Item 1. Business
Item 1. “Business”, Part I; Item 1A. “Risk Factors”, Part I; Item 3. “Legal Proceedings”, Part I
and Part II; Item 7. “Management’s Discussion and Analysis of Financial Condition and Results of Operations”. Among
other things, for those statements, we claim the protection of safe harbor for forward-looking statements contained in the Private Securities
Litigation Reform Act of 1995. Any forward-looking statements set forth in this presentation speak only as of the date of this presentation.
We do not undertake to update any of these forward-looking statements to reflect events or circumstances that occur after the date hereof.
We are in various stages of seeking to determine whether Ampligen® will be effective in the treatment of multiple types of viral
diseases, cancers, and immune-deficiency disorders and the presentation sets forth our current and anticipated future activities. These
activities are subject to change for a number of reasons. Significant additional testing and trials will be required to determine whether
Ampligen® will be effective in the treatment of these conditions. Results obtained in animal models do not necessarily predict results
in humans. Human clinical trials will be necessary to prove whether or not Ampligen® will be efficacious in humans. No assurance
can be given as to whether current or planned clinical trials will be successful or yield favorable data and the trials are subject to
many factors including lack of regulatory approval(s), lack of study drug, or a change in priorities at the institutions sponsoring other
trials. Even if these clinical trials are initiated, we cannot assure that the clinical studies will be successful or yield any useful
data or require additional funding. Among the studies are clinical trials that provide only preliminary data with a small number of subjects,
and no assurance can be given that the findings in these studies will prove true or that the study or studies will yield favorable results.
Some of the world’s largest pharmaceutical companies and medical institutions are working on a treatment for COVID-19. Even if
Ampligen® proves effective in combating the virus, no assurance can be given that our actions toward proving this will be given first
priority or that another treatment that eventually proves capable will not make our efforts ultimately unproductive, as multiple vaccines,
and some treatments, are now available and major pharma companies are working to develop their own disease treatments. No assurance can
be given that future studies will not result in findings that are different from those reported in the studies referenced in this Report.
Operating in foreign countries carries with it a number of risks, including potential difficulties in enforcing intellectual property
rights. In addition, many countries, including Argentina, are still dealing with COVID-19 outbreaks and have made that their primary
focus. We believe that this may be delaying our commercialization of Ampligen® in Argentina until COVID-19 is more under control.
We cannot assure that our potential foreign operations will not be adversely affected by these risks.
7
Our
filings are available at www.aimimmuno.com. The information found on our website is not incorporated by reference into this Report and
is included for reference purposes only.
SUMMARY
RISK FACTORS
General
Risk Related to our Business
●
We
may require additional financing which may not be available.
●
We
may continue to incur substantial losses and our future profitability is uncertain.
●
Our
drug and related technologies are investigational and subject to regulatory approval. If we are unable to obtain regulatory approval
in a timely manner, or at all, our operations will be materially harmed and our stock adversely affected.
●
The
COVID-19 coronavirus or other global pandemics could adversely impact our business, including our clinical trials. We cannot predict
the ultimate effects of the COVID-19 virus on our business.
●
We
may be subject to product liability claims from the use of Ampligen, Alferon N Injection, or other of our products which could negatively
affect our future operations. We have limited product liability and clinical trial insurance.
●
Uncertainty
of health care reimbursement for our products.
●
There
are risks of liabilities associated with handling and disposing of hazardous materials.
●
We
rely upon information technology and any failure, inadequacy, interruption, or security lapse of that technology, including any cybersecurity
incidents, could harm our ability to operate our business effectively.
●
The
loss of services of key personnel could hurt our chances for success.
●
GAAP requires estimates, judgements and assumptions which inherently contain
uncertainties.
●
We
currently, and may in the future, have assets held at financial institutions that may exceed the insurance coverage offered by the
Federal Deposit Insurance Corporation, and the loss of such assets would have a severe negative affect on our operations and liquidity.
Risks Associated with Our Products
●
The development of Ampligen is subject to significant risks.
●
The development of Alferon N Injection is subject to significant risks.
●
Possible
side effects from the use of Ampligen or Alferon N Injection could adversely affect potential revenues and physician/patient acceptability
of our product.
Risks
Related to our activities associated with Ampligen’s potential effectiveness as a treatment for COVID-19 or Post-Covid Conditions
●
It
is not possible to predict the future of COVID-19, and related Post-COVID Conditions, as a global public health threat or the development
of related therapies. No assurance can be given that Ampligen will aid in or be applied to the treatment of this virus.
●
Operating
in foreign countries carries with it many risks.
Risks
Associated with Our Intellectual Property
●
We
may not be profitable unless we can protect our patents and/or receive approval for additional pending patents.
●
The
patent position of biotechnology and pharmaceutical firms is highly uncertain and involves complex legal and factual questions.
●
There
can be no assurance that we will be able to obtain necessary licenses if we cannot enforce patent rights we may hold. In addition,
the failure of third parties from whom we currently license certain proprietary information or from whom we may be required to obtain
such licenses in the future, to adequately enforce their rights to such proprietary information, could adversely affect the value
of such licenses to us.
●
There
is no guarantee that our trade secrets will not be disclosed or known by our competitors.
Risks
Associated with Our R&D
●
We
cannot predict what additional studies and/or additional testing or information may be required by the FDA. Accordingly, we are unable
to estimate the nature, timing, costs and necessary efforts to complete these projects nor the anticipated completion dates. In addition,
we have no basis for estimating when material net cash inflows may commence. We have yet to generate significant revenues from the sale
of these developmental products.
8
Risks
Associated with Our Manufacturing
●
Our
Alferon N Injection Commercial Sales were halted due to lack of finished goods inventory. If we are unable to gain the necessary
FDA approvals related to Alferon N Injection, or if we are unable to identify a CMO or CMOs that meet our requirements, then our
operations would most likely be materially and/or adversely affected.
●
There
are no long-term agreements with suppliers of required materials and services for Ampligen and there are a limited number of raw
material suppliers. If we are unable to obtain the required raw materials and/or services, we may not be able to manufacture Ampligen.
●
There
are limited number of organizations in the United States available to provide the final manufacturing steps of formulation, fill,
finish and packing sets for Alferon N Injection and Ampligen.
●
There
is no assurance that, upon success, manufacture of a drug on a limited-scale basis for investigational use would lead to a successful
transition to commercial, large-scale production.
●
We
have limited manufacturing experience for Ampligen and Alferon N Injection. We may not be profitable unless we can produce Ampligen,
Alferon N Injection or other products in commercial quantities at costs acceptable to us.
Risks
Associated with Our Licensing/Collaborations/Joint Ventures
●
If
we are unable to achieve licensing, collaboration and/or joint ventures, our marketing strategy for Ampligen will be part of the
differing health care systems around the world along with the different marketing and distribution systems that are used to supply
pharmaceutical products to those systems.
Risks
Associated with Our Marketing and Distribution
●
We
have limited marketing and sales capability. If we are unable to obtain additional distributors and our current and future distributors
do not market our products successfully, we may not generate significant revenues or become profitable.
Risks
Associated with Our Competition
●
Rapid
technological change may render our products obsolete or non-competitive.
●
Our
products may be subject to substantial competition.
Risks
Associated with an Investment in Our Common Stock
●
The
market price of our stock may be adversely affected by market volatility
●
Sales
of a significant number of shares of our common stock in the public markets, or the perception that such sales could occur, could
depress the market price of our common stock.
●
Provisions
of our Certificate of Incorporation and Delaware law could defer a change of our Management, which could discourage or delay offers
to acquire us.
●
Our
business, financial condition and operating results could be negatively affected as a result of actions by activist investors.
AVAILABLE
INFORMATION
We
file electronically with the United States Securities and Exchange Commission, or SEC, our annual reports on Form 10-K, quarterly reports
on Form 10-Q, current reports on Form 8-K, and amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the
Securities Exchange Act of 1934, as amended. We make available on our website at www.ao-inc.com free of charge, copies of these reports
as soon as reasonably practicable after filing these reports with, or furnishing them to, the SEC. We are subject to the information
and periodic reporting requirements of the Exchange Act and, in accordance therewith, we file periodic reports, proxy statements and
other information with the SEC. Such periodic reports, proxy statements and other information are available for inspection and copying
at the website of the SEC www.sec.gov . You also may obtain a free copy of our annual reports on Form 10-K, quarterly reports on
Form 10-Q, current reports on Form 8-K, proxy statements and amendments to those reports on the day of filing with the SEC on our website
at http://www.aimimmuno.com under the Investor Relations tab for SEC Filings or by contacting the Investor Relations Department
by calling (833) 475-8247 or (352) 448-7797 or sending an e-mail message to AIM@jtcir.com. Our Internet website and the information contained
on that website, or accessible from our website, is not intended to be incorporated into this Annual Report on Form 10-K or any other
filings we make with the SEC.
OUR
PRODUCTS
Our
primary pharmaceutical product platform consists of Ampligen (rintatolimod), a first-in-class drug of large macromolecular double-stranded
(ds) RNA (ribonucleic acid) molecules, and our FDA-approved natural alpha-interferon product, Alferon N Injection.
9
Ampligen®
Ampligen
is approved for sale in Argentina (to 2026) for severe CFS and is an experimental drug in the United States currently undergoing clinical
development for the treatment of certain cancers and ME/CFS. Over its developmental history, Ampligen has received various designations,
including Orphan Drug Product Designation (FDA and EMA), Treatment protocol (e.g., “Expanded Access” or “Compassionate”
use authorization) with Cost Recovery Authorization (FDA) and “promising” clinical outcome recognition based on the evaluation
of certain summary clinical reports (“AHRQ” or Agency for Healthcare Research and Quality). Based on the results of published,
peer-reviewed pre-clinical studies and clinical trials, we believe that Ampligen may have broad-spectrum antiviral and anti-cancer properties.
We
believe that nucleic acid compounds represent a potential new class of pharmaceutical products designed to act at the molecular level
for treatment of many human diseases. Ampligen represents the first drug in the class of large (macromolecular) dsRNA molecules to apply
for NDA review. There are two forms of nucleic acids: deoxyribonucleic acid (“DNA”) and ribonucleic acid (“RNA”).
DNA is a group of naturally occurring molecules found in chromosomes, the cell’s genetic machinery. RNA is a group of naturally
occurring informational molecules which orchestrate a cell’s behavior which, in turn, regulates the action of groups of cells,
including the cells which comprise the body’s immune system. RNA directs the production of proteins and regulates certain cell
activities including the activation of an otherwise dormant cellular defense against viruses and tumors. Our drug technology utilizes
specifically configured RNA and is a selective Toll-like Receptor 3 (“TLR3”) agonist that can be administered intravenously,
intranasally and intraperitoneally. Ampligen has been assigned the generic name rintatolimod by the United States Adopted Names Council
(“USANC”) and has the chemical designation poly(I):poly(C12U).
Expanded
Access Program/Early Access Programs/clinical trials of Ampligen that have been conducted or that are ongoing include studies of the
potential treatment of patients with pancreatic cancer, renal cell carcinoma, malignant melanoma, non-small cell lung cancer, ovarian
cancer, breast cancer, colorectal cancer, prostate cancer, ME/CFS, Hepatitis B, HIV, COVID-19 and Post-COVID conditions.
We
have received approval of our NDA from ANMAT for the commercial sale of Ampligen in the Argentine Republic for the treatment of severe
CFS. The product will be marketed by GP Pharm, our commercial partner in Latin America. Shipment of the drug product to Argentina was
initiated in 2018 to complete the release testing by ANMAT needed for commercial distribution. In September 2019, we received clearance
from the FDA to ship Ampligen to Argentina for the commercial launch and subsequent sales. In June 2020, we received import clearance
from ANMAT to import the first shipment of commercial grade vials of Ampligen into Argentina. We are currently working with GP Pharm
on the commercial launch of Ampligen in Argentina. Commercialization in Argentina will require, among other things, GP Pharm to establish
disease awareness, medical education, creation of an appropriate reimbursement level, design of marketing strategies and completion of
manufacturing preparations for launch and ANMAT conducting a final inspection of the product and release tests before granting final
approval to begin commercial sales. AIM has supplied GP Pharm with the Ampligen required for testing and ANMAT release. This testing
and approval process is ongoing due to ANMAT’s internal processes. Once final approval by ANMAT is obtained, GP Pharm will begin
distributing Ampligen in Argentina. We continue to pursue our Ampligen NDA, for the treatment of CFS with the FDA.
The
FDA has authorized an open-label expanded access treatment protocol (AMP-511) allowing patient access to Ampligen in a study under which
severely debilitated CFS patients have the opportunity to be on Ampligen to treat this serious and chronic condition. The AMP-511 protocol
started in the 1990s and is ongoing. The data collected from the AMP-511 protocol through clinical sites provide safety information regarding
the use of Ampligen in patients with CFS. We are establishing an enlarged database of clinical safety information which we believe will
provide further documentation regarding the absence of autoimmune disease associated with Ampligen treatment. We believe that continued
efforts to understand existing data, and to advance the development of new data and information, will ultimately support our future filings
for Ampligen and/or the design of future clinical studies that the FDA requested in a CRL. The FDA approved an increased reimbursement
level from $200 to $345 per 200 mg vial of Ampligen, due to increased production costs; which was re-authorized in 2021 and again in
2022. At this time, we do not plan on passing this adjustment along to the patients in this program. In October 2020, we received IRB
approval for the expansion of the AMP-511 Expanded Access Program clinical trial for ME/CFS to include patients previously diagnosed
with SARS-CoV-2 following clearance of the virus, but who still demonstrate chronic fatigue-like symptoms that we refer to as Post-COVID
conditions. As of December 31, 2023, there are 10 patients enrolled in this open-label expanded access treatment protocol. In July 2022,
AIM reported positive preliminary results based on data from the first four Post-COVID Condition patients enrolled in the study. The
data show that, by week 12, compared to baseline, the investigators observed what they considered a clinically significant decrease in
fatigue-related measures. To date, there have been eight such Post-COVID patients treated in this study.
In
May 2016, we entered into a five-year agreement with myTomorrows, a Netherlands based company, for the commencement and management of
an Early Access Program (“EAP”) in Europe and Turkey related to ME/CFS. Pursuant to the agreement, as amended, myTomorrows
also is managing all Early Access Programs and Special Access Programs in Europe, Canada, and Turkey to treat pancreatic cancer and ME/CFS
patients. The agreement was automatically extended for a period of 12 months on May 20, 2021; has been automatically extended for 12
months on each subsequent May 20; and will continue to be automatically extended for periods of 12 months every May 20 until terminated
or the terms of the agreement are met.
10
In
June 2018, Ampligen was cited as outperforming two other TLR3 agonists — poly IC and natural double stranded RNA — in creating
an enhanced tumor microenvironment for checkpoint blockade therapy in the journal of Cancer Research (http://cancerres.aacrjournals.org/content/early/2018/05/31/0008-5472.CAN-17-3985).
In a head-to-head study in explant culture models, Ampligen activated the TLR3 pathway and promoted an accumulation of killer T cells
but, unlike the other two TLR3 agonists, it did so without causing regulatory T cell (Treg) attraction. These findings were considered
important because they indicate that Ampligen selectively reprograms the tumor microenvironment by inducing the beneficial aspects of
tumor inflammation (attracting killer T cells), without amplifying immune-suppressive elements such as regulatory T cells. The study
was conducted at the University of Pittsburgh and Roswell Park as a part of the NIH-funded P01 CA132714 and Ovarian Cancer Specialized
Program of Research Excellence (“SPORE”).
In
2018, we completed production of two commercial-size batches of more than 16,000 vials of Ampligen, following its “Fill & Finish”
at Jubilant HollisterStier, the Contract Manufacturing Organization. These lots passed all required testing for regulatory release for
human use and are being used for multiple programs, including: the treatment of ME/CFS; the pancreatic cancer EAP in the Netherlands;
and will continue to be used for ongoing and future clinical studies in oncology. Additionally, two lots of Ampligen were manufactured
in December 2019 and January 2020 at Jubilant HollisterStier and we recently issued a purchase order for a total of $1,432,257 to manufacture
additional lots of Ampligen at Jubilant. The current manufactured lots of Ampligen have been fully tested and released for commercial
product launch in Argentina and for clinical trials. Additionally, in December 2020, we added Pii as a “Fill & Finish”
provider to enhance our capacity to produce Ampligen. This addition amplifies our manufacturing capability by providing redundancy and
cost savings. The contracts augment our active and in-process fill and finish capacity.
Alferon
N Injection®
Alferon
N Injection is the registered trademark for our injectable formulation of natural alpha interferon. Alferon N Injection is the only natural-source,
multi-species alpha interferon currently approved for sale in the United States and Argentina for the intralesional (within lesions)
treatment of refractory (resistant to other treatment) or recurring external genital warts in patients 18 years of age or older. Alferon
N Injection is also approved in Argentina for the treatment of refractory patients that failed or were intolerant to treatment with recombinant
interferons. Certain types of human papilloma viruses (“HPV”) cause genital warts, a sexually transmitted disease (“STD”).
According to the CDC, HPV is the most common sexually transmitted infection, with approximately 79 million Americans — most in
their late teens and early 20s — infected with HPV. In fact, the CDC states that “HPV is so common that nearly all sexually
active men and women get the virus at some point in their lives.” Although they do not usually result in death, genital warts commonly
recur, causing significant morbidity and entail substantial health care costs.
Interferons
are a group of proteins produced and secreted by cells to combat diseases. Researchers have identified four major classes of human interferon:
alpha, beta, gamma and omega. Alferon N Injection contains a multi-species form of alpha interferon. The worldwide market for injectable
alpha interferon-based products has experienced rapid growth and various alpha interferon injectable products are approved for many major
medical uses worldwide. Alpha interferons are manufactured commercially in three ways: by genetic engineering, by cell culture, and from
human white blood cells. All three of these types of alpha interferon are or were approved for commercial sale in the United States.
Our natural alpha interferon is produced from human white blood cells. The potential advantages of natural alpha interferon over recombinant
(i.e., synthetic) interferon produced and marketed by other pharmaceutical firms may be based upon their respective molecular compositions.
Natural alpha interferon is composed of a family of proteins containing many molecular species of interferon. In contrast, commercial
recombinant alpha interferon products each contain only a single species. Researchers have reported that the various species of interferons
may have differing antiviral activity depending upon the type of virus. Natural alpha interferon presents a broad complement of species,
which we believe may account for its higher activity in laboratory studies. Natural alpha interferon is also glycosylated (i.e., partially
covered with sugar molecules). Such glycosylation is not present on the currently U.S.-marketed recombinant alpha interferons. We believe
that the absence of glycosylation may be in part responsible for the production of interferon-neutralizing antibodies seen in patients
treated with recombinant alpha interferon. Although cell culture-derived interferon is also composed of multiple glycosylated alpha interferon
species, the types and relative quantity of these species are different from our natural alpha interferon.
Alferon
N Injection [Interferon alfa-n3 (human leukocyte derived)] is a highly purified, natural-source, glycosylated, multi-species alpha interferon
product. There are essentially no neutralizing antibodies observed against Alferon N Injection to date and the product has a relatively
low side-effect profile. The recombinant DNA derived alpha interferon formulations have been reported to have decreased effectiveness
after one year of treatment, probably due to neutralizing antibody formation (See “Manufacturing” and “Marketing/Distribution”
sections below for more details on the manufacture and marketing/distribution of Alferon N Injection). The production of new Alferon
N Injection Active Pharmaceutical Ingredient, or API, is currently on hold. We do not know when, if ever, our products will be generally
available for commercial sale for any indication. Additionally, on May 9, 2023, we were granted a U.S. Patent for a method for preventing
or reducing antigenic drift or viral reassortment in a host animal comprising determining if a host animal has been exposed to or infected
by an avian influenza virus and administering to the exposed host animal alpha-interferon.
11
PATENTS
AND NON-PATENT EXCLUSIVITY RIGHTS
We
consider patent exclusivity as a crucial component of our business. As of December 31, 2023, we had 54 patents worldwide with 66 additional
pending patent applications comprising our intellectual property.
We
continually review our patents to determine if they have continuing value. Please see “Note 4: Patents, and Trademark Rights, Net”
under Notes to the Consolidated Financial Statements for more information on these patents.
There
are no current patent litigation proceedings involving us.
Orphan
drug designation
U.S.
Orphan drug designation qualifies sponsors for incentives including:
●
Tax
credits for qualified clinical trials
●
Exemption
from user fees
●
Potential
seven years of market exclusivity after FDA approval
We
have received Orphan Drug Designation (ODD) from the FDA for Ampligen used in the treatment of Chronic Fatigue Syndrome, HIV, Metastatic
Melanoma, Renal Cell Carcinoma, Pancreatic Adenocarcinoma and Ebola Virus Disease.
In
the European Union, ODD carries ten years of market exclusivity after receiving marketing authorization. We have received ODD from the
EU for Ampligen used in the treatment of Ebola Virus Disease and Pancreatic Adenocarcinoma and for Alferon used in the treatment of Middle
East Respiratory Syndrome.
RESEARCH
AND DEVELOPMENT (“R&D”)
Our
general focus during the past several fiscal years has been on expanding the market potential of Ampligen through investigation of efficacy
(in vitro and in vivo) in different immune-based disorders including cancer and CFS. We also have focused on research and development
of potential prophylactic and therapeutic applications for the treatment of COVID-19, including the long-term effects of COVID-19.
Immuno-Oncology
The
potential of Ampligen as an immuno-oncology therapeutic has been a major focus of AIM since our current leadership took over in 2016.
We have been working with the University of Pittsburgh’s chemokine modulation research initiative, which includes the use of Ampligen
as a potential adjuvant to modify the tumor microenvironment (“TME”) with the goal of increasing anti-tumor responses to
check point inhibitors (“CPI”). As part of this collaboration, we have supplied Ampligen to the University. The study, under
the leadership of Robert P. Edwards, MD, chair of gynecologic services at Magee-Women’s Hospital of the University of Pittsburgh
School of Medicine, and Professor of Surgery Pawel Kalinski, M.D., Ph.D., at Roswell Park, Buffalo, N.Y., involved the chemokine modulatory
regimen developed by Dr. Kalinski’s group and successfully completed the Phase 1 dose escalation in patients with resectable colorectal
cancer.
Multiple
Ampligen clinical trials are underway or recently completed at major university cancer centers testing whether tumor microenvironments
can be reprogrammed to increase the effectiveness of cancer immunotherapy, including checkpoint inhibitors. The underway trials include:
●
Pancreatic
Cancer Trial - The Phase 2 AMP-270 clinical trial is a randomized, open-label, controlled,
parallel-arm study with the primary objective of comparing the efficacy of Ampligen versus
a no treatment control group following FOLFIRINOX for subjects with locally advanced pancreatic
adenocarcinoma. Secondary objectives include comparing safety and tolerability. The AMP-270
is expected to enroll approximately 90 subjects in up to 30 centers across the U.S. and Europe.
In March 2022, the FDA granted clearance to proceed with the study. In April 2022, we executed
a work order with Amarex to manage the clinical trial. In August 2022, we received IRB approval
of the trial protocol and so announced the trial’s commencement. The authorization
to proceed with the Phase 2 pancreatic cancer clinical trial has been received with potential
sites in the Netherlands at Erasmus MC under Prof. C.H.J. van Eijck, and also at major cancer
research centers in the United States such as The Buffett Cancer Center at the University
of Nebraska Medical Center (UNMC). The study is recruiting patients. (https://clinicaltrials.gov/ct2/show/NCT05494697).
12
●
Advanced
Recurrent Ovarian Cancer
○
Results
of the Phase 1 portion of a Phase 1/2 study of intraperitoneal chemo-immunotherapy in advanced recurrent ovarian cancer were published
in the American Association for Cancer Research publication, Clinical Cancer Research (Clin Cancer Res January 19, 2022 DOI: 10.1158/1078-0432.CCR-21-3659).
The study results represent an important extension of prior studies using human tumor explants that showed Ampligen’s potentially
important role as a TLR3 agonist acting synergistically with high-dose IFNα and celecoxib to selectively enhance Teff cell-attractants
while suppressing Treg-attractants in the tumor microenvironment with a concomitant increase in the Teff/Treg ratio. The importance
of boosting the Teff/Treg ratio in the tumor microenvironment is that it is associated with the conversion of ‘cold’
tumors into ‘hot’ tumors, which have an increased sensitivity to chemo-immunotherapy and an improved chance of showing
tumor regression. The Phase 1 portion was designed to establish intraperitoneal safety. The Phase 2 portion of the study is planned
to be conducted in the future. https://clinicaltrials.gov/ct2/show/NCT02432378
○
A
Phase 2 study of advanced recurrent ovarian cancer using cisplatin, pembrolizumab, plus Ampligen; up to 45 patients to be enrolled;
enrollment has commenced, and numerous patients have commenced treatment. We announced interim data from the study demonstrating
that evidence of increased biomarkers associated with T cell chemotaxis and cytolytic function was seen when combining Ampligen,
pembrolizumab and cisplatin. Increases of these biomarkers in the tumor microenvironment have been correlated with favorable tumor
responses. Interim results announced March 2022 detailed an observed clinical response rate of 61% includes two complete and three
partial tumor responses, plus three patients with stable disease among the 13 evaluable patients. An important priority will be to
confirm these findings through continuing to enroll patients onto this study. https://clinicaltrials.gov/ct2/show/NCT03734692
In
March 2021, we were granted a patent by the Netherlands Patent Office with granted patent claims that include, but are not limited to,
the use of Ampligen as a combination cancer therapy with checkpoint blockade inhibitors (e.g. pembrolizumab, nivolumab). Interim data
from an investigator-initiated, Phase 2, single-arm, efficacy/safety trial demonstrated that evidence of increased biomarkers associated
with T cell chemotaxis and cytolytic function was seen when combining Ampligen, pembrolizumab and cisplatin. It is critical to note that
increases of these biomarkers in the tumor microenvironment have been correlated with favorable tumor responses. All told, the study
has seen an Objective Response Rate (ORR) of 38.5%; a study of pembrolizumab alone in the treatment of advanced recurrent ovarian
cancer found ORR of 8.1% and 9.9% across two cohorts. We believe that the positive data makes this patent have heightened potential.
Similar patents are pending in other countries.
●
Stage
4 Metastatic Triple Negative Breast Cancer - Phase 1 study of metastatic triple-negative breast cancer using chemokine modulation
therapy, including Ampligen and pembrolizumab. Eight patients were enrolled and 6 patients were evaluable. https://www.clinicaltrials.gov/ct2/show/NCT03599453 .
The key findings announced in April 2022 included:
○
The
pre-determined primary endpoint of efficacy was met (increase in CD8 in TME).
○
Uniform
increase of immune markers upon treatment was observed: CD8 mRNA (6.1-fold; p-0.034), GZMB mRNA (3.5-fold; p=0.058), ratios of CD8
/FOXP3 and GZMB/FOXP3 (5.7-fold; p=0.036, and 7.6-fold; p=0.024 respectively), thus successfully meeting the pre-determined primary
endpoint in the study (increase in CD8 in TME).
○
In
addition, an increase in CTL attractants CXCL10 (2.6-fold; p=0.104) and CCL5 (3.3-fold; p=0.019) was observed. In contrast, Treg
marker FOXP3 or Treg attractants CCL22 or CXCL12 were not enhanced.
○
Three
patients had stable disease lasting 2.4, 2.5 and 3.8 months, as of data cut off September 1, 2021.
○
An
additional patient (non-evaluable) had a partial response (breast tumor autoamputation) with massive tumor necrosis in the post-CKM
biopsy.
13
●
Stage
4 Colorectal Cancer Metastatic to the Liver - Phase 2a study of Ampligen as a component of chemokine modulatory regimen on colorectal
cancer metastatic to liver; recruitment has been completed; 19 patients were enrolled and 12 patients were evaluable for the primary
endpoint https://clinicaltrials.gov/ct2/show/NCT03403634 . The key findings announced in April 2022 included:
○
The
study’s primary endpoint was met, evidenced by increased CD8a expression post-treatment (p=0.046).
○
Saw
increase in the CD8a/CD4 (p=0.03), CD8a/FOXP3 (p<0.01) and GZMB/FOXP3 (p<0.01) ratios.
○
The
expression of CTL-attracting chemokines CCL5 (p=0.08), CXCL9 (p=0.05), and CXCL10 (p=0.06) were increased, while expression of the
Treg/MDSC attractant CXCL12 (p=0.07) was decreased post-treatment.
○
Median
OS was 10.5 (90% CI 2.2-15.2) months, and the median PFS was 1.5 (90% CI 1.4, 1.8) months.
○
No
tumor responses were seen. The treatment was well tolerated. Of all enrolled patients (N=19), adverse events were noted in 74% of
patients, with the most common being fatigue (58%). Grade 3 or higher adverse events were rare (5%).
●
Early-Stage
Prostate Cancer - Phase 2 study investigating the effectiveness and safety of aspirin and Ampligen with or without interferon-alpha
2b (Intron A) compared to no drug treatments in a randomized three-arm study of patients with prostate cancer before undergoing radical
prostatectomy. Patient enrollment has been initiated in this study designed for up to 45 patients. The study is temporarily suspended
due to the Merck discontinuation of Intron-A production. Roswell Park has had a Type-C meeting with the FDA and is currently performing
the necessary experiments to replace Intron-A with a generic alpha-interferon. We expect this trial to resume in the near future.
https://clinicaltrials.gov/ct2/show/NCT03899987
●
Early-Stage
Triple Negative Breast Cancer - The objective of this Phase 1 study is to evaluate the safety and tolerability of a combination
of Ampligen, celecoxib with or without Intron A, when given along with chemotherapy in patients with early-stage triple negative
breast cancer. The now completed (as of September 2022) topline results from the study confirm
the positive findings that were previously presented at the 2022 Society for Immunotherapy of Cancer (SITC) 37 th
Annual Meeting in a poster presentation
titled Safety and efficacy of de-escalated neoadjuvant chemoimmunotherapy of triple negative breast cancer (TNBC) using
chemokine-modulating regimen (rintatolimod, IFN-α2b, celecoxib) . The
primary endpoint of the study was safety and tolerability. The results demonstrated that treatment was well-tolerated with mostly
grade 1 or 2 treatment-related adverse events (TRAEs) without dose-limiting toxicities (DLTs) or delayed or immune-related toxicities.
DLT was defined as grade 3 or higher toxicities within the first 3 weeks. Secondary endpoints included pCR rate where 5/9 (56%) of
patients attained pCR and 1 more patient attained ypTmic. Tumor and blood biomarkers were also analyzed in exploratory studies. https://clinicaltrials.gov/ct2/show/NCT04081389
●
Refractory
Melanoma — Roswell Park Comprehensive Cancer Center (“Roswell Park”), in a clinical trial fully funded by the
National Cancer Institute (NCI), has commenced patient enrollment in its Phase 2 study in subjects with primary PD-1/PD-L1 resistant
melanoma. The Phase 2 study will evaluate type-1 polarized dendritic cell (αDC1) vaccine in combination with tumor-selective
chemokine modulation (“CKM”) comprised of Interferon alpha 2b, Ampligen (rintatolimod) and Celecoxib. Up to 24 patients
are to be enrolled. The study was temporarily suspended due to the Merck discontinuation of Intron-A production but has since resumed
recruitment (See: https://www.clinicaltrials.gov/show/NCT04093323 ).
●
Metastatic
or Unresectable Triple Negative Breast Cancer – This phase ½a trial tests the safety, side effects, and best dose
of chemokine modulation therapy (CKM) (rintatolimod, celecoxib, and interferon alpha 2b) in combination with pembrolizumab for the
treatment of patients with triple negative breast cancer that has spread from where it first started (primary site) to other places
in the body (metastatic) or that cannot be removed by surgery (unresectable). The study is recruiting subjects.
https://clinicaltrials.gov/study/NCT05756166
Additional
Progress and Analysis Related to Pancreatic Cancer
In
January 2017, the EAP established under our agreement with myTomorrows to enable access of Ampligen to ME/CFS patients was extended to
pancreatic cancer patients beginning in the Netherlands. myTomorrows is our exclusive service provider in Europe and Turkey and will
manage all EAP activities relating to the pancreatic cancer extension of the program. In February 2018, the agreement with myTomorrows
was extended to cover Canada to treat pancreatic cancer patients, pending government approval. There have been no physician requests
to date that would cause the program to move forward with the approval process.
14
A total of 42 pancreatic cancer patients initially
received treatment with Ampligen immuno-oncology therapy under the EAP program at Erasmus MC in the Netherlands; that initial program
has since continued to expand and proceed with additional patients to be treated with Ampligen supervised by Prof. C.H.J. van Eijck, MD.
In March 2024, the team at Erasmus MC published a thorough data analysis in an article titled “ Rintatolimod in Advanced Pancreatic
Cancer enhances Anti-Tumor Immunity through Dendritic Cell-Mediated T Cell Responses ” in the journal Clinical Cancer
Research . The positive clinical findings relate to changes in the tumor microenvironment after Ampligen use. We are working with our
Contract Research Organization, Amarex Clinical Research LLC, to seek FDA “fast-track.” We have applied for fast-track status;
have received denials to date; and are currently working through the FDA process to provide all the materials and information required
to achieve fast-track status.
In
January 2023, we entered into an external sponsored collaborative clinical research agreement with Erasmus MC and AstraZeneca. Under
the agreement, Erasmus MC is planning to perform an investigator-initiated clinical study, entitled “Combining anti-PD-L1 immune
checkpoint inhibitor durvalumab with TLR-3 agonist rintatolimod in patients with metastatic pancreatic ductal adenocarcinoma for therapy
effect. DURIPANC Study,” in which it will use study drugs provided by both AstraZeneca and us. In June 2023 we received the required
approvals from the Central Committee on Research Involving Human Subjects, which is the Competent Authority for the review of clinical
trials in the Netherlands, and the Medical Ethics Review Committee Erasmus MC, which is the governing ethics board. The study is open
and has dosed its first subject.
Additionally:
●
In
December 2020, the FDA granted Ampligen Orphan Drug Designation status for the treatment of pancreatic cancer. The Orphan Drug Designation
program provides orphan status to drugs and biologics which are defined as those intended for the treatment, prevention or diagnosis
of a rare disease or condition, which is one that affects less than 200,000 persons in the United States or meets cost recovery provisions
of the act. The status helps incentivize the treatment of therapies to treat unmet medical needs by providing a company with seven
years of exclusivity rights once a drug reaches market.
●
In
February 2021, our subsidiary, NV Hemispherx Biopharma Europe, received formal notification from the European Commission (“EC”)
granting Orphan Medicinal Product Designation for Ampligen as a treatment for pancreatic cancer. Orphan products, once commercially
approved in the European Union (“EU”), receive benefits including up to ten years of protection from market competition
from similar medicines with similar active component and indication for use that are not shown to be clinically superior.
In
June 2021, Ampligen was featured in a publication containing state-of-the-art methodologies in the peer-reviewed medical journal Cancers
as a potential treatment option for cancer patients who are infected with SARS-CoV-2. The study’s authors stated that Ampligen
has the potential to reduce the severity of the deadly respiratory disease COVID-19. According to laboratory data presented in the publication,
“Rintatolimod [Ampligen] activated the innate and the adaptive immune systems by activating a cascade of actions in human pancreatic
cancer cells”, including:
●
Stimulation
of interferon regulatory factors and activation of the interferon signaling pathway,
●
Production
of immunomodulatory activity and
●
Induction
of the expression of MHC class I and II histocompatibility
The
full journal article is titled: “ Rintatolimod Induces Antiviral Activities in Human Pancreatic Cancer Cells: Opening for an
Anti-COVID-19 Opportunity in Cancer Patients? ” Cancers is a peer-reviewed, open access journal of oncology published
semimonthly online by MDPI. The study’s authors include Prof. C.H.J. van Eijck, MD, PhD, the lead investigator at Erasmus Medical
Center in the Netherlands.
In
October 2021, we and Amarex submitted an IND application with the FDA for a planned Phase 2 study of Ampligen as a therapy for locally
advanced or metastatic late-stage pancreatic cancer. In December 2021, the FDA responded with a Clinical Hold on the proposed study.
We submitted our response to the FDA in February 2022. In March 2022, we received notification from the FDA that the Clinical Hold was
released and cleared, meaning that we are now able to proceed with the study specifically to treat locally advanced pancreatic cancer
patients. In August 2022, we received IRB approval of the trial protocol and so announced the trial’s commencement. The study is
recruiting patients.
Positive
data was published in March 2022 in a manuscript titled, “ Rintatolimod (Ampligen®) enhances numbers of peripheral B cells
and is associated with longer survival in patients with locally advanced and metastasized pancreatic cancer pre-treated with FOLFIRINOX:
a single-center named patient program ,” in Cancers Special Issue: Combination and Innovative Therapies for Pancreatic Cancer .
In the single-center, named-patient program, patients with locally advanced pancreatic cancer (LAPC) or metastatic disease were treated
with Ampligen for 6 weeks, at 2 doses per week with 400 mg per infusion. The study found that Ampligen improved the median survival of
these patients. The study’s primary endpoints were the Systemic Immune-Inflammation Index (SIII), the Neutrophils to Lymphocyte
Ratio (NLR), and absolute counts of 18 different populations of circulating immune cells as measured by flow cytometry. Secondary endpoints
were progression-free survival (PFS) and overall survival (OS). The median overall survival in the Ampligen group was 19 months, compared
to a historical control group and subgroup (7.5 and 12.5, respectively) that did not receive Ampligen.
15
Also
in March 2022, we announced that study data evaluating the direct effects of Ampligen on human pancreatic ductal adenocarcinoma (PDAC)
cells was accepted for presentation at the 15th Annual International Hepato-Pancreato-Biliary Association World Congress in New York,
NY. For the study, three PDAC cell lines (CFPAC-1, MIAPaCa-2, and PANC-1) were treated with various concentrations of Ampligen and their
corresponding vehicle control. The proliferation and migration effects were examined using in-vitro assays and the molecular effect was
examined by targeted gene expression profiling. Additionally human PDAC samples were used to validate the expression of toll-like receptor
3 (TLR3) by immunohistochemistry. Results from the study demonstrated Ampligen decreased the proliferation and migration ability of CFPAC-1
cells. In addition, it decreased the proliferation of MIAPaCa-2 cells and the migration of PANC-1 cells. However, it did not have a dual
effect in MIAPaCa-2 and PANC-1 cells. Interestingly, TLR3 was highly expressed in CFPAC-1 cells, low expressed in MIAPaCa-2 and not expressed
in PANC-1. Gene expression analysis revealed the upregulation of interferon-related genes, chemokines, interleukins and cell cycle regulatory
genes. The heterogeneity of TLR3 expression was confirmed in human PDAC samples. Based on these results, treating pancreatic cancer with
Ampligen may have a direct anti-tumor effect in pancreatic cancer cells expressing TLR-3.
Ampligen
as a Potential Antiviral
Following
the SARS-CoV-1 outbreak in 2002-03, Ampligen exhibited excellent antiviral properties and protective survival effect in NIH-contracted
studies of SARS-CoV-1-infected mice, which is very similar to SARS-CoV-2, the novel virus that causes COVID-19.
●
The
Barnard 2006 study ( https://journals.sagepub.com/doi/abs/10.1177/095632020601700505 ) found that Ampligen reduced virus lung
levels to below detectable limits.
●
The
Day 2009 study ( https://www.sciencedirect.com/science/article/pii/S0042682209005832 ) found that, instead of 100% mortality,
there was 100% protective survival using Ampligen.
We
compared key transcription regulatory sequences of SARS-CoV-1 to SARS-CoV-2 and found significant similarities, suggesting highly probable
extension of the antiviral effects of Ampligen in the earlier NIH-contracted SARS experiments to COVID-19. The SARS-CoV-2 virus –
which causes COVID-19 – shares important genomic and pathogenic similarities with SARS-CoV-1 (hence its name). Since Ampligen has
shown antiviral activity against more distantly related coronaviruses, there was a reasonable probability that the antiviral effects
of Ampligen against SARS-CoV-1 will likely extend to SARS-CoV-2, and as discussed below, recently, Ampligen has demonstrated ex vivo
antiviral activity against SARS-CoV-2. We believe that this creates a compelling case for clinical trials to evaluate Ampligen as a potential
tool in the fight against COVID-19.
Since
the late 2019 outbreak of SARS-CoV-2, we have been actively engaged in determining whether Ampligen could be an effective treatment for
this virus or could be part of a vaccine. We believe that Ampligen has the potential to be both an early-onset treatment for and prophylaxis
against SARS-CoV-2. We believe that prior studies of Ampligen in SARS-CoV-1 animal experimentation may predict similar protective effects
against the new virus.
In
February 2020, we filed three provisional patent applications related to Ampligen in our efforts toward joining the global health community
in the fight against the deadly coronavirus (See: https://aimimmuno.com/press-release/aim-immunotech-files-provisional-patent-application-for-the-use-of-ampligenr-as-a-potential-therapy-for-covid-19-induced-chronic-fatigue/).
Our three provisional patent applications include: 1) Ampligen as a therapy for the coronavirus; 2) Ampligen as part of a proposed intranasal
universal coronavirus vaccine that combines Ampligen with inactivated coronavirus, conveying immunity and cross-protection and; 3) a
high-volume manufacturing process for Ampligen. Under the Patent Cooperation Treaty of 1970, which provides international protections
for patents, these three provisional patent applications were converted into two international patent applications based on the date
of their filings.
In
August 2020, we contracted Amarex to act as our Clinical Research Organization and provide regulatory support with regard to a possible
clinical trial testing Ampligen’s potential as a COVID-19 prophylaxis via intranasal delivery.
Beginning
in April 2020, we entered into confidentiality and non-disclosure agreements with numerous companies for the potential outsourcing of
the production of polymer, enzyme, placebo as well as Ampligen, and one Contract Research Organization, Amarex, which will provide regulatory
and monitoring support related to a clinical trial testing Ampligen’s intranasal safety and potential as a COVID-19 prophylaxis
via intranasal delivery.
16
In
May 2020, the FDA authorized an IND for Roswell Park to conduct a Phase 1/2a study of a regimen of Ampligen and interferon alpha in cancer
patients with COVID-19 infections. This clinical trial, sponsored by Roswell Park in collaboration with us, will test the safety of this
combination regimen in patients with cancer and COVID-19, and the extent to which this therapy will promote clearance of the SARS-CoV-2
virus from the upper airway. Several subjects have been treated. It is planned that the phase 1/2a study will enroll up to 44 patients
in two stages. Phase 1 will see 12-24 patients receiving both Ampligen and interferon alpha-2b at escalating doses. Once that initial
phase is complete, further study participants will be randomized to two arms: one receiving the two-drug combination and a control group
who will not receive Ampligen or interferon alpha but will receive best available care. We are a financial sponsor of the study and will
provide Ampligen at no charge for this study. In November 2020, the first patient in the study had been enrolled and treated. This study
was amended to add 20 patients, with 10 randomized to receive a single dose of Ampligen and 10 patients to receive current best therapies.
(See clinicaltrials.gov/NCT04379518 ). Due to a shortage of qualifying subjects with COVID-19 and cancer as a result of the positive
impact of vaccinations and treatments for COVID-19, Roswell is seeking approval to expand the qualifying subject criteria to include
other diseases lethal to immuno-compromised cancer patients, such as influenza. Accordingly, the study is temporarily suspended while
seeking said approvals.
We
also entered into a specialized services agreement with Utah State University and have supplied Ampligen to support the University’s
Institute for Viral Research in its research into SARS-CoV-2. The Utah State results show that Ampligen was able to decrease SARS-CoV-2
infectious viral yields by 90% at clinically achievable intranasal Ampligen dosage levels.
In
October 2020, we received IRB approval for the expansion of the AMP-511 Expanded Access Program clinical trial for ME/CFS to include
patients previously diagnosed with SARS-CoV-2, but who still demonstrate chronic fatigue-like symptoms. Patients in the trial are treated
with our flagship pipeline drug Ampligen. In January 2021, we commenced with the treatment of the first previously diagnosed COVID-19
patient with long-COVID symptoms (i.e., Long Hauler) also known as Post-COVID Conditions in the AMP-511 study. Enrollment of post-COVID
patients continues in the study.
In
January 2021, we entered into a Sponsor Agreement with CHDR to manage a Phase 1 randomized, double-blind study to evaluate the safety
and activity of repeated intranasal administration of Ampligen. AIM funded and sponsored the study. This study was designed to assess
the safety, tolerability and biological activity of repeated administration of Ampligen intranasally. A total of 40 healthy subjects
received either Ampligen or a placebo in the trial, with the Ampligen given at four escalating dosages across four cohorts, to a maximum
level of 1,250 micrograms. The study was completed, and the Final Safety Report reported no Serious or Severe Adverse Events at any dosage
level. We believe that the trial is a critical step in our ongoing efforts to develop Ampligen as a potential prophylaxis or treatment
for COVID-19 and other respiratory viral diseases. Amarex provided us with monitoring support during the trial.
Additionally,
we filed two COVID-19-related provisional patent applications in the third quarter of 2021. In August, we filed an application for Ampligen
as both an intranasal and an intravenous therapy for what we describe as Post-COVID conditions. The people suffering from Post-COVID
conditions, including some young adults, can be afflicted with severe difficulties in concentrating; serious memory problems; and the
inability to live an active lifestyle, to work and even to perform everyday tasks. Early data has demonstrated that patients with symptoms
of Post-COVID conditions being treated with Ampligen in the ongoing AMP-511 Expanded Access Program have reported improvements in fatigue
symptoms. Similarly, in ME/CFS, data supports the claim that Ampligen improves fatigue symptoms. Then in September 2022, we filed a patent
application for Ampligen as a potential early-onset intranasal therapy designed to enhance and expand infection-induced immunity, epitope
spreading, cross-reactivity and cross-protection in patients exposed to a wide range of RNA respiratory viruses, such as influenza, Rhinoviruses
and SARS-CoV-2.
In
addition to securing these two provisional patent applications, we also moved forward with proposed studies in these areas and with Pre-Investigational
New Drug Applications in September 2021. One pre-IND was for a Phase 2, two-arm, randomized, double-blind, placebo-controlled, multicenter
study to evaluate the efficacy and safety of Ampligen in patients experiencing Post-COVID conditions (originally referred to as Post-COVID
Cognitive Dysfunction (PCCD) and has been revised to Post-COVID conditions).
Ampligen
as a Treatment for Post-COVID Conditions
In
July 2023, we enrolled and dosed the first patient in our Phase 2 study evaluating Ampligen® as a potential therapeutic for people
with post-COVID conditions (“AMP-518”). We announced in August 2023 that the study had met the planned enrollment of 80 subjects
ages 18 to 60 years who have been randomized 1:1 to receive twice-weekly intravenous infusions of Ampligen or placebo for 12 weeks, with
a follow-up phase of two weeks. All patients have completed the study and topline data was reported in February 2024.
17
On
May 9, 2023, we were granted a U.S. Patent for a method for preventing or reducing antigenic drift or viral reassortment in a host animal
comprising determining if a host animal has been exposed to or infected by an avian influenza virus and administering to the exposed
host animal alpha-interferon.
Myalgic
Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Myalgic
Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), also known as Chronic Fatigue Immune Dysfunction Syndrome (“CFIDS”)
and Chronic Fatigue Syndrome (CFS), is a serious and debilitating chronic illness and a major public health problem. ME/CFS is recognized
by both the government and private sector as a significant unmet medical need, including the U.S. National Institutes of Health (“NIH”),
FDA and the CDC. The CDC states on its website at https://www.cdc.gov/me-cfs/ that “ Myalgic encephalomyelitis/chronic
fatigue syndrome (ME/CFS) is a serious, long-term illness that affects many body systems. People with ME/CFS are often not able to do
their usual activities. At times, ME/CFS may confine them to bed. People with ME/CFS have severe fatigue and sleep problems. ME/CFS may
get worse after people with the illness try to do as much as they want or need to do. This symptom is called post-exertional malaise
(PEM). Other symptoms can include problems with thinking and concentrating, pain, and dizziness. ”
Many
severe ME/CFS patients become completely disabled or totally bedridden and are afflicted with severe pain and mental confusion even at
rest. ME/CFS is characterized by incapacitating fatigue with profound exhaustion and extremely poor stamina, sleep difficulties and problems
with concentration and short-term memory. It is also accompanied by flu-like symptoms, pain in the joints and muscles, tender lymph nodes,
sore throat and new headaches. A distinctive characteristic of the illness is a worsening of symptoms following physical or mental exertion,
which do not subside with rest.
The
high number of younger people being hospitalized for COVID-19 suggests considerable numbers of people in the prime of their lives may
have a COVID-induced ME/CFS-like illness in their future. According to a 2016 journal article, the estimated annual cost of lost productivity
related to ME/CFS was $9-37 billion in the United States, and for direct medical costs it was $9-14 billion.
In
June of 2020, we filed a provisional patent application for, among other discoveries, the use of Ampligen as a potential early-onset
therapy for the treatment of COVID-19 induced chronic fatigue.
Many
survivors of the first SARS-CoV-1 epidemic in 2003 continued to report chronic fatigue, difficulty sleeping and shortness of breath months
after recovering from the acute illness. “After one year, 17% of patients had not returned to work and 9% more had not returned
to their pre-SARS work levels,” according to Simmaron Research. Now there is increasing evidence that patients with COVID-19 can
develop a similar, ME/CFS-like illness. These patients are commonly referred to as “Long Haulers.”
In
October 2020, we received IRB approval for the expansion of the AMP-511 Expanded Access Program clinical trial for ME/CFS to include
patients previously diagnosed with SARS-CoV-2 following clearance of the virus, but who still demonstrate chronic fatigue-like symptoms.
For more information on our AMP-511 Expanded Access Program, please see “ OUR PRODUCTS: Ampligen ” above.
In
November 2020, we announced the publication of statistically significant data detailing how Ampligen could have a considerable positive
impact on people living with ME/CFS when administered in the early stages of the disease. The data were published in PLOS ONE ,
a peer-reviewed open access scientific journal published by the Public Library of Science. AIM researchers found that the TLR3 agonist
Ampligen substantially improved physical performance in a subset of ME/CFS patients.
As
noted above in Overview; General; Ampligen as a treatment for ME/CFS , we have long been focused on seeking the FDA’s approval
for the use of Ampligen to treat ME/CFS. In fact, in February 2013, we received a CRL from the FDA for our Ampligen NDA for ME/CFS, stating
that we should conduct at least one additional clinical trial, complete various nonclinical studies and perform a number of data analyses.
While
developing a comprehensive response to the FDA and a plan for a confirmatory trial for the FDA NDA, we proceeded independently in Argentina
and, in August 2016, we received approval of an NDA from ANMAT for commercial sale of Ampligen in the Argentine Republic for the treatment
of severe CFS. In September 2019, we received clearance from the FDA to ship Ampligen to Argentina for the commercial launch and subsequent
sales. On June 10, 2020, we received import clearance from ANMAT to import the first shipment of commercial grade vials of Ampligen into
Argentina. The next steps in the commercial launch of Ampligen include ANMAT conducting a final inspection of the product and release
tests before granting final approval to begin commercial sales. This testing and approval process is currently delayed due to ANMAT’s
internal processes. Once final approval by ANMAT is obtained, GP Pharm will begin distributing Ampligen in Argentina.
18
We
plan on a comprehensive follow through with the FDA regarding the use of Ampligen as a treatment for ME/CFS. We have learned a great
deal since the FDA’s CRL and plan to adjust our approach to concentrate on specific ME/CFS symptoms. Responses to the CRL and a
proposed confirmatory trial are being worked on now by our R&D team and consultants.
Other
Diseases
In
Europe, the EMA has approved the Orphan Medicinal Products Designation for Ampligen as a potential treatment of Ebola virus disease and
for Alferon N Injection as a potential treatment of MERS.
We
concluded our series of collaborations designed to determine the potential effectiveness of Ampligen and Alferon N Injection as potential
preventive and/or therapeutic treatments for Ebola-related disorders. Although we believe that the threat of both MERS and Ebola globally
may reemerge in the future, it appears that the spread of these disorders has diminished.
In
April 2021, we entered into an MTA with the University of Cagliari Dipartimento di Scienze della Vita e dell’Ambiente (“UNICA”),
an educational institution, under the laws of Italy, located in Monserrato (Cagliari), Italy. The MTA relates to the research and development
of the effects of Ampligen and its ability to induce interferon production in several cell lines, and also on the ability of the Ebola
virus protein VP35 to bind to viral dsRNA and impede interferon’s upregulation and activity, and on Ampligen’s ability to
reverse VP35 inhibition of interferon production in biological systems. The data analysis was published in the peer-reviewed journal
Antiviral Research , in a manuscript titled “Ebola virus disease: In vivo protection provided by the PAMP restricted TLR3
agonist rintatolimod and its mechanism of action.” We believe that the analysis supports a dual mechanism of action when Ampligen
is used as a prophylactic therapy against Ebola Virus Disease.
In
May 2021, we filed a U.S. Provisional Patent Application for Ampligen as a potential therapeutic to possibly slow, halt, or reverse the
progression of Alzheimer’s disease.
In
November 2022, we received notice that the FDA had granted Orphan Drug Designation to Ampligen for the treatment of Ebola virus disease.
MANUFACTURING
ANMAT
in Argentina approved Ampligen for commercial distribution for the treatment of CFS in 2016. Shipment of the drug product to Argentina
was initiated in 2018 to complete the release testing by ANMAT needed for commercial distribution. In September 2019, we received clearance
from the FDA to ship Ampligen to Argentina for the commercial launch and subsequent sales. In June 2020, we received import clearance
from ANMAT to import the first shipment of commercial grade vials of Ampligen into Argentina. We are currently working with GP Pharm
on the commercial launch of Ampligen in Argentina (See “Our Products; Ampligen” above).
Following
our approval in Argentina, in 2017 we engaged Jubilant HollisterStier (“Jubilant”) to be our authorized CMO for Ampligen.
Two lots of Ampligen consisting of more than 16,000 units were manufactured and released in 2018; these lots have been designated for
human use in the United States in the cost recovery CFS program and for expanded oncology clinical trials. The production of additional
polymer (Ampligen intermediates) took place in 2019 at our New Brunswick facility. Additionally, Jubilant manufactured two more lots
of Ampligen in December 2019 and January 2020. The current manufactured lots of Ampligen have been fully tested and released for commercial
product launch in Argentina and for clinical trials. In addition, we have supplied GP Pharm with the Ampligen required for testing and
ANMAT release. Once final approval by ANMAT is obtained, we anticipate that GP Pharm will begin distributing Ampligen in Argentina.
In
December 2020, we added Pii as a “Fill & Finish” provider to enhance our capacity to produce Ampligen. This addition
amplifies our manufacturing capability by providing redundancy and cost savings. The contracts augment our existing fill and finish capacity.
We are prepared to initiate the production of additional Ampligen when and if needed.
In
June 2022 we entered into a lease agreement with the New Jersey Economic Development Authority for a 5,210 square-foot, state-of-the-art
R&D facility at the New Jersey Bioscience Center (NJBC), primarily consisting of two separate laboratory suites. The lease commenced
on July 1, 2022, and runs through August 31, 2027, but can be extended for an additional five-year period. The facility is AIM’s
operations, research and development center.
19
Our
business plan calls for the utilization of one or more CMOs to produce Ampligen API. While we believe we have sufficient Ampligen API
to meet our current needs, we are also continually exploring new efficiencies so as to maximize our ability to fulfill future obligations.
In this regard, on December 5, 2022, we entered into a Master Service Agreement and a Quality Agreement with Sterling Pharma Solutions
(“Sterling”) for the manufacture of our Poly I and Poly C12U polynucleotides and transfer of associated test methods at Sterling’s
Dudley, UK location to produce the polymer precursors to manufacture the drug Ampligen. We are utilizing Sterling’s expertise to
refine our approach to polymer production. While we believe we have sufficient Ampligen API to meet current needs, we are also continually
exploring new efficiencies in order to maximize its ability to fulfill future obligations. In March 2023, we submitted a work order for
a total of $1,432,257 to manufacture additional lots of Ampligen at Jubilant.
Our
second product, Alferon N Injection, is approved by the FDA for commercial sales in the United States for the treatment of genital warts.
It is also approved by ANMAT in Argentina for commercial sales for the treatment of genital warts and in patients who are refractory
to treatment with recombinant interferons. Commercial sales of Alferon N Injection in the United States will not resume until new batches
of commercial filled and finished product are produced and released by the FDA. We will need the FDA’s approval to release commercial
product once we have identified our new manufacturing approach and submitted satisfactory stability and quality release data. Currently,
we are not manufacturing Alferon N Injection and there is no definitive timetable to resume production.
Licensing/Collaborations/Joint
Ventures
To
enable potential availability of Ampligen to patients on a worldwide basis, we have embarked on a strategy to license the product and/or
to collaborate and/or create a joint venture with companies that have the demonstrated capabilities and commitment to successfully gain
approval and commercialize Ampligen in their respective global territories of the world. Ideal partners would have the following characteristics:
well-established global and regional experience and coverage; robust commercial infrastructure; a strong track record of successful development
and registration of in-licensed products; and a therapeutic area fit (e.g., ME/CFS, immuno-oncology).
MARKETING/DISTRIBUTION
In
May 2016, we entered into a five-year exclusive Renewed Sales, Marketing, Distribution and Supply Agreement (the “Agreement”)
with GP Pharm. Under this Agreement, GP Pharm was responsible for gaining regulatory approval in Argentina for Ampligen to treat severe
CFS in Argentina and for commercializing Ampligen for this indication in Argentina. We granted GP Pharm the right to expand rights to
sell this experimental therapeutic into other Latin America countries based upon GP Pharm achieving certain performance milestones. We
also granted GP Pharm an option to market Alferon N Injection in Argentina and other Latin America countries (See “Our Products;
Ampligen” above). The GP Pharm contract was extended in May 2021, and will now end on May 24, 2024. In August 2021, ANMAT granted
a five-year extension to a previous approval to sell and distribute Ampligen to treat severe CFS in Argentina. This extends the approval
until 2026.
In
May 2016, we entered into a five-year agreement (the “Impatients Agreement”) with Impatients, N.V. (“myTomorrows”),
a Netherlands-based company, for the commencement and management of an EAP in Europe and Turkey (the “Territory”) related
to ME/CFS. Pursuant to the agreement, myTomorrows, as our exclusive service provider and distributor in the Territory, is performing
EAP activities. These activities will be directed to (a) the education of physicians and patients regarding the possibility of early
access to innovative medical treatments not yet the subject of a Marketing Authorization (regulatory approval) through named-patient
use, compassionate use, expanded access and hospital exemption, (b) patient and physician outreach related to a patient-physician platform,
(c) the securing of Early Access Approvals (exemptions and/or waivers required by regulatory authorities for medical treatments prior
to Marketing Authorization) for the use of such treatments, (d) the distribution and sale of such treatments pursuant to such Early Access
Approvals, (e) pharmacovigilance (drug safety) activities and/or (f) the collection of data such as patient-reported outcomes, doctor-reported
experiences and registry data. We are supporting these efforts and supplying Ampligen to myTomorrows at a predetermined transfer price.
In the event that we receive Marketing Authorization in any country in the Territory, we will pay myTomorrows a royalty on products sold.
Pursuant to the Impatients Agreement, the royalty would be a percentage of Net Sales (as defined in the Impatients Agreement) of Ampligen
sold in the Territory where Marketing Authorization was obtained. The formula to determine the percentage of Net Sales will be based
on the number of patients that are entered into the EAP. We believe that disclosure of the exact maximum royalty rate and royalty termination
date could cause competitive harm. However, to assist the public in gauging these terms, the actual maximum royalty rate is somewhere
between 2% and 10% and the royalty termination date is somewhere between five and fifteen years from the First Commercial Sale of a product
within a specific country. The parties established a Joint Steering Committee comprised of representatives of both parties to oversee
the EAP. No assurance can be given that activities under the EAP will result in Marketing Authorization or the sale of substantial amounts
of Ampligen in the Territory. The agreement was automatically extended for a period of 12 months on May 20, 2021; has been automatically
extended for 12 months on each subsequent May 20; and will continue to be automatically extended for periods of 12 months every May 20
until terminated or the terms of the agreement are met.
In
January 2017, ANMAT granted a five-year extension to a previous approval to sell and distribute Alferon N Injection (under the brand
name “Naturaferon”) in Argentina. This extended the approval until 2022. A request to extend the approval beyond 2022 has
been filed and is still under review. In February 2013, we received ANMAT approval for the treatment of refractory patients that failed
or were intolerant to treatment with recombinant interferon, with Naturaferon in Argentina.
20
In
January 2017, the EAP through our agreement with myTomorrows designed to enable access of Ampligen to ME/CFS patients was extended to
pancreatic cancer patients beginning in the Netherlands. myTomorrows is our exclusive service provider in the Territory and will manage
all EAP activities relating to the pancreatic cancer extension of the program.
In
August 2017, we extended our agreement with Asembia LLC, formerly Armada Healthcare, LLC, to undertake the marketing, education and sales
of Alferon N Injection throughout the United States. This agreement has expired. We were in discussions with Asembia about the possibility
of continuing the relationship, while also exploring the possibility of working with other, similar companies. However, we still do not
foresee an immediate need for this service and continue to push this search further out in our expected timeline.
In
February 2018, we signed an amendment to the EAP with myTomorrows. This amendment extended the Territory to cover Canada to treat pancreatic
cancer patients, pending government approval. In March 2018, we signed an amendment to the EAP with myTomorrows, pursuant to which myTomorrows
will be our exclusive service provider for special access activities in Canada for the supply of Ampligen for the treatment of ME/CFS.
In
December 2020, we entered into a signed Letter of Agreement with myTomorrows for the delivery of Ampligen for the treatment of up to
16 pancreatic cancer patients. In November 2021, we entered into a signed Letter of Agreement with myTomorrows for the delivery of Ampligen
for the treatment of up to an additional 5 pancreatic cancer patients. In March 2022, we entered into a signed Letter of Agreement with
myTomorrows for the delivery of Ampligen for the treatment of up to an additional 10 pancreatic cancer patients. In November 2022, we
entered into a signed Letter of Agreement with myTomorrows for the delivery of Ampligen for the treatment of up to an additional 10 pancreatic
cancer patients.
COMPETITION
The
major pharmaceutical competitors for Ampligen include Pfizer, GlaxoSmithKline, Merck & Co., Novartis and AstraZeneca. Biotech competitors
include Baxter International, Fletcher/CSI, AVANT Immunotherapeutics, AVI BioPharma and Genta.
GOVERNMENT
REGULATION
Regulation
by governmental authorities in the U.S. and foreign countries is and will be a significant factor in the manufacture and marketing of
our products and our ongoing research and product development activities. Ampligen and other products developed from the ongoing research
and product development activities will require regulatory clearances prior to commercialization. In particular, new drug products for
humans are subject to rigorous pre-clinical and clinical testing as a condition for clearance by the FDA and by similar authorities in
foreign countries. The process of seeking these approvals, and the ongoing process of compliance with applicable statutes and regulations,
has and will continue to require the expenditure of substantial resources. Any failure by us or our collaborators or licensees to obtain,
or any delay in obtaining, regulatory approvals could materially adversely affect the marketing of any products developed by us and our
ability to receive product or royalty revenue. We have received Orphan Drug designation for certain therapeutic indications, which we
believe might under certain conditions help to accelerate the process of drug development and commercialization. Alferon N Injection
is only approved for use in intralesional treatment of refractory or recurring external genital warts in patients 18 years of age or
older. Use of Alferon N Injection for other applications requires regulatory approval.
We
are subject to various federal, state and local laws, regulations and recommendations relating to such matters as safe working conditions,
laboratory and manufacturing practices, the experimental use of animals and the use of and disposal of hazardous or potentially hazardous
substances, including infectious disease agents, used in connection with our research work.
For
more information about the current status of Alferon N Injection and Ampligen, please see “Our Products” above. See also,
“ Our drug and related technologies are investigational and subject to regulatory approval. If we are unable to obtain regulatory
approval in a timely manner, or at all, our operations will be materially harmed and our stock adversely affected ” in Part
II; Item 1A “Risk Factors”.
HUMAN
CAPITAL
As
of December 31, 2023, we had personnel consisting of 26 full-time employees and two part-time employees. Six of the combined personnel
are engaged in our research, development, clinical and manufacturing efforts, with 22 performing regulatory, general administration,
data processing, including bio-statistics, financial and investor relations functions. We have no union employees.
Employee
Engagement
Our
business results depend in part on our ability to successfully manage our human capital resources, including attracting, identifying,
and retaining key talent. Factors that may affect our ability to attract and retain qualified employees include employee morale, our
reputation, competition from other employers, and availability of qualified individuals. We believe our commitment to our human capital
resources is an important component of our mission. We provide all employees with the opportunity to share their opinions in open dialogues
with our human resources department and senior management.
21
Compensation,
Benefits and Wellness
We
offer fair, competitive compensation and benefits that support our employees’ overall wellness. Further, the health and wellness
of our employees are critical to our success. While we have been successful in attracting skilled and experienced scientific personnel,
there can be no assurance that we will be able to attract or retain the necessary qualified employees and/or consultants in the future.