UNITED
STATES
SECURITIES
AND EXCHANGE COMMISSION
WASHINGTON,
D.C. 20549
FORM
10-K
(Mark
One)
FOR THE FISCAL YEAR ENDED DECEMBER
31, 2021
OR
FOR
THE TRANSITION PERIOD FROM _________TO__________
COMMISSION
FILE NUMBER 001-40943
BIOFRONTERA
INC.
(Exact
name of registrant as specified in its charter)
120 Presidential Way, Suite 330
Woburn, Massachusetts 01801
(Address of principal executive offices) (Zip code)
(781)245-1325
(Registrant’s
telephone number, including area code)
Securities
registered pursuant to Section 12(b) of the Act:
Common Stock, par value $0.001 per share BFRI The Nasdaq Stock Market LLC
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 (§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. ☐
Indicate
by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act). Yes ☐ No☒
As
of June 30, 2021, the last day of the registrant’s most recently completed second fiscal quarter, there was no public market for
the registrant’s common stock. The registrant’s common stock began trading on the NASDAQ Capital Market on October 29, 2021.
As of April 7, 2022, the aggregate market value of the common stock held by non-affiliates of the registrant was approximately
$36.8 million, based on the closing price of the registrant’s common stock on April 7, 2022.
As
of April 7, 2022, there were 17,104,749 shares outstanding of the registrant’s common stock, par value $0.001 per
share.
DOCUMENTS
INCORPORATED BY REFERENCE:
None.
TABLE
OF CONTENTS
PART I.
Item 1. Business 4
Item 1A. Risk Factors 25
Item 1B. Unresolved Staff Comments 56
Item 2. Properties 56
Item 3. Legal Proceedings 56
Item 4. Mine Safety Disclosures 56
PART II.
Item 6. Reserved 59
Item 7A. Quantitative and Qualitative Disclosures About Market Risk 72
Item 8. Financial Statements and Supplementary Data F-1
Item 9A. Controls and Procedures 73
Item 9B. Other Information 73
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 73
PART III.
Item 10. Directors, Executive Officers and Corporate Governance 73
Item 11. Executive Compensation 76
Item 14. Principal Accountant Fees and Services 85
PART IV.
Item 15. Exhibit and Financial Statement Schedules 86
SIGNATURES 89
BASIS
OF PRESENTATION
As used in this Annual
Report on Form 10-K for the fiscal year ended December 31, 2021 (the “Form 10-K”), unless the context otherwise requires,
references to “we,” “us,” “our,” the “Company,” “Biofrontera” and
similar references refer to Biofrontera Inc. References in this Form 10-K to the “Biofrontera Group” refer
to Biofrontera AG and its consolidated subsidiaries, Biofrontera Pharma GmbH (individually, “Biofrontera Pharma”),
Biofrontera Bioscience GmbH (individually “Biofrontera Bioscience”), Biofrontera Neuroscience GmbH (individually “Biofrontera
Neuroscience”), Biofrontera Development GmbH (individually “Biofrontera Development”). References in this
Form 10-K to “Ferrer” refer to Ferrer Internacional S.A. References in this Form 10-K to Biofrontera’s
“Licensors” refer collectively to Biofrontera Pharma, Biofrontera Bioscience and Ferrer. References in this Form
10-K to “Ameluz Licensor” refer collectively to Biofrontera Pharma and Biofrontera
Bioscience. References in this annual report to “Maruho” refer to Maruho Co., Ltd., and references to “Maruho
Deutschland” refer to Maruho Deutschland GmbH, Maruho’s wholly owned subsidiary. References in this Form 10-K
to “Cutanea” refer to Cutanea Life Sciences, Inc., which was acquired by Biofrontera in 2019 (“Cutanea acquisition”).
SPECIAL
NOTE REGARDING FORWARD-LOOKING STATEMENTS
The
following discussion of our financial condition and results of operations should be read in conjunction with our audited consolidated
financial statements and the related notes, which appear elsewhere in this Form 10-K. This Form 10-K,
including the section titled “Management’s Discussion and Analysis of Financial Condition and Results of Operations,”
may contain predictive or “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act
of 1995. All statements, other than statements of historical facts, in this annual report, including statements regarding our strategy,
future operations, regulatory process, future financial position, future revenue, projected costs, prospects, plans, objectives of management
and expected market growth, are forward-looking statements. The words “believe”, “anticipate”, “intend”,
“expect”, “target”, “goal”, “estimate”, “plan”, “assume”, “may”,
“will”, “predict”, “project”, “would”, “could” and similar expressions are
intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words.
You
should read this Form 10-K and the documents that we have filed as exhibits completely and with the understanding that our actual
future results may be materially different from what we expect. While we have based these forward-looking statements on our current expectations
and projections about future events, we may not actually achieve the plans, intentions or expectations disclosed in or implied by our
forward-looking statements, and you should not place undue reliance on our forward-looking statements. These forward-looking statements
are subject to risks, uncertainties and assumptions about us and accordingly, actual results or events could differ materially from the
plans, intentions and expectations disclosed in or implied by the forward-looking statements we make. Factors that could cause such differences
include, but are not limited to:
● our ability to achieve and sustain profitability;
● our ability to compete effectively in selling our licensed products;
● changes in our relationship with our Licensors;
● our Licensors’ ability to manufacture our licensed products;
● market risks regarding consolidation in the healthcare industry;
● the fact that product quality issues or product defects may harm our business;
● any product liability claims;
● our ability to transition to being a public company;
Our
forward-looking statements do not reflect the potential impact of any future acquisitions, mergers, dispositions, joint ventures or investments
that we may make. We do not assume any obligation to update any forward-looking statements, whether as a result of new information, future
events or otherwise, except as required by law. Any forward-looking statements speak only as of the date on which they are made, and
we undertake no obligation to publicly update or revise any forward-looking statements to reflect events or circumstances that may arise
after the date of this Annual Report on Form 10-K, except as required by applicable law. Investors should evaluate any statements made
by us in light of these important factors.
PART
I
Item
1. Business
Overview
We are a U.S.-based biopharmaceutical company specializing
in the commercialization of pharmaceutical products for the treatment of dermatological conditions, in particular, diseases caused primarily
by exposure to sunlight that result in sun damage to the skin. Our licensed products primarily focus on the treatment of actinic
keratoses, which are skin lesions that can sometimes lead to skin cancer. We also market a topical antibiotic for treatment of impetigo,
a bacterial skin infection.
Our principal licensed product is Ameluz®,
which is a prescription drug approved for use in combination with the Ameluz Licensor’s Food and Drug Administration (“FDA”)
approved medical device, the RhodoLED® lamp series, for photodynamic therapy, or PDT (when used together, “Ameluz®
PDT”) in the United States for the lesion-directed and field-directed treatment of actinic keratoses of mild-to-moderate
severity on the face and scalp. We are currently selling Ameluz® for this indication in the U.S. under an
exclusive amended and restated license and supply agreement, as amended (“Ameluz
LSA”), dated as of June 16, 2021, by and among us and the Ameluz Licensor.
See “Business—Commercial Partners and Agreements—Biofrontera Pharma and Biofrontera Bioscience”
in this Form 10-K for more information. Under the Ameluz LSA, we hold the exclusive license to
sell Ameluz® and the RhodoLED® lamp series comprising the BF-RhodoLED® and the new, more
advanced RhodoLED® XL in the United States for all indications currently approved by the FDA as well as all future FDA-approved
indications identified under the Ameluz LSA. We have the authority under the Ameluz LSA in certain circumstances to take over
clinical development, regulatory work and manufacturing from the Ameluz Licensor, with respect to the FDA applications and clinical studies
identified in the Ameluz LSA, if they are unable or unwilling to perform these functions appropriately. However, the Ameluz Licensor
does not have any obligation under the Ameluz LSA, to perform or finance clinical trials to promote new indications beyond those
identified in the Ameluz LSA. As further described below, under the Ameluz LSA, further extensions of the approved indications
for Ameluz® photodynamic therapy in the United States are anticipated.
Our second prescription drug licensed product in
our portfolio is Xepi® (ozenoxacin cream, 1%), a topical non-fluorinated quinolone that inhibits bacterial growth. Currently,
no antibiotic resistance against Xepi® is known and it has been specifically approved by the FDA for the treatment of
impetigo, a common skin infection, due to Staphylococcus aureus or Streptococcus pyogenes. It is approved for use in the United States
in adults and children 2 months and older. We are currently selling Xepi® for this indication in the United States under
an exclusive license and supply agreement, as amended (“Xepi LSA”), with Ferrer
that was assumed by Biofrontera on March 25, 2019 through our acquisition of Cutanea Life Sciences, Inc.
On March 25, 2019,
we acquired Cutanea from Maruho Co., Ltd. In November 2018, Cutanea launched Xepi®, a prescription cream for the treatment
of impetigo. The acquisition of Cutanea in March 2019 enabled us to market an FDA-approved drug that has already been introduced in the
U.S. market. Although recent developments with respect to the third-party manufacturer that was providing our supply of Xepi®
have impacted the timing of sales expansion and improved market positioning, –– we believe that Xepi®
has the potential to be another innovative product with a large market potential in our portfolio.See
“Management’s Discussion and Analysis of Financial Condition and Results of Operations—Critical Accounting Estimates—Intangible
Assets and Impairment Assessment” in this Form 10-K.
As
a licensee, we rely on our licensors to conduct clinical trials in order to pursue extensions to the current product indications approved
by the FDA. Currently, the Ameluz Licensor has submitted applications to the FDA for the following indications with respect to our flagship
licensed product Ameluz® and the RhodoLED® lamp series. These studies are all being pursued as part of
the Investigational New Drug Application that the Ameluz Licensor submitted to the FDA in 2017 for the development of Ameluz®/BF-RhodoLED®
lamp to treat superficial basal cell carcinoma.
Clinical Phase
Product Indication / comments Pre-clinical I II III Approval process Status
(2) Phase II and Phase III trials not required for label change.
We
have the authority under the Ameluz LSA with respect to each of the indications described in the table above (as well as certain other
clinical studies identified in the Corrected Amendment to the Ameluz LSA) in certain circumstances to take over clinical development,
regulatory work and manufacturing from the Ameluz Licensor, if they are unable or unwilling to perform these functions appropriately.
The Ameluz Licensor may choose, but has no obligation under the Ameluz LSA, to seek FDA approval with respect to additional indications.
The pursuit of any additional indications beyond those identified in the Ameluz LSA would need to be separately negotiated between
us and the Ameluz Licensor.
The
current development pipeline is intended to expand commercialization in the United States of Ameluz®, as a combination
product with the RhodoLED® lamp series, by means of marketing additional indications for our licensed products. The Ameluz
LSA entitles us to an exclusive license in the United States of the products covered under the Ameluz LSA which includes any future indications
that the Biofrontera Group may pursue with the FDA.
We currently do not have the ability to conduct any
clinical trials, nor do we exercise any control over the progress of clinical trials for our licensed products. Under the Ameluz
LSA and the Xepi LSA, our Licensors control clinical development for the applicable licensed product. With respect to each of the FDA
applications and clinical studies identified in the Ameluz LSA and under certain circumstances, for example, if the Ameluz Licensor fails
to pursue mutually beneficial clinical development, we may choose to organize and finance trials and subtract the cost from the transfer
price of future shipments.
We
are unaware of any immediate or near-term plans of Ferrer for a U.S.-market focused development pipeline.
Our
Strategy
Our
principal objective is to increase the sales of our licensed products. The key elements of our strategy include the following:
Our
strategic objectives also include further expansion of our product and business portfolio through various methods to pursue selective
strategic investment and acquisition opportunities to expand and support our business growth.
Our
Product Portfolio
Ameluz®
and the RhodoLED® Lamp Series
Our
principal marketed licensed product is Ameluz®. Ameluz® is used in combination with the RhodoLED®
lamp or the new and more advanced RhodoLED XL, each an FDA approved medical device, in photodynamic therapy to selectively
remove actinic keratosis, a chronic, pre-cancerous skin condition with the potential of progression to invasive skin cancer. We
are currently selling Ameluz® in the United States on an exclusive basis through the Ameluz LSA.
In
general, photodynamic therapy is a two-step process:
During
this process, energy from the light activates the photosensitizer. In photodynamic therapy, the activated photosensitizer transfers energy
to oxygen molecules found in cells, converting the oxygen into a highly reactive oxygen species (ROS), which destroys or alters
the sensitized cells.
Ameluz® is a photosensitizer which is activated by the red
light generated by our RhodoLED® lamps to create the reactive oxygen species that will cause necrosis or apoptosis of the
targeted cells. Biofrontera Pharma is considered the responsible manufacturer for Ameluz® by the FDA. Biofrontera Pharma
currently manufactures through a single unaffiliated contract manufacturer in Switzerland, Glaropharm AG, and has recently signed an agreement
with a second unaffiliated contract manufacturer located in Germany, Pharbil Waltrop GmbH, to ensure stability of the supply chain.
Photodynamic
therapy can be a highly selective treatment that targets specific cells while minimizing damage to normal surrounding tissues.
It also can allow for multiple courses of therapy. Hence the mode of action of photodynamic therapy requires destruction of the altered
cells, temporary local skin reactions and inflammation of the treated area might be expected. In the Ameluz Licensor’s
Phase III trials, the resulting redness and/or inflammation resolved within 1 to 4 days in most cases; in some cases, however, it persisted
for 1 to 2 weeks or even longer. Topical application of a photosensitizer nevertheless should be combined with informing the patients
to avoid direct sunlight and/or to wear protective clothing and sunscreen for some days after the treatment. Patients’ indoor
activities are generally unrestricted except that they are told to avoid bright lights. The degree of selectivity and period of skin
photosensitivity varies among different photosensitizers and is also related to the drug dose given. Unless activated by light, photosensitizers
have no direct photodynamic therapy effects.
The RhodoLED® PDT-lamp series uses
LEDs emitting red light at a wavelength of approximately 635 nm specifically designed for photodynamic therapy to activate
the photosensitizer. The red light emitted by the RhodoLED® lamp series is outside the infrared range, reducing the likelihood
for discomfort from warming. Other light wavelengths can also activate the photosensitizer, but red light is known for penetrating
the skin deepest. The RhodoLED® lamp series is assembled at the Ameluz Licensor’s corporate headquarters
in Leverkusen, Germany. Supply of the lamp is regulated via our Ameluz LSA. As such, Biofrontera Pharma is considered the responsible
manufacturer of the RhodoLED® lamp series by the FDA.
We
believe the BF-RhodoLED® lamp combines a controlled and consistent emission of light at the required wavelength with simplicity
of design, user-friendliness and energy efficiency. The BF-RhodoLED® lamp contains a fan used to blow air over the treated
skin surface and power settings for the fan. The lamp is approved in the United States by the FDA as a combination product for use in
treatment of actinic keratosis with Ameluz®.
In
late October 2021, the new, larger RhodoLED® XL was approved by the FDA in combination with Ameluz® for
the treatment of mild and moderate actinic keratoses on the face and scalp, which corresponds to the current approval of Ameluz®.
The new PDT-lamp enables the illumination of larger areas, thus allowing the simultaneous treatment of several actinic keratoses
distant from each other. The treatment parameters of the new RhodoLED® XL, such as light dose, illumination time and wavelength
of light are identical to the predecessor model BF-RhodoLED®. In order to meet the FDA’s strict requirements for
the manufacture of a class III medical device, production of the new lamp has, similar to the older model, been established at the Ameluz
Licensor’s headquarters in Leverkusen. The BF-RhodoLED® model will continue to be offered in the US market.
History
of Approved Indications and Active Applications
Following the centralized European regulatory approval
by the European Commission for Ameluz® (“love the light”) 78 mg/g Gel for the treatment of actinic keratoses
of mild-to-moderate severity on the face and scalp in December 2011, the Ameluz Licensor received approval from the FDA in
the United States in May 2016. Under the approval, Ameluz® is to be marketed in combination with photodynamic therapy
using the BF-RhodoLED® lamp for lesion-directed and field-directed treatment of actinic keratoses of mild-to-moderate
severity on the face and scalp. Thus, in the United States, Ameluz® is to be used in combination with exposure to light
using the BF-RhodoLED® lamp. Through our Ameluz LSA, we launched the commercialization of Ameluz® and the
BF-RhodoLED® lamp for the treatment actinic keratosis in the United States in October 2016.
For the Ameluz Licensor’s
medical device products BF-RhodoLED® and RhodoLED® XL, three priority patent applications have been filed.
The first one was submitted by the Ameluz Licensor as a PCT application to the EPO on June 5, 2019. The corresponding national
phase in the U.S. was initiated by the Ameluz Licensor on November 17, 2020. The international application was published on December
10, 2020. Two more applications were submitted by the Ameluz Licensor to the United States Patent and Trademark Office (“USPTO”),
one on October 15, 2020, and the other one on March 29, 2021. All three applications aim at protecting both hardware and software in
the Biofrontera Group’s PDT-lamps and thus could, once granted, also protect Ameluz® itself in the United States,
due to the specifics of the FDA’s combination approval.
An
international patent application entitled “Photodynamic therapy comprising two light exposures at different wavelengths”
was filed by Biofrontera Bioscience on August 23, 2018, which describes a combined PDT (photodynamic therapy) modality. The invention
relates to the application of a composition comprising a photosensitizer followed by two consecutive exposures of the treatment area
to light, firstly natural daylight and secondly light of a wavelength corresponding to the absorption of the photosensitizer. This application
has been nationalized in seven countries including the United States and regionalized as a European patent application.
On
December 2, 2021, Biofrontera AG announced that the USPTO had issued a Notice of Allowance for the U.S. patent application number 17/234,490,
titled “Illumination for Photodynamic Therapy,” that covers an innovative, pain-reducing illumination protocol for photodynamic
therapy. Subsequently, the patent was granted in February 2022.
On
December 8, 2021, Biofrontera AG announced that the USPTO has issued a Notice of Allowance for Biofrontera Pharma GmbH’s U.S. patent
number 17/215,785 (‘785 patent), titled “Illumination device for photodynamic therapy, method for treating a skin disease
and method for operating an illumination device,” which protects a number of innovations relating to the RhodoLED XL®
lamp. Subsequently, the patent was granted in January 2022.
Actinic
keratoses
Actinic
keratoses are superficial potentially pre-cancerous skin lesions caused by chronic sun exposure that may, if left untreated, develop
into a form of potentially life-threatening skin cancer called squamous cell carcinoma. Actinic keratoses typically appear on sun-exposed
areas, such as the face, bald scalp, arms or the back of the hands, and are often elevated, flaky, and rough in texture, and appear on
the skin as hyperpigmented spots.
According
to The Skin Cancer Foundation, actinic keratosis affects approximately 58 million people in the United States, and, if left untreated,
up to 5-10 percent of actinic keratoses lesions develop into squamous cell carcinomas every year. 1 On
average, this transformation into squamous cell carcinoma occurs within two years of formation of the initial actinic keratosis lesion.
1
“Actinic Keratosis Overview – A Common Precancer.” The Skin Cancer Foundation, March 31, 2022,
www.skincancer.org/skin-cancer-information/actinic-keratosis
Squamous
cell carcinoma is an uncontrolled growth of abnormal cells arising in the squamous cells, which reside in the skin’s upper layer
(the epidermis). Squamous cell carcinomas often appear as scaly red patches, open sores, elevated growths with a central depression,
or warts; and they may crust or bleed. They can become disfiguring and sometimes deadly if allowed to grow. According to The Skin Cancer
Foundation, squamous cell carcinoma has been the second most common form of skin cancer, but its incidence has been rapidly increasing.
According to The Skin Cancer Foundation, more than one million cases of squamous cell carcinoma are diagnosed each year in the United
States, and it has been estimated that as many as 15,000 people die from the disease each year in the United States. Incidence of the
disease has increased by 200% in the past three decades in the United States and it has recently matched the incidence of basal cell
carcinoma in the Medicare fee-for-service population, which had been the most common form of human cancers.
Actinic
keratosis typically develops on areas of chronic sun exposed skin. The necessity to treat actinic keratosis arises from the inherent
risk of progression to invasive skin cancer, the chronic character of the disease and the potentiated risk for patients with multiple
actinic keratoses. The American Academy of Dermatology
recommends treating actinic keratosis to reduce your risk of developing skin cancer2. This is in agreement
with recommendations made by the European Academy of Dermatology and Venereology, who also highlight the additional treatment of the
surrounding photodamaged skin in case multiple lesions are present. International treatment guidelines list photodynamic therapy as the
“gold standard” for treating actinic keratosis, especially multiple actinic keratoses and the surrounding photodamaged skin3.
Market
Overview for Treatment of Actinic Keratosis
Actinic
keratosis is a disease that is most frequent in the Caucasian, light-skinned population. Only a fraction of these patients is currently
being treated. Actinic keratoses are treated using a wide range of methods. The traditional methods of treating actinic keratoses are:
● cryotherapy, or the deep freezing of skin;
● simple curettage;
● self-applied topical prescription products; and
While
any one of these treatment options can be effective, each has specific limitations and side effects.
Cryotherapy
is non-selective; this means it cannot target specific tissues and affects all tissues in the area of application. Cryotherapy can be
painful at the site of freezing and can cause blistering and loss of skin pigmentation, leaving temporary or permanent white spots. In
addition, there is no standardized treatment protocol with Cryotherapy, thus, the results are not uniform and can depend on the skill
or technique of the healthcare provider treating the patient.
Simple
curettage is generally most useful for one or a few individual lesions, but not for a large number of lesions, and it leaves permanent
scars.
Topical
prescription products such as 5-fluorouracil cream requires twice-a-day application by the patient for approximately 2 to 4 weeks, resulting
in inflammation, redness and erosion or rawness of the skin. Following the treatment, up to several weeks of healing may be required.
Imiquimod or diclofenac, other topical prescription products, require extended applications of cream, lasting up to 3 or 4 months, during
which the skin is often very red and inflamed. Tirbanibulin is a recent FDA-approved topical (12/2020) with shorter treatment and less
irritation, yet lower disease clearance rates. With all topical products, even those with a relatively short course of treatment, patient
compliance remains an issue, as many patients discontinue treatment once the skin irritation begins.
Markets
and competitive landscape
The United States
is the largest market for our flagship product Ameluz® in combination with the RhodoLED® lamp series.
According to The Skin Cancer Foundation, actinic keratosis (“AK”) affects approximately 58 million people
in the United States.4 In 2021, an estimated 13.2 million treatments for actinic keratosis were performed. In
the United States, the most common treatment for actinic keratosis remains cryotherapy, with approximately 11.4 million procedures performed
in 2021 and an 86.4% market share. Topical drugs for the treatment of AK took a market share of about 11.8% in the reporting year, followed
by PDT drugs at 1.8%. Simple curettage is generally not used to treat actinic keratosis in the United States. The 2021 AK market
has grown 4% over 2020.
2
“Guidelines of care for the management of actinic keratosis.” Journal of the American Academy of Dermatology, April
2, 2021, https://www.jaad.org/article/S0190-9622(21)00502-8/fulltext
3
Werner RN, Stockfleth E, Connolly SM, et al. Evidence- and consensus-based (S3) Guidelines for the Treatment of Actinic Keratosis
- International League of Dermatological Societies in cooperation with the European Dermatology Forum - Short version. J Eur Acad Dermatol
Venereol. 2015;29(11):2069-2079. doi:10.1111/jdv.13180
4 “Actinic
Keratosis Overview – A Common Precancer.” The Skin Cancer Foundation, March 31, 2022, www.skincancer.org/skin-cancer-information/actinic-keratosis
The
chart below displays the relative percentages of these actinic keratosis treatments:
The
overall market, or total number of AK treatments, declined in 2020 due to the coronavirus pandemic. In the United States, we saw a cumulative
12.2% decline from 2019 levels. Rising infection rates and the associated official recommendation by the American Academy of Dermatology
to provide patients with remote diagnosis and treatment whenever possible led to significantly declining patient numbers and widespread,
albeit temporary, closures of physicians’ offices. In 2021, the total AK market grew by 4%. The PDT market grew at the same
rate as the AK market; however, Ameluz® grew at 9%. The market share within the PDT drug segment for Ameluz®
was 25.6%, compared to approximately 24.5% in the previous year. Biofrontera was able to improve our market position versus
the competing PDT drug despite the lingering effects of the pandemic on dermatology patient office visits.
The
chart below shows the relative percentages of the PDT market share:
Our
goal is to continue to improve the market positioning of Ameluz® to become the leading PDT drug for the treatment of AK
in the United States. In addition, we see the opportunity to expand the PDT market as a therapy for the treatment of actinic keratosis
as the first option compared to cryotherapy, especially in patients with more than 15 lesions. We believe dermatologists have favored
cryotherapy to treat actinic keratosis because of a favorable reimbursement regime; however, we believe that there is treatment guideline
pressure towards field-directed therapy (as opposed to single lesion therapy), which may also help support sales of photodynamic therapy
treatments.
The
primary competing PDT drug in the United States is Levulan®, which has been approved for the treatment of minimally to
moderately thick actinic keratoses of the face or scalp in combination with PDT with a blue light source since 1999. Levulan®
was the only FDA-approved product on the U.S. market for the PDT treatment of actinic keratosis (in accordance with the applicable
prescribing information) until our company launched Ameluz® in the United States in October 2016 (Galderma sold Metvix®
in the U.S. market only for a short period and withdrew the product in 2013).
In
addition, in August 2017, the Ameluz Licensor agreed with the FDA on the requirements for the potential approval of its application to
extend Ameluz® PDT for the treatment of superficial basal cell carcinoma in the United States. See “—Our
Licensors’ Research and Development Programs—Current Clinical Trials for Ameluz® for the U.S. Market”.
If the Ameluz Licensor obtains FDA approval for such label extension, we expect that Ameluz® would be at that
time the only drug in the United States approved for the indication of treatment of superficial basal cell carcinoma with
PDT. Under the Ameluz LSA, we would have the exclusive license to market Ameluz® PDT in the United States for such indication.
We
expect that our ability to compete in the PDT-market will be based upon such factors as:
● the efficacy from treatment with Ameluz® photodynamic therapy;
● the recurrence rates from treatment with Ameluz® photodynamic therapy;
● the ease of administration of our formulation for photodynamic therapy;
● the ability of our drug to provide both lesion-and field-directed treatment;
● the number of required doses;
● the cosmetic outcome and improvement of skin impairment; and
● our continued efforts to develop further indications.
Based
on the above market and competitive analysis, we believe there is substantial market potential and room for growth in the U.S. and we
believe that this data provides the best information available to us relating to the present market for actinic keratosis treatments
in the United States. We also base our business planning activities on these data.
Xepi®
As
described in the section “—Commercial Partners and Agreements—Ferrer Internacional S.A.”, the acquisition
of Cutanea Life Sciences, Inc. in March 2019 has enabled Biofrontera Inc. to market an FDA-approved drug that had been recently introduced
in the U.S. market. Xepi® (ozenoxacin cream, 1%) is a topical prescription medicine approved for the treatment of impetigo,
a common skin infection caused by bacteria (Staphylococcus aureus or Streptococcus pyogenes). Xepi® acts by blocking the
action of two enzymes essential for bacterial DNA replication: DNA-gyrase and topoisomerase IV. Because of this dual mechanism of action,
Xepi® is believed to show a low tendency to induce resistant bacteria. Currently, no antibiotic resistance against Xepi®
is known. It has been specifically approved by the FDA also for the treatment of antibiotic-resistant bacteria Staphylococcus aureus
or Streptococcus pyogenes. The approved indication is the topical treatment of impetigo due to Staphylococcus aureus or Streptococcus
pyogenes in adult and pediatric patients 2 months of age and older.
Impetigo
is a common and highly contagious bacterial skin infection caused by bacteria. The bacteria that can cause impetigo include Group
A beta-hemolytic streptococcus and Staphylococcus aureus. It occurs most frequently in children 2 to 5 years old, but people of any age
can be affected. Impetigo causes red sores that most often appear on the face, neck, arms, and legs. These sores can turn into blisters
that open and form a yellowish crust. Transmission of the disease is by direct contact and poor hygiene can increase the spread. Anyone
can get impetigo, and they can get it more than once. Although impetigo is a year-round disease, it occurs most often during the warm
weather months.5 There are more than 3 million cases of impetigo in the United States every year.5
Possible
complications of impetigo6 can include:
● Worsening or spreading of the infection
● Scarring, which is more common with ecthyma
Impetigo
caused by beta-hemolytic strep bacteria can cause:
● Kidney damage (poststreptococcal glomerulonephritis)
● Fever, joint, and other problems (rheumatic fever)
Although
impetigo rarely leads to serious complications, effective treatment with drugs like Xepi® can shorten how long impetigo
lasts.
5
How to Treat Impetigo and Control This
Common Skin Infection | FDA
6From
CLS link to Johns Hopkins Impetigo | Johns Hopkins Medicine
Treatment
decisions should consider resistance pattern of Staphylococcus aureus as antibiotic ineffectiveness resulting from bacterial resistance
makes infections more difficult to control, worsens prognosis, and increases healthcare costs. Increasing resistance to known antibiotics
is a serious concern for doctors. The World Health Organization has declared antimicrobial resistance as one of the top 10 global public
health threats facing humanity. The cost of resistance to our economy and health system is significant. In a 2009 study titled “Hospital
and Societal Costs of Antimicrobial Resistant Infections in a Chicago Teaching Hospital: Implications for Antibiotic Stewardship,”
13.5% of patients had antimicrobial resistance resulting in a 6.5% attributable mortality rate and a per patient incremental cost of
$100,000 per resistant infection. If impetigo spreads to a community, it may also trigger the spread of resistant strains, such as MRSA,
with poor prognoses for patients over time. According to the FDA, 90% of MRSA community acquired infections present as skin and soft
tissues infections, whereby patients infected with MRSA are 64% more likely to have complications than those infected with the non-resistant
forms. In the US 78% of bacterial skin and soft tissue infections are due to MRSA.3
Market
and competitive landscape
The
market for topical antibiotics is driven by generics with mupirocin being the top choice of topical antibiotics across all specialties.
In
2021, over 13 million prescriptions were written for mupirocin for a range of conditions. According to prescription data from IQVIA,
dermatologists account for approximately 12% of the annual topical antibiotic prescriptions written or about 1.4 million prescriptions.
The
chart below displays the utilization of mupirocin by specialty in 2021:
Considering
the above market analysis, we believe there is a considerable growth potential for Xepi®.
Our
Licensors’ Research and Development Programs
We
are a sales organization with focus on commercializing our portfolio of licensed products that are already FDA-approved. Research and
development efforts for label extensions in order to optimize the market positioning of the products are the responsibility of the respective
licensor and are governed by the respective LSAs. Currently, there are no clinical trials being conducted for Xepi®.
However,
in the future, we may conduct our own clinical trials to better the market positioning of Ameluz and increase our revenue potential.
Any clinical trials we conduct for indications that are sought as part of the current clinical trials described below in “Current
Clinical Trials for Ameluz® for the U.S. Market” would require the approval of and close collaboration with
the Biofrontera Group.
3
Antimicrobial resistance (who.int); Hospital and Societal Costs of Antimicrobial-Resistant Infections in a Chicago Teaching
Hospital: Implications for Antibiotic Stewardship | Clinical Infectious Diseases | Oxford Academic (oup.com).
Current
Clinical Trials for Ameluz® for the U.S. Market
Phase
III study for the treatment of superficial basal cell carcinoma (sBCC)
In
August 2017, the Ameluz Licensor agreed with the FDA on the requirements necessary to obtain approval for our application of Ameluz®
PDT for the treatment of superficial basal cell carcinoma in the U.S. Under the Ameluz Licensor’s agreed plan with the FDA,
the application could be based on a single additional Phase III placebo-controlled pivotal trial to be conducted in the U.S., in which
Ameluz® PDT will be compared to placebo PDT. The Ameluz Licensor will be required to present as primary clinical
endpoint a combined read-out of clinical and histological clearance. In December 2017, the Ameluz Licensor submitted an investigational
new drug application with the FDA for the proposed Phase III study protocol to evaluate Ameluz® PDT for the treatment
of superficial basal cell carcinoma, and the FDA performed a special protocol assessment.
Following
the discussion with the FDA, the Ameluz Licensor initiated a study with the primary objective of comparing the efficacy of Ameluz®
PDT with PDT using just the vehicle that is used to deliver the active ingredient in Ameluz®, in combination with
BF-RhodoLED® illumination, in the treatment of superficial basal cell carcinoma. A randomized, double blind, vehicle-controlled
multicenter Phase III study is being performed by the Ameluz Licensor to evaluate the safety and efficacy of Ameluz® in
combination with the BF-RhodoLED® lamp. Secondary objectives include the evaluation of the safety and secondary efficacy
parameters (including stratification according to lesion size, location, patient age and sex) related to Ameluz® in combination
with the BF-RhodoLED® lamp, also including clinical clearance of additional treated lesions on the same patients. The
double-blind clinical observation period for each patient will be up to 7 months (up to four weeks screening and pre-randomization period,
and three or six months double blind part of the study) followed by a 5-year follow-up period after the start of the last PDT cycle.
The recruitment phase started in the third quarter of 2018. Due to the study protocol mandated by the FDA, the recruitment process
has taken and will likely take a considerable amount of time. As of now over 73% of the patients have been recruited. A
total of 18 clinical sites are currently participating in the study.
Phase
I safety study evaluating PDT with three tubes of Ameluz®
In
December 2021, the Ameluz Licensor commenced patient enrollment for its Phase I safety study to evaluate the safety and tolerability
of PDT for the treatment of mild-to-severe AK on the face and scalp using three tubes of Ameluz® together with the new
RhodoLED® XL lamp. The non-randomized, open-label, multicenter study evaluates the safety and tolerability of Ameluz®
in the treatment of AK located on the face and scalp with PDT together with the new RhodoLED® XL lamp. The study
includes 100 patients with mild to severe AK. Each patient will receive the content of three tubes of Ameluz® for a field-directed
treatment of AK. A total of eight clinical sites are participating in the study.
The
Phase I study follows a maximal-usage pharmacokinetics (“PK”) clinical study that was completed in October 2020 and
the results were submitted to the FDA in early 2021. The
objective of the study was to evaluate the safety of patients after applying three tubes of Ameluz® to the skin by investigating
the amount of active ingredient that enters the blood stream. Further parameters related to the safety of patients undergoing such treatment
were also investigated. The FDA acknowledged the results of the PK study. However, the regulatory agency subsequently requested another
safety study focusing on transient adverse events before amending the product information, which currently limits use to one tube of
Ameluz® per treatment.
Phase
II study for the treatment of moderate to severe acne
In
December 2021, the Ameluz Licensor started patient recruitment for the phase IIb study evaluating the safety and efficacy of Ameluz®
in combination with the PDT-lamp BF-RhodoLED for the treatment of moderate to severe acne with Ameluz®-PDT.
The
multicenter, randomized, double blind phase II study with four arms uses conventional Ameluz®-PDT and includes 126 adult patients
suffering from moderate to severe acne, who will be treated with Ameluz®-PDT or placebo. Efficacy and safety of Ameluz®-PDT will
be tested with respect to incubation periods of one and three hours compared to placebo. The primary endpoint of the study is the absolute
change in the number of inflammatory lesions and an improvement in symptoms. To ensure collection of highly consistent data across all
participating sites, the study will combine clinical assessments performed by the physicians conducting the study with a cutting-edge,
FDA-approved, artificial intelligence analysis platform that will provide a lesion count along with a severity assessment. A total of
seven sites are participating in the study.
Sales,
marketing and distribution
We
are currently selling our portfolio of licensed products in the United States through the use of our own commercial organization. We
have a single sales force who markets all our licensed products across the dermatology space.
We
launched the commercialization of Ameluz® in combination with the RhodoLED® lamp for the treatment of actinic
keratosis in the United States in October 2016. Prior to launch, and with the help of a consulting firm specializing in market access,
we analyzed the reimbursement mechanisms for photodynamic therapy in the U.S. healthcare system. Ameluz® is distributed
as a “buy-and-bill” drug that is purchased by the dermatologist, rather than distribution through pharmacies.
Based
on our experience, we concluded that we could most effectively market our products by using our own sales force, which we train to sell
our drug Ameluz® (in combination with the RhodoLED® lamp series) and Xepi®.
During 2016, we hired 26 employees for our U.S. marketing and sales efforts, and we launched the commercialization of Ameluz®
and RhodoLED® lamp for actinic keratosis in the U.S. in October 2016.
Since
then, we have continued to build our organization in the United States, added the FDA-approved prescription drug Xepi®
to our portfolio in March 2019 and, as of December 31, 2019, we had over 70 employees in our salesforce and field based supporting functions
in the medical and reimbursement field. However, due to measures and regulations implemented by governments worldwide in an attempt to
control the COVID-19 pandemic, and the reduced demand for our products that this caused, we had to reduce our U.S. workforce in March
2020 and implemented a mandatory furlough program, under which all employees were required to take temporary periods of unpaid time off.
As of December 31, 2020, we had 56 employees. We have since re-filled the key positions for our U.S. operations with qualified and experienced
employees. As of December 31, 2021, we have 69 employees of which 35 are sales positions including management. We are considering
additional expansion of our sales and office staff as we expand our commercial footprint.
We
centralize our customer sales support and back-office functions through our headquarters in Woburn, Massachusetts. We use Cardinal Health
as our third-party logistics partner for warehousing and distribution. To mitigate risk of business interruption, product is stored and
shipped from two warehouses, either La Verne, Tennessee or Reno, Nevada, depending on geographical ship-to locations. We intend to continue
our development of our sales and marketing infrastructure to effectively target the broad range of dermatologic prescribers. To further
our development, we plan to expand our headcount, increase our investment in market research and brand development, further develop our
distribution capabilities and explore broader payer relationships and coverage.
Significant
Customers
At
December 31, 2021, no customer represented more than 10% of the net accounts receivable balance. For the year ended December 31, 2021,
no customer represented more than ten percent of net revenues.
Intellectual
Property
We
do not own any patents or trademarks. We license the rights and trademarks related to the products we sell. See “—Commercial
Partners and Agreements” for more information regarding the terms of our license agreements for Ameluz® and
Xepi®.
The
patent family that protected the technology relating to the combination of a nanoemulsion with 5-aminolevulinic acid, the
active ingredient in Ameluz®, against copying by competitors expired on November 12, 2019. This patent family included
U.S. Patent No. 6,559,183, which, prior to its expiration, served as a material, significant and possibly the only barrier to entry into
the U.S. market by generic versions of Ameluz®. Although the process of developing generic topical dermatological products