Item 1A. Risk Factors 35
Item 1B. Unresolved Staff Comments 61
Item 2. Properties 61
Item 3. Legal Proceedings 61
Item 4. Mine Safety Disclosures 61
PART II
Item 6. Reserved 62
Item 7A. Quantitative and Qualitative Disclosures About Market Risk 71
Item 8. Financial Statements and Supplementary Data 71
Item 9A. Controls and Procedures 71
Item 9B. Other Information 71
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 71
PART III
Item 10. Directors, Executive Officers and Corporate Governance 72
Item 11. Executive Compensation 72
Item 14. Principal Accountant Fees and Services 72
PART IV
Item 15. Exhibits and Financial Statement Schedules 73
i
PART I
FORWARD-LOOKING STATEMENTS
This Annual Report on Form 10-K, including sections entitled “Business,”
“Risk Factors,” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations”
and other materials accompanying this Annual Report on Form 10-K contain forward-looking statements or incorporate by reference forward-looking
statements. Statements, other than statements of historical facts, contained in this document, including statements regarding our business,
operations and financial performance and conditions, as well as our plans, objectives and expectations for our business operations and
financial performance and condition, are forward-looking statements. These statements relate to future events or to our future financial
performance and involve known and unknown risks, uncertainties and other factors which may cause our actual results, performance or achievements
to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements.
In some cases, you can identify these forward-looking statements by terminology such as “believes,” “expects,”
“potential,” “continues,” “may,” “will,” “should,” “seek,” “approximately,”
“predict,” “intend,” “plans,” “estimates,” “anticipates” or the negative version
of these terms or other comparable terminology.
These forward-looking statements include, but are not limited to, statements
about:
● expectations regarding the safety and efficacy of our product candidates;
● expectations regarding potential market size;
● developments and projections relating to our competitors and industry;
● our ability to remain listed on the Nasdaq Capital Market, or Nasdaq;
● the impact of government laws and regulations;
● the timing or likelihood of regulatory filings and approvals;
● our ability to protect our intellectual property position; and
1
We undertake no obligation to update or revise
any of the forward-looking statements contained in this Annual Report on Form 10-K after the date of this report, except as required by
law or the rules and regulations of the U.S. Securities and Exchange Commission, or SEC. We caution readers not to place undue reliance
on forward-looking statements. Our actual results could differ materially from those discussed in this Annual Report on Form 10-K. The
forward-looking statements contained in this Annual Report on Form 10-K, and other written and oral forward-looking statements made by
us from time to time, are subject to certain risks and uncertainties that could cause actual results to differ materially from those anticipated
in the forward-looking statements, including the risks, uncertainties and assumptions identified under the heading “Risk Factors”
in this Annual Report on Form 10-K.
SUMMARY OF RISKS AFFECTING
OUR BUSINESS
Below is a summary of
the principal factors that make an investment in our securities speculative or risky. This summary does not address all of the risks that
we face. Additional discussion of the risks and uncertainties summarized in this risk factor summary, and other risks and uncertainties
that we face, are set forth in Part I, Item 1A, Risk Factors, and should be carefully considered, together with other information in this
Annual Report on Form 10-K and our other filings with the SEC before making investment decisions regarding our securities.
● We have a limited operating history and have never generated any revenues.
2
Item 1. Business.
Overview
We are a New York City based
clinical-stage biopharmaceutical company committed to identifying and advancing transformative therapies for the treatment of cancer and
rare diseases. We were founded on the principle of applying modern scientific, regulatory or manufacturing advancements to established
mechanisms in order to create new development opportunities. We prioritize creativity, diverse perspectives, integrity and tenacity to
expedite our goal of bringing life-changing therapies to people with limited treatment options.
Our portfolio includes two
development programs utilizing TARA-002, an investigational cell therapy based on the broad immunopotentiator, OK-432, which was originally
granted marketing approval by the Japanese Ministry of Health and Welfare as an immunopotentiating cancer therapeutic agent. This cell
therapy is currently approved in Japan and Taiwan for LMs, and multiple oncologic indications. We have secured worldwide rights to the
asset excluding Japan and Taiwan and have begun to explore its use in oncology and rare disease indications. TARA-002 was developed from
the same master cell bank of genetically distinct group A Streptococcus pyogenes as OK-432 (marketed as Picibanil® in Japan
and Taiwan by Chugai Pharmaceutical Co., Ltd., or Chugai Pharmaceutical). We are currently developing TARA-002 in non-muscle invasive
bladder cancer, or NMIBC, and in LMs.
Our lead oncology program
is TARA-002 in NMIBC, which is cancer found in the tissue that lines the inner surface of the bladder that has not spread into the bladder
muscle. Bladder cancer is the sixth most common cancer in the United States, with NMIBC representing approximately 80% of bladder cancer
diagnoses. Approximately 65,000 patients are diagnosed with NMIBC in the United States each year. Very few new therapeutics have been
approved for NMIBC since the 1990s and the current standard of care for NMIBC includes intravesical Bacillus Calmette–Guérin,
or BCG. The mechanism of TARA- 002 is similar to BCG. TARA-002 and BCG are intravesically administered and elicit both a Th1 type immune
response and locally activated generally similar array of cytokines and immune cells.
In October 2021, we announced
that the Office of Tissues and Advanced Therapies Division, or the OTAT Division, of the FDA’s Center for Biologics Evaluation and
Research, or CBER, cleared our Investigational New Drug, or IND, application for TARA-002 in NMIBC. We have commenced a Phase 1 dose-finding,
open-label clinical trial to evaluate TARA-002 in treatment-naïve and treatment-experienced NMIBC patients with high-grade carcinoma
in situ and high-grade papillary tumors (Ta). In the initial dose escalation phase of the trial, patients will receive six weekly intravesical
doses of TARA-002. The primary objective of the trial is to evaluate the safety, tolerability and preliminary signs of anti-tumor activity
of TARA-002, with the goal of establishing a recommended dose for a future Phase 2 clinical trial.
We are also pursuing TARA-002
in LMs, which are rare, non-malignant cysts of the lymphatic vascular system that primarily form in the head and neck region of children
before the age of two. In July 2020, the FDA granted Rare Pediatric Disease designation for TARA-002 for the treatment of LMs. OK-432,
the originator therapy to TARA-002, has been the standard of care in LMs in Japan for over 20 years. In addition to the clinical experience
in Japan, we have secured the rights to a dataset from one of the largest ever conducted Phase 2 trials in LMs, in which OK-432 was administered
via a compassionate use program led by the University of Iowa to over 500 pediatric and adult patients. We have an IND for TARA-002 for
LMs with the Vaccines and Related Products Division of the FDA, or Vaccines Division, and in October 2021 we submitted the completed confirmatory,
current Good Manufacturing Practices (cGMP) comparability data for TARA-002 in relation to OK-432 as part of the IND. We are engaged with
the FDA to align on a development plan for TARA-002 in LMs.
3
The third development program in our portfolio is intravenous, or IV,
Choline Chloride, an investigational phospholipid substrate replacement therapy initially in development for patients receiving parenteral
nutrition, or PN, who have intestinal failure associated liver disease, or IFALD. IV Choline Chloride has been granted Orphan Drug Designation
by the FDA for this indication and has also been granted Fast Track Designation for the treatment of IFALD. Following a positive end of
Phase 2 meeting with the FDA, we received feedback on a potential design of the studies necessary to complete a registration package for
IV Choline Chloride for the treatment of IFALD, including a Phase 1 pharmacokinetic, or PK, trial and a Phase 3 clinical trial. Prior
to initiating these clinical trials, we are conducting a prevalence study to enhance understanding of the PN patient population and we
plan to use this information to determine the next steps for the development program. In September 2021, we reported results of the retrospective
part of the prevalence study, which supported the significant unmet medical need in patients dependent on PN who have IFALD. We are currently
conducting the prospective part of the study, which is a multi-center, cross-sectional observational study that will assess the prevalence
of choline deficiency, as well as cholestasis and steatosis, in patients dependent on PN.
We had been pursuing an additional program, Vonapanitase, a recombinant
human elastase. Following a review of the research, preclinical, and clinical data of Vonapanitase, we have determined to cease further
development of this product candidate at this time.
We have devoted substantial
efforts to the development of these programs and do not have any approved products and have not generated any revenue from product sales.
TARA-002 has not yet been approved for use for treatment of NMIBC, LMs or any other indications. We do not expect to generate revenues
in the near-term, if ever. To finance our current strategic plans, including the conduct of ongoing and future clinical trials and further
research and development costs, we will need to raise additional capital.
Our Product Candidate Pipeline
The following chart summarizes
the current status of our product candidate pipeline:
** Granted Orphan Drug and Fast Track Designations by the U.S. FDA
† Phase 1 PK study to be conducted in addition to Phase 3
Our Corporate Strategy:
We are an oncology and rare
disease company focused on identifying and acquiring or licensing de-risked assets and optimizing and/or accelerating their development.
Leveraging the drug development and commercialization experience of our management team, our goal is to build a leading biopharmaceutical
company focused on bringing life-saving therapies to patients with significant unmet needs.
4
1. Pursue development of TARA-002 for the
treatment of NMIBC and Advance Phase 1 clinical trial.
We have recently commenced a Phase 1 clinical trial to assess the safety
and tolerability of TARA-002 in patients with high-grade NMIBC, involving a dose escalation phase in which we are evaluating the safety,
tolerability and preliminary signs of anti-tumor activity of TARA-002 to determine dosage for a future Phase 2 clinical trial. We then
intend to further assess safety and preliminary signs of anti-tumor activity of TARA-002 in an expanded cohort of our Phase 1 clinical
trial.
2. Align with the FDA on a development plan
and regulatory pathway for TARA-002 in LMs.
Based on the robust dataset for the originator product OK-432 in LMs
and the full Clinical Study Report, or CSR of the randomized Phase 2 clinical trial of OK-432 in LMs led by the University of Iowa, we
are encouraged by the potential for TARA-002 to treat patients with LMs. We are engaged with the FDA to align on a development plan for
TARA-002 in LMs.
3. Complete prospective prevalence study
of patients receiving PN and who have IFALD to refine a development pathway for IV Choline Chloride.
We are currently conducting
a prospective prevalence study to enhance understanding of the PN patient population and plan to use this information to inform the next
steps for the development program. We received FDA feedback on a potential design of the studies necessary to complete a registration
package for IV Choline Chloride for the treatment of IFALD, including a Phase 1 pharmacokinetic study and a Phase 3 trial.
4. Explore opportunities to expand our pipeline
while maintaining a disciplined approach to investment.
We intend to explore the
use of TARA-002 in combination with other therapies and identify additional opportunities to develop TARA-002 in indications beyond NMIBC
and LMs. We plan to conduct non-clinical experiments and modeling to better characterize the potential benefits of combination therapy
with TARA-002, particularly in NMIBC. In addition, our leadership team has a strong track record of licensing, acquiring and optimizing
product candidates and we intend to leverage this skill set to identify opportunities for potential combination opportunities for TARA-002,
in NMIBC and other oncology indications. The immunological activity of TARA-002’s originator product, OK-432, has been effectively
interrogated in patients in a long list of indications. We plan to continue to carefully evaluate the case reports and the literature
and perform non-clinical characterization studies to better understand the mechanism of action of TARA-002 and its potential activity
in indications beyond NMIBC and LM in which there is unmet need.
Our Pipeline
TARA-002 / OK-432
TARA-002, our lead program,
is an investigational cell therapy developed from the master cell line of the same genetically distinct Streptococcus pyogenes
(group A, type 3) Su strain as OK-432, a broad immunopotentiator marketed as Picibanil® in Japan and Taiwan by Chugai Pharmaceutical.
We are using the same regulatory starting materials as OK-432 and manufacture TARA-002 using an updated version of the same proprietary
processes used to manufacture OK-432. We have designated this product candidate as TARA-002 in order to differentiate the regulatory path
in the United States and other geographies from that of OK-432 in Japan.
5
We entered into an agreement with Chugai Pharmaceutical in June 2019,
as amended in July 2020, to support our development of TARA-002. The agreement provides us with exclusive access to certain materials
and documents relating to OK-432 including the master cell bank of Streptococcus pyogenes used in the manufacturing of OK-432.
Additionally, the agreement provides technical support during a certain period. We have utilized the materials, proprietary manufacturing
process and technical support provided by Chugai Pharmaceutical to produce TARA-002 at a cGMP-compliant facility in the United States.
Under the agreement with Chugai Pharmaceutical, we have sole responsibility for the development and commercialization of TARA-002 worldwide,
excluding Japan and Taiwan. This agreement is exclusive through June 17, 2030 or following any termination of the agreement by either
party.
In Japan, OK-432 is indicated
for: the treatment of lymphangiomas (lymphatic malformations); the prolongation of survival time in patients with gastric cancer (postoperative
cases) or primary lung cancer in combination with chemotherapy; and the reduction of cancerous pleural effusion or ascites in patients
with lung cancer or gastrointestinal cancer respectively, head and neck cancer (maxillary cancer, laryngeal cancer, pharyngeal cancer,
and tongue cancer) and thyroid cancer that are resistant to other drugs.
We plan to pursue development of TARA-002 for the treatment of NMIBC
and LMs initially in the United States, and plan to also seek approval in Europe and other regions in the future and may also explore
additional indications where its utility as an immunostimulant has been hypothesized to be of therapeutic benefit.
TARA-002 in NMIBC
Disease Overview
Bladder cancer is the sixth
most common cancer in the United States, with NMIBC representing approximately 80% of bladder cancer diagnoses. NMIBC is cancer found
in the tissue that lines the inner surface of the bladder that has not spread into the bladder muscle. There are three subtypes of NMIBC:
Ta (non-invasive papillary carcinoma), Tis (carcinoma in situ or CIS), and T1 (carcinoma invading the lamina propria). Among the types
of NMIBC, Ta accounts for most NMIBC cases (70%), whereas T1 and CIS account for 20% and 10%, respectively.
Based on currently available treatment data, we believe that there
are approximately 30,000 incident cases of High-Grade NMIBC per year that would be appropriate for treatment with TARA-002 in the United
States. There are 65,000 incident cases of NMIBC in the United States every year, of these, approximately 45% (approximately 30,000) are
made up of High-Grade tumor types that are considered higher risk, and therefore candidates for immunotherapies, such as TARA-002. In
addition, NMIBC has one of the highest rates of recurrence with three-year rate estimated at up to 80%.
Treatment:
Treatment for NMIBC is typically targeted to reduce unresectable persistence,
recurrence after resection and to prevent disease progression to muscle-invasive bladder cancer. The initial treatment for NMIBC includes
cystoscopy and complete transurethral resection of the bladder tumor (TURBT) for papillary Ta or T1, or biopsy for CIS. A single postoperative
instillation of intravesical chemotherapy is recommended in patients with low risk of progression, and for patients with intermediate
and high-risk disease, a longer course of intravesical therapy is administered. The most efficacious intravesical agent to date has been
BCG, a live attenuated form of Mycobacterium bovis. BCG has been the subject of multiple supply shortages in the past decade due
to the inability to meet demand to treat the large population of patients with NMIBC, resulting in strategies to conserve the use of the
therapy. There has been a significant increase in bladder cancer recurrence and progression with an escalated number of patients who require
cystectomy. As such, with the current BCG shortage and limited effective alternate therapies or dosing strategies, there continues to
be a significant unmet need for treatment options for patients with NMIBC.
6
Manufacturing:
We plan to manufacture TARA-002
using an equivalent, but modernized, proprietary manufacturing process as is used to produce OK-432 by Chugai Pharmaceutical, starting
with a master cell line propagated by us but utilizing the same genetically distinct strain of Streptococcus pyogenes (A group,
type 3) Su strain as OK-432. We have contracted a contract development and manufacturing organization, or CDMO, to manufacture TARA-002.
TARA-002 for the Treatment of Lymphatic
Malformations
Disease Overview:
We are working to align with
the FDA on a regulatory pathway and development plan for TARA-002 for the treatment of LMs. LMs are rare, non-malignant cystic masses
that primarily form in the head and neck region of children before the age of two. The International Society for the Study of Vascular
Anomalies classifies LMs as either macrocystic, microcystic, or mixed cystic. Macrocystic and microcystic LMs are differentiated by the
size of the fluid-containing portion of the malformation. Macrocystic LMs are characteristically large, fluid-filled cysts with a thin
endothelial lining. Macrocystic LMs are composed of cysts greater than 2 cubic centimeters in size and present as a soft, fluid-filled
swelling beneath normal or slightly discolored skin. Macrocystic LMs are usually located in the antero-lateral cervical region of the
neck; however, it is possible for this type of LM to originate in other areas of the body. In contrast, microcystic LMs have very limited
internal space with a thick irregular endothelial lining. Microcystic LMs are comprised of cysts less than 2 cubic centimeters in size
and are often composed of micro-lymphatic channels that integrate and infiltrate normal soft tissue. Microcystic LMs can involve both
superficial and deep aspects including muscle and bone. Microcystic LMs can thicken or swell causing enlargement of surrounding soft tissue
and bones and can be found on any area of the skin or mucous membrane. Mixed cystic LMs are comprised of varying degrees of both macrocystic
and microcystic LMs.
While the exact prevalence
of LMs is not known, in the United States, the condition is thought to be present in approximately one in every 4,000 live births and
we believe there are approximately 1,400-1,800 LM cases per year.
Treatment:
Outside of Japan and Taiwan,
the standard of care is surgical excision, which is associated with high rates of recurrence and complications. There are no approved
pharmacotherapies for LMs, except in Japan and Taiwan where OK-432 is approved. In these countries, OK-432 has been the standard of care
for LMs for over 25 years.
Treatment of LMs varies depending
on the symptoms and complications that present themselves. The standard of care outside Japan and Taiwan for the treatment of LMs is either
a partial or complete surgical excision of the cysts. While surgery is the standard approach to the treatment of LMs in the head and neck,
the region is a difficult area to operate on because of the large number of important anatomical structures in the area. Major venous
and arterial trunks travel through the neck, as do important nerves. Surgery on such malformations frequently results in high rates of
recurrence and complications including life-long chronic conditions, such as damage to nerves and other important structures of the head
and neck.
Clinical Development
When OK-432 is administered locally for LMs, it is hypothesized that
innate immune cells within the cyst are activated and produce a strong immune cascade. Neutrophils and monocytes infiltrate the cyst and
various cytokines, including interleukins IL-6, IL-8, IL-12, interferon, or IFN, -gamma, tumor necrosis factor, or TNF-alpha, and vascular
endothelial growth factor (VEGF) are secreted by immune cells within the cyst in response to the presence of OK-432. In concert, these
immune activities induce a strong local inflammatory reaction in the cyst wall, resulting in fluid drainage, shrinkage and fibrotic adhesion
of the cyst.
7
A randomized, phase 2 clinical
trial led by the University of Iowa studied the use of OK-432 in patients with LM from 1998 to 2005. Most eligible subjects were between
6 months and 18 years of age with macrocystic or mixed cystic LMs (with ≥ 50% macrocytic disease) of the head and/or neck. There were
three treatment groups: immediate treatment (ITG), delayed treatment (DTG), and open label treatment group. The immediate treatment group
received treatment with OK-432 upon diagnosis. The delayed treatment group received OK-432 treatment following a six-month observation
period; the cross-over design was intended to investigate spontaneous resolution. The open-label treatment group included infants younger
than six months of age, adults older than 18 years of age, patients with LMs involving sites other than the head and neck (such as the
axilla, thorax, and extremities), and patients treated on an emergent basis. The open label treatment group were treated immediately with
OK-432. Response to therapy was measured by quantitating change in lesion size. Clinical success was defined as a complete (90% to 100%)
or substantial (60% to 89%) response to treatment based on radiographically confirmed shrinkage in lesions.
Results presented in this
report were based on a retrospective analysis of source verified data that included the full dataset of subjects enrolled in the Phase
2 randomized clinical trial between January 1998 and August 2005, including data in the published study (Smith et al. 2009) that included
subjects enrolled between January 1998 and November 2004.
Overall, 310 subjects were
enrolled with intent to treat: 246 subjects were randomized to the immediate (ITG, N=171) and delayed (DTG, N=75) treatment groups; 64
subjects were nonrandomized and assigned to the open-label group. Analysis of the primary efficacy endpoint (N=150) demonstrated clinical
success (complete and/or substantial response) in 69% of patients in the ITG 6 months after enrollment, while 7.5% of patients in the
DTG experienced spontaneous regression of a LM during this time interval (p < 0.0001)). When the results were analyzed by lesion type
across all treatment groups, a successful outcome was observed in 84% and 60% of patients with macrocystic and mixed cystic LM, respectively.
None of the patients with microcystic LM demonstrated clinical success with OK-432 therapy. The results of the retrospective analysis
were consistent with the results observed in the original analysis (Smith et al. 2009).
Figure 1: the primary endpoint was met with 69%
of patients in the immediate treatment group had a complete or substantial response to OK-432 while 7.5% of patients in the delayed treatment
group had a complete or substantial response after six months of observation and before treatment.
ǂ Clinical Success was defined as complete or substantial response.
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Figure 2: patients with radiographically confirmed
macrocystic lesions had the greatest likelihood of clinical success and in those patients with mixed lesions, clinical success was also
present.
ǂ Clinical Success was defined as complete or substantial response.
** Results were analyzed by lesion type across all treatment groups.
Safety Profile
The most common adverse events with treatment were local injection
site reactions, fever, fatigue, and decreased appetite, with resolution within two weeks. Treatment emergent serious adverse events or
SAEs, (treatment emergent SAEs are defined as any SAE occurring or worsening on or after the first dose of study drug and within 35 days
after the last dose of study drug) associated with OK-432 treatment were reported in 4.1% of patients, with the most severe events being
airway obstruction and facial paralysis due to massive swelling post-injection that required tracheostomy and hospitalization. Both of
these events were reported as resolved.
The safety findings from the sponsor-conducted retrospective analysis
are consistent with the original analysis reported in Smith et al. 2009, and with safety data in published studies in approximately 865
patients with LMs after treatment with OK-432.
Preclinical Development:
A comprehensive preclinical development program for OK-432, including
in vitro and in vivo pharmacology and toxicology studies, was conducted by Chugai Pharmaceutical to support the filing of
a NDA with the Japan Pharmaceuticals and Medical Devices Agency. We believe these studies may help inform the design of a development
plan for TARA-002 in LMs.
9
Regulatory Interactions:
In July 2020, the FDA granted Rare Pediatric Disease designation for
TARA-002 for the treatment of LMs. The FDA grants Rare Pediatric Disease designation for serious diseases that primarily affect children
ages 18 years or younger and fewer than 200,000 persons in the United States. Under the FDA’s Rare Pediatric Disease Priority Review Voucher
program, a sponsor who receives an approval of a NDA or BLA for a product for the prevention or treatment of a rare pediatric disease
may be eligible for a voucher, which can be redeemed to obtain priority review for any subsequent marketing application or may be sold
or transferred.
We are encouraged by the robust dataset for OK-432 in LMs, which will
inform our development of TARA-002 and which we believe could help support the potential filing of a BLA for TARA-002 in LMs. At the FDA’s
request, we submitted the full CSR of the randomized Phase 2 clinical trial of OK-432 in LMs led by the University of Iowa to our open
IND. We are engaged with the FDA to align on a development plan for TARA-002 in LMs and subsequently initiate a clinical trial in LM patients.
Manufacturing Plans:
TARA-002
will be manufactured using an equivalent, but modernized, proprietary manufacturing process as is used to produce OK-432 by Chugai Pharmaceutical.
Starting with a master cell line propagated by us but utilizing the same genetically distinct strain of Streptococcus pyogenes
(A group, type 3) Su strain as OK-432. We have contracted a CDMO, to manufacture TARA-002.
IV Choline Chloride
for the treatment of Intestinal Failure Associated Liver Disease
Background:
IV
Choline Chloride is an IV substrate replacement therapy initially in development for patients receiving PN who have IFALD.
Choline
is a known important substrate for phospholipids that are critical for healthy liver function. Because patients receiving PN cannot sufficiently
absorb adequate levels of choline and no available PN components contain sufficient amounts of choline to correct this deficit, they often
experience a prolonged progression to hepatic failure and death, with the only known intervention being a dual small bowel / liver transplant.
If approved, IV Choline Chloride would be the first approved therapy for IFALD. It has been granted ODD by the FDA for the treatment of
IFALD and the prevention of choline deficiency in PN patients. We are currently undertaking a multinational prevalence study to enhance
understanding of the PN patient population.
We have entered into a license agreement with Dr. Alan Buchman for
exclusive rights to the IND, ODD and other regulatory assets related to IV Choline Chloride, as well as exclusive rights to the data from
previously conducted Phase 1 and Phase 2 clinical trials led by Dr. Buchman.
The
results of a randomized, controlled, Phase 2 clinical trial demonstrated that treatment with IV Choline Chloride resulted in normalization
of plasma-free choline concentrations, improvement of hepatic steatosis, and statistically significant improvement in cholestasis in patients
dependent on PN.
We had an end of Phase 2 meeting with the FDA in November 2018 and
received the FDA’s feedback on the design of studies necessary to complete the registration package for IV Choline Chloride for
the treatment of IFALD, including a Phase 1 pharmacokinetic study and Phase 3 trial.
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Disease Overview:
IFALD
is a rare hepatic/metabolic disease. IFALD, which occurs in patients dependent upon PN, is characterized by choline deficiency, hepatic
steatosis, cholestasis, and rapid progression of liver disease through to hepatic failure and death, in the absence of intestine-liver
transplant. IFALD carries a relatively poor prognosis, with a 15-34% death rate within one to four years. When IFALD presents in children,
mortality is even higher, with studies reporting death rates of 23-40% within 18 months. A patient is considered to have IFALD if she/he:
Many patients receiving PN
are entirely dependent on PN for their nutritional needs. PN delivers nearly all the macro and micro-nutrients necessary for survival
in their patients, with the notable exception of choline. Consequently, patients dependent on PN support have been shown to be choline
deficient. Patients dependent upon PN are unable to synthesize sufficient levels of choline and malabsorption limits the bioavailability
of choline chloride from the PN diet. The American Society for Parenteral and Enteral Nutrition and the Academy of Nutrition and Dietetics’
Dietitians in Nutrition Support both recommend that choline be developed and routinely included in PN products; however, there are currently
no FDA-approved choline chloride PN products.
Dependence on PN and resulting choline deficiency often leads to IFALD,
which is the most common adverse outcome in chronic PN adult patients that is associated with death. Low free choline plasma concentrations
are associated with alanine aminotransferase, or ALT, aspartate aminotransferase, or AST, and ALP elevations as well as steatosis (fatty
liver) and cholestasis (when bile from the liver stops or slows), all indicators of ongoing liver damage.
Clinical History:
In a Phase 2 randomized,
double-blind, controlled 24-week clinical trial, patients (n=15) receiving nightly PN for > 85% of their nutritional needs (for at
least 12 weeks prior to entry) were randomized to receive via IV infusion (10-12 hours) their usual PN with placebo (n = 8), or PN to
which 2g IV Choline Chloride was added (n = 7).
In the IV Choline Chloride
group, mean choline levels were within or greater than the estimated normal range (i.e., 6.7 to 26.9 nmol/mL) throughout the 24-week trial
and quickly returned to baseline levels when treatment was discontinued.
Steatosis:
Upon conversion of the quantification of computed tomography, or CT,
values to magnetic resonance imaging proton density fat fraction, or MRI-PDFF, significant differences in the least square, or LS, mean
change from baseline in estimated MRI-PDFF were observed in the IV Choline Chloride group in comparison to placebo group at Week 4 through
Week 24, demonstrating a clinically meaningful and statistically significant reduction in steatosis. When LS mean percent changes from
baseline in MRI-PDFF were compared between treatment groups, significant differences in LS mean changes (range, 31.7% to 53.6%) were observed
from Weeks 4 to 24 with p-values of 0.0009 to 0.0297 favoring the IV Choline Chloride group.
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Figure 3. Liver CT Images: Before and After Treatment with IV Choline
Chloride
Alkaline Phosphatase:
At baseline, LS mean ALP concentration was 239.3 ± 118.93 in
the IV Choline Chloride group and 148.1 ± 100.2 in the placebo group. The mixed model for repeated measures, or MMRM, analyses
demonstrated statistically significant decreases in ALP concentrations at Week 12 (p = 0.008), Week 16 (p = 0.005), Week 20 (p = 0.007),
and Week 24 (p = 0.005) for the IV Choline Chloride group, demonstrating a reduction in cholestasis. A trend towards significance was
observed at Week 4 (p = 0.076) and Week 6 (p = 0.056). At Week 34, 10 weeks after discontinuation of IV Choline Chloride treatment, LS
mean change from baseline in ALP concentrations still demonstrated statistically significant decreases (p = 0.002), demonstrating a significant
improvement in cholestasis with treatment with IV Choline Chloride (Figure 4).
In the subgroup of subjects with ALP concentration
> 1.5x upper limit of normal (ULN) at baseline, (n=7), mean values at baseline were comparable between the IV Choline Chloride and
placebo groups (294.20 ± 87.947 versus 277.00 ± 128.693, respectively). In the sub-group analysis, improvement in ALP was
consistent and substantial, with 20-30% improvement over 12-24 weeks of treatment. Statistical significance was observed at 12, 16, and
20 weeks.
In the description of the trials above and
elsewhere in this Annual Report on Form 10-K, n represents the number of patients in a particular group and p or p-values represent
the probability that random chance caused the result (e.g., a p-value of 0.001 means that there is a 0.1% probability
that the difference between the placebo group and the treatment group is purely due to random chance). A p-value of less
than or equal to 0.05 is a commonly used criterion for statistical significance, and may be supportive of a finding of efficacy by
regulatory authorities.
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Figure 4. Improvement in Cholestasis1: All Patients
1 Protara Therapeutics re-analysis of patient CRF’s, data on file.
* MMRM method used for imputation.
Preclinical Development:
Table 1. Preclinical Studies Conducted by us for
IV Choline Chloride
Study Type Brief Description
Evaluation of Transporter Inhibition by Choline Chloride in Caco-2 Cells
Evaluation of Cytochrome P450 Induction by Choline Chloride in Human Hepatocytes
Evaluation of Transporter Inhibition by Choline Chloride in Caco-2 Cells
Assessment of Choline as a Substrate of Human BSEP Mediated Transport
GLP Combined Single-dose IV Neurobehavioral and Respiratory Study
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Clinical Development Plan:
We have received feedback from the FDA on a number of key aspects of
the overall clinical program necessary for registration, including a Phase 1 pharmacokinetic study and a Phase 3 clinical trial. We completed
a retrospective, observational study of patients dependent on PN for 6 or more months. The objective of the study was to understand the
incidence of cholestasis, a hallmark pathology of IFALD in this patient population by measuring serum alkaline phosphatase (ALP) levels
greater than 1.5 times the upper limit of normal ULN as a key marker of cholestasis. Results of the study showed: 31% of all patients,
irrespective of baseline levels, presented with ALP levels greater than 1.5 times the ULN at any given time during 6 to 36 months. In
addition, approximately 28% of all patients had persistent ALP elevations greater than 1.5 times the ULN at 36 months. At baseline, approximately
23% of patients presented with ALP levels greater than 1.5 times the ULN with approximately 76% presenting with greater than 1.5 times
the ULN at any given time during 6 to 36 months and approximately 59% with persistent ALP elevations greater than 1.5 times the ULN at
36 months. While medical management demonstrated some improvement in ALP levels, it was not sufficient for managing ALP levels over the
long term in patients on PN. Results support further exploration in patient population to determine rates of choline deficiency and steatosis.
We have initiated a prospective observational study to further characterize the prevalence of choline deficiency, as well as cholestasis
and steatosis. We plan to use information from this prospective study to determine the appropriate next steps for the development program.
Manufacturing Plans:
We have manufactured sufficient
amounts of cGMP drug substance and drug product to initiate the planned clinical trials. Scale up for commercial demand is ready and will
commence when appropriate. Our end-to-end manufacturing of IV Choline Chloride is conducted in the United States by a cGMP-compliant CDMO.
Vonapanitase
As a result of the Merger (as defined below), we acquired the product
candidate, Vonapanitase, a recombinant human elastase that we previously developed for the improvement of vascular access outcomes in
patients with chronic kidney disease, undergoing or preparing for hemodialysis, and as a treatment for patients with symptomatic peripheral
artery disease. We have reviewed the research, preclinical and clinical data of Vonapanitase and have determined to cease further development
of this product candidate at this time.
Collaborations and License Agreements
Chugai Agreement
On June 17, 2019, we entered into an agreement, or the Chugai Agreement
with Chugai Pharmaceutical, a company organized and existing under the laws of Japan. Chugai Pharmaceutical has developed and commercialized
a therapeutic product, OK-432 (Existing Product), in Japan and Taiwan, or the Chugai Territory and owns and controls certain materials
and documents related to the Existing Product (the “Chugai Materials”). Pursuant to the Chugai Agreement, Chugai Pharmaceutical
has provided us with certain materials and documents relating to the Existing Product and has provided certain technical services to us
for our development and commercialization in territories other than the Chugai Territory, or the Protara Territory of a new therapeutic
product, or the New Product or TARA-002 comparable to the Existing Product beginning on the effective date of the Chugai Agreement and
ending on June 30, 2020, or any other date to be agreed to by the parties, or the Chugai Service Period, Chugai Pharmaceutical will exclusively
provide the Existing Product and Chugai Materials to us and will not provide the Existing Product or Chugai Materials to any third parties
during the Chugai Service Period, other than for medical, compassionate use and/or non-commercial research purposes. Additionally, beginning
on the effective date of the Chugai Agreement and ending on the fifth anniversary of such date or upon the termination of the Chugai Agreement,
whichever comes earlier, Chugai Pharmaceutical shall not provide Chugai Materials or technical support to any third-party for the purpose
of development and commercialization in the Protara Territory of a therapeutic product comparable to the Existing Product. We are responsible,
at our sole cost and expense, for the development and commercialization of the New Product in the Protara Territory.
On July 14, 2020, we entered into an amended agreement with Chugai
Pharmaceutical, or the Amended Chugai Agreement, with an effective date as of June 30, 2020. The Chugai Amendment extended the date through
which Chugai will exclusively provide the Existing Product and materials to us from June 30, 2020 to June 30, 2021, extended the date
through which Chugai will not provide materials or technical support to any third-party for the purpose of development and commercialization
in a given area from the fifth anniversary to the eleventh anniversary of the original effective date (extended to June 17, 2030) and
provides that, in addition to the designated fee provided upon the initial indication approval in the Chugai Pharmaceutical Agreement,
we will pay Chugai a designated fee for each additional indication approval.
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As consideration for Chugai
Pharmaceutical’s performance under the Chugai Agreement, we agreed to pay Chugai Pharmaceutical a payment in the low, single-digit
millions, which payments shall be made in two installments with an initial payment in July 2020, and the remaining majority of the payment
payable upon FDA approval of the New Product.
We granted Chugai Pharmaceutical
a right of first refusal on terms to be negotiated between the parties for a license related to the New Product-relevant information,
data and documentation and inventions to develop and commercialize the New Product in the Chugai Territory. We will be responsible for
manufacturing and supplying or causing our CDMO to manufacture and supply the New Product to Chugai Pharmaceutical.
The Chugai Agreement shall
remain in full force and effect until the first anniversary of the date of FDA approval of the New Product, unless terminated sooner,
or the Chugai Term. Following the Chugai Service Period and during the Chugai Term, Chugai Pharmaceutical may terminate the Chugai Agreement,
in whole or in part, without cause, by providing us 90 days prior written notice. Following such termination, we would maintain exclusive
access to Chugai Materials, subject to the termination clauses outlined below. We may terminate the Chugai Agreement, in whole only, by
providing Chugai Pharmaceutical 90 days prior written notice if (i) we decide to discontinue the New Product development; (ii) we decide
that the FDA’s requirements for the New Product are not likely to be met; or (iii) the FDA identifies a safety issue regarding the
New Product.
In addition, either party
may terminate the Chugai Agreement, in whole or in part, in the event that the other party materially breaches the Chugai Agreement and
fails to cure the breach within 30 days of written notice. Either party may terminate the Chugai Agreement in its entirety immediately
upon notice to the other party if such other party: (i) is dissolved or liquidated or takes any corporate action for such purpose; (ii)
becomes insolvent or is generally unable to pay, or fails to pay, its debts as they become due; (iii) files or has filed against it a
petition for voluntary or involuntary bankruptcy or otherwise becomes subject to any proceeding under any domestic or foreign bankruptcy
or insolvency laws; (iv) makes or seeks to make a general assignment for the benefit of creditors; or (v) applies for or has a receiver,
trustee, custodian or similar agent appointed by order of any court to take charge of or sell any material portion of its property or
business.
In the event that we undergo
a change of control, Chugai Pharmaceutical may terminate the Chugai Agreement upon 90 days written notice to us, absent a written pledge
by the new controlling party of its agreement to fulfill and undertake all obligations of ours and to be bound by the Chugai Agreement.
Sponsored Research and License Agreement
On November 28, 2018, we
entered into a sponsored research and license agreement, or the Research Agreement with The University of Iowa, or the University, pursuant
to which the University will provide access to certain program data related to Chugai Pharmaceutical’s OK-432 and will assist us
in conducting certain clinical studies. As consideration for the University’s performance under the Research Agreement, we will
pay the University $30,000 per year in funding for the project, taking into consideration the time spent by University employees required
for the Project. The parties also agree to discuss in good faith potential additional funding required for completion of the project pursuant
to the Research Agreement as applicable and necessary. In addition, within 45 days of approval of the TARA-002 BLA by the FDA, we will
pay a one-time approval milestone to the University, the amount of which depends on the usefulness of the program data in TARA-002’s
BLA filing, and the milestone amount will range from $0 to $1 million. We will also be responsible for certain tiered royalties on annual
net sales of products for the indication, which royalty rates are in the low single digit percentages. These royalty rates are also subject
to a reduction in the event that regulatory authorities determine that the program data is not sufficient for regulatory approval on its
own and additional pediatric efficacy and safety clinical studies are required. In the event that the annual net sales surpass certain
dollar amount thresholds, we will need to make certain additional milestone payments following the close of the calendar quarter in which
each milestone is reached, with the payments ranging from $62,500 to $125,000.
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We may terminate the Research
Agreement upon 30 days prior written notice to the University. Either party may terminate the project under the Research Agreement and
all commitments and obligations with respect thereto upon 30 days prior written notice to the other party. In the event of any termination
of the project under the Research Agreement by the University, (a) the University agrees to complete certain phases of the project and
(b) we will continue to provide annual funding until the completion of the second phase of the project. Upon termination of the project
by us, the Agreement will terminate and we will reassign to the University the IND.
Choline License Agreement
On September 27, 2017, we entered into a choline license agreement,
or the Choline Agreement, with Alan L. Buchman, M.D., pursuant to which Dr. Buchman granted us an exclusive, worldwide, non-transferable
license in and to certain licensed orphan designations, a certain licensed IND, certain existing study data and to certain licensed know-how
to develop, make, use, sell, offer for sale and import the licensed product during the term of the Choline Agreement. We are solely responsible
for all fees and expenses related to the undertaking of the Choline Agreement, including all due diligence obligations, regulatory authority
fees, attorney fees and consulting fees. During the term of the Choline Agreement, Dr. Buchman may not work with any third parties on
any product competing with the licensed product. In consideration for the rights and licenses granted under the Agreement, we made an
initial upfront payment of $50,000 payable to Dr. Buchman.
Certain milestone and royalty
payments may also be payable to Dr. Buchman. Pursuant to the Choline Agreement, we paid Dr. Buchman $50,000 in October 2019 because we
had not received at least $5 million in working capital from any source or in any manner as of October 15, 2019. Also, we paid Dr. Buchman
an additional $550,000 milestone upon the closing of the Private Placements (as defined herein) following the consummation of the Merger
(as defined herein) following our receipt of at least $5 million in working capital.
Regardless of whether development
or commercialization is undertaken by us under the Choline Agreement, commencing on November 21, 2022 and during the term of the Choline
Agreement, we shall pay Dr. Buchman a minimum annual royalty that ranges between $25,000 and $75,000.
We owe Dr. Buchman sales
royalties based on aggregate net sales of IV Choline Chloride in each calendar quarter, with the royalty rates ranging from 5.0% to 10.5%
based on the amount of net sales. In the event of development or commercialization activity by any sublicensees, we also agreed to pay
Dr. Buchman a royalty in the mid-single digit percentage of (i) net cash receipts after payment of taxes received by us from sublicensees
for their sales of licensed products and (ii) any other consideration received by us from such sublicensees; in each case, including a
fair monetary value for any transaction that is not a bona fide arms-length transaction or that is for consideration other than monetary.
Further, in the event of a sale or transfer of a priority review voucher regarding the license product, regardless of whether any development
or commercialization activity is undertaken by us or our sublicensees, we agreed to pay Dr. Buchman a milestone payment representing the
mid-single digit percentage of (i) net cash receipts after payment of taxes and (ii) any other consideration; in each case, received by
us, our affiliates, or our sublicensees, including a fair monetary value for any transaction that is not a bona fide arms-length transaction
or that is for consideration other than monetary.
We shall also pay Dr. Buchman
up to an aggregate of up to $775,000 in additional milestone payments upon the achievement of various regulatory approval milestones.
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The Choline Agreement will
remain in full force and effect until the last sale of the licensed product under the Choline Agreement. After we received the FDA’s
written minutes regarding its initial FDA meeting concerning the development of the first licensed product for one or more of the licensed
indications, we paid an additional payment of $100,000 to Dr. Buchman and elected not terminate the Choline Agreement. The Choline Agreement
may be terminated by Dr. Buchman if, following regulatory approval of a licensed product, we have not made our first sale of a licensed
product within such country within a specified time period. We may terminate the Choline Agreement for convenience upon 90 days’
prior written notice to Dr. Buchman. Dr. Buchman may terminate the Choline Agreement for non-payment of any payment due that has not been
cured. Either party may terminate the Choline Agreement if the other party is in material breach and has not cured such breach within
60 days’ notice. In addition, Dr. Buchman may terminate the Choline Agreement upon 60 days’ prior written notice if (a) we
cease or threaten to cease to carry on our business; (b) a petition or resolution for the making of an administration order or for the
bankruptcy, winding-up or dissolution of us is presented or passed; (c) we file a voluntary petition in bankruptcy or insolvency; (d)
a receiver or administrator takes possession of our assets or (e) any similar procedure is commenced against us in the United States.
License Agreement
On December 22, 2017, we entered into a license agreement, or the License
Agreement with The Feinstein Institute for Medical Research, a not-for-profit corporation organized and existing under the laws of New
York, or the Institute. The Institute owns, by assignment, a U.S. patent related to the treatment of fatty liver disease in humans. Pursuant
to the License Agreement, the Institute granted us an exclusive, worldwide license, with the right to grant sublicenses to non-affiliate
third parties, to develop, make, have made, use, sell, offer for sale and import certain products for use in the field of fatty liver
disease in humans receiving total parenteral nutrition, by administering, as monotherapy, a pharmaceutical composition comprising intravenous
choline, wherein the fatty liver disease is selected from IFALD, non-alcoholic fatty liver, non-alcoholic steatohepatitis, or NASH, NASH-associated
liver fibrosis, or non-alcoholic cirrhosis. Notwithstanding the exclusive rights granted to us, the Institute shall retain the right to
make, use and practice such patents in its own laboratories solely for non-commercial scientific purposes and for continued non-commercial
research.
As consideration for the
license grant, we agreed to pay the Institute tiered royalties of between 1.0% and 1.5% of all net sales. In addition, we agreed to pay
the Institute a low double digit percentage of net proceeds resulting from agreements entered into within two years from the effective
date of the License Agreement and a mid-single digit percentage of net proceeds resulting from agreements entered into thereafter. We
also agreed to make certain license maintenance payments of $15,000 beginning on the second anniversary of the effective date of the License
Agreement and continuing upon every anniversary thereafter until the first commercial sale of a licensed product. Beginning on the first
anniversary of the effective date of the License Agreement after the first commercial sale of a licensed product and every anniversary
of the effective date of the License Agreement thereafter, we shall pay the Institute $30,000 as a license maintenance fee. Such license
maintenance fees are non-refundable but are creditable against future royalty payments due to the Institute during the 12-month period
following each such anniversary.
We agreed to make certain
one-time milestone payments in the aggregate amount of $375,000 upon the achievement of certain regulatory approval milestones, of which
$100,000 was paid on January 28, 2020 upon us having consummated the Private Placements.
Unless terminated earlier,
the License Agreement will expire upon the expiration of the last to expire patent under the License Agreement. We may terminate the License
Agreement by giving the Institute 60 days prior notice. Either party may terminate the License Agreement in the event of a default or
breach by the other party that has not been cured within 60 days of such notice. If we (i) make an assignment for the benefit of creditors
or if proceedings for a voluntary bankruptcy are instituted on behalf of us; (ii) is declared bankrupt or insolvent or (iii) is convicted
of a felony relating to the manufacture, use or sale of the licensed products or a felony relating to moral turpitude, the Institute may
terminate the License Agreement.
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Intellectual Property
Our intellectual property
is critical to our business and we strive to protect it, including by obtaining and maintaining patent protection in the U.S. and internationally
for our product candidates, novel biological discoveries, epitopes, new therapeutic approaches and potential indications, and other inventions
that are important to our business. Throughout the development of our product candidates, we will seek to identify additional means of
obtaining patent protection that would potentially enhance commercial success. We also rely upon
trade secrets, know-how, continuing technological innovation and in-licensing opportunities to develop and maintain our proprietary position.
The patent positions of biotechnology
companies like us are generally uncertain and involve complex legal, scientific and factual questions. We recognize that the ability to
obtain patent protection and the degree of such protection depends on a number of factors, including the extent of the prior art, the
novelty and non-obviousness of the invention, and the ability to satisfy the enablement requirement of the patent laws. In addition, the
coverage claimed in a patent application can be significantly reduced before the patent is issued, and its scope can be reinterpreted
after issuance. Consequently, we may not obtain or maintain adequate patent protection for any of our product candidates. Any patents
that we hold may be challenged, circumvented or invalidated by third parties.
Our commercial success will also depend in part on not infringing the
proprietary rights of third parties. In addition, we have licensed rights under proprietary technologies of third parties to develop,
manufacture and commercialize specific aspects of our products and services. It is uncertain whether the issuance of any third-party patent
would require us to alter our development or commercial strategies, alter our processes, obtain licenses or cease certain activities.
The expiration of patents or patent applications licensed from third parties or our breach of any license agreements or failure to obtain
a license to proprietary rights that it may require to develop or commercialize our future technology may have a material adverse impact