UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 10-K
(Mark One)
☒ Annual Report Pursuant To Section 13 or
15(d) Of The Securities Exchange Act Of 1934
For the fiscal year endedDecember 31,
2023
or
☐ Transition Report Pursuant To Section 13
or 15(d) Of The Securities Exchange Act Of 1934
For the transition period from _____ to _____
COMMISSION FILE NUMBER: 001-36374
ACTINIUM PHARMACEUTICALS, INC.
(Exact name of registrant as specified in its charter)
100 Park Ave., 23rd Floor
New York, NY10017
(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
Securities registered
pursuant to Section 12(g) of the Act: None
Indicate by check mark if the registrant is a
well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☐ No ☒
Indicate by check mark if the registrant is not
required to file reports pursuant to Section 13 or Section 15(d) of the Act. Yes ☐ No ☒
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
☐
Indicate by check mark whether the registrant
is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company, or an emerging growth company.
See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,”
and “emerging growth company” in Rule 12b-2 of the Exchange Act.
Large accelerated filer ☐ Accelerated filer ☐
Non-accelerated filer ☒ Smaller reporting company ☒
Emerging growth company ☐
If an emerging growth company, indicate by check
mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting
standards provided pursuant to Section 13(a) of the Exchange Act. ☐
Indicate by check mark whether the registrant
has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial
reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or
issued its audit report. ☐
If securities are registered pursuant to Section
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. ☐
Indicate by check mark whether any of those error
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). ☐
Indicate by check mark whether the registrant
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, 2023, 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, 2023 was $200,262,958.
As of March 27, 2024, 29,396,411 shares of common
stock, $0.001 par value per share, were outstanding.
Table of Contents
Item 1. Business 1
Item 1A. Risk Factors 30
Item 1B. Unresolved Staff Comments 61
Item 1C. Cybersecurity 61
Item 2. Properties 61
Item 3. Legal Proceedings 61
Item 4. Mine Safety Disclosures 61
Item 6. Reserved 62
Item 7A. Quantitative and Qualitative Disclosures About Market Risk 69
Item 8. Financial Statements and Supplementary Data F-1
Item 9A. Controls and Procedures 70
Item 9B. Other Information 70
Item 9C Disclosure Regarding Foreign Jurisdictions That Prevent Inspections 70
Item 10. Directors, Executive Officers and Corporate Governance 71
Item 11. Executive Compensation 83
Item 12. Security Ownership of Certain Beneficial Owners and Management 87
Item 14. Principal Accountant Fees and Services 89
Item 15. Exhibits, Financial Statement Schedules 90
Signature Page 94
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” or the “Company”)
develops targeted radiotherapies intended to meaningfully improve survival for patients with relapsed or refractory cancer who have failed
existing therapies. Our vision is to build a specialty, hospital-focused, radiotherapeutics company that develops and markets medicines
for patients who are treated primarily in large quaternary care hospitals and their catchment areas. We are deploying our technology platform,
which we believe to be industry-leading, and intellectual property, with over 230 issued and pending patents worldwide, to develop ARCs,
or Antibody Radiation Conjugates, and next-generation radiotherapies against validated cancer targets.
Pipeline Highlights
We intend to leverage the
clinical data of our lead product candidates, Iomab-B and Actimab-A, to potentially improve outcomes in patients with relapsed or refractory
acute myeloid leukemia (“r/r AML”) by launching two radiotherapy drugs over the next several years to address the significant
unmet need for better outcomes from treatment with therapeutics or from undergoing a bone marrow transplant (“BMT”).
We also intend to further advance Iomab-B beyond acute myeloid leukemia
(“AML”), based on promising data as a disease control and conditioning agent for various other blood cancers. Based on early
clinical trial results, we are also working on a next-generation conditioning program, Iomab-ACT, for rapidly growing cell and gene therapies.
Our Next Generation ARC Pipeline
AML is an aggressive, heterogeneous disease that is difficult to treat.
Over 50% of AML patients develop relapsed or refractory disease within one year of being afflicted and have an extremely poor prognosis
and dismal survival. Currently, a BMT is regarded as being able to provide the best treatment outcome and is the only curative regimen
available for AML patients, however, access is limited to less than 20% of all AML patients, as patients must be 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, the challenge of the transplant itself or post-transplant complications.
1
Our Iomab-B and Actimab-A product candidates have the potential to
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, an ARC that is comprised of the anti-CD45 apamistamab and the radioisotope iodine-131 (“I-131”), is being developed
as a targeted bridging therapy candidate that we believe could provide both disease control and conditioning in one agent. We believe
the results from our Phase 3 Study of Iomab-B in Elderly Relapsed or Refractor AML “SIERRA trial” demonstrate the possibility
for unprecedented access to a BMT and improved survival in unfit patients who are currently not considered transplantable in routine clinical
practice. We are developing Actimab-A, an ARC comprised of the anti-CD33 lintuzumab and the radioisotope actinium-225 (“Ac-225”),
as a targeted therapy candidate for fit patients. Actimab-A has demonstrated an extension in survival in a proof-of-concept study and
is poised for advanced development and program expansion in collaboration with the National Cancer Institute (“NCI”). Together,
we believe these two product candidates could provide us the opportunity to transform the treatment of AML, especially in the relapsed
and refractory segment which represents over 50% of AML patients.
Iomab-B was evaluated in
the randomized SIERRA trial and met the primary endpoint of durable Complete Remission (“dCR”) with a high degree of
statistical significance (p<0.0001). In February 2023, we announced full SIERRA trial results, demonstrating unprecedented
transplant access and improved outcomes in patients with r/r AML, with double 1-year and median overall survival (“OS”)
compared to control-arm patients. These data were presented at the 2023 Tandem Meetings aka the Transplantation & Cellular
Therapy (“TCT”) 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 from the SIERRA
trial may provide the opportunity, if we are able to obtain U.S. Food and Drug Administration (“FDA”) approval, to
establish Iomab-B as a potential new standard of care.
The results from the SIERRA trial have been and are expected to be
presented at the most prestigious and high-impact bone marrow transplant and hematology medical conferences, nuclear medicine conferences
and nursing congresses. This wide exposure is helping broaden the awareness of Iomab-B among members of these relevant medical and scientific
communities as we and our partner Immedica Pharma AB (“Immedica”) prepare for potential commercialization in the US and European,
Middle East and North Africa (“EUMENA”) region subject to FDA and marketing authorization application (“MAA”)
approvals, respectively. Including TCT, the SIERRA Phase 3 results have now been highlighted in oral presentations at several U.S. and
European bone marrow transplant, hematology, nuclear medicine and nursing conferences attended by key Iomab-B stakeholders, including
bone marrow transplant physicians, hematologists and nuclear medicine physicians.
2
Iomab-B SIERRA trial data
presentations include:
● Oncology Nursing Society (“ONS”) 48th Annual Congress, April 2023
● European Hematology Association (“EHA”) 2023 Hybrid Congress, June 2023
● Society of Hematologic Oncology (“SOHO”) 2023 Annual Meeting, September 2023
We believe that the medical
and scientific communities present at these events took note of the positive SIERRA clinical trial results and their potential positive
impact in treating elderly r/r AML patients, the safety and tolerability of Iomab-B and the successful administration of Iomab-B infusions
at various BMT centers, which was done without increasing radiation exposure risks to treating nursing staff. The SIERRA results were
awarded the Henry N. Wagner, Jr., Abstract of the Year award at SNMMI, representing the top selection out of more than 1,500 abstracts
accepted for presentation, which we believe highlights the recognition by the nuclear medicine community.
Iomab-B SIERRA trial data
presented in an oral presentation at ASH in December 2023 detailed survival outcomes of patients with a TP53 mutation enrolled in the
SIERRA trial, highlighting improved survival in patients who received Iomab-B. A total of 37 patients (24.2%) enrolled in the SIERRA trial
had a TP53 mutation with 17 patients randomized to the Iomab-B arm and 20 patients randomized to the control arm of the study. Median
OS for TP53 negative patients receiving Iomab-B was 6.37 months and 5.72 months for TP53 positive patients. In the control arm (including
crossover patients), the median OS for TP53 positive patients was 2.96 months. Iomab-B was shown to significantly improve outcomes in
TP53 positive patients (initial randomization and crossover patients) with a median OS of 5.49 months versus 1.66 months in patients that
did not receive Iomab-B (hazard ratio 0.23, p-value=0.0002). These results for patients with a TP53 mutation were also accepted for oral
presentation at the EBMT 50th Annual Meeting in Glasgow, UK to be held on April 14 through April 17, 2024. Most recently, at
the 2024 Tandem Meetings held from February 21 through February 24, 2024, in San Antonio, Texas, five abstracts were accepted for two
oral presentations and three poster presentations. Two posters detailed results and findings from the SIERRA trial of Iomab-B, including
outcomes in patients with a TP53 mutation and dosimetry details and another poster for a Phase 1 study demonstrating safety and lymphodepletion
from Iomab-ACT conditioning with CD19 CAR-T therapy. In an oral presentation, data from the SIERRA trial highlighted the outcomes and
safety of Iomab-B in patients 65 years and older that were similar to what we presented for the overall SIERRA population, and the second
oral presentation highlighted unprecedented BMT engraftment in patients receiving a therapeutic dose of Iomab-B, and demonstration of
successful donor chimerism was presented. The data presented from the SIERRA trial highlight the opportunity for Iomab-B to provide better
access and outcomes in these hard-to-treat sub-groups, including patients with a TP53 mutation and those 65 years of age and older.
We continue to advance our efforts
to file our Biologics License Application (“BLA”) for Iomab-B to the FDA and support Immedica, our EUMENA commercial partner,
with the MAA for Iomab-B with the European Medicines Agency (“EMA”). We conducted a successful meeting with the FDA where
we received positive feedback regarding our Chemistry, Manufacturing and Controls (“CMC”) package for Iomab-B and have been
assigned a BLA number. We have also submitted a meeting request with the FDA to continue to discuss the clinical and non-clinical sections
of our BLA package prior to submitting our BLA filing and expect to hold this meeting in the second quarter of 2024. As part of the MAA
filing process, Immedica has conducted meetings to review the SIERRA trial clinical and CMC data with its rapporteur and co-rapporteur,
representatives of EU member states designated to lead the evaluation of an MAA application, and following those meetings Immedica is
proceeding with its MAA filing for Iomab-B. Based on our current assumptions, we believe we may be able to receive regulatory approval
for Iomab-B in 2025. We are committed to working to bring Iomab-B to patients globally, as there are a significant number of patients
with r/r AML globally. Europe represents a large commercial market opportunity with approximately twice as many transplants performed
compared to the United States. We also plan to seek approvals in Canada, Latin America and the Asia-Pacific region following U.S. or EU
approval, either ourselves or in collaboration with potential future partners.
3
We are also working on a next-generation
conditioning program, Iomab-ACT, for the rapidly growing cell and gene therapy market. We have a National Institutes of Health (“NIH”)-funded
ongoing proof-of-concept study with Memorial Sloan Kettering Cancer Center (“MSKCC”) using single agent Iomab-ACT as conditioning
in place of traditional fludarabine and cyclophosphamide (“Flu/Cy”) to achieve improved lymphodepletion prior to CD19 CAR-T
treatment in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (“ALL”) or diffuse large B-cell lymphoma
(“DLBCL”). The consistent CD45 expression on select immune and hematopoietic cells leads to potent lymphodepletion and
reduced cytokine release syndrome (“CRS”) and immune effector cell–associated neurotoxicity syndrome (“ICANS”)
with a single dose administered in an outpatient setting. The NIH grant was recently extended to fund the ongoing clinical trial with
MSKCC. In March 2024, we announced a new clinical trial that will study Iomab-ACT as targeted conditioning prior to patients receiving
an FDA approved commercial CAR-T therapy. This trial will be conducted at the University of Texas Southwestern and will start recruiting
patients following FDA review and clearance of the study. To our knowledge, this is the first time a targeted radiotherapy conditioning
regimen will be used prior to a commercial CAR-T therapy.
We have an industry-leading
clinical development program investigating Actimab-A, a CD33 targeting ARC conjugated to the potent alpha radiation emitting isotope Ac-225,
that has been studied in approximately 150 patients treated over six 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, including chemotherapies and targeted
agents utilizing its potential mechanistic synergies. We are attempting to leverage the mutation-agnostic ability of Ac-225 to establish
Actimab-A as a backbone therapy in AML, an extremely heterogenous and radiosensitive disease.
We believe our Actimab-A +
CLAG-M therapeutic combination trial results in r/r AML validate this approach. Phase 1 results from the Actimab-A + CLAG-M combination
trial showed high response rates and minimal residual disease (“MRD”) negativity, translating to a survival benefit in patients
who are typically expected to live two to four months. On September 6, 2023, updated data from the Actimab-A + CLAG-M combination trial
was presented at SOHO where 1-year OS for patients with prior venetoclax treatment was 46% and 48% in all patients receiving Actimab-A
+ CLAG-M treatment. In patients who received a transplant, the median OS was 24 months or more.
In 2023, we announced the
NCI Cooperative Research and Development Agreement (“CRADA”) 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 approve all protocols and has full rights
to all data. The NCI CRADA provides for Actinium to supply Actimab-A and for NCI to cover all clinical trial execution and development
expenses. The NCI CRADA is anticipated to have a material balance sheet sparing impact over the next several years. We expect the NCI
to initiate further development of Actimab-A in combination with CLAG-M and other targeted agents to broaden the scope of its development
in r/r AML.
Our Phase 1 data showed the
combination of Actimab-A + venetoclax was well-tolerated with responses, including a CR and a partial response in early dose-escalation
cohorts. Additionally, at SOHO, we presented the first-ever preclinical data demonstrating the potential synergy of Actimab-A with FLT3
(Fms-like tyrosine kinase 3) inhibitors gilteritinib and midostaurin. FLT3 is one of the most commonly mutated genes in AML and is associated
with aggressive disease with poor outcomes. Actimab-A was shown to have single-agent activity against FLT3 mutant AML cell lines, supporting
its mutation-agnostic mechanism, and enhanced the anti-leukemic activity of the FLT3 inhibition in vitro.
CD33-expressing myeloid derived
suppressor cells, (“MDSCs”), are present within the tumor microenvironment and exert immunosuppressive effects. In April 2023,
we presented preclinical data at the Association for Cancer Research (“AACR”) Annual Meeting that depicted Actimab-A’s
role in the tumor microenvironment to overcome immunosuppression driven by MDSCs. We believe that our findings show that Actimab-A has
the potential to selectively deplete MDSCs in lung, colorectal and other cancers. Actimab-A also demonstrated statistically significant
depletion of human MDSCs compared to Mylotarg, a CD33-targeted antibody-drug conjugate (“ADC”) in colorectal cancer (p<0.01),
highlighting the potent cytotoxicity and potential therapeutic benefit of radiotherapy compared to naked antibodies or ADCs. Actimab-A
demonstrates the advantages of ARCs over ADCs by using the power of radiation, against which cells have no known resistance or repair
mechanism. Radiation can cause double stranded breaks in DNA, which lead to cancer cell death. At the Society of Immunotherapy of Cancer
(“SITC”) 38th Annual Meeting on November 4, 2023, data was presented highlighting Actimab-A’s unique
ability to target and deplete MDSCs and restore T-cell proliferation and effector response. SPECT/CT imaging confirmed uptake of Actimab-A
in a humanized non-small cell lung cancer model, indicating enrichment of CD33+ MDSCs in the tumor microenvironment. We believe that the
data continues to support our objective to demonstrate the potential for Actimab-A to be a backbone therapy to broadly improve antitumor
activity of immunotherapies and other targeted therapeutic modalities.
4
To realize the broader development potential for Actimab-A, we are
exploring its role as a maintenance therapy for various indications through our research and development (“R&D”) efforts. Despite advances in therapeutics, a major
concern remains, with relapse risk greater than 50% for adults with high-risk AML. The goal of maintenance therapy is to improve overall
survival and eradicate MRD. Having demonstrated 72% MRD negativity rate in r/r AML patients who received Actimab-A + CLAG-M and achieved
CR/CRi (Complete Remission with incomplete count recovery), we aim to develop a treatment strategy in the maintenance setting utilizing
Actimab-A alone or in various combinations.
Our ARC product
candidates are intended to combine the targeting ability of monoclonal antibodies (“mAb”) with the cell-killing ability
of radioisotopes. Our ARC product candidates target antigens that are expressed on certain cancer cell types and are able to
destroy cellular DNA and kill these cells with the energy that they emit. We are deploying our technology platform, which we believe to be industry-leading,
and intellectual property, with over 230 issued patents and pending patent applications worldwide, to develop ARCs and
next-generation targeted radiotherapies that we intend to be ideally suited for particular disease indications and patient populations. We are
working on several preclinical programs that include novel approaches to validated cancer targets, as well as novel targets that
show immense potential for radiotherapeutic approaches. We have several ongoing programs in solid tumors at the pre-clinical stage
with investigational new drug (“IND”) enabling studies underway. Our research collaborations with large pharmaceutical
and biotech companies such as Astellas Pharma Inc. (“Astellas”), AVEO Oncology/LG Chem (“LG Chem”), and
EpicentRx, Inc. (“EpicentRx”) established our work with immunotherapies and in solid tumors in 2023 and years prior.
Preclinical pharmacology studies with our targeted radiotherapeutics directed at validated cancer targets have shown strong
improvement in tumor growth inhibition in various preclinical tumor models, prompting our efforts in multiple solid tumor
programs.
At year-end 2023, we had approximately $76.7 million of cash on hand. As
of March 27, 2024, our unaudited cash on hand of $84.3 million is expected to fund operations into the second half of 2026, which we believe
will provide a path for Actinium to potentially achieve regulatory approvals for Iomab-B in the U.S., EUMENA, and other regions, advance
Actimab-A through multiple trials in front-line and r/r AML settings to realize our vision. In addition, we expect to continue to advance
Iomab-ACT for cell and gene therapy conditioning, advance key R&D solid tumor programs and realize the value of our Ac-225 manufacturing
technology and know-how.
Market Opportunity
The market opportunity for
Iomab-B and Actimab-A, as depicted in the diagram below, exists for AML therapies 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. Today, less than 20% of all AML patients and less than 5% of r/r AML patients
are able to access a BMT, currently the only potentially curative option. Most patients receiving BMT are fit, in remission 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.
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. In a retrospective analysis of
commercial payer data published in the Journal of Managed Care & Specialty Pharmacy, total mean episode costs for patients with
r/r AML were approximately $439 thousand, with hospitalization as the largest contributor to cost. Over 50% of patients diagnosed
with AML will develop relapsed or refractory disease, with a median age of 68 years at diagnosis. In the U.S., 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. Despite 11 new approved therapies since 2017, no significant advancements have
been made toward a cure and there is an important unmet medical need for better therapeutics, which provides the opportunity for
Actimab-A. 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.
5
In the U.S. and the five largest countries in Western Europe (France, Germany,
Italy, Spain and the United Kingdom, which we refer to as “EU5”), we believe there is the potential market opportunity to
address more than 85 thousand r/r AML patients, as shown above. Globally, the number of BMTs performed has doubled in the last 10 years,
with an estimated ~70 thousand allogeneic BMTs performed annually. Europe represents 40% of BMTs, the largest share of any continent globally.
Similar to the U.S., we believe the EUMENA market opportunity for Iomab-B has favorable commercial dynamics where the majority of the
estimated7,200 BMTs performed in AML patients (approximately twice the number of BMTs performed in the U.S.) are concentrated in major
centers that treat the majority of patients in each country and region.
Iomab-B has also 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 a potential opportunity
to expand the market for Iomab-B beyond AML via label expansion. In the U.S., there are approximately 185,000 patients diagnosed annually
with blood cancers (e.g., leukemia, lymphoma, and myeloma) that are treatable with BMT, of which, 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 and reach approximately 93,000 patients in the U.S. by 2030 based on the current
pipeline of therapies. The CAR-T market size in terms of revenue is estimated to grow at a CAGR of approximately 11% over the next 5 plus
years. Currently, there are six CAR T-cell therapies approved by the FDA that are used to treat patients with lymphomas, leukemia and
multiple myeloma, which collectively had total sales over $3.5 billion in 2023. 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 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. We believe
an opportunity exists for Iomab-ACT to potentially generate significant revenue, if it can provide one or more clinical benefits related
to lower CRS, less neurotoxicity, longer duration of response or a higher overall success rate of cellular therapy due to benefits of
targeted conditioning.
6
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 or refractory disease
in cancer indications with high unmet medical need, with limited or no competition, and where the primary delivery of care occurs in large
comprehensive cancer care centers, is the appropriate strategy for our company. We believe that 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 ARC product candidates, Iomab-B and Actimab-A.
We intend to transform the
treatment of AML with our Iomab-B and Actimab-A product candidates, each of which has demonstrated extension of survival in the most difficult-to-treat
patients who are typically expected to survive for 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 the clinical evidence with these product candidates, we intend to develop and commercialize these two radiotherapy drugs, starting
with Iomab-B and followed by Actimab-A, if approved, with the goal of improving 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
We believe 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% 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 we believe will enable us to deploy a relatively
small commercial organization and operate an appropriately sized supply chain.
7
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 r/r 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:
8
In keeping with our strategic vision over the next several years, we
plan to first focus on ensuring an Iomab-B approval and successful launch into core BMT centers in the U.S. and working with our partner
Immedica to support its commercial success. We intend to expand the Iomab-B label and its revenue stream while progressing the development
of Actimab-A by leveraging the NCI CRADA. We will endeavor to progress the development of Iomab-ACT to proof-of-concept and explore potential
partnerships as a means to achieve commercialization. Our solid tumor programs are expected to progress toward the clinic as we continue
to build out our commercial footprint into the top 100 hospitals, which we hope will position us to develop our ARCs in line with our
vision. With commercial dynamics aligning favorably for a successful Iomab-B launch and with late-stage development of Actimab-A planned
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.
Our ARC Pipeline
We have strategically focused
our development efforts in areas where there is a significant unmet medical need. Our novel Antibody Radiation Conjugates or ARCs have
the potential to positively impact the outcomes of people living with hard-to-treat diseases such as r/r AML and we are developing both
therapeutic and induction/conditioning agents for this purpose. Outside of AML, our ARC pipeline development offers the opportunity to
enhance the value proposition of cell and gene therapies with our clinical stage targeted conditioning programs.
9
AML Focused ARC Programs – Iomab-B
and Actimab-A
Our ARC product candidates,
Iomab-B and Actimab-A, 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 ARC 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 (induction) 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 potential 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 trial conducted in Germany
from 2015 to 2022 explored outcomes in patients proceeding to BMT but enrolled r/r AML patients FIT to tolerate sequential conditioning,
an intensive, salvage chemotherapy-based regimen. Scheitleg et al. presented their findings at ASH in December 2022 titled, In Patients
with Relapsed/Refractory AML Sequential Conditioning and Immediate Allogeneic Stem Cell Transplantation (allo-HCT) Results in Similar
Overall and Leukemia-Free Survival Compared to Intensive Remission Induction Chemotherapy Followed By Allo-HCT: Results from the Randomized
Phase III ASAP Trial or (the “ASAP trial”). 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.
10
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. However, we believe the ASAP trial results
support the use of Iomab-B, which is intended to enable patients with active r/r AML to proceed directly to BMT, without first achieving
CR with salvage induction chemotherapy. By doing so, we seek to reduce the amount and severity of toxicities, allowing patients to receive
their BMT in better physical condition, reducing the need for in-patient hospital admissions, providing a pharmacoeconomic benefit, increasing
access to potentially curative BMT and improve patient outcomes. We believe 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 could 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. 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.
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 approximately 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 addressed 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.
11
We believe the SIERRA results presented in the late-breaker session at
the 2023 Tandem Meetings, support Iomab-B’s value proposition of enabling both improved access and outcomes of a BMT, thereby providing
a curative option for r/r AML 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 was 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 6-months
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.
12
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 6-months 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 (“ITT”) 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.
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 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.
13
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.
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 6 months 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 (Complete Remission with partial hematologic recovery) or crossing over, patient
not receiving BMT, or a patient relapse or death.
14
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 on to 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%).
Grade ≥3 Treatment-Emergent Adverse Events
in Transplanted Patients Through Day 100 Post-HCT
15
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 the 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 a 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
At the 2024 Tandem Meetings,
Iomab-B SIERRA trial data in an oral presentation detailed survival outcomes of patients with a TP53 mutation enrolled in the SIERRA
trial, highlighting improved survival in patients who received Iomab-B. A total of 37 patients (24.2%) enrolled on the SIERRA trial had
a TP53 mutation with 17 patients randomized to the Iomab-B arm and 20 patients randomized to the control arm of the study. Median OS
for TP53 negative patients receiving Iomab-B was 6.37 months and 5.72 months for TP53 positive patients. In the control arm (including
crossover patients), the median OS for TP53 positive patients was 2.96 months. Iomab-B was shown to significantly improve outcomes in
TP53 positive patients (initial randomization and crossover patients) with a median OS of 5.49 months versus 1.66 months in patients
that did not receive Iomab-B (hazard ratio 0.23, p-value=0.0002). These results for patients with a TP53 mutation were also accepted
for oral presentation at the EBMT 50th Annual Meeting in Glasgow, UK to be held on April 14 through April 17, 2024. In a second
oral presentation, data from the SIERRA trial highlighted the outcomes and safety of Iomab-B in patients 65 years and older that were
similar to what we presented for the overall SIERRA population. The data presented from the SIERRA trial highlight the opportunity for
Iomab-B to provide better access and outcomes in these hard-to-treat sub-groups, including patients with a TP53 mutation and those 65
years of age and older.
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 plan to commercialize
Iomab-B in the U.S. The commercial opportunity is supported by favorable dynamics, summarized by the “Three Ps and Two Cs”:
16
We believe the favorable commercial
dynamics for Iomab-B in the U.S. are further supported by the foundation of core competencies, developed during the successful execution
of the SIERRA trial at leading high-volume BMT centers. We established and actively managed an 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 KOLs 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 exclusively
licensed the EUMENA commercial rights for Iomab-B to Immedica, an independent pharmaceutical company headquartered in Sweden. Immedica
is solely responsible for the commercialization of the product. 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 are an estimated ~7,200 BMTs for AML in EUMENA, two times that of the U.S.,
performed in a concentrated number of centers. The incidence rate of AML in Europe is 3.7 per 100,000, or approximately 27,500 new patients
per year. Iomab-B has been granted Orphan Drug Designation by the EMA and has received positive Scientific Advice from EMA prior to the
start of the SIERRA trial. Immedica has had rapporteur and co-rapporteur meetings to discuss the SIERRA trial clinical and CMC data, and
based on these meetings is proceeding with its MAA filing for Iomab-B.
Background on Iomab-B
Iomab-B is a first-in-class
ARC consisting of apamistamab, an anti-CD45 mouse antibody conjugated to radioactive 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 use these data as we plan for label expansion of Iomab-B. Iomab-B has been
granted Orphan Drug Designation from the FDA and has patent protection into 2037.
Actimab-A – CD33 targeting ARC –
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, using the mutation-agnostic mechanism of action of Actimab-A. There is no known resistance mechanism
to targeted ARCs, making Actimab-A a candidate for a variety of combinations. The scientific rationale 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