PLUS THERAPEUTICS, INC. Management’s Discussion and Analysis of Financial Condition and Results of Operations (form 10-K)

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PLUS THERAPEUTICS, INC. Management's Discussion and Analysis of Financial Condition and Results
of Operations (form 10-K)


Our Management’s Discussion and Analysis of Financial Condition and Results of
Operations includes the following sections:

  • Overview that discusses our business and some of the relevant trends.



           •       Results of Operations that includes a detailed discussion
                   of our revenue and expenses.



           •       Liquidity and Capital Resources which discusses key
                   aspects of our statements of cash flows, changes in our
                   financial position and our financial commitments.






Overview

Plus Therapeutics, Inc. is a U.S. pharmaceutical company developing innovative,
targeted radiotherapeutics for adults and children with rare
and difficult-to-treat cancers. Our novel radioactive drug formulations and
therapeutic candidates are designed to deliver safe and effective doses of
radiation to tumors. To achieve this, we have developed innovative approaches to
drug formulation, including encapsulating radionuclides such as Rhenium isotopes
with nanoliposomes and microspheres. Our formulations are intended to achieve
elevated patient absorbed radiation doses and extended retention times such that
the clearance of the isotope occurs after significant radiation decay, which
will contribute and provide less normal tissue/organ exposure and improved
safety margins.

Traditional approaches to radiation therapy for cancer such as external beam
radiation have many disadvantages including continuous treatment for 4-6 weeks
(which is onerous for patients), that the radiation damages healthy cells and
tissue, and that the amount of radiation delivered is very limited and,
therefore, is frequently inadequate to fully destroy the cancer.

Our targeted radiotherapeutic platform and unique investigational drugs have the
potential to overcome these disadvantages by directing higher, more powerful
radiation doses at the tumor-and only the tumor-potentially in a single
treatment. By minimizing radiation exposure to healthy tissues while
simultaneously maximizing efficacy, we hope to reduce the toxicity of radiation
for patients, improving their quality and life expectancy. Our radiotherapeutic
platform, combined with advances in surgery, nuclear medicine, interventional
radiology, and radiation oncology, affords us the opportunity to target a broad
variety of cancer types.

Our lead radiotherapeutic candidate, Rhenium-186 NanoLiposome (“186RNL”) is
designed specifically to target central nervous system (CNS) cancers including
recurrent glioblastoma, leptomeningeal metastases, and pediatric brain cancers
by direct localized delivery utilizing approved standard-of-care tissue access
such conduction enhanced delivery (“CED”) and intraventricular brain catheters
(Ommaya reservoir). Our recently acquired radiotherapeutic
candidate, Rhenium-188 NanoLiposome Biodegradable Alginate Microsphere
(“188RNL-BAM”) is designed to treat many solid organ cancers including primary
and secondary liver cancers.

Our headquarters and manufacturing facilities are Texas are in proximity to
world-class cancer institutions and researchers. Our dedicated team of
engineers, physicians, scientists, and other professionals are committed to
advancing our targeted radiotherapeutic technology for the benefit of cancer
patients and healthcare providers worldwide and our current pipeline is focused
on treating rare and difficult-to-treat cancers with significant unmet medical
needs.

Pipeline

Our most advanced investigational drug, 186RNL, is a patented radiotherapy
potentially useful for patients with central nervous system (CNS) and other
cancers. Preclinical study data describing the use of 186RNL for several cancer
targets have been published in peer-reviewed journals. Besides glioblastoma,
leptomeningeal metastases, and pediatric brain cancer, 186RNL has been reported
to have potential applications for head and neck cancer, ovarian cancer, breast
cancer and peritoneal metastases.

The 186RNL technology was part of a licensed radiotherapeutic portfolio that we
acquired from NanoTx, Corp. (“NanoTx”) on May 7, 2020. The licensed
radiotherapeutic has been evaluated in preclinical studies for several cancer
targets and we have an active $3.0 million award from U.S. National Institutes
of Health/National Cancer Institute
which will provide financial support for the
continued clinical development of 186RNL for recurrent glioblastoma through the
completion of a Phase 2 clinical trial including enrollment of up to 55
patients. Thus far, 23 patients have been treated in the Phase 1 clinical trial
and the Phase 2 clinical trial has not yet been initiated.

We are currently conducting the ReSPECT-GBM and ReSPECT-LM clinical trials for
recurrent glioblastoma (GBM) and leptomeningeal metastases (LM), respectively.
In addition, we anticipate seeking FDA IND approval for the ReSPECT-PBC clinical
trial for pediatric brain cancer (PBC) in late 2022 or early 2023.

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186RNL versus External Beam Radiation Therapy

186RNL is a novel injectable radiotherapy designed to deliver targeted, high
dose radiation directly into glioblastoma tumors in a safe, effective, and
convenient manner that may ultimately prolong patient survival. 186RNL is
composed of the radionuclide Rhenium-186 and a nanoliposomal carrier, and is
infused in a highly targeted fashion, directly into the tumor via precision
brain mapping and convection enhanced delivery (CED). Potential benefits of
186RNL compared to standard external beam radiotherapy or EBRT include:

•The 186RNL radiation dose delivered to patients may be up to 20 times greater
than what is possible with commonly used external beam radiation therapy (EBRT).
•186RNL can be visualized in real-time during administration, possibly giving
clinicians better control of radiation dosing and distribution.
•186RNL potentially more effectively treats the bulk tumor and microscopic
disease that has already invaded healthy tissue.
•186RNL is infused directly into the targeted tumor, bypassing the blood brain
barrier, which reduces radiation exposure to healthy cells, in contrast to EBRT
which passes through normal tissue to reach the tumor, continuing its path
through the tumor, hence being less targeted and selective.
•186RNL is given during a single, short, in-patient hospital visit, and is
available in all hospitals with nuclear medicine and neurosurgery, while EBRT
requires out-patient visits 5 days a week for approximately 4-6 weeks.

ReSPECT-GBM Trial for Recurrent GBM

Glioblastoma is the most common, complex, and aggressive primary brain cancer in
adults. Annually in the U.S., there are 12,900 glioblastoma (GBM) cases
diagnosed and approximately 10,000 patients succumb to the disease each
year. The average life expectancy with primary glioblastoma is less than 24
months, with a one-year survival rate of 40.8% and a five-year survival rate of
only 6.8%. GBM often causes and presents with headaches, seizures, vision
changes and other significant neurological complications. Despite the best
available medical treatments to eliminate the initial brain tumor, some
microscopic disease frequently remains, with tumor regrowth within months.
Approximately 90% or more of patients with primary GBM experience tumor
recurrence. Complete surgical removal of GBM is not typically possible and GBM
is often resistant or quickly develops resistance to most available therapies.
Even today, the treatment of GBM remains a significant challenge and it has been
nearly a decade since the FDA approved a new therapy for this disease.

For recurrent GBM, there are few currently approved treatments that in the
aggregate, provide only marginal survival benefit. Furthermore, these therapies
are associated with significant side effects, which limit dosing and prolonged
use.

While EBRT has been shown to be safe and effective in many malignancies
including glioblastoma but the maximum possible administered dose is limited by
toxicity to the normal tissues surrounding the malignancy. In contrast, targeted
radiopharmaceuticals that precisely deliver radiation in the form of beta
particles such as Iodine-131 for thyroid cancer, are known to be very safe and
effective and minimize exposure to normal cells and tissues.

Interim results from our ongoing Phase 1/2a ReSPECT-GBM trial, suggest beta
particle energy from our lead investigational drug 186RNL may also have utility
in treating glioblastoma and other malignancies. More specifically, the
preliminary data from ReSPECT-GBM indicates that radiation, in the form of high
energy beta particles or electrons, can be effective against glioblastoma. Thus
far, we have been able to deliver up to 740 Gy of absorbed radiation to tumor
issue without significant or dose limiting toxicities. In comparison, current
EBRT protocols for recurrent glioblastoma typically recommend a total maximum
dose of about 35 Gy.

In September 2020, the U.S. Food and Drug Administration (“FDA”) granted both
Orphan Drug designation and Fast Track designations to 186RNL for the treatment
of patients with glioblastoma.

186RNL is presently under clinical investigation in a multicenter, sequential
cohort, open-label, volume and dose escalation study of the safety,
tolerability, and distribution of 186RNL given by CED to patients with recurrent
or progressive malignant glioma after standard surgical, radiation, and/or
chemotherapy treatment (NCT01906385). The study uses a modified Fibonacci dose
escalation, followed by a planned expansion at the maximum tolerated dose (MTD)
/ maximum feasible dose (MFD) to determine efficacy. The trial is funded through
Phase 2 in large part by a NIH/NCI grant. The planned enrollment in the NIH/NCI
grant is 21 patients in the dose-escalation part of the study and 34 patients in
the expansion cohort. The study is in its 8th dosing administration cohort and
is under development and internal review to potentially advance to a Phase 2 or
registration trial.

At the Society for Neuro-Oncology Annual Meeting in November 2021, Plus
presented patient data which at that time included the results for 22 patients
treated in the ReSPECT trial. The trial, thus far, has shown that CED in
recurrent GBM patients is

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feasible. Median absorbed dose to the tumor volume across all subjects in the
first eight cohorts (n=22) was 267.5 Gy (range 8.9-740). In a subset of patients
in whom tumor coverage was greater than or equal to 75%, the median absorbed
dose was 405 Gy (range 146-593). By contrast, the median absorbed doses to the
whole brain and the total body across all subjects were 0.55 Gy (range
0.001-2.728) and 0.09 Gy (range 0.001-0.182), respectively. Small doses, as
delivered to the body, are typically well-tolerated. Based on observed and
reported patient protocol activity and all available adverse event (AE) data,
186RNL has been well-tolerated. No AEs with an outcome of death or study
drug-related serious AEs have been reported. Furthermore, no patient was
discontinued from the study because of an AE. All AEs have been mild or moderate
(Grade 1 or 2) in intensity, except for one case of Grade 3 vasogenic edema,
which was considered by the investigator to be unrelated to the study drug. AEs
considered by the investigator to be at least possibly related to 186RNL have
included Grade 1 to 2 skin and soft tissue infection, intermittent cephalgia,
neck and jaw pain, nausea with or without vomiting, constipation, increased
lethargy, difficulty walking (gait disturbance), worsening double vision, and
dysuria. Scalp discomfort and tenderness related to the surgical procedure has
also been reported.

In the 22 subjects with recurrent GBM receiving a single administration of
186RNL, the mean & median OS for all 22 patients as of November 2021 was 48.1 &
33.1 weeks, respectively, with 7 patients alive. In a subset of 13 patients
receiving a presumed therapeutic absorbed radiation dose to the tumor (>100 Gy),
the mean & median OS was 64.8 & 47.1 weeks, respectively, with 7 of 13 patients
alive. In contrast, in 9 patients receiving a presumed sub-therapeutic absorbed
radiation dose to the tumor (<100 Gy), the mean and median OS was 23.9 & 22.3
weeks, respectively. A Kaplan-Meier curve comparing patients with presumed
therapeutic vs. sub-therapeutic radiation dose to the tumor showed a
statistically significant difference between the groups (p=.0002). It is
hypothesized that targeted infusion of 186RNL into the tumor by CED, bypassing
the blood-brain barrier and normal brain and external tissues, significantly
spares normal tissues from radiation exposure and potential toxicity and
concentrates radiation to the tumor and surrounding region of interest.

ReSPECT-LM Clinical Trial for Leptomeningeal Metastases

Leptomeningeal Metastases or LM is a rare complication of cancer in which the
disease spreads to the membranes (meninges) surrounding the brain and spinal
cord. The incidence of LM is growing and occurs in approximately 5% of people
with late-stage cancer, or 110,000 people in the U.S. each year. It is highly
lethal with an average 1-year survival of just 7%. LM occurs with cancers that
are most likely to spread to the central nervous system. The most common cancers
to spread to the leptomeninges are breast cancer, lung cancer, melanoma and
gastrointestinal cancers—though most solid tumors have the potential for LM
spread.

The ReSPECT-LM Phase 1 clinical trial (ClinicalTrials.gov NCT05034497) is
predicated in part upon preclinical studies in which tolerance to doses
of 186RNL as high as 1,075 Gy was shown in animal models with LM without
significant observed toxicity. Furthermore, treatment led to marked reduction in
tumor burden in both C6 and MDA-231 LM models.

In October 2021, the FDA announced clearance of our Investigational New Drug
(IND) application for 186RNL for the treatment of LM. Subsequently, in November
2021
, the FDA granted a Fast Track designation for 186RNL for the treatment of
leptomeningeal metastases. The Company initiated the trial and began screening
patients for the ReSPECT-LM Phase 1 clinical trial in Q4 2021.

The ReSPECT-LM multi-center, sequential cohort, open-label, dose escalation
study is evaluating the safety, tolerability, and distribution of 186RNL via
intrathecal infusion to the ventricle of patients with LM after standard
surgical, radiation, and/or chemotherapy treatment. The primary endpoint of the
study is the incidence and severity of adverse events and dose limiting
toxicities.

ReSPECT-PBC Clinical Trial for Pediatric Brain Cancer

In August 2021, we announced plans for treating pediatric brain cancer at the
2021 American Association of Neurological Surgeons (AANS) Annual Scientific
Meeting
. In July 2021, we reported that we had received FDA feedback pertaining
to a pre-IND meeting briefing package in which the FDA stated that we are not
required to perform any additional preclinical or toxicology studies.

Currently, the Company plans to investigate the use of 186RNL in 2 pediatric
bran cancers. High-grade glioma (HGG) is a rare, fast-growing CNS tumor that
forms in glial cells of the brain and spinal cord. It can be found almost
anywhere within the CNS, but is most commonly within the supratentorium in
children ages 15-19. HGG tumors in children act differently from those in
adults, causing headaches, seizures, and difficulty achieving developmental
milestones depending on the tumor location. Approximately 360-400 children are
diagnosed with HGG annually in North America and the 5-year survival rate is
approximately 20%. In contrast to HGG, ependymoma is a rare, slow- or
fast-growing (depending on the grade) primary CNS tumor that forms in ependymal
cells in the brain and spinal cord-and may spread throughout the CNS, though
infrequently. All ependymomas can recur, but patients are often tumor-free for
years before testing shows tumor regrowth, either at the initial tumor site or
elsewhere within the CNS. Symptoms

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depend on tumor location and size, usually including irritability,
sleeplessness, vomiting, nausea, back pain, arm/leg weakness, and headaches.

Approximately 250 children are diagnosed with ependymoma annually in the U.S.
while 71% of children with Grade II and 57% with Grade III survive 5 years from
diagnosis.

Based on the aggregate preclinical and clinical work completed to date in adult
recurrent glioblastoma, we hypothesized that 186RNL may offer potential clinical
benefit for PBCs, such as high-grade glioma and ependymoma. We intend to submit
an IND application to the FDA for 186RNL for the treatment of PBC (high-grade
glioma and ependymoma) in late 2022 or early 2023.

Rhenium-188 NanoLiposome Biodegradable Alginate Microsphere Technology

In January 2022, we announced that we licensed Biodegradable Alginate
Microsphere (BAM) patents and technology from The University of Texas Health
Science Center at San Antonio
(“UT Health Science Center at San Antonio“) to
expand our tumor targeting capabilities and precision radiotherapeutics
pipeline. We intend to combine our Rhenium NanoLiposome technology with the BAM
technology to create a novel radioembolization technology. Initially, we intend
to utilize the Rhenium-188 isotope, 188RNL-BAM foer the intra-arterial
embolization and local delivery of a high dose of targeted radiation for a
variety of solid organ cancers such as hepatocellular cancer, hepatic
metastases, pancreatic cancer and many others.

Preclinical data from an ex vivo embolization experiment in which Tc-BAM was
intra-arterially delivered to a bovine kidney perfusion model was presented at
the recent 2021 Society of Interventional Radiology (SIR) Annual Scientific
Meeting
. The study concluded that the technology required for radiolabeling BAM
could successfully deliver, embolize and retain radiation in the target organ.
188RNL-BAM is a preclinical investigational drug we intend to further develop
and move into clinical trials. Specifically, in 2022, we intend to transfer
the 188RNL-BAM technology from UT Health Science Center at San Antonio,
fabricate and scale the drug product, and complete certain preclinical studies
to support a future FDA IND submission. Our likely initial clinical target is
liver cancer which is the 6th most common and 3rd deadliest cancer worldwide. It
is a rare disease with increasing U.S. annual incidence (42,000) and deaths
(30,000).

Recent Developments

UT Health Science Center San Antonio (UTHSA) License Agreement

On December 31, 2021, we entered into an exclusive license agreement with UT
Health Science Center
at San Antonio for the global rights to develop and
commercialize Rhenium-188 NanoLiposome biodegradable alginate microspheres
(188RNL-BAM). Under the license agreement with UT Health Science Center at San
Antonio
, we are required to use commercial reasonable efforts to develop the
188RNL-BAM product candidate acquired under the license agreement. Further, we
are subject to future milestone, earn-out and other payments to UT Health
Science Center
at San Antonio all of which are tied to our commercialization and
sale activities for product candidates.

Piramal Master Services Agreement

On January 8, 2021, we entered into a Master Services Agreement (the “MSA”) with
Piramal Pharma Solutions, Inc. (“Piramal”), for Piramal to perform certain
services related to the development, manufacture, and supply of our RNL-Liposome
Intermediate Drug Product. The MSA includes the transfer of analytical methods,
development of microbiological methods, process transfer and optimization,
intermediate drug product manufacturing, and stability studies for us. The
transfer will be performed at Piramal’s facility located in Lexington,
Kentucky
. The parties contemplate that the MSA will lead to clinical and
commercial supply agreements between us and Piramal.

The MSA has a term of five years and will automatically renew for successive
one-year terms unless either party notifies the other no later than six months
prior to the original term or any additional terms of its intention to not renew
the MSA. We have the right to terminate the MSA for convenience upon thirty
days’ prior written notice. Either party may terminate the MSA upon an uncured
material breach by the other party or upon the bankruptcy or insolvency of the
other party.

Recent Financings

Refer to the “Liquidly and Capital Resources” section below for information on
our recent financings.


Exercise of Warrants

In February 2021, certain warrant holders exercised warrants to purchase 896,500
shares of our common stock for total exercise proceeds of $2.0 million.

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Results of Operations

Development revenue

We did not recognize any revenue or related costs during 2021. We recognized a
total of $0.3 million in revenue for the year ended December 31, 2020, as well
as $0.3 million in qualified expenditures for those periods. Our Biomedical
Advanced Research and Development Authority
(“BARDA”) contract was terminated in
December 2019 and the contract close out process was completed during 2020.

Research and development expenses

Research and development expenses include costs associated with the design,
development, testing, and enhancement of our product candidates, payment of
regulatory fees, laboratory supplies, pre-clinical studies, and clinical
studies.

The following table summarizes the components of our research and development
expenses for the years ended December 31, 2021 and 2020 (in thousands):

                                             Years ended December 31,
                                              2021               2020
Research and development                  $      5,248       $      2,668
Share-based compensation                            75                 32

Total research and development expenses $ 5,323 $ 2,700

The increase in research and development expenses of $2.6 million for the year
ended December 31, 2021 as compared to the same period in 2020 was due primarily
to an increase in developments costs of 186RNL of $2.2 million as we ramp up to
plan for the pivotal trial, an increase in personnel costs including recruiting
expenses and share-based compensation of $0.3 million due to increased headcount
and grants of share based awards, and an increase in other professional services
of $0.1 million.

We expect aggregate research and development expenditures to increase in
absolute dollars during 2022 due to the expected costs of development of
the 186RNL™ therapy acquired from NanoTx and development expenses related to 188
RNL-BAM.

In process research and development acquired from UT Heather Science Center at
San Antonio and NanoTx

In process research and development acquired from UT Heather Science Center at
San Antonio in the amount of $250,000 represents the upfront cash payment. In
process research and development acquired from NanoTx in the amount of $781,000
represents the upfront cash payment of $400,000 and fair value of 230,769 shares
of common stock, with fair value of $1.65 per share, issued to NanoTx in
accordance with the terms of the License Agreement.

General and administrative expenses

General and administrative expenses include costs for administrative personnel,
legal and other professional expenses, and general corporate expenses. The
following table summarizes the general and administrative expenses for the years
ended December 31, 2021 and 2020 (in thousands):

                                               Years ended December 31,
                                                2021               2020
General and administrative                  $      6,322       $      6,191
Share-based compensation                             531                215

Total general and administrative expenses $ 6,853 $ 6,406

General and administrative expenses increased by $0.4 million during the year
ended December 31, 2021, as compared to the same period in 2020, primarily due
to an increase of share-based compensation expenses of $0.3 million as more
share-based awards were granted during 2021 as well as increased grant date fair
value of the awards, as compared with 2020.

We expect general and administrative expenditures to remain generally consistent
in 2022 as compared with the year ended December 31, 2021, subject to litigation
cost which is not predictable at this time.

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Share-based compensation expenses

Share-based compensation expenses include charges related to options and
restricted stock awards issued to employees, directors and non-employees. We
measure stock-based compensation expenses based on the grant-date fair value of
any awards granted to our employees. Such expense is recognized over the
requisite service period.

The following table summarizes the components of our share-based compensation
expenses for the years ended December 31, 2021 and 2020 (in thousands):

                                     Years ended December 31,
                                     2021                 2020

Research and development $ 75 $ 32
General and administrative

                531                  215

Total share-based compensation $ 606 $ 247

The increases in our share-based compensation was due to increases in grants of
share-based options during 2021 as compared to 2020, as well as higher
grant-date fair value of share-based awards during 2021 compared with 2020.
Refer to Note 13 for weighted average assumptions used in valuation of our stock
options as of the grant date.

Financing items

The following table summarizes interest income, interest expense, and other
income and expense for the years ended December 31, 2021 and 2020 (in
thousands):

                                                   Years ended December 31,
                                                   2021               2020
Interest income                                         19                   50
Interest expense                                      (932 )             (1,107 )
Change in fair value of liability instruments            6                2,400
Total                                           $     (907 )     $        1,343



The decrease in interest expense for the year ended December 31, 2021 as
compared to the same period in 2020 was primarily due to the repayments of debt
principal of $0.3 million in 2021 and $5.3 million in 2020, respectively. The
changes in fair value of our warrant liabilities are primarily due to
reclassification of liability-classified warrants to equity during 2020 (see
Note 12), as well as fluctuations in the valuation inputs for the warrants. See
Note 3 to the consolidated financial statements included elsewhere herein for
disclosure and discussion of our warrant liabilities.

We expect interest expense in 2022 to decrease as compared with 2021 due to
scheduled debt principal repayments starting on November 1, 2021. As disclosed
in Note 12 to the consolidated financial statements included elsewhere herein,
in 2020 we entered into revised Series U warrant agreements with certain Series
U warrant holders. The amended Series U warrants meet the requirements for
equity classification under authoritative accounting guidance and are no longer
subject to fair value accounting post amendment. The remaining Series U warrants
accounted for as liabilities are immaterial.

Liquidity and Capital Resources

Short-term and long-term liquidity

The following is a summary of our key liquidity measures at December 31, 2021
and 2020 (in thousands):

                              As of December 31,
                               2021          2020

Cash and cash equivalents $ 18,400 $ 8,346

Current assets              $    19,724     $ 9,175
Current liabilities               5,870       8,539
Working capital             $    13,854     $   636


For the periods presented, operating losses have been funded primarily from
outside sources of invested capital in our common stock, proceeds raised from
the Loan and Security Agreement. We believe that our cash and cash equivalents
of $18.4 million at December 31, 2021 and the net proceeds of approximately $7.9
million
received so far during 2022 from the issuance of

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common stock will enable the Company to fund its current and planned operations
for at least the next twelve months and beyond from the date these consolidated
financial statements were issued.

We have had, and we will continue to have, an ongoing need to raise additional
cash from outside sources to fund our future clinical development programs and
other operations. Our inability to raise additional cash would have a material
and adverse impact on operations and would cause us to default on our loan.

On January 14, 2022, we entered into an Equity Distribution Agreement (the “2022
Distribution Agreement”) with Canaccord Genuity LLC (the “Agent”, or
“Canaccord”), pursuant to which we may issue and sell, from time to time, shares
of its common stock having an aggregate offering price of up to $5,000,000 (the
“Shares”), depending on market demand, with the Agent acting as an agent for
sales. Sales of the Shares may be made by any method permitted by law deemed to
be an “at the market offering” as defined in Rule 415(a)(4) of the Securities
Act of 1933, as amended (the “Securities Act”), including, without limitation,
sales made directly on or through the Nasdaq. As of the date of filing of this
Form 10-K, we issued 1,000,000 shares under the 2022 Distribution Agreement for
net proceeds of approximately $0.9 million.

On October 23, 2020, we entered into the 2020 Distribution Agreement with
Canaccord, pursuant to which we could issue and sell, from time to time, our
common stock in “at the market” offerings, depending on market demand, with
Canaccord acting as an agent for sales. During the year ended December 31, 2020,
we issued 1,616,331 shares under the 2020 Distribution Agreement for net
proceeds of approximately $3.2 million. During 2021, we issued 2,179,193 shares
under the 2020 Distribution Agreement for net proceeds of $6.3 million. As of
December 31, 2021, there were no remaining shares to issue and sell under the
2020 Distribution Agreement.

On September 30, 2020, we entered into the 2020 Purchase Agreement and a
registration rights agreement with Lincoln Park, pursuant to which Lincoln Park
committed to purchase up to $25.0 million of our common stock. During the year
ended December 31, 2020, we issued 353,113 shares, excluding 180,701 shares
issued as commitment fee, under the 2020 Purchase Agreement for net proceeds of
approximately $0.7 million. During 2021, we issued 5,685,186 shares of our
common stock under the 2020 Purchase Agreement for total proceeds of $12.5
million
. During January 2022, we issued 5,665,000 shares of common stock for net
proceeds of approximately $7.0 million under the 2020 Purchase Agreement. We no
longer have any additional shares of common stock registered to sell under the
2020 Purchase Agreement, and at this time, we do not intend to register any
additional shares of common stock under the 2020 Purchase Agreement.

On March 29, 2020, we entered into the Ninth Amendment, pursuant to which, among
other things, Oxford agreed to defer the start date of principal repayment to
November 1, 2021. In addition, on April 1, 2020, we made a $5.0 million paydown
of principal upon execution of the Ninth Amendment. As a result of this Ninth
Amendment, the term of the Term Loan has been extended from September 1, 2021 to
June 1, 2024, with all other major terms remained consistent.

Capital Resources

We continue to seek additional capital through strategic transactions and other
financing alternatives. Without additional capital, current working capital and
cash generated from sales will not provide adequate funding for research and
product development activities at their current levels. If sufficient capital is
not raised, we will at a minimum need to significantly reduce or curtail our
research and development and other operations, and this would negatively affect
our ability to achieve corporate growth goals. Although the stock markets and
our stock price have recovered to some extent in recent weeks, there may likely
be continued market volatility due to the pandemic or other events, which could
cause our stock price to decline. This in turn will likely negatively impact our
ability to raise funds through equity-related financings. Further, a continued
global economic downturn may impair our ability to obtain additional financing
through other means, such as strategic transactions or debt financing. The
overall deterioration of the credit and financial markets due to the COVID-19
pandemic will likely generally reduce our ability to obtain additional financing
to fund our operations.

Should we be unable to raise additional cash from outside sources or if we are
unable to do so in a timely manner or on commercially reasonable terms, it would
have a material adverse impact on our operations.

Cash (used in) provided by operating, investing and financing activities for the
years ended December 31, 2021 and 2020 is summarized as follows (in thousands):

                                                         Years Ended December 31,
                                                           2021              2020
Net cash used in operating activities                  $     (10,280 )     $  (8,434 )
Net cash used in investing activities                            (82 )          (493 )
Net cash provided by (used in) financing activities           20,416            (319 )

Net increase (decrease) in cash and cash equivalents $ 10,054 $ (9,246 )


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Operating activities

Net cash used in operating activities for the year ended December 31, 2021 was
$10.3 million compared to $8.4 million in the same period of 2020. Overall, our
operational cash use increased during the year ended December 31, 2021 as
compared to the same period in 2020, due primarily to increased expenditures for
our research and development activities.

Investing activities

Net cash used in investing activities for the year ended December 31, 2021 were
related to purchases of fixed assets of $144,000, offset by proceeds of $62,000
from sale of property and equipment. Net cash used in investing activities for
year ended December 31, 2020 was primarily related to cash payments of $0.4
million
made for in process research and development assets from NanoTx, and
$0.1 million for purchases of fixed assets.

Financing Activities

Net cash provided by financing activities for year ended December 31, 2021 was
primarily related to sales of common stock of $18.7 million, net of offering
cost through the 2020 Purchase Agreement with Lincoln Park and the Distribution
Agreement with Canaccord, as well as $2.0 million from exercise of warrants,
offset by principal repayment of the Oxford term loan of $0.3 million. Net cash
used for financing activities for the year ended December 31, 2020 was related
to repayment of $5.3 million of the Term Loan in April 2020 (consisting of $5.0
million
principal and $0.3 million of related final payment), and cash payments
of $0.1 million for our finance leases, offset by cash proceeds received from
issuance of common stock of $4.0 million and warrant exercises of $1.1 million.

Critical Accounting Policies and Significant Estimates

The preparation of financial statements in conformity with accounting principles
generally accepted in the United States requires us to make estimates and
assumptions that affect the reported amounts of our assets, liabilities,
revenue, and expenses, and that affect our recognition and disclosure of
contingent assets and liabilities.

While our estimates are based on assumptions we consider reasonable at the time
they were made, our actual results may differ from our estimates, perhaps
significantly. If results differ materially from our estimates, we will make
adjustments to our financial statements prospectively as we become aware of the
necessity for an adjustment.

We believe it is important for you to understand our most critical accounting
policies, which are included in Note 2 of the consolidated financial statements
in Item 8.

Recent Accounting Pronouncements

See Note 2 to the Consolidated Financial Statements included elsewhere herein
for disclosure and discussion of new accounting standards.

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