapies designed to target the products of mutated genes that are drivers
of human malignancies. These therapies are called small molecule targeted therapies. Our company has obtained the option to license
small molecule technologies that we believe we can develop into product candidates that can deliver novel treatments for cancer
patients whose cancers are caused by mutated genes and for whom existing therapies are limited in effectiveness. The first of
these technologies comprises small molecules that potently inhibit the products of RAS oncogenes. RAS oncogenes are the most frequently
mutated family of genes in human cancer, responsible for almost a third of all human malignancies, and almost half of the three
most lethal cancers ( i.e ., lung cancer, colorectal cancer and pancreatic cancer). To date there are no approved therapies
that are effective in countering their tumorigenic effects. Our second technology consists of small molecules that interfere with
the Wnt/APC/β-catenin biochemical pathway through the inhibition of phosphodiesterase 10 (“PDE10”). Mutations
in this pathway are involved in most human colorectal cancers, the second leading cause of cancer deaths in the United States,
as well as in the hereditary cancer predisposition syndrome, familial adenomatous polyposis (“FAP”), which gives rise
to colorectal cancer. As is true for RAS-driven cancers, to date there are no approved therapies specifically for cancers that
carry mutations in the Wnt/APC/β-catenin pathway genes.
Previously we discovered and developed
a gene therapy, inodiftagene vixteplasmid (“inodiftagene”), designed to treat early stage bladder cancer. We developed
this gene therapy in six clinical trials in pancreatic cancer, ovarian cancer, and bladder cancer. Based on these preliminary
clinical studies, we planned and initiated a clinical trial designed as the basis for potential regulatory approval of inodiftagene.
This clinical trial, the Phase 2 Codex trial, was initiated in December 2018, enrolling patients through the following year.
We terminated the program in November 2019 based on our assessment that the observed preliminary efficacy of inodiftagene
in bladder cancer was insufficient to support regulatory approval.
In parallel to the now-terminated inodiftagene
program, our corporate goals for 2019 called for the expansion of our pipeline, and we determined to move toward small molecule
anti-cancer therapeutics. In September 2019, we entered into a collaboration and license agreement (the “Collaboration
Agreement”) with ADT Pharmaceuticals, LLC (“ADT”) pursuant to which we agreed to use commercially reasonable
efforts to conduct research and development activities with respect to the pan-RAS and PDE10/β-catenin programs under the
oversight of a jointly established steering committee. In addition, ADT granted us an exclusive option to license its small molecule
technologies. The Collaboration Agreement covers two proprietary classes of molecules: (1) inhibitors of RAS, and (2) inhibitors
of the Wnt/APC/β-catenin pathway via PDE10. Pursuant to the Collaboration Agreement, we have an exclusive option to license
the suite of intellectual property covering these molecules, with granted patents that extend to 2034.
We believe we will be able to develop these
molecules into product candidates to provide new therapies for patients with cancers whose pathogenesis depends on mutant RAS
oncogenes, or on mutations in the Wnt/APC/β-catenin pathway. Both of these genetic lesions cause enormous human suffering
by reason of the cancers they cause. These genes are primarily responsible for lung, colorectal, and pancreatic cancers, the most
common lethal cancers, among others. Mutations in one of the RAS genes are present in more than 30% of all human cancers, making
these the most frequent oncogenic mutations in cancer. The Wnt/APC/β-catenin pathway genes are mutated in approximately 90%
of colorectal cancers.
5
The impact of RAS and Wnt/APC/β-catenin
mutations can be best understood by considering cancer incidence and death rates in the United States. According to the American
Cancer Society, in 2020, it is expected that more than 1.8 million new cases of cancers will be diagnosed in the United States,
and approximately 606,520 people in the United States are expected to die of cancer. More than 30% of these cancers have RAS mutations.
The cancers with the highest estimated mortality rates in the United States for 2020 are lung cancer (approximately 136,000 deaths),
colorectal cancer (approximately 53,000 deaths), and pancreatic cancer (approximately 47,000 deaths), which together are estimated
to account for over 235,000 deaths in 2020 in the United States alone. These three cancer types are largely driven by mutant RAS.
Globally, the epidemiologic profile is similar. The Wnt/APC/β-catenin pathway is similarly implicated in a large number of
lethal cancers. Approximately 90% of colorectal cancers carry mutations in either the adenomatous polyposis coli (“APC”)
gene or in the CTNNB1 gene that encodes β-catenin. This translates into approximately 48,000 deaths due to colorectal cancer
carrying Wnt/APC/β-catenin pathway mutations in the United States alone. Additionally, the involvement of the Wnt/APC/β-catenin
pathway in the hereditary cancer syndrome FAP via mutations in the APC gene affects approximately 16,000 additional patients in
the United States.
The RAS oncogenes are heavily implicated
in the genesis of a broad spectrum of cancers as the most common oncogenic alterations known. There are three members of the RAS
family of genes: KRAS, HRAS, and NRAS. Of the most frequently lethal cancer types, lung cancers (non-small cell lung cancers,
“NSCLC”) have mutations in one of the RAS family of genes in approximately 35% of cases; colorectal cancers carry
RAS mutation in approximately 45% of cases; and pancreatic cancers carry RAS mutations in over 95% of cases. We estimate that
the total addressable population of patients with RAS-mutation driven solid tumors alone is more than 165,000 patients per year
in the US. This enormous toll of cancer morbidity and mortality suggests that therapies directed at tumors carrying mutated forms
of RAS are urgently needed.
Treating cancers that carry mutated oncogenes
by discovering and developing small molecule inhibitors of the mutated protein products of the oncogene is one of the most successful
cancer treatment paradigms that exists. Approved small molecule targeted drugs include inhibitors of the oncogenic breakpoint
cluster region-Abelson murine leukemia viral oncogene homolog 1 (“BCR-ABL”) including imatinib, dasatinib, and ponatinib
in leukemia; inhibitors of oncogenically mutated epidermal growth factor receptor (“EGFR”) in NSCLC including erlotinib
and osimertinib; inhibitors of mutated anaplastic leukemia kinase (“ALK”) in NSCLC such as crizotinib and brigatinib;
and many others. However, there are no approved inhibitors for mutated members of the RAS family of oncogenes. Until very recently,
the unique biochemistry and biology of the RAS family had resisted efforts of cancer biologists to discover and develop drugs
capable of inhibiting the activity of the mutated protein. However, in 2014 work by Shokat and others led to new approaches to
the discovery of small molecules capable of inhibiting a particular mutated form of RAS, known as KRAS G12C. This designates a
mutation in the KRAS member of the RAS family, in which an amino acid at position 12 is altered due to a mutation in the encoding
gene. In 2019, this work led to the first demonstration in the clinic of anti-tumor response associated with treatment with KRAS
G12C inhibitors under development by Amgen and Mirati Therapeutics. We believe the significance of these successes is field-altering,
as for the first time there is evidence that inhibition of mutated RAS isoforms may be undertaken in the same manner as other
successful small molecule targeted therapies had shown possible against other mutated oncogenes. In other words, RAS has become
a clinically validated target. However, KRAS is only one of three mutated isoforms of the RAS family, and only approximately 11%
of KRAS mutations are of the G12C type. This means that while these observations have proven that RAS-directed therapy using small
molecule inhibitors is possible with clinical effect, results so far are confined to a small subset of patients carrying a particular
mutation. That said, the values of the companies pursuing KRAS G12C inhibitors has grown by many billions of dollars during 2019.
Our lead focus is our pan-RAS program,
which we believe is poised to take advantage both of the fact that RAS inhibition has been shown to be clinically valid, and initial
successes by existing therapies have been confined to a fraction of tumors that carry RAS mutations. A broadly-acting pan-RAS
inhibitor with the potential to treat RAS-driven cancers regardless of RAS isoform or mutation would be clinically useful. We
believe our RAS-inhibitor molecules have potential for RAS inhibition in a broad variety of clinical settings.
The characteristics one would need in such
inhibitors include: selectivity for activated RAS; potency against cells harboring mutant RAS; consistency of biochemical data
with RAS inhibition (as opposed to other pathway points of inhibition); evidence for binding RAS directly; in vivo anti-tumor
activity; and immunological stimulation in vivo consistent with other clinical RAS inhibitors.
6
Our small molecule inhibitors have been
demonstrated to have these characteristics. Our lead RAS-inhibitor molecules are novel structures that share an indene core. These
molecules potently inhibit growth of tumor cells harboring mutant RAS, while having greater than 100-fold selectivity over cells
with normal RAS activity. Inhibitory activity has been observed with low nanomolar potency in KRAS-, HRAS-, and NRAS-driven tumor
cell models with a variety of mutations across a variety of tumor types. This activity is observable in both monolayer cultures,
and in 3-D spheroid cultures, which may have higher predictive value for anti-tumor activity. These compounds inhibit downstream
signaling through RAF and PI3K pathways, which is consistent with their acting directly on RAS, as opposed to another pathway
molecule. They initiate cell-cycle arrest and induce apoptosis, consistent with cell killing. Importantly, the inhibitors demonstrate
blockade of GTP loading of RAS in the nucleotide-free state in cell-free biochemical assays, suggesting that their mechanism of
action is through interference of GTP-mediated signaling. They have exhibited in vivo activity in RAS-mutant tumor models.
Finally, an emerging characteristic of RAS inhibition is the stimulation of anti-tumor immunity. This has been shown with AMG
510, a KRAS G12C inhibitor presently in the clinic, and it suggests that effective RAS inhibition stimulates several anti-tumor
immune mechanisms. Our inhibitors have been shown to similarly stimulate anti-tumor T-cell-mediated immune mechanisms, suggesting
that their mechanism is indeed effected through RAS.
We have identified lead compounds with
the desired biologic and biochemical characteristics with regard to effecting pan-RAS inhibition. We are undertaking additional
structural studies and medicinal chemistry to identify a clinical lead compound. We anticipate that we will identify a clinical
development lead compound in the next 12 to18 months, followed by 12 months of Investigational New Drug (“IND”) application-enabling
studies. We believe this will allow us to initiate our first in human trial in 2022. Initial clinical studies will enroll patients
with RAS mutations and advanced solid tumors. The clinical development of other targeted therapies in tumors with genetically
defined driver mutations, including the development plans for the KRAS G12C inhibitors presently under investigation, suggests
that there is a path to accelerated approval based on a single well-designed multi-center single-arm study. We would then pursue
the expansion of indications to additional tumor types, earlier lines of therapy, and combination studies, with additional trials.
Our focus initially will be on the pan-RAS-inhibitor
program. Our second program, the PDE10/β-catenin program, will proceed in collaboration with ADT. This program’s suite
of small molecules selectively and potently inhibit PDE10 and suppress Wnt/APC/β-catenin signaling in preclinical models.
PDE10 inhibition has been shown to downregulate β-catenin expression and inhibits polyp and tumor growth. We have identified
molecules that are orally bioavailable, and, in our preliminary mouse models, have been shown to inhibit the development of intestinal
polyposis and colon cancer, and the growth of pulmonary metastases. Initial plans for continued preclinical development of the
PDE10/β-catenin program will be funded by ADT using Small Business Innovation Research (“SBIR”) grants to ADT.We
believe we are positioned for the successful development of small molecule inhibitors. We believe that our pan-RAS and PDE10/β-catenin
programs have substantial promise to lead to new development candidates with the potential to treat lethal tumors harboring RAS
and Wnt/APC/β-catenin pathway mutations in the United States and globally.
In January 2020, our board of directors
approved management’s recommendation to close our office and laboratories located in Israel. Following the closure of the
Israeli facilities at the end of May 2020, our sole remaining office was located in Cambridge, Massachusetts. Under circumstances
related our restructuring this office has not been in use for a large part of the year and our lease for this office in Cambridge,
Massachusetts terminated on February 28, 2021. We are allowed, however, to continue using this address to receive mail.
On July 2, 2020, our Chief Executive
Officer, Dr. Frank Haluska, sent a letter to the Chairman of our board of directors outlining Dr. Haluska’s belief
that events had occurred that were sufficient to trigger his ability to resign for “Good Reason” under his employment
agreement. Our board of directors informed Dr. Haluska that it disagreed with the letter’s assertions regarding “Good
Reason” and treated the letter as a constructive resignation effective as of July 2, 2020. On July 12, 2020, Dr. Frank
Haluska tendered his written resignation from our board of directors, effective immediately. Dr. Haluska referenced the matters
articulated in his letter of July 2, 2020, and the Company’s response and actions following receipt of the letter as
the basis for his resignation from the Board. It is our position, based on advice from our legal counsel, that Dr. Haluska
resigned without Good Reason, is not entitled to severance, and we will contest any and all claims for severance. Prior to the
appointment of Mr. Neil Cohen as interim Chief Executive Officer in October 2020 (see below), our board of directors
handled all matters related to CEO duties.
On October 20, 2020, we appointed
Mr. Neil Cohen as interim Chief Executive Officer of Anchiano, effective immediately. Mr. Cohen continues to serve as
a member of our board of directors. The Company also appointed Andrew Fine to serve as our Chief Financial Officer, effective
immediately. Mr. Fine previously served as our Interim Chief Financial Officer pursuant to a subcontracting agreement.
In light of business circumstances, and
in order to conserve cash and preserve optionality while alternatives are being identified and assessed, we made a decision during
July 2020 to undertake reductions in headcount and other cost saving measures. These included plans to temporarily reduce
our internal and external research and development work on the Company’s pan-RAS-inhibitor program until there is greater
clarity regarding Anchiano’s ability to fund the program. We continue to undertake actions for the promotion of the program
and its assets and towards strengthening the protection of all related intellectual property.
On December 14, 2020 we entered into
an Agreement and Plan of Merger with Chemomab, an Israeli limited company and a clinical-stage biotech company focusing on the
discovery and development of innovative therapeutics for fibrosis-related diseases with high unmet need, which included the proposed
Merger of CMB Acquisition Ltd., a wholly owned subsidiary of ours, with Chemomab as the surviving company, subject to shareholder
approval. A shareholder meeting has been scheduled for March 15, 2021 to approve the Merger and related proposals. For more
information regarding Chemomab and the proposed Merger, see the proxy statement/prospectus we filed with the SEC on February 12,
2021 and that can be found at this link: https://www.sec.gov/Archives/edgar/data/1534248/000110465921021553/tm211883-6_424b3.htm
Our Product Pipeline
Our preclinical programs are summarized
below and consist of two preclinical programs. We have a partnership with ADT related to two small molecule development programs
targeting oncogenic pathways, focused on RAS and PDE10/β-catenin, respectively.
7
Our Therapeutics Pipeline
Pan-RAS
Program : Our highest priority program targets oncogenic mutations in the RAS family of genes ( i.e. , KRAS,
HRAS, and NRAS gene families), which are present in more than 30% of cancers. RAS plays a pivotal role in signal transduction
pathways leading to tumor cell proliferation and survival. Our pan-RAS program has identified novel indene-based small molecules
that exhibit potent and selective inhibition of activated RAS signaling regardless of isoform or mutation, or pan-RAS inhibition.
PDE10/ß-catenin
Program : Genetic alterations in components that make up the Wnt signaling pathway, which includes APC and β-catenin,
are prevalent in a number of cancer types, occurring in more than 80% of colorectal cancers. Our PDE10/ß-catenin program
has identified small molecules that selectively and potently inhibit PDE10 and suppress Wnt/APC/β-catenin signaling in preclinical
models. PDE10 inhibition has been shown to down regulate β-catenin expression and inhibits polyp and tumor growth. We believe
it has potential for application in the treatment of cancer as well as spontaneous and familial polyposis syndromes.
Inodiftagene
vixteplasmid : Previously we discovered and developed a gene therapy, inodiftagene, designed to treat non-muscle
invasive bladder cancer (“NMIBC”). We had developed this gene therapy in six clinical trials in pancreatic cancer,
ovarian cancer, and bladder cancer. Based on these preliminary clinical studies, we determined to test this product candidate
in a clinical trial designed as the basis for potential regulatory approval. This clinical trial, the Codex trial, was initiated
in December 2018, enrolling patients through the following year. In November 2019, we discontinued the pivotal Phase
2 Codex study. After a thorough analysis of the data, we determined that there was a low probability of surpassing the pre-defined
futility threshold at the planned interim analysis, which required 10 complete responses in 35 patients. As of November 14,
2019, 16 patients were evaluable after the first disease assessment on treatment; of these, three, or 19%, had experienced a complete
response. The data also indicated a low probability of achieving an efficacy profile that in our estimation would be necessary
to support regulatory approval. The safety data on the investigational product were consistent with those observed in prior preliminary
clinical trials. In April 2020 we notified Yissum Technology Transfer Company of the Hebrew University Ltd. (“Yissum”)
that as a result of our decision to discontinue clinical development of inodiftagene, we will cease payments to maintain intellectual
property (“IP”) we licensed from Yissum that supported the development and as related to a licensing and development
agreement between the parties (“License Agreement”). In August 2020 we agreed with Yissum on termination of the
License Agreement and return of the IP.
8
Pan-RAS Program
Background
According to the National Cancer Institute,
mutations in the RAS family of genes ( i.e. , KRAS, HRAS, and NRAS) are the most frequent oncogenic mutations in cancer,
present in over 30% of all cancers. These mutations are involved in more than 181,000 cancer deaths per year (more than 30% of
606,000 deaths) in the United States alone. The three most lethal cancers, lung cancer, colorectal cancer and pancreatic cancer,
are driven largely by mutant RAS. Of these cancer types, non-small cell lung cancers (“NSCLC”) have mutations in the
RAS family of genes in approximately 35% of cases; colorectal cancers carry RAS mutation in approximately 45% of cases; and pancreatic
cancers carry RAS mutations in over 95% of cases. Taken together, in these three cancer types, RAS mutations account for more
than 100,000 lethal cases of cancer per year in the United States. The World Health Organization estimates that in 2018, the most
common causes of cancer death are lung cancer (1.76 million deaths) and colorectal cancer (862,000 deaths). According to the National
Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Program, five-year survival outcomes in advanced NSCLC, colorectal
cancer and pancreatic cancer are particularly dismal - 5%, 14% and 3%, respectively.
We estimate that the total addressable
population of patients with RAS-mutation driven solid tumors alone totals more than 165,000 patients per year in the United States.
These morbidity and mortality rates suggest that therapies directed at tumors carrying mutated forms of RAS are urgently needed.
Taken together, these statistics suggest
that the patient population that could benefit from effective therapy targeting RAS mutations is large. The U.S. annual incidence
of NSCLC, colorectal cancer, and pancreatic cancer combined is approximately 395,000 patients, of which approximately 295,00 are
advanced cases. We estimate that this translates into approximately 130,000 addressable patients annually with RAS-mutated advanced
solid tumors in the United States in these three indications. We estimate that other solid tumors will add approximately 35,000
additional addressable patients for a total annual addressable patient population of 165,000 in the United States. RAS mutations
are similarly frequent globally. Despite success in development of therapies targeting other genetic drivers in cancer, there
have been no approved RAS inhibitors to date. The frequency of RAS mutations in cancer, the high mortality associated with the
disease, and the lack of any approved targeted therapies creates a significant clinical need.
RAS plays a pivotal role in cell signal
transduction pathways leading to tumor cell proliferation and survival. RAS, a membrane bound protein, resides in an inactive,
or GDP-bound, state. Following stimulation, RAS releases guanosine triphosphate (“GDP”) and forms a transient nucleotide-free
state, subsequently binding with guanosine triphosphate (“GTP”). Active, or GTP-bound, RAS engages specific RAS effector
proteins ( e.g. , RAF, PI3K), resulting in activation of pathways leading to cell proliferation and survival. Oncogenic activation
of RAS occurs mainly via mutations in codons 12, 13 and 61—with a shift to the GTP-bound state and constitutive activation
of RAS effector pathways.
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RAS Signaling Pathway
Abbreviations:
EGFR
=
epidermal
growth factor receptor,
ERK
=
extracellular
signal-regulated kinase
GRB2 =
growth factor receptor-bound
protein 2
MEK =
mitogen activated
protein kinase
P =
phosphorylated
PI3K =
phosphatidylinositol
3-kinase
PIP2 =
phosphatidylinositol
(4,5)-bisphosphate
PIP3 =
phosphatidylinositol
(3,4,5)-trisphosphate
SOS =
son of sevenless
The understanding of the oncogenic properties
of RAS has driven the search for anti-RAS therapeutics for several decades. However, mutant RAS has long been viewed as “undruggable”
directly due to its minute structural differences from wild-type RAS, its smooth surface and lack of deep pockets for binding
of small molecule inhibitors. Initial attempts to inhibit mutant RAS focused on inhibition of farnesyltransferase, responsible
for posttranslational modifications associated with correct localization of the protein. However, this line of investigation has
been unsuccessful to date in clinical trials. More recently, a previously unrecognized pocket of RAS—the Switch II Pocket
(“SII-P”)—was discovered in the inactive GDP-bound form. Compounds have been identified that selectively target
the cysteine mutation at codon 12 (also known as the KRAS G12C mutation) and bind covalently to RAS G12C, targeting SII-P and
preventing loading of GTP and engagement of effectors. A number of KRAS G12C mutation inhibitors are currently in Phase 1 clinical
trials ( e.g. , Amgen Inc.’s AMG-510 and Mirati Therapeutics, Inc.’s MRTX849), with early clinical data
reporting evidence of activity in KRAS G12C mutation-positive cancers, particularly NSCLC. These drugs have generated enormous
excitement, with the most advanced drug, AMG-510, showing an overall response rate (“ORR”) of 48% in 23 evaluable
NSCLC patients with eight out of 11 responders remaining in response and on treatment. Similarly, MRTX849 has shown a 50% ORR
in six patients with NSCLC in its initially presented Phase 1 data set.
We believe the significance of these successes
is field-altering, as for the first time there is evidence that inhibition of mutated RAS isoforms may be undertaken in the same
manner as other successful small molecule targeted therapies had shown possible against other mutated oncogenes. In other words,
RAS has become a clinically validated target. However, these current investigational drugs are mutation specific—with G12C
representing approximately 9% of RAS mutations in cancer. As shown below, KRAS represents the most commonly mutated isoform of
RAS, and there is a spectrum of activating mutations that have been observed with this isoform. This means that only approximately
11% of the KRAS mutations can be addressed with G12C inhibitors. A variety of activating mutations have also been observed with
the HRAS and NRAS isoforms, which remain unaddressed. While these observations have proven that RAS-directed therapy using small
molecule inhibitors is possible with clinical effect, results so far are confined to a small subset of patients carrying a particular
mutation. That said, the market capitalization of the companies pursuing KRAS G12C inhibitors has grown by many billions of dollars
during 2019.
10
Frequency of RAS Mutations by Tumor Type (cancers with
>5% RAS mutation frequency)
Adapted from: Cox et al., Nat Rev Drug Discov, 2014
Frequency of Specific KRAS mutations in KRAS-Mutated Lung,
Colorectal, Pancreatic and Biliary Tract Cancers
Adapted from: Vasan et al., Clinical cancer research,
2014
We believe that our pan-RAS program is
poised to take advantage both of the fact that RAS inhibition has been shown to be clinically valid, and that initial successes
have been confined to a fraction of tumors that carry RAS mutations. A broadly acting RAS inhibitor with the potential to treat
RAS-driven cancers regardless of RAS isoform or mutation ( i.e ., a pan-RAS inhibitor) would be clinically useful. It is
also not yet well understood what resistance mechanisms to KRAS G12C mutation inhibitors will develop in the clinic. A pan-RAS
inhibitor may be clinically preferable in KRAS G12C mutation-positive patients if resistance to KRAS G12C mutation inhibitors
leads to mutations in other RAS isoforms or other KRAS mutations, and may also have utility in such patients who have been treated
previously with a KRAS G12C mutation inhibitor. There is a clear need to continue to develop new and more effective direct inhibitors
of RAS, preferably with broad activity against the multiple RAS isoforms and various mutations. Given the frequency of RAS mutations
overall, a pan-RAS inhibitor would have potential to address a substantial proportion of cancer patients—significantly more
than any other genetic target for which drugs have been developed to date (and, we estimate, approximately 11 times more patients
than are addressable by the KRAS G12C mutation inhibitors). Therefore, our pan-RAS program is our highest priority.
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Our Approach
Our lead RAS inhibitor molecules are novel
indene derivatives of sulindac, a well-studied and clinically utilized anti-inflammatory agent with activity against cells carrying
mutated RAS. Our RAS inhibitor molecules have been engineered to eliminate cyclooxygenase-2 (“COX-2”) inhibitory activity,
present in sulindac, to lessen the potential cardiovascular side effects observed with sulindac and other related drugs.
We believe our RAS inhibitor molecules
have potential for RAS inhibition in a broad variety of clinical settings, because they exhibit the characteristics we believe
are necessary in a pan-RAS inhibitor. Our RAS inhibitor molecules potently, selectively, and reversibly inhibit growth of tumor
cells harboring mutant RAS, while having greater than 100-fold selectivity over cells with normal RAS activity. Inhibitory activity
has been observed with low nanomolar potency (<10 nM) in KRAS-, HRAS-, and NRAS-driven models with a variety of mutations (e.g.
KRAS G12C, G13D, G12V, G12S; HRAS G12D; and NRAS Q61K) across a variety of tumor types, which suggests that these molecules could
have utility across the broad spectrum of RAS mutations and tumor types in which these mutations have been observed to drive cancer.
This potent activity is observable in both monolayer cultures, and in 3-D spheroid cultures, which may have higher predictive
value for anti-tumor activity. These compounds inhibit downstream signaling through RAF and PI3K pathways, which is consistent
with their acting directly on RAS, as opposed to another pathway molecule. They initiate cell-cycle arrest and induce apoptosis,
consistent with cell killing. Importantly, the inhibitors demonstrate blockade of GTP loading of RAS in the nucleotide-free state
in cell-free biochemical assays, suggesting that their mechanism of action is through interference of GTP-mediated signaling.
They have exhibited in vivo activity in RAS mutant tumor models. Finally, an emerging characteristic of RAS inhibition
is the stimulation of anti-tumor immunity. This has been shown with AMG 510, a KRAS G12C inhibitor presently in the clinic, and
it suggests that effective RAS inhibition stimulates several anti-tumor immune mechanisms. Our inhibitors have been shown to similarly
stimulate anti-tumor T-cell-mediated immune mechanisms. These multiple lines of evidence are all consistent with the characteristics
one would expect to observe with a drug that is killing cells by direct inhibition of RAS.
We believe these molecules have potential
for RAS inhibition in a broad variety of clinical settings. Over the next 12-18 months our main goals are to understand the specific
mechanism of action and physical basis of binding of the compounds to RAS, and to optimize the initially identified series of
compounds to identify a lead development candidate.
One of our lead compounds in the pan-RAS
program, ANC 007 (also referred to as MCI-062), has been observed to have less than 10 nanomolar cellular potency in monolayer
cultures of tumor cells harboring mutant RAS. Similar potency was observed in 3D spheroid cultures, which are cell cultures that
are permitted to grow in all three dimensions and are considered by some to be more predictive of in vivo activity than
monolayer culture. Cell lines with wild-type (“WT”) RAS and concurrent upstream mutations (e.g. EGFR) that signal
through RAS display similar inhibition to cell lines with mutated RAS. Cell lines with WT RAS in the absence of upstream activation
are less sensitive (>100-fold selectivity), regardless of downstream activating mutations. Sensitivity to ANC 007 can be conferred
by transduction of HT-29 cells (WT RAS) with mutant RAS. This means that mutated (or activated) RAS is required for the activity
of the drug. These observations are consistent with the inhibition of RAS regardless of isoform, and regardless of the mutations
tested. In addition, they suggest that the activation of RAS (by mutation or upstream signaling) is a key feature of selectivity.
If this key finding of pan-RAS inhibition with this series of compound can be translated into a drug candidate exhibiting similar
broad activity in vivo , we believe the clinical potential is substantial.
12
Potent and Selective Pan-RAS Inhibition with ANC 007
Source:
Keeton et al., AACR 2019; Mattox et al. AACR 2019; McConnell et al. AACR 2017; Data on File. ANC 007 has previously been
referred to as MCI-062.
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Potent and Selective RAS Inhibition of Monolayer and
Spheroid Culture with ANC 007
Panels:
· A,
B, C, D: Growth inhibitory activity of ANC 007 (MCI-062) was tested using
the CellTiter-Glo luminescence assay.
· E:
Inhibition of colony formation was tested on a five different cell lines
using ANC 007. BcPC-3 is a pancreatic cell line with non-mutated, or wild type, RAS.
Other four cell lines carry RAS mutations.
· F:
Replication incompetent retrovirus encoding HRAS-G12V mutant or empty
vector was prepared by transfection of A293T cells with packaging and envelope plasmids.
Crude supernatant collected and used to tranduce HT29 colon cancer cells. Stable pools
of each were expanded and expression of HRAS was characterized by western blot.
Source:
Keeton et al., AACR 2019; Mattox et al. AACR 2019; Data on File.
ANC 007 has been shown to inhibit signaling
through RAF and PI3K pathways ( i.e. , nodes in the signal transduction cascade that are downstream (distal) to RAS), which
suggests that the node of inhibition is RAS itself, rather than one of the effectors further downstream. As shown below, treatment
of MIA-PaCa-2 pancreatic cancer cells with KRAS G12C results in inhibition of signaling of the MAPK pathway as evidenced by inhibition
of phosphorylation of CRAF, MEK, and ERK. AKT phosphorylation is also inhibited. The observation that both sides of the signaling
pathways downstream from RAS (RAF/MEK/ERK and AKT) are inhibited suggests that the node of inhibition is RAS itself, rather than
one of the effectors further downstream. MAPK signaling in KRAS G13D mutant HCT-116 colon cancer cells is inhibited in vivo
as well.
14
Inhibition of Downstream Signaling Through RAF and PI3K
Pathways with ANC 007
Panels:
· A,
ANC 007 (MCI-062) reduced RAS-GTP levels and inhibits activation of downstream
RAS signaling in MIA-PaCa-2 pancreatic cancer cells Cells were treated with vehicle or
ANC 007 for 24 hours in serum-free media and subsequently stimulated with 30 ng/mL EGF
for 10 minutes. RAS- GTP levels after treatment were determined by the active RAS pull-down
using GST-RAF1- RBD/glutathione agarose and detection by Western blotting. Detection
of phospho-protein levels was performed by Western blot.
· B,
ANC 007 inhibits activation of downstream RAS signaling and activates
anti-tumor immunity in murine RAS mutant colon cancer model. Mice were implanted in the
right flank with 10 million HCT- 116 tumor cells per mouse. ANC 007-treated mice received
5 mg/kg MCI-062 twice daily by peritumoral administration. Vehicle-treated mice received
5% DMSO/5% cremophor EL/90% water once daily by peritumoral administration. RAS-GTP levels
in tumor lysates were determined by the active RAS pull-down and detection by Western
blotting. Levels of MAPK proteins and immune markers were determined by Western blotting
with the whole tumor lysate. Each lane corresponds to an individual animal.
Source:
Keeton et al., AACR 2019; Mattox et al. AACR 2019.
15
To initially characterize
the molecular mechanism of action of ANC 007, it has been tested in cell-free biochemical assays utilizing recombinant KRAS in
order to evaluate the potential for direct binding of the drug to the RAS protein. Incubation of ANC 007 with nucleotide-free
KRAS followed by addition of GTP led to a concentration dependent reduction of RAS-GTP levels in an RBD pull-down experiment.
This effect was not observed when ANC 007 was incubated with GTP-loaded RAS. The RBD assay utilizes the Ras-binding domain (RBD)
of the RAS effector kinase Raf1 which been shown to bind specifically to the GTP-bound form of RAS proteins, making it an ideal
tool for affinity purification of GTP-Ras. This experiment suggests ANC 007 directly inhibits GTP binding to RAS when RAS is in
the nucleotide-free state but not in the GTP-bound state. Similarly, in a guanine nucleotide exchange assay, which uses a fluorescently-labeled
guanine nucleotide analogue (MANT-GTP) to evaluate nucleotide binding to RAS, addition of ANC 007 to nucleotide-free KRAS inhibits
MANT-GTP binding. We believe the results of these cell-free experiments indicate that the mechanism of ANC 007 involves direct
binding to RAS to exert its effect. Further work, including such structural biology methodologies as x-ray crystallography, are
planned to more specifically elucidate the mechanism of action and binding contacts of these compounds.
Inhibition of GTP Binding to Recombinant KRAS in Cell-Free
Biochemical Assays Under Nucleotide-Free (nf) Conditions with ANC 007
Panels:
· A,
ANC 007 (MCI-062) inhibits GTP binding to recombinant nucleotide-free
RAS in RBD pull-down experiment. Nucleotide-free recombinant WT-KRAS was prepared by
incubation with 20 mM EDTA on ice. ANC 007 or vehicle was incubated 1 h with nucleotide-free
WT-KRAS, followed by addition of GTP and an additional 30 min incubation (left) or, ANC
007 was incubated with WT-KRAS after addition of GTP (GTP-bound, right). RAS-GTP levels
after treatment were determined by the active RAS pull-down assay using GST-RAF1-RBD/glutathione
agarose and detection by Western blotting.
· B,
ANC 007 inhibits GTP binding to recombinant nucleotide-free RAS in guanine
nucleotide exchange assay. Nucleotide-free recombinant WT-KRAS was prepared by incubation
with 20 mM EDTA on ice. Nucleotide free KRAS was incubated with ANC 007 or vehicle for
1 h on ice, followed by addition of an excess of MgCl 2 with fluorogenic MANT-GTP.
Recombinant KRAS not treated with EDTA (GTP-KRAS) was included as a control indicator
of intrinsic turnover rate. The development of fluorescence reflecting MANT-GTP
binding to KRAS was monitored over the course of a 45 min incubation.
16
Source: Mattox et al. AACR 2019; Data on File.
ANC 007 has exhibited potent anti-tumor
activity in RAS-driven tumor models in mice, consistent with the cell based in vitro data. As shown below, ANC 007 inhibited
tumor growth by intratumoral administration in KRAS mutant colon tumor xenograft models (HCT116 and CT26 cell lines).
In Vivo Antitumor Activity in RAS-driven Tumor Models
with ANC 007
Panels:
· A:
ANC 007 (MCI-062) inhibits growth of KRAS mutant HCT-116 tumor cells in
a subcutaneous mouse xenograft model. Athymic nude mice were implanted in the right flank
with 10 million tumor cells per mouse. Mice were treated once daily by intratumoral administration.
Control mice received vehicle only (5% DMSO/5% cremophor EL/90% water) once daily by
intratumoral administration. N=8 mice for vehicle group, n=7 mice for 5 mg/kg ANC 007
group, n=4 mice for 10 mg/kg ANC 007 group.
· B:
Mice were implanted in the right flank with one million CT-26 tumor cells
per mouse. ANC 007 treated mice received 5 mg/kg ANC 007 twice daily by peritumoral administration.
Vehicle-treated mice received 5% DMSO/5% cremophor EL/90% water once daily by peritumoral
administration. Shown on left is control (vehicle-treated) mice and on the right are
mice treated with ANC 007.
17
As shown below, in an immune competent
mouse RAS-mutant tumor model, ANC 007 suppressed tumor growth in association with decreased PD-L1 levels in tumors; decreased
PD-1 in T-cells; increased proportion of CD4+ and CD8+ T-cells in tumors; and reduced Treg cells in tumors (as evidenced by Foxp3
expression). Similar effects on the tumor immune microenvironment have been observed with KRAS G12C inhibitors, including AMG-510,
and this stimulation of anti-tumor immunity appears to be an emerging characteristic of RAS inhibition itself. These lines of
evidence suggest that effective RAS inhibition stimulates several anti-tumor immune mechanisms., and ANC 007 has been shown to
similarly stimulate these anti-tumor T-cell-mediated immune mechanisms.
Inhibition of Tumor Growth with ANC 007 Associated with
Activation of Antitumor Immunity
Panels:
·
A: ANC 007 (MCI-062) reduces
PD-L1 expression in RAS driven tumor model. Mice were implanted in the right flank with one million CT26 tumor cells per mouse.
ANC 007-treated mice received 5 or 10 mg/kg ANC 007 once daily by intratumoral administration. Vehicle-treated mice received
5% DMSO/5% cremophor EL/90% water once daily by intratumoral administration. RAS-GTP levels in tumor lysates were determined
by the active RAS pull-down and detection by Western blotting. of immune markers was performed on whole tumor lysate.
·
B, C, D, E:
ANC 007 reduces PD-1, increases proportion of CD4+ and CD8+ T-cells, and reduces Tregs. Subcutaneous CT-26
murine tumors were excised from vehicle or ANC 007 treated mice, and digested for 1 h using the gentle-MACS dissociator and
murine tumor digestion protease cocktail. Following digestion, single cell suspensions were recovered by passage through
a cell strainer, and cell counts were normalized by quantitation using a hemacytometer. Fluorescently labelled antibodies
used to quantitate the indicated cell populations by flow cytometry.
Preclinical Development
We initiated development of a series of
compounds that exhibit pan-RAS inhibition as detailed in the experiments above. The lead compounds demonstrate low nM IC50 potency
against all RAS isoforms and all mutants tested, in cell lines of several histologies, and in monolayers and spheroids; inhibit
RAS signaling; induce cell cycle arrest and apoptosis; inhibit binding of GTP to nucleotide-free RAS; bind to the GTP catalytic
domain, in computational structural studies; inhibit mutant RAS-driven tumor growth in vivo ; and demonstrate in vivo
activation of anti-tumor immunity that includes the down-regulation of PD-L1. Over the next 12-18 months we plan to (1) replicate
and expand on the data generated previously by ADT, including further characterization of the biological activity of the compounds;
(2) undertake structural biology investigations to understand the specific mechanism of action and physical basis of the
compounds binding to RAS; and (3) optimize the initially identified series of compounds, including ANC 007, to identify a
lead development candidate for further preclinical and then clinical development. The preclinical work will be primary performed
by a contract research organization(s) (“CRO”), with oversight and strategic guidance by us.
18
We have internally initiated experiments
with ANC 007 and have replicated key cell-based data, including monolayer and spheroid cell viability and colony forming assays,
with results consistent with those generated by ADT for the molecule across multiple cell lines and RAS mutations. This work has
independently confirmed similar potency and selectivity results with ANC 007 to those presented.
A key aspect of developing these compounds
is to gain a detailed understanding of their mechanism of action and binding to RAS. To that end, we have embarked on a suite
of biophysical and structural biology studies, including techniques such as nano differential scanning fluorimetry (nanoDSF),
microscale thermophoresis (MST), protein nuclear magnetic resonance (NMR) and x-ray crystallography to understand specifically
how these compounds bind to the RAS protein. This data will be crucial to understanding how this family of compounds exert their
effect and learnings will be integrated into the medicinal chemistry strategy in order to develop an optimized product candidate.
ANC 007 and related compounds require further optimization in order to identify a suitable clinical candidate. Evaluation of orally
bioavailable candidates will include work up of ADME (absorption, distribution, metabolism, and excretion) profile, in vivo
pharmacokinetic profile and efficacy, as well as initial assessment of in vivo toxicity. From the time of lead candidate
nomination, we anticipate that it will take approximately 12 months to perform IND-enabling studies and submit an IND for First
in Human studies, which we would anticipate to commence in 2022.
Clinical Development Plan and Regulatory Pathway
Clinical development will be initiated
once a lead product candidate has been nominated, all necessary IND-enabling studies have been performed and an IND application
has been successfully submitted to and accepted by the U.S. Food and Drug Administration (“FDA”) and adequate financing
has been secured. Initial Phase 1 clinical investigation will be performed in patients with advanced solid tumors harboring a
RAS mutation, with the objective of identifying a recommended Phase 2 dose and to evaluate the safety and tolerability of the
product candidate, as well as to evaluate preliminary anti-tumor activity. Given the initial clinical activity observed in lung
cancer with the KRAS G12C inhibitors in the clinic, we anticipate that NSCLC may be an area of initial focus, as well as colorectal
and pancreatic cancer (given the prevalence of RAS mutations in these cancers). However, we anticipate that this study would enroll
patients with multiple tumor types as long as a RAS mutation is present.
The clinical development path of other
targeted therapies in genetically defined tumors, such as those with EGFR, ALK, ROS1 and TRK aberrations, suggest that there exists
the opportunity for accelerated clinical development of a RAS inhibitor as well, provided the investigational drug exhibits high
response rate with clinically meaningful duration in a well-defined population with a significant unmet medical need. As in these
prior examples, accelerated approval may be initially granted on the basis of a single well-executed, multi-center single arm,
Phase 2 study (with the potential for different cohorts based on tumor type to support multiple indications in a single study).
Given the clinical proof of concept observed in NSCLC with the G12C inhibitors, we anticipate prioritizing RAS mutant NSCLC patients
previously treated with standard of care ( i.e ., platinum-based chemotherapy/checkpoint inhibitors) as an initial pivotal
cohort. Other potential pivotal cohorts include advanced CRC, after 5-FU/oxaliplatin/irinotecan, and advanced pancreatic adenocarcinoma,
after 5-FU or gemcitabine based therapy. Given the clinical need and the size of the patient population we anticipate this study
would proceed rapidly.
After approval in an initial indication,
we would then pursue indication expansion with additional tumor types, earlier lines of therapy, and combination therapy (including
with chemotherapy, other targeted therapies and checkpoint inhibitors, which have shown potential for synergy with RAS inhibition
preclinically). Beyond initial pivotal cohort considerations, we will investigate RAS mutation in other appropriate tumor types
such as bladder cancer and melanoma, and consider the potential for tumor agnostic indication, particularly in rare tumors and/or
tumor types with infrequent RAS mutations, which is another area with potential for approval based on Phase 2 data. Patients who
have failed G12C-specific inhibitor would also be a defined cohort to evaluate early on—given the hypothesis that resistance
here may be mediated by other RAS isoforms or mutations.
A robust translational medicine effort
is needed as clinical and biomarker data may point to differential activity based on activating mutation or specific RAS gene,
if so development will need to take these considerations into account (patient selection).
19
An appropriately expansive clinical development
plan will contemplate how to move into investigation of first line treatment once activity is observed in the refractory setting.
Confirmatory studies for initial indication(s) can be randomized Phase 3 studies in earlier lines of therapy with standard
of care comparators. This may likely involve investigation of combination therapy, and therefore we plan for early evaluation
of combination safety and preliminary efficacy, based on tumor types showing activity in monotherapy evaluation to potentially
inform confirmatory studies and other indication expansion, depending on tumor type/setting. Combinations may be with chemotherapy,
checkpoint inhibitors and other rational combination partners based on emerging molecular mechanisms of resistance to RAS inhibition.
Beyond first line treatment in the advanced/metastatic
setting, earlier stage disease/adjuvant setting is an exciting space to consider given the potential to significantly alter the
course of disease. Moving targeted therapy into the adjuvant space has been challenging, but success has been seen with checkpoint
inhibition and smart trial design ( e.g. , durvalumab in Stage III NSCLC). These are longer trials compared to metastatic
setting, but the relatively large RAS patient populations ( e.g. , in NSCLC and colorectal cancer) make this attractive/feasible
to consider. Finally, an additional area to consider, based on the preclinical data, is patients with RAS WT tumors with upstream
activation who have failed targeted therapy/standard of care—such as Her2 mutant NSCLC and EGFR mutant NSCLC ( e.g. ,
T790M/C797S ‘triple mutant’).
As mentioned above,
in light of business circumstances and in order to conserve cash and preserve optionality while alternatives are being identified
and assessed, we made a decision during July 2020 to undertake reductions in headcount and other cost saving measures. These
included plans to temporarily reduce our internal and external research and development work on the Company’s RAS Program
until there is greater clarity regarding Anchiano’s ability to fund the program. We continue to undertake actions for the
promotion of the program and its assets and towards strengthening the protection of all related intellectual property.
PDE10/β-catenin Program
Background
Genetic alterations in components that
make up the Wnt signaling pathway, which includes APC and β-catenin, are prevalent in a number of cancer types, occurring
in approximately 90% of colorectal cancers. This translates into approximately 48,000 deaths annually due to colorectal cancer
carrying Wnt/APC/β-catenin pathway mutations in the Unites States alone. Additionally, germline mutations of APC lead to
the hereditary cancer syndrome, FAP, which affects approximately 16,000 additional patients in the United States annually.
Wnt signaling controls the level of intracellular
activated β-catenin, a key effector of oncogenic signal transduction, and oncogenic alterations in Wnt, APC, or β-catenin
all result in elevated and uncontrolled levels of β-catenin. Wnt signaling is initiated upon binding of secreted Wnt ligands
to Frizzled receptors and low-density lipoprotein receptor-related protein (“LRP”) co-receptors, which induces phosphorylation
of Dishevelled (“Dvl”). Phosphorylated Dvl then associates with Axin, leading to dissociation of the β-catenin
destruction complex (which includes APC and GSK3β). Free β-catenin then accumulates in the cytoplasm and translocates
to the nucleus. Mutations which activate the Wnt pathway all culminate in the accumulation of high levels of oncogenic β-catenin
in the cell nucleus. Therefore, we believe a successful intervention in this pathway requires lowering β-catenin levels or
otherwise inhibiting it. β-catenin, a transcription factor, has been considered historically to be an “undruggable”
target, lacking the deep binding pockets present in enzymes and receptors. As a result, drug screening efforts have primarily
focused on other pathway components.
Recent studies have shown that PDE10 is
overexpressed during early stages of tumorigenesis and is essential for tumor cell growth. PDE10 inhibition increases cyclic GMP
levels in tumor cells to activate protein kinase G (PKG) signaling leading to the degradation of the oncogenic pool of β-catenin
to suppress critical proteins essential for tumor cell proliferation and survival. For the foregoing reasons, we believe that
targeting PDE10 provides a novel approach to selectively suppress β-catenin mediated transcriptional activity.
20
Wnt/APC/β-catenin and PDE10 pathways
Adapted from Li et al., Oncogene, 2014
Abbreviations:
5’GMP
=
guanosine
monophosphate
cGMP
=
cyclic
guanosine monophosphate
GTP
=
guanosine
triphosphate
NO
=
nitric
oxide
PDE10
=
phosphodiesterase
type 10
pGC
=
particulate
guanylyl cyclase
PKG
=
protein
kinase G
sGC
=
soluble
guanylyl cyclase
TCF
=
T-cell
factor
Our Approach
Our PDE10/ β-catenin program has identified
small molecule indene derivatives that selectively and potently inhibit PDE10 and suppress Wnt/APC/β-catenin signaling in
preclinical models. PDE10 inhibition has been shown to down regulate β-catenin expression and inhibits polyp and tumor growth.
It has potential for application in the treatment of cancer as well as spontaneous and familial polyposis syndromes. Our orally
available small molecule PDE10 inhibitors have unique advantages over known PDE10 inhibitors with potential for development in
FAP, colon, lung, liver, breast and other cancers.
Inhibition of PDE10 induces cGMP/PKG signaling
to phosphorylate and induce degradation of β-catenin to suppress key proteins essential for tumor cell proliferation and
survival. PDE10 knockdown (“KD”) or inhibition with small molecules inhibits growth and colony formation of colon,
lung, and breast tumor cells.
21
PDE10 overexpression in colon tumor cells; inhibition
blocks colony formation and ß-catenin/Tcf transcription.
Panels:
·
A: Differential PDE10 levels
in normal colonocytes (NCM460) and colon tumor cells as measured by Western blot.
·
B: PDE10 siRNA knockdown
inhibits colony formation of HT29 colon tumor cells.
·
C: PDE10 siRNA suppresses
Tcf transcription of key regulatory genes (e.g., survivin, cyclin D, myc, etc.).
·
D: Treatment of HT29 cells
with PDE10 inhibitor ANC 094 (also referred to as ADT-094) leads to reduction of ß-catenin and products of Tcf transcription
as measured by Western blot.
Source:
Li et al., Oncogene, 2015; Data on File .
One representative compound in this program,
ANC 061 (also referred to as MCI-030) inhibits PDE10 to activate cGMP/PKG signaling, resulting in the phosphorylation and degradation
of the oncogenic pool of β-catenin to selectively inhibit the growth of colon tumor cells in vitro. Oral administration to
mice with the Apc+/min-FCCC genotype (a mouse strain with the APC mutation that produces an augmented incidence of colorectal
adenomas and small intestinal cancers, used as a model to study polyposis syndromes and colon cancer) significantly inhibited
incidence and multiplicity of colon adenomas and carcinomas in a dose-dependent fashion. Further in vivo studies with ANC
061 are in progress at Fox Chase Cancer Center to confirm these findings. These studies are funded by NCI, and if proof of concept
is established there is the potential to further develop this compound in FAP in collaboration with NCI through its PREVENT Cancer
Preclinical Drug Development Program.
22
Inhibition of Colon Tumorigenesis in the Apc Min
Model
Panels:
·
A,
ANC 061 (MCI-030) induced a dose dependent decrease in adenoma incidence from 94.74% in control mice to 76.19% in mice treated
with 1000 parts per million (ppm) ANC 061 and 57.80% of mice treated with 1500 ppm ANC 061.
·
B,
Adenoma multiplicity was also significantly reduced from 4.0 in the control group to 2.9 in mice treated with 1000 ppm ANC
061, and to 1.95 in mice treated with 1500 ppm ANC 061.
·
C,
A reduction in micro adenomas was also observed.
·
D,
Multiplicity of flat adenomas was abolished in mice receiving 1500 ppm and reduced in mice treated with 1000 ppm ANC 061 from
0.32 per mouse in the control group to 0.24, respectively.
·
E, Incidence
of mice with cancer was reduced from 10.53% in the vehicle group to 4.76% in mice treated with 1000 ppm ANC 061 and to 0%
in mice treated with 1500 ppm ANC 061, n=19-21.
Source: Ward et al., AACR 2019.
Another compound in this program, ANC 030
(also referred to as MCI-048) administered orally inhibits tumor growth in an orthotopic lung cancer mouse model without apparent
toxicity. ANC 030 significantly extends survival in the A549 mouse model from a median 44 to 77 days with 25% of mice surviving
until the end of the experiment. It was also effective in multiple other mouse models of lung and breast cancer, including models
of metastasis.
23
Inhibits Lung Tumorigenesis in A549 Lung Cancer Model
Panels:
·
A, The A549 human lung
adenocarcinoma cells with luciferase (Luc) tag were generated using lentiviral particles expressing luciferase gene driven
by a CMV promoter and a stable A549Luc clone was selected. Female athymic nude mice were implanted with 1x10 6 A549Luc
cells intrathoracically. Mice were treated by oral gavage once a day with the vehicle (Maalox) or MCI-048 at doses of
25, 50, or 100 mg/kg (n = 7/group) starting five days before tumor cell implantation. After implantation, treatment
continued for 4 additional weeks. Tumor growth was monitored weekly through the detection of the bioluminescence of
the A549Luc cells using In Vivo Imaging System (IVIS, IVIS Spectrum, Caliper Life Sciences). Signal intensity was quantified
as the average number of photons emitted from a mouse within the chest cavity (Living Image software, version 4.3.1.)
·
B, Female athymic nude
mice were implanted with 1x10 6 cells per mouse of cultured A549 human lung adenocarcinoma cells into the intrathoracic
space of the left lung on Day 0. Animals were randomly assigned to two treatment groups (n=15) on Day 1 and treated
with either MCI-048 formulated in Maalox by oral gavage at a dose of 100 mg/kg once daily for 8 weeks or with Maalox using
the same schedule starting on Day 1. All surviving mice were euthanized on Day 151.
Source: Zhu et al. AACR 2019
24
Preclinical Development
We initiated development of a series of
compounds that exhibit potent PDE10 inhibition and induce degradation of β-catenin to suppress key proteins essential for
tumor cell proliferation and survival. Initial plans for continued preclinical development will be funded with ADT using SBIR
grants to ADT. While we are excited by the potential for this program, we have made the decision to initially prioritize advancement
of our pan-RAS program. Once a product candidate has been nominated for IND-enabling studies in the pan-RAS program, we plan to
allocate resources for development of the PDE10/ β-catenin program. We estimate approximately six months will be necessary
from that time for lead optimization and product candidate nomination. From lead candidate nomination, we anticipate approximately
12 months to perform IND enabling studies and submit an IND for First in Human studies. Development of the program could potentially
be accelerated with additional resources.
Clinical Development Plan and Regulatory Pathway
Clinical development will be initiated
once a lead product candidate has been nominated, all necessary Investigational New Drug (IND) enabling studies have been performed
and an IND application has been successfully submitted to and accepted by the USA. Initial Phase 1 clinical investigation in cancer
will be performed in patients with advanced solid tumors, focusing on tumor types where the Wnt/APC/β-catenin pathway is
implicated such as colorectal cancer, hepatocellular carcinoma, breast cancer and lung cancer, with the objective of identifying
a recommended Phase 2 dose and to evaluate the safety and tolerability of the product candidate, as well as to evaluate preliminary
anti-tumor activity. We anticipate that colorectal cancer may be an initial indication of focus in pivotal development, given
the prominence of the Wnt/APC/β-catenin pathway in this disease. Subsequent development will be dependent on the signs of
activity observed. If efficacy data allows (i.e. high response rate with meaningful duration of response in an indication of high
unmet need), an accelerated approval path based on Phase 2 data may be considered. If not, a more traditional approach with a
randomized Phase 3 program comparing to standard of care treatment will be required.
A separate development path in FAP may
also be pursued. This would initiate with a Phase 1 dose escalation study in healthy volunteers (single dose) and FAP patients
(multiple dose). A randomized Phase 3 program in patients with FAP is anticipated to be required for registration.
As mentioned above,
in light of business circumstances, and in order to conserve cash and preserve optionality while alternatives are being identified
and assessed, we made a decision during July 2020 to undertake reductions in headcount and other cost saving measures. These
included plans to temporarily reduce our internal and external research and development work on the Company’s PDE10/β-catenin
Programs until there is greater clarity regarding Anchiano’s ability to fund the program. We continue to undertake actions
for the promotion of the program and its assets and towards strengthening the protection of all related intellectual property.
Collaborations and License Agreements
ADT
In September 2019, we entered into
the Collaboration Agreement with ADT pursuant to which we agreed to use commercially reasonable efforts to conduct research and
development activities with respect to the pan-RAS and PDE10/β-catenin programs under the oversight of a steering committee
jointly established with ADT. ADT is a private company focused on discovering, developing and securing patent protection for novel
molecules that inhibit activated RAS- or Wnt-mediated signaling pathways that drive the growth of many human cancers. ADT’s
technology currently comprises a broad, novel proprietary small-molecule class, encompassing at least two distinct mechanistic
subclasses that share a common chemical core; one subclass targets RAS and the other subclass inhibits PDE10 to activate cGMP/PKG
signaling and induce degradation of the oncogenic pool of β-catenin.
Under the terms of the Collaboration Agreement,
we were granted an exclusive option to license the RAS and PDE10/β-catenin programs in exchange for a $3.0 million upfront
payment to ADT and will fund certain research activities. At any time through obtaining an IND designation, we will have the option
to exclusively license the compounds we develop worldwide and will be responsible for all aspects of preclinical and clinical
development and global commercialization. If we exercise our option, we will pay ADT an option exercise fee and will be responsible
for development and commercialization of any compounds or products containing any compounds under the pan-RAS and PDE10/ß-catenin
programs. We will also incur additional payment obligations to ADT for any product candidates developed under the pan-RAS and
PDE10/ß-catenin programs, including milestone payments based on certain events with respect to product development and regulatory
achievements, and royalty payments based on net sales of any commercialized products. We are responsible for all aspects of development
for the pan-RAS and PDE10/ß-catenin programs. We also have the option to sublicense the licenses granted to us by ADT.
25
In connection with the Collaboration Agreement,
we also entered into a Consulting and Collaboration Research Support Agreement with ADT (the “Support Agreement”),
whereby ADT provides support services for our research and development activities with respect to the pan-RAS and PDE10/ß-catenin
programs, including providing key research and discovery personnel, in exchange for a fee.
ADT may terminate the Collaboration Agreement
in the event of a material default in any of our material obligations under the Collaboration Agreement (following a cure period).
In the event the Collaboration Agreement is terminated, all licenses and options granted to us will be terminated and we will
not be able to develop the compounds under the pan-RAS and PDE10/ß-catenin programs or any products containing such compounds.
The Collaboration Agreement also restricts assignment except to a successor of substantially all of the business to which the
Collaboration Agreement relates, whether in a merger, sale of stock, sale of assets, reorganization or other transaction.
Yissum
On November 14, 2005, we entered into
the License Agreement with Yissum, which was subsequently amended several times, most recently in November 2013. Yissum granted
us an exclusive, worldwide license for the development, use, manufacture and commercialization of products arising out of patents
owned by, and patent applications filed by Yissum in connection with the H19 and IGF2-P4 genes. Yissum retained right, title and
interest in the products, technologies or other inventions arising out of our research and development of these patents and patent
applications, except for intellectual property developed with funding from the Israel Innovation Authority (“IIA”),
which will be owned by us and transferred to Yissum only upon our dissolution or termination of the License Agreement or upon
a decision by the IIA that it no longer requires us to own the intellectual property developed with its funding. We have the right
to grant sub-licenses to third parties in accordance with the terms set forth in the License Agreement.
In November 2019, we discontinued
the pivotal Phase 2 Codex study, evaluating the gene therapy inodiftagene in patients with BCG-unresponsive NMIBC. After a thorough
analysis of the data, we determined that there was a low probability of surpassing the pre-defined futility threshold at the planned
interim analysis, which required 10 complete responses in 35 patients. At the time we discontinued the study, 16 patients were
evaluable after the first disease assessment on treatment, of which three patients, or 19%, had experienced a complete response.
The data also indicated a low probability of achieving an efficacy profile that in the company’s estimation would be necessary
to support regulatory approval. The safety data on the investigational product were consistent with those observed in prior trials.
In April 2020 we notified Yissum that
as a result of our decision to discontinue clinical development of inodiftagene, we will cease payments to maintain intellectual
property (“IP”) we licensed from Yissum that supported the development and as related to the License Agreement. In
August 2020 we agreed with Yissum on termination of the License Agreement, we destroyed or returned all IP documentation
to Yissum, and Yissum and we mutually waived, released and discharged the other from all claims of any type.
26
Our Competitive Strengths
Our technologies are small molecule targeted
therapies that are directed against two pathways that have been long understood to contribute fundamentally to the pathogenesis
of human cancer, the RAS pathway and the Wnt/APC/β-catenin biochemical pathway. We are initially focusing on our pan-RAS
program, and we are developing compounds that exhibit pan-RAS cytotoxicity.
We believe we can develop these compounds
into product candidates, and that our competitive strengths put us in a unique position for success if we pursue the path towards
further development after the review of strategic alternatives, as follows:
·
Our product candidates are targeted therapies.
We believe that the application of small molecule targeted therapy approaches to pan-RAS inhibition has a high
likelihood of success. The development of small molecule targeted therapies against the products of mutated driver oncogenes
is one of the most productive endeavors in the field of cancer therapy. Mutated driver oncogenes cause cancer cell proliferation,
the first and most fundamental hallmark of cancer. The RAS genes are the most common example of such mutated driver oncogenes.
These cancer genes have been identified by natural selection as being critical drivers of malignant proliferation and they
are prime therapeutic targets. This potential for therapeutic exploitation has in turn been coupled with progress in physical
methods and chemical engineering that allow the design of small molecules that directly inhibit the function of the key mutated
driver genes. This approach has resulted in successful therapies for cancers whose genetic alterations include mutations in
a variety of oncogenes. An important observation from this field is that, in general, preclinical data, both in vitro
and in vivo , have been very strongly predictive for the development of these therapies. If the physical inhibition
of the target molecule can be established and characterized by structural, chemical and biochemical methods and the target
gene is a mutated positively acting driver gene, then preclinical activity correlates strongly with clinical activity. The
RAS family of genes are driver oncogenes, the most commonly mutated oncogenes known. We believe that our existing preclinical
data demonstrating and characterizing small molecule pan-RAS inhibition forms the foundation for development of these molecules
into product candidates that can be used in clinical settings.
·
Our molecules are first-in-class molecules.
There are no small molecule targeted therapies that have successfully been shown to exhibit pan-RAS inhibitory
activity, and whose mechanism of action involves direct inhibition of RAS. A variety of approaches to RAS inhibition have
been tested, including interference with the intracellular localization and processing of RAS, inhibition of its binding to
other signaling molecules, and other approaches. Current clinical–stage investigational drugs, such as AMG-510, have
been shown to bind to and directly inhibit the KRAS G12C mutation, a subset of mutant RAS proteins. KRAS is one of 3 RAS family
genes, and approximately 9% of RAS mutations are KRAS G12C mutations. To our knowledge, no other pan-RAS inhibitors like our
molecules are currently being tested.
·
Our preclinical data strongly support
the activity of our molecules against cancer. The characteristics one would predict in molecules with preclinical
pan-RAS inhibitory activity include: selectivity for activated RAS; nanomolar potency against cells harboring mutant RAS;
consistency of biochemical data with RAS inhibition (as opposed to other pathway points of inhibition); evidence for binding
RAS directly; in vivo anti-tumor activity; and immunological stimulation in vivo consistent with other clinical
RAS inhibitors. Our small molecule inhibitors have been demonstrated to have these characteristics, and we believe we can
develop our molecules into product candidates that will have potential for pan-RAS inhibition in a variety of clinical settings.
27
·
Recent data have validated cancer treatment
with a RAS inhibitor. Until recently, the unique biochemistry and biology of the RAS gene family had resisted
efforts of cancer biologists to discover and develop drugs capable of inhibiting the activity of the mutated protein. However,
recent developments have led to the discovery of small molecules capable of inhibiting a particular mutated form of RAS, known
as KRAS G12C. Preliminary successes of drugs under development such as AMG-510 and MRTX849, are field-altering, as for the
first time there is evidence that inhibition of mutated RAS isoforms may be undertaken in the same manner as other successful
small molecule targeted therapies had shown possible against other mutated oncogenes. In other words, RAS is a clinically
validated target susceptible to small-molecule targeted therapy approaches.
·
Our development plan addresses substantial
unmet needs. Despite the preliminary success demonstrated by AMG 510 and MRTX849, KRAS is only one of three
mutated isoforms of the RAS gene family, comprising approximately 85% of RAS mutations, and only approximately 11% of KRAS
mutations are of the G12C type. A number of tumor types have large proportions of mutations in other RAS isoforms. Melanoma
exhibits mutations in RAS in approximately 30% of cases, almost all of which are in NRAS. Of the 55% of colorectal cancers
that carry RAS mutations, 5% are NRAS. Approximately half of the mutations in multiple myeloma are in NRAS. The RAS mutations
in thyroid cancer and acute myeloid leukemia are predominantly NRAS (approximately 5-15% (depending on sub-type) and 15% respectively)
. Bladder and head and neck cancers carry largely HRAS mutations. This means that while recent observations have proven that
RAS-directed therapy using small molecule inhibitors is possible with clinical effect, results so far are confined to a small
subset of patients carrying a particular mutation. In a larger sense, even though preliminary success has been demonstrated
by KRAS G12C mutation inhibitors, at this time there are no approved inhibitors of mutated RAS in cancers that carry these
genetic lesions. We believe there is much potential for broader treatment of RAS-mutated tumors, for treatment of tumors that
have become resistant after KRAS G12C mutation-inhibitor therapy, for earlier line treatment and for combination therapy,
and we believe that we can develop our molecules into product candidates capable of potentially meeting these broader needs.
Intellectual Property
While our policy is to obtain patents by
application, license or otherwise, to maintain trade secrets and to seek to operate without infringing on the intellectual property
rights of third parties, technologies related to our business have been rapidly developing in recent years. Additionally, patent
applications that we may file or license from third parties may not result in the issuance of patents, and our current or future
issued patents may be challenged, invalidated or circumvented. Therefore, we cannot predict the extent of claims that may be allowed
or enforced against our patents, nor be certain of the priority of inventions covered by pending third-party patent applications.
If third parties prepare and file patent applications that also claim technology or therapeutics to which we have rights, we may
have to engage in proceedings to determine priority of invention, which could result in substantial costs to us, even if the eventual
outcome is favorable. Moreover, because of the extensive time required for clinical development and regulatory review of products
we may develop, it is possible that the patent or patents on which we rely to protect such products could expire or be close to
expiration by the commencement of commercialization, thereby reducing the value of such patent. Loss or invalidation of certain
of our patents, or a finding of unenforceability or limited scope of certain of our intellectual property, could have a material
adverse effect on us. See “ Risk Factors—Risks Related to Our Intellectual Property and Potential Litigation .”
28
In addition to patents, we rely on trade
secrets and know-how to develop and maintain our competitive position. Trade secrets and know-how can be difficult to protect.
We seek to protect our proprietary processes, in part, by confidentiality agreements and invention assignment agreements with
our employees, consultants, scientific advisors, contractors and commercial partners. These agreements are designed to protect
our proprietary information. We also seek to preserve the integrity and confidentiality of our data, trade secrets and know-how
by maintaining physical security of our premises and physical and electronic security of our information technology systems. While
we have confidence in these individuals, organizations and systems, such agreements or security measures may be breached, and
we may not have adequate remedies for any breach. In addition, our trade secrets may otherwise become known or be independently
discovered by competitors or others.
Pan-RAS and PDE10/β-catenin Program Patents
Pursuant
to the Collaboration Agreement, we have been granted an exclusive option to license patent rights for our pan-RAS and PDE10/ b -catenin
programs. This patent portfolio includes three issued U.S. patents, 2 issued Japanese patents, and one issued patent in each of
China, Australia, Europe and Hong Kong directed to RAS inhibitor compounds, prodrugs and methods of use. In addition to this we
have two pending related U.S. patent applications directed to RAS and PDE10 inhibitor compounds and corresponding foreign pending
counterpart patent applications, and one Patent Cooperation Treaty (“PCT”) patent application directed to RAS inhibitor
compounds. The issued patents, and pending U.S. patent applications, if issued, will expire in 2035. We expect any patents based
on the PCT application, if we continue to pursue patent protection in the United States and elsewhere, if issued, to expire in
2039.
Additional Technologies
·
BC-821  - Our licensed
patent portfolio includes two issued U.S. patents directed to composition of matter and method of use, and related issued
foreign patents and patent applications. We expect these patents and patent application, if issued, to expire between 2028
and 2029.
·
Cancer-Specific TNF-α and DTA mutual
expression vector  - Our licensed patent portfolio includes one U.S. patent directed to nucleic acid
vectors and related issued foreign patents. We expect these patents to expire in 2026.
·
H19 targeted siRNA for cancer  - Our
licensed patent portfolio includes one issued U.S. patent directed to composition of matter, and related foreign patents.
We expect these patents to expire in 2026.
·
H19 targeted siRNA for rheumatoid arthritis  -
Our licensed patents include one issued U.S. patent directed to methods for treating rheumatoid arthritis, and related foreign
patents. We expect these patents to expire in 2028.
Marketing, Sales and Distribution
Given our stage of development, we do not
have any internal sales, marketing or distribution infrastructure or capabilities. In the event we receive regulatory approval
for a future product candidate and secure adequate funding, we intend, where appropriate, to consider commercialization relationships.
In addition, we may consider out-licensing some or all of our worldwide patent rights to more than one party to achieve the fullest
development, marketing and distribution of any future product we develop.
29
Competition
Competition in the development of human
cancer therapeutics, in particular targeted therapies, is intense and rapidly evolving. We face competition both in the United
States and internationally from small and large private and publicly traded biotechnology and pharmaceutical companies, government
agencies, universities and other research institutions. Many of our competitors have substantially greater resources and capabilities,
in the form of financing, development, manufacturing, and commercialization, than we do. Our ability to create value for our shareholders
depends on our ability to successfully develop product candidates that have differentiated benefits from competing drugs and biologics,
that are either in development or commercially available. While we believe our approach, expertise, focus and intellectual property
provide us with a competitive advantage, we are aware of several companies that inhibit the same molecular target, and in some
cases in the same population, being pursued by us. We believe our primary competitors by program and target are as follows:
Pan-RAS
Program : We are not aware of any competitors with development programs or molecules in clinical testing that target
mutations across all three RAS family of genes (HRAS, KRAS, and NRAS). We are aware of several competitors with clinical and preclinical
development programs that directly target one or more mutations in KRAS family of genes, including Mirati Therapeutics, Inc.,
Amgen, Inc., Boehringer Ingelheim AG, Merck & Co., Inc., and others. It is likely that other companies are
also researching inhibitors in the HRAS and NRAS families of genes. We will continue to monitor scientific and patent publications
for the emergence of other potential competitors.
PDE10/β-catenin
Program : We are aware of several companies that have PDE10 inhibitor programs in preclinical or clinical development,
including among others, H. Lundbeck A/S, Omeros Corporation, and Celon Pharma SA –mainly focused on CNS indications. Likewise,
we are aware of several companies that have β-catenin inhibitor program in preclinical or clinical development, including
among others, PRISM Pharma Co., Ltd, and Fog Pharmaceuticals, Inc. We will continue to monitor scientific and patent publications
for the emergence of other potential competitors.
Government Regulation
We are subject to extensive regulation
by the various national health regulatory authorities, such as the FDA, Health Canada and other national, state and provincial
regulatory agencies.
U.S. Food and Drug Administration
The research, development, and marketing
authorization of drugs and other pharmaceutical products in the United States is subject to the Federal Food, Drug, and Cosmetic
Act (the “FFDCA”), which empowers the FDA to require extensive non-clinical and clinical toxicity testing before a
new drug or biologic is deemed safe and effective and receives marketing authorization. Following initial laboratory and animal
testing that show that investigational use in humans is reasonably safe, a drug can be studied in clinical trials in humans under
an IND in accordance with the regulations at 21 CFR 312.
In order to satisfy FDA data requirements,
an extensive battery of preclinical experiments to assess the safety of such new drugs are conducted, followed by two or three
phases of clinical trials before they are considered for widespread human use. Upon successful completion of a future clinical
trial program, we may be in a position to manufacture and market our prospective pharmaceutical products. The marketing authorization
of our products would be conditional upon obtaining the approval of health authorities in each country in which they would be
marketed, including, but not limited to, the FDA and the EMA. FDA regulations govern the following activities that we may perform,
or that have been performed on our behalf, to ensure that drugs that we develop are safe and effective for their intended uses:
30
·
preclinical (animal)
testing including toxicology studies;
·
submission of an
IND;
·
human testing in
clinical trials, Phases 1, 2 and 3;
·
recordkeeping and
retention;
·
pre-marketing review
through submission of a new drug application (“NDA”);
·
drug manufacturing,
testing and labeling, which must comply with current good manufacturing practice (“cGMP”) regulations;
·
drug marketing,
sales and distribution; and
·
post-marketing study
commitments (Phase 4), post-marketing pharmacovigilance surveillance, complaint handling, reporting of deaths or serious injuries,
product sample retention, manufacturing deviation reporting and repair or recall of drugs.
Failure to comply with
applicable regulatory requirements can result in enforcement action by the FDA, which may include any of the following sanctions:
·
warning letters,
untitled letters, fines, injunctions, consent decrees and civil penalties;
·
disqualification
of clinical investigator and/or sponsor from current and future studies;
·
clinical hold on
clinical trials;
·
operating restrictions,
partial suspension or total shutdown of production;
·
refusal to approve
an NDA;
·
post-marketing withdrawal
of approval; and
·
criminal
prosecution.
The FDA’s preclinical and IND requirements
The first step to obtaining FDA approval
of a new drug involves development, purification and pre-clinical testing of a pharmaceutically active agent in laboratory animals.
Once appropriate preclinical data have been generated to demonstrate that the drug is reasonably safe for initial testing in humans,
an IND can be prepared and submitted to the FDA for review. In the IND review process, FDA physicians and scientists evaluate
the proposed clinical trial protocol, chemistry and manufacturing controls, pharmacologic mechanisms of action of the drug and
toxicological effects of the drug in animals and in vitro . Within 30 days of the IND submission, the drug review division
of the FDA may contact the filer regarding potential concerns and, if necessary, implement a clinical hold until certain issues
are resolved satisfactorily. If the FDA does not take any action, the filer may proceed with clinical trials on the 31st day.
Clinical trials
Clinical trials represent the pre-market
testing ground for unapproved drugs, generally taking several years to complete. Before testing can begin, an institutional review
board (“IRB”) must have been reviewed and approved for the use of human subjects in the clinical trial. During clinical
trials, an investigational compound is administered to humans and evaluated for its safety and effectiveness in treating, preventing
or diagnosing a specific disease or condition. The clinical trials generally consist of Phase 1, Phase 2, and Phase 3 testing.
During clinical trials, the FDA and IRBs closely monitor the studies and may suspend or terminate trials at any time for a number
of reasons, such as finding that patients are being exposed to an unacceptable health risk. The results of clinical trials are
critical factors in the approval or disapproval of a new drug.
31
Submission and review of an NDA
An NDA requesting approval to market the
drug for one or more indications may be submitted to the FDA once sufficient data has been gathered through preclinical and clinical
testing. The application includes all relevant data available from pertinent preclinical and clinical trials, including negative
or ambiguous results as well as positive findings, together with detailed information relating to the drug’s chemistry,
manufacturing, controls and proposed labeling, among other things. In most cases, the submission of an NDA is subject to a substantial
application fee.
The FDA has 60 days from its receipt of
an NDA to determine whether the application will be accepted for filing based on the agency’s threshold determination that
it is sufficiently complete to permit substantive review. Once the NDA submission is accepted for filing, the FDA begins an in-depth
substantive review. NDAs receive either standard or priority review. The FDA has a goal of ten months from the date of filing
to review and act on a standard NDA for a new molecular entity. A drug representing a significant improvement over existing therapy
in the treatment, prevention or diagnosis of a disease may receive priority review.
The FDA has various specific programs,
including Fast Track, Breakthrough Therapy, Accelerated Approval and Priority Review, each of which is intended to expedite the
process for reviewing drugs, and in certain cases involving Accelerated Review, permit approval of a drug on the basis of a surrogate
endpoint. Even if a drug qualifies for one or more of these programs, the FDA may later decide that the drug no longer meets the
conditions for qualification or that the time period for FDA review or approval will be shortened. Fast Track designation facilitates
the development and expedites the review of drugs to treat serious or life-threatening diseases or conditions and fill unmet medical
needs. Although this designation does not affect the standards for approval, the FDA will attempt to facilitate early and frequent
meetings with a sponsor of a Fast Track designated drug.
The FDA reviews an NDA to determine, among
other things, whether the drug is safe and effective and whether the facility in which it is manufactured, processed, packaged
or held meets standards designed to assure the product’s continued safety, quality and purity. The review process is often
significantly extended by FDA requests for additional information or clarification. The FDA may refer the application to an advisory
committee for review, evaluation and recommendation as to whether the application should be approved. The FDA is not bound by
the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.
Before approving an NDA, the FDA typically
will inspect the facility or facilities where the drug is manufactured. The FDA will not approve an application unless it determines
that the manufacturing processes and facilities are in compliance with cGMP requirements and are adequate to assure consistent
production of the drug within required specifications. In addition, before approving an NDA, the FDA will typically inspect one
or more clinical trial sites to assure compliance with good clinical practice requirements.
After evaluating the NDA and all related
information, including the advisory committee recommendation, if any, and inspection reports regarding the manufacturing facilities
and clinical trial sites, the FDA may issue an approval letter, or, in some cases, a complete response letter. A complete response
letter generally contains a statement of specific conditions that must be met in order to secure final approval of the NDA and
may require additional clinical or preclinical testing for the FDA to reconsider the application. Even with submission of this
additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.
If and when those conditions have been met to the FDA’s satisfaction, the FDA will typically issue an approval letter. An
approval letter authorizes commercial marketing of the drug with specific prescribing information for specific indications.
If a product receives regulatory approval,
the approval may be significantly limited to specific diseases, subpopulations, and dosages or the indications for use may otherwise
be limited, which could restrict the commercial value of the product. In addition, the FDA may require us to conduct Phase 4 testing,
which involves clinical trials designed to further assess a drug’s safety and/or effectiveness after NDA approval and may
require testing and surveillance programs to monitor the safety of approved products which have been commercialized.
32
Pervasive and continuing regulation in the United States
After a drug is approved for marketing
and enters the marketplace, numerous regulatory requirements continue to apply. These include, but are not limited to:
·
The
FDA’s cGMP regulations require manufacturers, including third-party manufacturers, to follow stringent requirements
for the methods, facilities and controls used in manufacturing, processing, testing and packing of a drug product;
·
Labeling
regulations and the FDA prohibitions against the promotion of drug for unapproved uses (known as off-label uses), as well
as requirements to provide adequate information on both risks and benefits during promotion of the drug;
·
Approval
of product modifications or use of the drug for an indication other than approved in the NDA;
·
Adverse
drug experience regulations, which require companies to report information on rare, latent or long-term drug effects not identified
during pre-market testing;
·
Post-market
testing and surveillance requirements, including Phase 4 trials, when necessary, to protect the public health or to provide
additional safety and effectiveness data for the drug; and
·
The
FDA’s recall authority, whereby it can ask, or under certain conditions order, drug manufacturers to recall from the
market a product that is in violation of governing laws and regulations.
After a drug receives approval, any modification
in conditions of use, active ingredient(s), route of administration, dosage form, strength or bioavailability, will require a
new clearance or approval, for which it may be possible to submit a supplemental NDA, referring to preclinical and certain clinical
studies presented in the drug’s original NDA, accompanied by additional clinical data necessary to demonstrate the safety
and effectiveness of the product with the proposed changes. Additional clinical studies may be required for proposed changes.
Fraud and abuse laws in the United States
A variety of U.S. federal and state laws
apply to the sale, marketing and promotion of drugs that are paid for, directly or indirectly, by U.S. federal or state healthcare
programs such as Medicare and Medicaid. The restrictions imposed by these laws are in addition to those imposed by the FDA, the
U.S. Federal Trade Commission and corresponding state agencies. Some of these laws significantly restrict or prohibit certain
types of sales, marketing and promotional activities by drug manufacturers. Violation of these laws may result in significant
criminal, civil and administrative penalties, including imprisonment of individuals, fines and penalties and exclusion or debarment
from United States federal and state healthcare and other programs. Many private health insurance companies also prohibit payment
to entities that have been sanctioned, excluded or debarred by U.S. federal agencies.
Anti-kickback statutes in the United States
The U.S. federal anti-kickback statute
prohibits, among other things, persons from knowingly and willfully soliciting, offering, receiving or providing remuneration,
directly or indirectly, in exchange for or to induce either the referral of an individual, or the furnishing, arranging for or
recommending of a good or service, for which payment may be made in whole or in part under a United States federal healthcare
program such as the Medicare and Medicaid programs. The definition of “remuneration” has been broadly interpreted
to include anything of value, including gifts, discounts, the furnishing of supplies or equipment, payments of cash and waivers
of payments. Several courts have interpreted the statute’s intent requirement to mean that, if any one purpose of an arrangement
involving remuneration is to induce referrals or otherwise generate business involving goods or services reimbursed in whole or
in part under federal healthcare programs, the statute has been violated. Penalties for violations include criminal penalties
and civil sanctions such as fines, imprisonment and possible exclusion from Medicare, Medicaid and other U.S. federal healthcare
programs. In addition, some kickback allegations have been claimed to violate the U.S. False Claims Act (as discussed below).
33
The federal anti-kickback statute is broad
and prohibits many arrangements and practices that are lawful in businesses outside of the healthcare industry. Recognizing that
the statute is broad and may technically prohibit many innocuous or beneficial arrangements, the Office of Inspector General of
the Department of Health and Human Services (“OIG”) has issued a series of regulations, known as “safe harbors.”
These safe harbors set forth provisions which, if met in form and substance, will assure healthcare providers and other parties
that they will not be prosecuted under the federal anti-kickback statute. The failure of a transaction or arrangement to fit precisely
within one or more safe harbors does not necessarily mean that it is illegal or that prosecution will be pursued. However, conduct
and business arrangements that do not fully satisfy an applicable safe harbor may result in increased scrutiny by government enforcement
authorities such as the OIG or the United States Department of Justice.
Many states have adopted laws similar to
the U.S. federal anti-kickback statute. Some of these state prohibitions are broader than the U.S. federal statute, and apply
to the referral of patients and recommendations for healthcare items or services reimbursed by any source, not only the Medicare
and Medicaid programs. Government officials have focused certain enforcement efforts on marketing of healthcare items and services,
among other activities, and have brought cases against individuals or entities with sales personnel who allegedly offered unlawful
inducements to potential or existing physician customers in an attempt to procure their business.
U.S. False Claims Act
The U.S. False Claims Act prohibits any
person from knowingly presenting, or causing to be presented, a false or fraudulent claim for payment by a federal healthcare
program or knowingly making, or causing to be made, a false statement or record in order to have a false claim paid or avoiding,
decreasing or concealing an obligation to pay money to the federal government. The federal government’s interpretation of
the scope of the law has in recent years grown increasingly broad. Most states also have statutes or regulations similar to the
U.S. False Claims Act, which apply to items and services reimbursed under Medicaid and other state programs, or, in several states,
apply regardless of the payor. Sanctions under these federal and state laws may include civil monetary penalties, exclusion of
a manufacturer’s products from reimbursement under government programs, criminal fines and imprisonment. Several drug manufacturers
have been prosecuted under the false claims laws for allegedly providing free drugs to physician customers with the expectation
that the physician customers would bill federal programs for the product. In addition, several recent cases against drug manufacturers
have alleged that the manufacturers improperly promoted their products for “off-label” use, outside of the scope of
the FDA-approved labeling.
U.S. Health Insurance Portability and Accountability
Act of 1996 (HIPAA)
HIPAA created a new federal healthcare
fraud statute that prohibits knowingly and willfully executing a scheme to defraud any healthcare benefit program, including private
payors. A violation of this statute is a felony and may result in fines, imprisonment or exclusion from government-sponsored programs.
Among other things, HIPAA also imposes new criminal penalties for knowingly and willfully falsifying, concealing or covering up
a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment
for healthcare benefits, items or services, along with theft or embezzlement in connection with a healthcare benefits program
and willful obstruction of a criminal investigation involving a federal healthcare offense. Further, HIPAA, as amended by the
Health Information Technology for Economic and Clinical Health Act of 2009, or HITECH, and their respective implementing regulations,
which also imposes certain obligations, including mandatory contractual terms, with respect to safeguarding the privacy and security
of individually identifiable health information of covered entities subject to the rule, such as health plans, healthcare clearinghouses
and certain healthcare providers as well as their business associates, independent contractors of a covered entity that perform
certain services involving the use or disclosure of individually identifiable health information on its behalf and their subcontractors
that use, disclose, access, or otherwise process individually identifiable health information.
34
U.S. Affordable Care Act Section 6002 (the Sunshine
Act)
Enacted in 2010 under the Affordable Care
Act of 2010, Public Law No. 111-148 (the “ACA”), the Physician Payments Sunshine Act is a national disclosure
program that promotes transparency by publishing data on the financial relationships between the healthcare industry (applicable
manufacturers) and healthcare providers (physicians and teaching hospitals) on a publicly accessible website. The Sunshine Act
requires that certain manufacturers of drugs, devices, biologicals, or medical supplies report payments or other transfers of
value made to physicians (defined to include doctors, dentists, optometrists, podiatrists, and chiropractors) and teaching hospitals
as well as certain ownership or investment interests held by physicians or their immediate family members to the Centers for Medicare &
Medicaid Services (CMS). Beginning in 2022, applicable manufacturers will also be required to report information regarding payments
and other transfers of value provided during the previous year to physician assistants, nurse practitioners, clinical nurse specialists,
certified nurse anesthetists, anesthesiologist assistants, and certified nurse-midwives. A violation of this act may result in
fines and/or civil liabilities. Any payment or transfer of value that is currently prohibited under the anti-kickback statute,
the U.S. False Claims Act, or other health care fraud and abuse laws may still be subject to fines, sanctions, or lawsuit.
Non-U.S. regulation
Marketing authorization requests outside
of the United States are subject to regulatory approval of the respective authorities in the country in which we would like to
market. The requirements governing the conduct of clinical trials, product licensing, pricing and reimbursement vary widely from
country to country. No action can be taken to market any product in a country until an appropriate application has been approved
by the regulatory authorities in that country. The current approval process varies from country to country, and the time spent
in gaining approval varies from that required for FDA approval. In certain countries, the sales price of a product must also be
approved prior to its marketing application approval. The pricing review period often begins after market approval is granted.
Even if a product is approved by a regulatory authority, satisfactory prices might not be approved for such product. In the European
Union, authorization can be obtained through one of the following pathways: (i) the “centralized” procedure,
described in greater detail below, with applications made directly to the EMA leading to the grant of a European marketing authorization
by the European Commission, (ii) the “decentralized procedure,” whereby companies may apply for simultaneous
authorization in more than one EU country of medicinal products that have not yet been authorized in any EU country, or do not
fall within the mandatory scope of the centralized procedure, (iii) the “mutual recognition” procedure, in which
applications are made to one or more member states, leading to national marketing authorizations mutually recognized by other
member states, or (iv) a “national authorization” application made to a single EU member state. Based on the
nature of our products, the marketing authorization will be through the centralized procedure.
The EMA is responsible for the centralized
procedure, which results in a single marketing authorization that is valid across the European Union. Applications through the
centralized procedure are submitted directly to the EMA. The procedure consists of three milestones:
(i)
Evaluation
by a scientific committee for up to seven months, at the end of which the committee adopts an opinion on whether the drug
should be approved for marketing. During this period, the EMA may send questions to the company, at which time the aforementioned
review clock stops until answers are provided.
(ii)
Formal
decision by the EMA’s Committee for Medicinal Products for Human Use, which is transmitted to the European Commission,
which issues a formal decision on the authorization of the product.
(iii)
Marketing
authorization: Once a European Community marketing authorization has been granted, the marketing-authorization holder can
begin to make the medicine available to patients and healthcare professionals in all EU countries.
Even after a company receives marketing
authorization, EU law regulates the distribution, classification for supply, labeling and packaging, and advertising of medicinal
products for human use. The European Union also regulates the manufacture of medicinal products, requiring cGMP, set forth in
the EU Guidelines to Good Manufacturing Practice — Medicinal Products for Human and Veterinary Use.
EU pharmacovigilance directives and regulations
require a company to establish post-market surveillance systems that include individual adverse reaction case reports, periodic
safety update reports, and company-sponsored post-authorization safety studies. If a medicinal product’s overall risk and
benefit profile is found to have changed significantly for any reason, it may be required to be varied, withdrawn, or have its
use suspended.
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Patent term restoration and extension
A patent claiming a new drug product may
be eligible for a limited patent term extension under the Drug Price Competition and Patent Term Restoration Act of 1984 (the
“Hatch-Waxman Act”) which permits a patent restoration of up to five years for patent term lost during product development
and FDA regulatory review. The restoration period granted is typically one-half the time between the effective date of an IND
and the submission date of an NDA, plus the time between the submission date of an NDA and the ultimate approval date. Patent
term restoration cannot be used to extend the remaining term of a patent past a total of 14 years from the product’s approval
date. Only one patent applicable to an approved drug product is eligible for the extension, and the application for the extension
must be submitted prior to the expiration of the patent in question. A patent that covers multiple drugs for which approval is
sought can only be extended in connection with one of the approvals. The PTO reviews and approves the application for any patent
term extension or restoration in consultation with the FDA.
Pharmaceutical coverage, pricing and reimbursement
Significant uncertainty exists as to the
coverage and reimbursement status of any products for which we may seek to obtain regulatory approval. In the United States and
other markets, sales of any future product for which we receive regulatory approval for commercial sale will depend in part on
the availability of reimbursement from third-party payors. Third-party payors include government health administrative authorities,
managed care providers, private health insurers and other organizations. The process for determining whether a payor will provide
coverage for a drug product may be separate from the process for setting the price or reimbursement rate that the payor will pay
for the drug product. Third-party payors may limit coverage to specific drug products on an approved list, or formulary, which
might not include all of the FDA-approved drug products for a particular indication. Third-party payors are increasingly challenging
the price and examining the medical necessity and cost-effectiveness of medical products and services, in addition to their safety
and efficacy. We may need to conduct expensive pharmacoeconomic studies in order to demonstrate the medical necessity and cost-effectiveness
of our prospective products, in addition to the costs required to obtain the FDA approvals. Additionally, a future product may
not be considered medically necessary or cost-effective. A payor’s decision to provide coverage for a drug product does
not imply that an adequate reimbursement rate will be approved. Adequate third-party reimbursement may not be available to enable
us to maintain price levels sufficient to realize an appropriate return on our investment in product development.
In March 2010, a significant healthcare
reform was signed into law in the United States. The healthcare reform law substantially changes the way healthcare will be financed
by both governmental and private insurers, and significantly impacts the pharmaceutical industry. The healthcare reform law contains
a number of provisions, including those governing enrollment in federal healthcare programs, reimbursement changes and fraud and
abuse, which has impacted existing government healthcare programs and resulted in the development of new programs, including Medicare
payment for performance initiatives and improvements to the physician quality reporting system and feedback program.
Additionally, the healthcare reform law:
·
Increased
the minimum level of Medicaid rebates payable by manufacturers of brand-name drugs from 15.1% to 23.1%;
·
Required
collection of rebates for drugs paid by Medicaid managed care organizations; and
·
Imposed
a non-deductible annual fee on pharmaceutical manufacturers or importers who sell “branded prescription drugs”
to specified federal government programs.
There have been executive, judicial and
Congressional challenges to certain aspects of the healthcare reform law. The U.S. Supreme Court is currently reviewing the constitutionality
of the healthcare reform law, although it is unknown when a decision will be made. It is unclear how the Supreme Court ruling,
other such litigation, and the healthcare reform measures of the Biden administration will impact the healthcare reform law and
our business.
In addition, there has been increasing
legislative and enforcement interest in the United States with respect to drug pricing practices. Specifically, there have been
several recent U.S. Congressional inquiries and proposed and enacted federal and state legislation designed to, among other things,
bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient programs, and reform
government program reimbursement methodologies for drugs. At the federal level, the Trump administration used several means to
propose or implement drug pricing reform, including through federal budget proposals, executive orders and policy initiatives.
It is unclear whether the Biden administration will work to reverse these measures or pursue similar policy initiatives. We expect
additional healthcare reform initiatives to be adopted in the future, particularly in light of the new presidential administration.
We also expect these initiatives to increase pressure on drug pricing. Further, it is possible that additional governmental action
is taken in response to the evolving effects of the COVID-19 pandemic.
36
In the European Union, pricing and reimbursement
schemes vary widely from country to country. Some countries provide that drug products may be marketed only after agreeing on
a reimbursement price. Some countries may require the completion of additional studies that compare the cost-effectiveness of
a particular drug to currently available therapies. For example, the European Union provides options for its member states to
restrict the range of drug products for which their national health insurance systems provide reimbursement and to control the
prices of medicinal products for human use. European Union member states may approve a specific price for a drug product or may
instead adopt a system of direct or indirect controls on the profitability of the company placing the drug product on the market.
Other member states allow companies to set their own prices for drug products, but monitor and control company profits. The downward
pressure on health care costs in general, particularly prescription drugs, has become intense. As a result, increasingly high
barriers are being erected to the entry of new products. In addition, in some countries, cross-border imports from low-priced
markets exert competitive pressure that may reduce pricing within a country. Any country that has price controls or reimbursement
limitations for drug products may not allow favorable reimbursement and pricing arrangements.
Environmental, Health and Safety Matters
We, our agents and our service providers,
including our manufacturers, may be subject to various environmental, health and safety laws and regulations, including those
governing air emissions, water and wastewater discharges, noise emissions, the use, management and disposal of hazardous, radioactive
and biological materials and wastes and the cleanup of contaminated sites. We believe that our business, operations and facilities,
including, to our knowledge, those of our agents and service providers, are being operated in compliance in all material respects
with applicable environmental and health and safety laws and regulations. All information with respect to any chemical substance
is filed and stored as a Material Safety Data Sheet, as required by applicable environmental regulations. Based on information
currently available to us, we do not expect environmental costs and contingencies to have a material adverse effect on us. However,
significant expenditures could be required in the future if we, our agents or our service providers are required to comply with
new or more stringent environmental or health and safety laws, regulations or requirements.
Employees
As of December 31, 2020, we had 3
employees based in Jerusalem, Israel and our Cambridge, Massachusetts office. The following table sets forth the total number
of full-time employees as of the periods indicated by function and geography:
As
of December 31,
2020
2019
Function:
Administrative
3
8
Research and development
0
8
Total
3
16
Geography:
Israel
2
9
Cambridge, Massachusetts, USA
1
7
Total
3
16
Local labor laws govern the length of the
workday and workweek, minimum wages for employees, procedures for hiring and dismissing employees, determination of severance
pay, annual leave, sick days, advance notice of termination, Social Security payments or regional equivalents, and other conditions
of employment and include equal opportunity and anti-discrimination laws. None of our employees is party to any collective bargaining
agreements. We generally provide our employees with benefits and working conditions beyond the required minimums. We have a good
relationship with our employees, and have never experienced any employment-related work stoppages.
Available Information
The SEC maintains an internet site that
contains reports, proxy and information statements, and other information regarding issuers that file electronically with the
SEC. Our filings with the SEC are available to the public through this website at http://www.sec.gov .
We maintain a corporate website at www.anchiano.com.
Our reports filed or furnished pursuant to Section 13(a) or 15(d) of the Exchange Act, including our Annual Reports
on Form 10-K, Quarterly Reports on Form 10-Q and Current Reports on Form 8-K, and amendments to those reports,
are accessible through our website, free of charge, as soon as reasonably practicable after these reports are filed electronically
with, or otherwise furnished to, the SEC. Information contained on, or that can be accessed through, our website is not incorporated
by reference into this Annual Report on Form 10-K, and you should not consider information on our website to be part of this
Annual Report on Form 10-K.
37
Text extracted from the filing as submitted to EDGAR. Formatting, tables and exhibits are simplified for reading; the original document is authoritative for anything you rely on.