UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 10-K
(Mark One)
☒ Annual Report Under Section 13 or
15(d) Of The Securities Exchange Act Of 1934
For the fiscal year endedDecember 31,
2022
or
☐ Transition Report Under Section 13 or 15(d)
Of The Securities Exchange Act Of 1934
For the transition period from _____ to _____
COMMISSION FILE NUMBER: 000-52446
ACTINIUM PHARMACEUTICALS, INC.
(Exact name of registrant as specified in its charter)
275 Madison Avenue, 7th Fl.
New York, NY10016
(Address of principal executive offices) (Zip Code)
(646)677-3870
Registrant’s telephone number, including
area code
Securities registered
pursuant to Section 12(b) of the Act:
Title of each class Trading symbol Name of exchange on which registered
Common stock, par value $0.001 ATNM NYSE American
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pursuant to Section 12(g) of the Act: None
Indicate by check mark if the registrant is a
well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☐ No ☒
Indicate by check mark if the registrant is not
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Indicate by check mark whether the registrant:
(1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months
(or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements
for the past 90 days. Yes ☒ No ☐
Indicate by check mark whether the registrant
has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (Section 232.405
of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit such files). Yes ☒ No
☐
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is a large accelerated filer, an accelerated filer, a non-accelerated filer, smaller reporting company, or an emerging growth company.
See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,”
and “emerging growth company” in Rule 12b-2 of the Exchange Act.
Large accelerated filer ☐ Accelerated filer ☐
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Emerging growth company ☐
If an emerging growth company, indicate by check
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standards provided pursuant to Section 13(a) of the Exchange Act. ☐
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has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial
reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or
issued its audit report. ☐
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12(b) of the Act, indicate by check mark whether the financial statements of the registrant included in the filing reflect the correction
of an error to previously issued financial statements. ☐
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corrections are restatements that required a recovery analysis of incentive-based compensation received by any of the registrant’s
executive officers during the relevant recovery period pursuant to §240.10D-1(b). ☐
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is a shell company (as defined in Rule 12b-2 of the act): Yes ☐ No ☒
The aggregate market value of voting stock held
by nonaffiliates of the registrant as of June 30, 2022, the last business day of the registrant’s most recently completed second
fiscal quarter, based on the closing price of the common stock on the NYSE American on June 30, 2022 was $119,589,361.
As of March 31, 2023, 25,729,370 shares of common
stock, $0.001 par value per share, were outstanding.
Table of Contents
Item 1. Business 1
Item 1A. Risk Factors 24
Item 1B. Unresolved Staff Comments 55
Item 2. Properties 55
Item 3. Legal Proceedings 55
Item 4. Mine Safety Disclosures 55
Item 6. Reserved 56
Item 7A. Quantitative and Qualitative Disclosures About Market Risk 63
Item 8. Financial Statements and Supplementary Data F-1
Item 9A. Controls and Procedures 64
Item 9B. Other Information 64
Item 9C Disclosure Regarding Foreign Jurisdictions That Prevent Inspections 64
Item 10. Directors, Executive Officers and Corporate Governance 65
Item 11. Executive Compensation 78
Item 12. Security Ownership of Certain Beneficial Owners and Management 82
Item 14. Principal Accountant Fees and Services 84
Item 15. Exhibits, Financial Statement Schedules 85
Signature Page 88
i
CAUTIONARY NOTE REGARDING FORWARD-LOOKING STATEMENTS
This Annual Report on Form 10-K (this “Report”)
contains forward-looking statements that involve risks and uncertainties, principally in the sections entitled “Description of Business,”
“Risk Factors,” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations.”
All statements other than statements of historical fact contained in this Report, including statements regarding future events, our future
financial performance, business strategy and plans and objectives of management for future operations, are forward-looking statements.
We have attempted to identify forward-looking statements by terminology including “anticipates,” “believes,” “can,”
“continue,” “could,” “estimates,” “expects,” “intends,” “may,”
“plans,” “potential,” “predicts,” “should,” or “will” or the negative of these
terms or other comparable terminology. Although we do not make forward-looking statements unless we believe we have a reasonable basis
for doing so, we cannot guarantee their accuracy. These statements are only predictions and involve known and unknown risks, uncertainties
and other factors, including the risks outlined under “Risk Factors” or elsewhere in this Report, which may cause our or our
industry’s actual results, levels of activity, performance or achievements expressed or implied by these forward-looking statements.
Moreover, we operate in a very competitive and rapidly changing environment. New risks emerge from time to time and it is not possible
for us to predict all risk factors, nor can we address the impact of all factors on our business or the extent to which any factor, or
combination of factors, may cause our actual results to differ materially from those contained in any forward-looking statements. All
forward-looking statements included in this document are based on information available to us on the date hereof, and we assume no obligation
to update any such forward-looking statements.
You should not place undue reliance on any forward-looking
statement, each of which applies only as of the date of this Report. Before you invest in our securities, you should be aware that the
occurrence of the events described in the section entitled “Risk Factors” and elsewhere in this Report could negatively affect
our business, operating results, financial condition and stock price. Except as required by law, we undertake no obligation to update
or revise publicly any of the forward-looking statements after the date of this Report to conform our statements to actual results or
changed expectations.
ii
PART I
ITEM 1. BUSINESS.
Description of Our Business
Actinium Pharmaceuticals, Inc. (“Actinium”) is a biopharmaceutical
company developing targeted radiotherapies to deliver cancer-killing radiation with cellular level precision to treat patients with high
unmet medical needs. Our vision is to build a specialty, hospital focused radiotherapeutics company that develops and markets medicines
for relapsed or refractory cancer patients who are treated primarily in large quaternary care hospitals and their catchment areas. We
intend to leverage the clinical data of our lead product candidates, Iomab-B and Actimab-A, to improve outcomes in patients with relapsed
or refractory acute myeloid leukemia (“r/r AML”) by launching two radiotherapy drugs in 5 years that address the significant
need for better outcomes from treatment with therapeutics or from undergoing a bone marrow transplant (“BMT”).
We also intend during this time frame to further advance Iomab-B outside
of acute myeloid leukemia (“AML”) based on promising data as a disease control and conditioning agent for various other blood
cancers. Based on early promising clinical trial results, we are also working on a lower dose next generation conditioning program, Iomab-ACT,
for rapidly growing cell and gene therapies.
Our Clinical Pipeline
AML is an aggressive, heterogeneous disease that is difficult-to-treat.
Most AML patients develop relapsed or refractory disease within one year and have an extremely poor prognosis and dismal survival. Currently,
a BMT is the only curative regimen available for AML patients, however, access is limited to AML patients who are fit enough to withstand
the challenges associated with this treatment. The majority of AML patients are considered not transplantable in routine clinical practice
as they are not fit enough to withstand the rigors of the patient journey which includes: therapy to attain a remission, conditioning
regimens to destroy diseased marrow, challenge of the transplant itself or post-transplant complications.
Our Iomab-B and Actimab-A product candidates fill the major unmet medical
needs in r/r AML in a complementary fashion as they are directed at different parts of the patient journey. Iomab-B is a targeted bridging
therapy that provides both disease control and conditioning in one agent. Results from a phase 3 trial has demonstrated unprecedented
access to a BMT and improved survival in unfit patients who are currently not considered transplantable in routine clinical practice.
Actimab-A is a targeted therapy for fit patients that has demonstrated an impressive extension in survival in a proof-of-concept study
and is poised for advanced development in collaboration with the NCI, or National Cancer Institute. Together, they provide us the opportunity
to transform the treatment of AML, especially in the relapsed and refractory segment which represents over 50% of AML patients.
1
On October 31, 2022, we announced topline results from the pivotal
Phase 3 Study of Iomab-B in Elderly Relapsed or Refractory AML or SIERRA trial, which demonstrated that Iomab-B met the primary endpoint
of durable Complete Remission (“dCR”) with a high degree of statistical significance (p<0.0001). On February 18, 2023,
we announced full trial results, demonstrating unprecedented access, improved outcomes and better safety and tolerability with double
1-year and median overall survival (“OS”) compared to control arm patients receiving Iomab-B at the 2023 Tandem Meetings aka
the Transplantation & Cellular Therapy Meetings of the American Society for Transplantation and Cellular Therapy (“ASTCT”)
and the Center for International Blood & Marrow Transplant Research (“CIBMTR”). We believe these results provide the opportunity
to establish Iomab-B as a new standard of care, and if approved, we intend to commercialize the product in the United States (“U.S.”).
On April 12, 2022, we announced a commercialization
agreement for Iomab-B with Immedica AB (“Immedica”) for exclusive rights in Europe, the Middle East and North Africa (“EUMENA”).
Actinium received an upfront payment of $35 million USD with the potential for an additional $417 million USD in regulatory and sales
milestones and mid-twenty percent royalties. The market in the EU region is attractive due to the higher incidence of AML and number of
BMT procedures compared to the U.S. with the same unmet patient need, and our partnership with Immedica positions us well to capitalize
on this opportunity.
Actimab-A is the industry-leading program, leveraging the potent alpha
radiation emitting isotope Actinium-225 (“Ac-225”) based on clinical development in approximately 150 patients treated over
6 clinical trials. The potent linear energy transfer emitted by Ac-225 has no known resistance mechanism. Actimab-A is being developed
in combination with other regimens to exploit mechanistic synergies and leverage the mutation-agnostic mechanism of action of Ac-225 with
the objective of establishing it as a backbone therapy in AML, an extremely heterogenous disease.
On December 10, 2022, we shared the Phase 1 results from the Actimab-A
CLAG-M combination trial at the American Society of Hematology (“ASH”) Annual Meeting & Exposition that showed high response
rates and minimal residual disease (“MRD”) negativity, translating to a meaningful survival benefit of 53%and 32%at one and
two years in patients who are typically expected to live two to four months. At the same meeting, we shared Phase 1 data showing that
the combination of Actimab-A + venetoclax was well-tolerated with responses, including a Complete Remission (“CR”) and a partial
response in early dose escalation cohorts. We believe the promise of these results paved the way for the NCI Cooperative Research and
Development Agreement (“CRADA”), announced on February 6, 2023, to develop Actimab-A for the treatment of patients with AML
and other hematologic malignancies.
Our differentiated R&D is further exemplified by our next-generation
Iomab-ACT conditioning program for rapidly growing cell and gene therapies, as well as our solid tumor and immunotherapy collaborations
with Astellas Pharma Inc. (“Astellas”), AVEO Oncology/LG Chem (“LG Chem”) and EpicentRx, Inc. (“EpicentRx”).
In addition, we have several other programs in solid tumors at the pre-clinical stage with investigational new drug (“IND”)
enabling studies ongoing and our extensive intellectual property (“IP”) portfolio includes over 200 issued patents and pending
patent applications worldwide.
We are actively working on launching an early access program (“EAP”)
for Iomab-B and intend to file a Biologics License Application (“BLA”) by year-end while preparing for a U.S. commercial launch
and working with our partner Immedica to support the Marketing Authorization Application (“MAA”) and commercialization in
the EU. Late-stage Actimab-A development is expected to begin in the second half of 2023 under the NCI CRADA and is anticipated to have
a material balance sheet sparing impact over the next several years. We expect to create significant value due to the combination of major
milestones and balance sheet strength with the approximately $100 million cash on hand at year-end 2022 projected to fund operations through
2025 as we continue to drive ahead with realizing our five-year plan.
Market Opportunity
The market opportunity for Iomab-B and Actimab-A, as depicted in the
diagram below, exists in AML and for cellular therapy conditioning in various blood cancers. We believe that Iomab-B and Actimab-A can
fill the major unmet medical needs in r/r AML in a complementary fashion as they are utilized in different parts of the patient treatment
journey. The incidence of AML is approximately 21,000 patients per year, with a prevalence of approximately 70,000 in the U.S., (approximately
27,500 new patients per year in Europe) and the disease has an outsized economic impact relative to its population size. Over 50% of patients
diagnosed with AML will develop relapsed or refractory disease, with a median age of 68 years at diagnosis. Despite 10 new approved therapies
since 2017, no significant advancements have been made toward a cure and there is a significant unmet need for better therapeutics, which
provide the opportunity for Actimab-A. Actimab-A is a targeted radiotherapy for fit patients that has demonstrated an impressive improvement
in survival in a proof-of-concept study and is poised for advanced development in collaboration with the NCI. Using Actimab-A in combination
with chemotherapy or a targeted therapy, we have the potential opportunity to treat both newly diagnosed or r/r AML patients, with the
potential addressable population comparable to the prevalence of patients with AML.
2
Today, less than 20% of AML patients are able to access a BMT, currently
the only potentially curative option. These patients are usually younger, fit, and able to withstand the challenges associated with this
treatment, leaving the large majority of AML patients ineligible for transplant. This provides an opportunity for Iomab-B, which has demonstrated
the ability to enable unfit patients to benefit from a BMT. Thus Iomab-B can potentially expand the market from the approximately 400
r/r AML patients who are transplanted currently to approximately 8,000 unfit patients that could be eligible for transplant. Iomab-B has
demonstrated the ability to improve BMT access with extended survival and potentially curative outcomes in several other hematological
diseases outside of AML. Several clinical trials in over 300 patients with myelodysplastic syndromes (“MDS”), acute lymphocytic
leukemia (“ALL”), Hodgkin’s lymphoma (“HL”), Non-Hodgkin lymphoma (“NHL”) and multiple myeloma
(“MM”) have demonstrated the same value proposition as in AML. This data provides an opportunity to expand the market for
Iomab-B beyond AML via label expansion. In the U.S., there are approximately 185,000 patients diagnosed with blood cancers (e.g., leukemia,
lymphoma, and myeloma) that are treatable with BMT, of which, only approximately 20,000 are transplanted, leaving greater than 165,000
patients who could potentially benefit from transplant. These patients do not receive a BMT today primarily because they are unfit with
active disease and are not considered eligible, as they cannot tolerate the rigors of therapy required to induce a remission and the conditioning
agents required to ablate the marrow prior to a BMT.
Beyond BMT, the opportunity exists for better conditioning in other
areas of cellular therapy such as CAR-T as well as gene therapies. The pipeline of CAR-T and gene therapies has rapidly expanded, with
the addressable patient population expected to nearly double in the next one to five years and reach approximately 93,000 patients in
the U.S. by 2030 based on the current pipeline. The CAR-T market size in terms of dollars is estimated to grow at a CAGR of approximately
11% over the next 5 plus years. The addressable market for Iomab-ACT is in line with the patient population for cellular therapy as all
patients receive conditioning of some type prior to these treatments. We will continue to develop Iomab-ACT, our lower dose, next generation
conditioning program for rapidly growing cell and gene therapies based on early promising results, ultimately with the value proposition
of improving overall access and outcomes for patients who need cellular or gene therapies.
Our Strategy
Actinium’s strategy is to build a fully-integrated, specialty
radiotherapeutics company focused on the top 100 cancer hospitals using the power of our platform to deliver new treatment options for
patient populations living with high unmet medical needs in hematology and oncology. We believe our focus on relapsed and refractory disease
in cancer indications with high unmet medical need, with limited or no competition, and where the primary delivery of care occurs in a
few large comprehensive cancer care centers, is the appropriate strategy for our company. The cell killing power of linear energy transfer
delivered via radiotherapeutics is unmatched by other technologies and we believe relapsed, refractory disease is an area where radiotherapeutics
can succeed over other approaches. However, radiotherapeutics must be delivered on a just-in-time basis, and commercial and supply chain
barriers are higher than with other types of medicines. The validity of our approach is demonstrated by our product development strategy
as well as the commercial and operating model that we are building for our lead product candidates, Iomab-B and Actimab-A.
3
We intend to transform the treatment of AML with our Iomab-B and Actimab-A
product candidates, each of which has demonstrated impressive extension of survival in the most difficult-to-treat patients who are typically
expected to survive two to four months. The r/r AML segment comprises over 50% of all AML patients. Actimab-A, a therapeutic agent, and
Iomab-B for induction and conditioning, can be used in a complementary fashion as depicted in the diagram below. Based on solid clinical
evidence with these product candidates, we intend to develop and commercialize these two radiotherapy drugs, starting with Iomab-B in
2024 and Actimab-A in 2027, if approved, to improve survival in patients with r/r AML.
Iomab-B and Actimab-A have the potential
to significantly improve r/r AML outcomes in a complementary manner
The operating model required to achieve our vision is attractive for
several reasons, including the concentrated point of care; the top 50 transplant centers account for approximately 75% of BMTs and the
top 100 hospitals treat over 50 percent of r/r AML patients. Further, there is significant overlap in the healthcare providers and ecosystem
required to diagnose, treat and care for r/r AML patients within these hospitals, which will enable us to deploy a relatively small commercial
organization and operate a supply chain without the need for large investments. Our product pipeline is targeting a broader opportunity
in conditioning via label expansion of Iomab-B into BMT for other blood cancers and with Iomab-ACT, our next generation conditioning program
for rapidly growing cell and gene therapies. Further, our solid tumor programs are initially directed at relapsed or refractory cancers,
a stage of disease where treatment is again concentrated in large hospitals, which account for a significant portion of patients. We believe
our strategy will enable us to build a successful company with high operating efficiencies and is feasible to achieve without requiring
a commercial partner.
Our strategic priorities are to:
4
In keeping with our strategic vision over the next five years, we would
first focus our energies on ensuring an Iomab-B approval and successful launch into core BMT centers to ensure commercial success. We
intend to expand the Iomab-B label and revenue stream in a capital efficient manner while progressing the development of Actimab-A by
leveraging the NCI CRADA and its balance sheet sparing opportunity. We will progress the development of Iomab-ACT to proof-of-concept
and explore partnerships as a means to achieve commercialization. Our solid tumor programs will progress toward the clinic as we continue
to build out our commercial footprint into the top 100 hospitals leaving us well-positioned to develop them in accordance with our vision.
With commercial dynamics aligning favorably for a successful Iomab-B launch and with late-stage development of Actimab-A in collaboration
with the NCI, we plan to deliver on our mission to transform the treatment of AML and patient outcomes, and create a highly differentiated,
specialty radiotherapeutics company focused on the top 100 large hospitals.
5
Our Product Pipeline
We have strategically focused our development
efforts in areas where there is a significant unmet medical need. We are developing a portfolio of novel radiotherapeutics that has the
potential to positively impact the outcomes of people living with hard-to-treat diseases such as r/r AML via both a therapeutic and induction/conditioning
agent. Outside of AML, our pipeline development offers the opportunity to enhance the value proposition of cell and gene therapies with
our targeted conditioning programs.
AML Focused Programs – Iomab-B
and Actimab-A
Our Iomab-B and Actimab-A product candidates are
focused on addressing the major unmet medical needs in r/r AML in a complementary manner and are directed at different parts of the patient
journey.
Iomab-B – Targeted Radiotherapeutic
for Induction and Conditioning. A potential new standard of care enabling a curative BMT in currently non-transplantable r/r AML patients
with poor survival prognosis
Opportunity to Change the Current Paradigm
for Accessing a BMT and Improving Outcomes
The current approach in preparing patients
for a BMT is to first induce a remission with therapeutic agents to reduce the disease burden and then suppress or destroy the
patient’s immune system, including the diseased bone marrow, with conditioning regimens prior to transplanting the healthy
donor hematopoietic stem cells, which are expected to restore normal bone marrow function following engraftment. As this approach
requires patients to withstand multiple challenges from non-targeted therapies, which include chemotherapy agents and/or total body
irradiation that are highly toxic, BMT is typically limited to FIT patients. Iomab-B is a targeted therapy that provides both
disease control and conditioning in one agent and is well-tolerated even by UNFIT patients who typically are not transplanted in
routine practice today. The SIERRA trial was designed to demonstrate that UNFIT patients with active disease could be
administered Iomab-B and proceed directly to a BMT without the need for inducing a remission and that this approach could result in
improved survival and curative outcomes. As seen by the positive results of the SIERRA trial detailed below, Iomab-B represents an
exciting new paradigm in the management of AML patients and establishes a potential new standard of care especially for UNFIT
patients in the relapsed or refractory setting.
A similar approach has also been tried in the Phase 3 ASAP trial but
with FIT patients. However, to avoid confusion between the potential of the approaches used in the ASAP and SIERRA trials, important distinctions
between these trials are depicted in the graphic below. The ASAP trial sought to demonstrate non-inferiority between two non-novel approaches
and found that outcomes similar to those of current practice could be achieved without first getting a patient into remission before taking
them to BMT by giving them sequential conditioning or treating them twice with non-targeted chemotherapy agents that are typically used
in this setting.
The ASAP approach is limited to only FIT patients as the UNFIT patients
treated in SIERRA could not tolerate ASAP’s highly toxic sequential conditioning approach. Sequential conditioning is not novel
as a similar trial to ASAP was conducted by the UK National Cancer Research Institute in 2019, which did not show any benefit from this
approach in high-risk AML and MDS patients (Craddock et al. Augmented Reduced Intensity Regimen Does Not Improve Postallogeneic Transplant
Outcomes in Acute Myeloid Leukemia. J Clin Oncol. 2021). The SIERRA trial results therefore can change the paradigm in transplant
because non-transplantable patients in routine clinical practice can benefit from a transplant with Iomab-B and have superior outcomes.
While both approaches in these trials support increased access to BMT, only Iomab-B is applicable to the unfit patients who comprise approximately
80%of r/r AML patients and can potentially expand the market for transplant.
6
Schetelig et al. Results from the Randomized
Phase III ASAP Trial. ASH 2022
Pivotal Phase 3 SIERRA Trial for Iomab-B (131Iodine-apamistamab)
The SIERRA trial was designed to demonstrate the
ability of Iomab-B to overcome challenges related to patient access to curative BMT. Unfortunately, approximately 30% of patients with
AML have primary refractory disease while 50% relapse quickly after achieving initial remission. Getting these patients with primary r/r
AML into remission is very challenging due to characteristics such as age, comorbidities, and disease features such as high-risk mutations
that contribute to lack of response to salvage therapies and limit treatment options.
Patients must be able to overcome several challenges related to curative
BMT. The first access challenge is that the patient needs to be in complete remission prior to BMT. The current clinical practice is not
to transplant patients with active AML as outcomes are poor due to high relapse rates. The National Comprehensive Cancer Network (“NCCN”)
guidelines also recommend treatment to achieve remission prior to transplant in patients with relapsed AML. The second challenge to access
is tolerance to current conditioning regimens. For older patients, myeloablative regimens are not an option due to intense toxicity and
mortality. The third challenge is the ability to achieve post-BMT remission and successful engraftment. Inadequate conditioning can lead
to graft failure, which is associated with very high mortality. Patients who fail to achieve a CR post-transplant have extremely poor
outcomes and a survival of a few weeks. The fourth challenge relates to BMT tolerability and post-BMT complications. The conditioning
and immunosuppressive regimens given to these patients put them at high risk for infectious complications and toxicity. In the SIERRA
trial, Iomab-B addresses all four of these challenges. Access to BMT is improved as CR is not needed pre-BMT given effective disease control
and targeted myeloablation. With better post-BMT engraftment, CR and lower complications, the SIERRA trial also addressed the challenges
related to improved outcomes through Iomab-B.
7
The SIERRA results, presented in the late-breaker session at the 2023
Tandem Meetings: Transplantation & Cellular Therapy Meetings of the ASTCT and the CIBMTR, support Iomab-B’s value proposition
of enabling both improved access and outcomes of a BMT, thereby providing a significant curative option for r/r patients, a segment that
represents approximately 50% of all AML patients and the majority not transplanted today. The design of the SIERRA trial is provided in
the figure below.
SIERRA: A Novel, Pivotal Phase 3 Study of
Iomab-B in r/r AML
The pivotal Phase 3 SIERRA trial is a 153-patient, randomized, multi-center,
controlled trial of Iomab-B in patients aged 55 and above with active r/r AML, who were heavily pre-treated and had high-risk characteristics.
Patients enrolled had blast counts of 5% or greater in the marrow or circulating blasts suggestive of active AML. In this study, Iomab-B
was compared to the control arm that allowed physician’s choice of over 20 available agents, including chemotherapies and/or targeted
therapies such as venetoclax (BCL-2 inhibitor), FLT3 inhibitors, IDH inhibitors and Mylotarg, reflecting current best treatment practices
attempting to get patients to CR. The control arm included recently approved AML therapies that were added to the SIERRA protocol as they
became available. The crossover arm was designed in SIERRA for an equipoise that offered Iomab-B to patients failing to achieve a CR on
the control arm with an intent to rescue them by taking them to transplant. Of note, SIERRA had highly restrictive optionality for post-transplant
maintenance. Patients with active, r/r AML are not considered eligible for BMT with current approaches and the SIERRA trial was the only
randomized Phase 3 trial to offer BMT as a treatment option for this patient population. These patients would not be offered BMT in standard
practice and therefore have dismal survival outcomes of two to three months. The primary endpoint of the SIERRA trial was dCR of 180 days
and the secondary endpoints are OS and Event-Free Survival (“EFS”). The comparison of OS in subjects randomized to the control
arm who crossed over to receive Iomab-B versus all others in the control group was an exploratory efficacy endpoint.
8
As seen in the graphic below, the primary endpoint of 6-month dCR was
met with a high degree of statistical significance (p<0.0001). 75% of patients (44/59) receiving Iomab-B achieved an initial remission
30 days after their BMT compared to 6.3% of patients (4/64) in the control arm. 22% of the patients receiving Iomab-B maintained dCR lasting
180 days or more despite limited optionality for post-transplant maintenance, while none of the patients on the control arm achieved dCR.
The current standard practice is to administer post-transplant maintenance therapy to reduce chances of relapse. The results presented
below are on a per protocol basis, which means that only data that was in strict adherence to the protocol without any deviations was
considered for the analysis. It is important to note that the p-value of the primary endpoint in the intent-to-treat analysis was <0.0001,
the same as the per protocol analysis.
SIERRA Results: Iomab-B Meets Primary Endpoint
with High Significance (p<0.0001)
As demonstrated in the OS graph below, patients who achieved 6-month
dCR had 92.3% 1-year survival and 59.9% 2-year survival. Median OS had not been reached in these patients. It is worth noting that two
years in CR is a significant milestone in this patient population, highly indicative of long-term survival and a possible curative outcome.
9
Overall Survival for Patients who Achieved
6-month dCR with Iomab-B
OS was one of the secondary endpoints of the
study. The Kaplan-Meier plot in the inset of the graph below shows Intent-to-Treat (“ITT”) OS results between the Iomab-B
arm and the control arm. Due to the crossover design, ITT analysis of OS was confounded by the early crossover of patients (within 28
days) from the control arm to the Iomab-B arm (57.1%). The effective rescue of these crossover patients by Iomab-B led to an outsized
contribution of the Iomab-B effect on control arm patients. As a result, median OS in the Iomab-B arm was similar to that in the control
arm and this secondary endpoint was not met in the ITT analysis.
In order to isolate the true impact of Iomab-B
on OS, one of the exploratory efficacy endpoints was the comparison of OS in subjects randomized to the control arm who crossed over to
receive Iomab-B versus all others in the control arm, as well as the control arm patients who did not crossover versus the Iomab-B arm.
The Kaplan-Meier plot of OS in the graphic below shows that this exploratory analysis demonstrated the clear benefit of Iomab-B over the
control arm. The median OS for the Iomab-B group was 6.4 months which was double the 3.2 months for the non-crossover patients in the
control arm. Patients who crossed over from the control arm to receive Iomab-B had a median OS of 7.1 months demonstrating further the
ability of Iomab-B to treat patients who are non-treatable by conventional means.
A similar pattern favoring the Iomab-B group was seen across the pre-defined
subgroups, where 1-year OS for Iomab-B was 26.1% compared with 13.1% for the non-crossover control arm. The 1-year OS for patients in
the crossover arm was 35.8%. This clearly demonstrates the OS benefit of Iomab-B over the control arm and two to three-fold improvement
in survival outcomes possible with its use.
10
Kaplan-Meier Plot of Overall Survival ‒
Iomab-B, Crossover, and Non-Crossover Control Arm
Iomab-B produced a significant and clinically meaningful improvement
in the secondary endpoint of EFS, with a 78% reduction in the probability of an event (Hazard Ratio=0.22, p<0.0001 for both per protocol
and ITT basis). EFS at 180 days for the Iomab-B arm was 28% compared to 0.2% for the control arm. In the SIERRA trial, an event is defined
as one of the following: a patient not achieving CR/CRp or crossing over, patient not receiving BMT, a patient relapsing or death.
In the figure below comparing EFS with Iomab-B
versus the control arm, the initial vertical drop in the curve in the Iomab-B arm represents those patients who did not achieve a remission
after Iomab-B or those who did not proceed to transplant, while the initial vertical drop in the curve in the control arm mainly represents
patients who did not achieve a remission with salvage therapy and either crossed over to Iomab-B or went onto best supportive care.
Event-Free Survival with Iomab-B Versus Control
Arm
The table below shows relevant adverse events
in transplanted Iomab-B patients. In these patients, incidence of sepsis was four times lower in the Iomab-B arm than the control arm
(6.1% vs. 28.6%). In addition, rates of other treatment related adverse events were lower in favor of Iomab-B, including febrile neutropenia
(43.9% vs. 50.0%), mucositis (15.2% vs. 21.4%) and acute graft versus host disease (“GVHD”) (26.1% vs. 35.7%).
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Grade ≥3 Treatment-Emergent Adverse Events
in Transplanted Patients Through Day 100 Post-HCT
With current treatment practice, patients who have r/r AML with active
disease, utilizing current conditioning agents have poor outcomes and very low survival rates. Using an Iomab-B led regimen, an unprecedented
number of patients were able to access transplant and were able to do so with active disease, eliminating need for achieving a CR in order
to transplant the patient. Thus, patients are also able to access BMT faster with Iomab-B, in less than half the time compared to conventional
care. Iomab-B represents an exciting new paradigm with the potential to establish a new standard of care in r/r AML setting, making it
possible for most patients to get to a successful transplant with Iomab-B with a portion of these patients having a long-term survival
benefit. As shown below, with an Iomab-B led regimen, the majority of patients who are non-transplantable in routine clinical practice
can be successfully transplanted, administering myeloablative radiation with reduced intensity conditioning tolerability to ultimately
achieve transformative survival outcome, changing the treatment paradigm for r/r AML patients.
Iomab-B – New Paradigm to Upend BMT
Access and Improve r/r AML Outcomes
Future Development and Life Cycle Management
for Iomab-B
The results of the Pivotal Phase 3 SIERRA trial
validate the value proposition of Iomab-B, and we believe it could establish unprecedented access to transplant (currently the only curative
option) with better safety and tolerability and improved outcomes, all of which could potentially make Iomab-B the new standard of care
for patients with r/r AML. We are actively working to launch an EAP and successfully file a BLA in the second half of 2023, and if approved,
we anticipate the commercial launch for Iomab-B in 2024.
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We intend to commercialize Iomab-B in the U.S.
The commercial opportunity is supported by favorable dynamics, summarized by the “Three Ps and Two Cs”:
The favorable commercial dynamics for Iomab-B in the U.S. are further
supported by the strong foundation of core competencies developed during the successful execution of the SIERRA trial at leading high-volume
BMT centers. We established and actively managed end-to-end supply chain, never missing a patient dose, and were able to treat 60% more
patients than expected due to the high number of crossover patients. We focused on operational excellence at the point of care, working
in partnership with leading Key Opinion Leaders and their teams to successfully execute SIERRA at a wide array of centers. As a result,
we have broad reach across leading BMT centers that account for 30% of BMT volume, which speaks to the concentration of the BMT market.
The positive SIERRA results of unprecedented access and outcomes along with our commitment to operational excellence provide a strong
foundation for our commercial team.
In April 2022, Actinium licensed the EUMENA commercial
rights for Iomab-B to Immedica, an independent pharmaceutical company headquartered in Sweden. Immedica has significant know-how and experience
in commercializing niche and specialty care products across Europe and the Middle East, with extensive regulatory and commercial expertise
and capabilities. Actinium will continue to be responsible for certain clinical development activities and Iomab-B manufacturing and will
retain commercialization rights in the U.S. and rest of the world. Currently, there an estimated ~7,200 BMTs for AML in EUMENA, two times
that of the U.S., performed in a concentrated of number of centers. The incidence rate of AML in Europe is 3.7 per 100,000, or ~27,500
new patients per year. Actinium received an upfront payment of $35 million USD with the potential for an additional $417 million USD in
regulatory and sales milestones and mid-twenty percent royalties. Iomab-B has been granted Orphan Drug Designation by the EMA and has
received positive Scientific Advice from EMA that the SIERRA trial can support a marketing authorization with filing expected in 2024.
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Background on Iomab-B
Iomab-B is a first in class targeted radiotherapy consisting of apamistamab,
an anti-CD45 mouse antibody conjugated to radioactive iodine 131 (“I-131”) designed to deliver targeted myeloablative radiation
to malignant and hematopoietic cells prior to allogeneic BMT. CD45 is uniquely expressed on blood cancer, immune and bone marrow stem
cells at high levels. Targeting CD45 enables delivery of high radiation doses directly to the bone marrow, with a median of 16 gray and
as high as 44.6 gray in the SIERRA trial, while minimizing radiation exposure to vital organs such as lungs, heart and gastrointestinal
tract, thereby producing myeloablative outcomes with an overall better safety profile and the tolerability of a reduced intensity regimen.
I-131 is a beta- and gamma-emitting radioisotope that works on the cell surface and does not need to be internalized. Developed at the
Fred Hutchinson Cancer Research Center (“FHCRC”), Iomab-B has been studied in multiple disease indications including leukemias,
lymphomas, MDS, and MM. Over 300 patients received Iomab-B through prior studies, demonstrating the potential for unprecedented access
to BMT, improved survival and tolerability, and we intend to leverage these data as we plan for label expansion of Iomab-B. Iomab-B has
been granted Orphan Drug Designation from the U.S. Food and Drug Administration (“FDA”) and has patent protection into 2037.
Actimab-A – CD33 targeting radiotherapeutic
– mutation agnostic mechanism of action has potential as combination backbone therapy in highly radiosensitive, mutation rich AML
Our Actimab-A (225Ac-lintuzumab
satetraxetan) program is focused on developing combinations with other AML treatment regimens with mechanistic synergies to establish
Actimab-A as a backbone therapy, leveraging the mutation-agnostic mechanism of action of Actimab-A. There is no known resistance mechanism
to targeted radiotherapies, making Actimab-A an attractive candidate for a variety of combinations. The scientific rational is to use
CLAG-M, a powerful chemotherapy regimen routinely used to treat patients with r/r AML, and then use Actimab-A for its precision targeting
ability that produces double-strand-DNA breaks that lead to cancer cell death to clear out residual disease. Actimab-A has demonstrated
clinically significant survival benefit in a proof-of-concept study and is poised for advanced development in collaboration with the NCI.
Actimab-A + CLAG-M Phase 1 Study Results
In collaboration with the Medical College of Wisconsin, the Actimab-A
+ CLAG-M Phase 1 trial was conducted in r/r AML patients. These patients had a median age of 63, failed two or more lines of therapy,
which includes 57% having received prior treatment with venetoclax, a BCL-2 inhibitor. 67% of these patients had adverse cytogenetics,
52% had a TP53 mutation, and 57% had a prior BMT. Median OS is typically two to four months for this patient population, with a median
OS of less than 3 months for patients who relapsed following venetoclax and a median OS less than 2 months for those with a TP53 mutation.
These trial results were presented as an oral
presentation at the ASH Annual Meeting on December 10, 2022. In this difficult-to-treat r/r AML population, the results demonstrate its
high potential. We reported 1-year survival of 53% and 2-year survival of 32%, which are as much as double what can be expected with currently
available therapies. The trial showed an Overall Response Rate (“ORR”) of 65% across all dose cohorts, 52% complete remission
rate, and a 75% MRD negativity rate. As highlighted in the figure below, the results are highly encouraging and show that the high rates
of responses and MRD negativity are translating to a meaningful survival benefit in these difficult-to-treat patients, who would otherwise
have dismal outcomes.
Actimab-A + CLAG-M – Impressive Response
and Survival Benefit in r/r AML
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Actimab-A + CLAG-M Compared to CLAG-M Alone
in r/r AML
Efficacy of CLAG-M has been reported in older studies (Halpern
and Walter. CLAG-M with dose-escalated mitoxantrone for adults with acute myeloid leukemia. Oncotarget 2018 and Mushtaq et al. Comparison
of Salvage Chemotherapy Regimens in Relapsed/Refractory Acute Myeloid Leukemia. ASH 2018) in patients with r/r AML, however, almost all
of these studies were conducted in the pre-targeted therapy era where no patients enrolled had prior venetoclax-based therapy, thus efficacy
data of CLAG-M in the current era, in patients exposed to prior venetoclax, or with other high-risk features, is limited. When combined
with Actimab-A, the combination has demonstrated a clinically significant survival benefit in a proof-of-concept study irrespective of
prior targeted treatment. Relapsed or refractory AML after failing venetoclax-based therapy is associated with dismal survival outcomes,
with a median OS of less than 3 months. In comparison, the combination trial of Actimab-A + CLAG-M led to 1-year survival of 59% and 2-year
survival of 32% in patients who failed prior venetoclax-based therapy, which compares very favorably to the traditional outcomes in these
patients.
Actimab-A + venetoclax Phase 1/2 Study Results
We are conducting a Phase 1/2 multi-center trial combining Actimab-A
+ venetoclax in both fit and unfit patients 18 years and older with r/r AML led by UCLA Medical Center. On December 10, 2022, data from
our Actimab-A + venetoclax combination trial was presented at the ASH Annual Meeting. We have demonstrated preclinically that combinations
of Actimab-A and venetoclax have mechanistic synergies. Overexpression of MCL-1, an anti-apoptotic protein, is associated with resistance
to venetoclax in AML. Actimab-A kills tumors cells with DNA double-strand breaks and downregulates MCL-1, which can (re-)sensitize AML
cells or reduce tumor resistance to venetoclax. The Actimab-A + venetoclax combination has been well-tolerated with responses, including
a CR and a partial response in early dose escalation cohorts. In our ongoing clinical trial, we are exploring the optimal dose of Actimab-A,
as well as the dosing regimen of the combination. We expect to present proof-of-concept of this study in the second half of 2023.
Advanced Development and Planning for Actimab-A
On February 6, 2023, we announced that we entered
into a CRADA with the NCI, part of the NIH, to develop Actimab-A for the treatment of patients with AML and other hematologic malignancies.
The NCI will serve as the regulatory sponsor for any clinical trials mutually approved by both parties to study Actimab-A, and the CRADA
will provide extensive support for and accelerate the development of Actimab-A alone or in combination with chemotherapy, immunotherapy,
targeted agents and other novel combinations. The CRADA studies will be overseen by the NCI in collaboration with Actinium’s clinical
development team, where Actinium has the right to review and approval all protocols and has full right to all data. This broad collaboration
may accelerate our Actimab-A development efforts with access to NCI’s vast network of over 2,000 clinical trial sites and its Myelomatch
program. Later this year, we will provide updates on our progress as we move into late-stage development with Actimab-A + CLAG-M, as well
as other developments with our venetoclax combination trial as part of our backbone development strategy.
Background on Actimab-A
Actimab-A is an anti-CD33 antibody linked to the potent alpha-emitting
radioisotope Ac-225. Actimab-A targets CD33, which is expressed in virtually all malignant cells in patients with AML regardless of cytogenetics
or mutations and enables potent alpha radiation to be directed against radiosensitive AML cells. These cells have no known resistance
or repair mechanisms when hit with the alpha particles from the Ac-225 isotope payload that cause double stranded DNA breaks. We believe
Actimab-A is the first radiotherapeutic for r/r AML and has the unique value proposition of broad applicability, a differentiated mechanism
of action, and targeted precision that is well-tolerated with minimal toxicity. Our CD33 development program is driven by data obtained
from approximately 150 AML patients in 6 trials and demonstrated single agent activity with high response rates, but was also associated
with prolonged neutropenia. A combination strategy was considered appropriate given the changing treatment landscape of AML; hence, based
on presumed mechanistic synergies, an investigator initiated trial of Actimab-A + CLAG-M and a company-sponsored Actimab-A + venetoclax
were developed and patients were enrolled into these studies.
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Conditioning Focused Programs
Iomab-B
We will further expand the Iomab-B franchise by focusing on lifecycle
management for label enhancement and indication expansion. Iomab-B data in five additional hematologic indications (i.e., MDS, ALL, HL,
NHL, and MM) provide the foundation to explore indication expansion opportunities to increase the total addressable market for Iomab-B.
Across early trials at the FHCRC, Iomab-B demonstrated similar improved access to BMT and outcomes. We will leverage these data with strong
results from the pivotal Phase 3 SIERRA trial to execute a comprehensive life cycle management strategy to further expand Iomab-B’s
role in a variety of malignant and non-malignant hematological disorders, We will continue to develop the Iomab-B franchise to potentially
address a broader market opportunity to address the over 165,000 patients diagnosed with cancers (e.g., leukemia, lymphoma, and myeloma),
who could potentially benefit from transplant, but are unable to access one today.
Iomab-ACT
Iomab-ACT is comprised of apamistamab, the same anti-CD45 antibody
as Iomab-B, but utilizes lower, nonmyeloablative levels of I-131 to achieve lymphodepletion for cellular therapies such as CAR-T or reduced
intensity conditioning for gene therapies. We intend to continue to develop the Iomab-ACT program designed specifically for use prior
to CAR-T and gene therapies, ultimately with a value proposition of improving overall access and outcomes for patients who need cellular
or gene therapies.
Preclinical data showed a single, low-dose of
Iomab-ACT demonstrated lymphodepletion and as CD45 positive immune cells are implicated in major CAR-T side effects, i.e., cytokine release
syndrome ("CRS") and immune effector cell–associated neurotoxicity syndrome (“ICANS"), Iomab-ACT has the potential
to be developed as a conditioning agent for CAR-T therapies. CRS and ICANS remain two most common toxicities of CAR-T therapies with severe
cases (>Grade 3) seen in >20% of patients and fatality rates between 0-10%. Due to its effect on host monocytes/macrophages, we
believe conditioning with Iomab-ACT will potentially reduce the incidence of CRS and ICANS.
Unlike chemotherapy, Iomab-ACT is targeted in
nature, and we expect it to potentially promote improved CAR-T cell expansion, resulting in responses that are higher and more durable.
We believe our Iomab-ACT program is highly differentiated when compared to fludarabine and cyclophosphamide (“Flu/Cy”) or
other chemotherapy-based regimens that are used as standard practice today for lymphodepletion prior to cell therapy.
We are studying Iomab-ACT in collaboration with MSKCC, for conditioning
prior to CAR-T therapy for patients with relapsed or refractory B-cell acute lymphoblastic leukemia (“B-ALL”) or diffuse large
B-cell lymphoma (“DLBCL”). This study funded by a NIH grant is the first-of-its-kind study to use a radiotherapeutic-based
conditioning regimen with CAR-T therapy. We have completed treatment of an initial cohort of three patients and will expand to a second
cohort. This study was presented at the ASH Annual Meeting in December 2022 as a trial-in-progress. We expect to present proof-of-concept
data from this study in 2023 and look forward to sharing more on our Iomab-ACT trial with MSKCC, along with future development plans in
the CAR-T space.
R&D and Preclinical Programs
Our R&D efforts yield differentiated, high-value
programs that demonstrate our experience across multiple validated cancer targets and isotopes and cover broad areas of focus leveraging
our clinical development experience across hematology, targeted conditioning, solid tumors, and next generation radiotherapies. Our programs
also inform the advancement of our Iomab-B, Actimab-A, and Iomab-ACT programs. Our research collaborations with Astellas, LG Chem, formerly
AVEO Oncology, and EpicentRx establish our work with immunotherapies and in solid tumors. We are working on several preclinical programs
which include novel approaches to established targets such as HER2 and HER3, as well as novel targets that show immense potential for
radiotherapeutic approaches. Underpinning our development programs is our expanded patent portfolio of over 200 issued patents and pending
patent applications worldwide.
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We have utilized our technology platform to develop our clinical portfolio
in hematology – Iomab-B and Actimab-A, in conditioning for transplant and as a therapeutic, respectively. In addition, our robust
platform been used to develop a pipeline of novel radiotherapeutic assets to drive company growth. Preclinical pharmacology studies with
our targeted radiotherapeutics such as HER3-ARC, HER2-ARC or CD33-ARC have shown dramatic improvement in tumor growth inhibition in various
preclinical tumor models as single agents or in combination with immunotherapy such as magrolimab, an anti-CD47 monoclonal antibody. These
results have prompted the team to spearhead efforts in multiple solid tumor programs.
Actinium’s lead solid tumor program is a targeted radiotherapy
against HER3, a pan-cancer target that is overexpressed in several solid tumor indications with high unmet need. In April 2022, we presented
the first HER3-targeted radiotherapeutic agent at the American Association for Cancer Research (“AACR”) Annual Meeting showing
potent tumor cell cytotoxicity, enhanced antitumor effects and significantly improved survival with an Ac-225 radiolabeled HER3 antibody
compared to a naked HER3 antibody in a preclinical non-small cell lung cancer (“NSCLC”) model. We have also demonstrated the
direct impact of targeted radiotherapy in modulating immune signals such as calreticulin upregulation to enhance tumor cell killing. Further,
we have leveraged the immunomodulatory effect(s) of targeted radiotherapy in combination with CD47 targeting agents such as magrolimab
for sustained tumor growth inhibition in mouse models of AML and NSCLC. These results were presented at the Society for Immunotherapy
of Cancer (“SITC”) Annual Meeting held in 2021.
Our R&D team continues to expand on capabilities
and technologies across therapeutic modalities, linker technologies and in vivo cancer models, and build significant visibility through
presentations at key conferences and publications in journals of high impact. Our R&D efforts are centered on the advancement of our
key programs with a robust “fast-to-clinic” approach in niche indications and are backed by an extensive IP estate that comprises
over 200 patents and patent applications including the methods of Ac-225 production.
Our Platform Technology
Our proprietary technology platform is built on
the core competency to produce targeted radiotherapeutics, and coupled with our know-how and IP, establishes our company in the development
of isotope-agnostic, multi-targeted products that may address the treatment of hard-to-treat diseases. In our clinical and preclinical
programs, we have utilized multiple isotopes including Ac-225, I-131 and Lutetium-177 directed at multiple targets in oncology and hematology
such as CD45, CD33, HER3, among others. Our targeted radiotherapies combine the cell-killing ability of radiation via a radioisotope payload
with a targeting agent, such as a monoclonal antibody.
In addition to developing targeted radiotherapies, we also own patents
related to the manufacturing of Ac-225 in a cyclotron. We have expertise in utilizing the alpha emitting isotope Ac-225 including clinical
experience in treating approximately 150 patients with our alpha-emitter-based therapies, “gold standard” linker technology
and five issued patents in the U.S. and 49 patents internationally related to the manufacturing or Ac-225 in a cyclotron, which we believe
has the potential to produce higher quantities of highly pure Ac-225 than current methods. When appropriate, we are well-positioned to
leverage this technology to produce Ac-225.
Intellectual Property
Our proprietary technology platform is supported
by IP, know-how and trade secrets that cover the generation, development, methods of use and manufacture of targeted radiotherapies and
their select components. Our IP covers various methods of use in multiple diseases, including indication, dose and scheduling, radionuclide
warhead, and therapeutic combinations.
As of March 2023, we have expanded our patent
portfolio to over 200 issued patents and pending patent applications worldwide, which we believe constitutes a valuable business asset.
Our IP includes 45 patent families, including key patents that relate primarily to our radiotherapeutic candidates. Our patent portfolio
includes 12 issued patents and 39 pending patent applications in the U.S., and 151 that are issued or pending internationally. The effective
lives of the issued patents in our portfolio, or patents that may issue from the pending applications in our portfolio, ranges from expirations