UNITED
STATES
SECURITIES
AND EXCHANGE COMMISSION
Washington,
D.C. 20549
FORM
10-K
(Mark
One)
For
the fiscal year ended December 31, 2022
or
For
the transition period from __________to _____________
Commission
file number: 001-36199
PULMATRIX,
INC.
(Exact
name of registrant as specified in its charter)
99 Hayden Avenue, Suite 390
(Address of principal executive offices) (Zip Code)
Registrant’s
telephone number, including area code (781) 357-2333
Securities
registered pursuant to Section 12(b) of the Exchange Act:
Title of each class Trading Symbol(s) Name of each exchange on which registered
Common Stock, par value $0.0001 per share PULM The NASDAQ Stock Market LLC
Securities
registered pursuant to Section 12(g) of the Exchange 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 Exchange 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. Yes ☐ No ☒
If
securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant
included in the filing reflect the correction of an error to previously issued financial statements. ☐
Indicate
by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation
received by any of the registrant’s executive officers during the relevant recovery period pursuant to §240.10D-1(b). ☐
Indicate by check mark whether the registrant
is a shell company (as defined in Rule 12b-2 of the Exchange Act). Yes ☐ No ☒
The
aggregate market value of the registrant’s voting and non-voting common equity held by non-affiliates computed by reference to
the price at which the common equity was last sold, as of June 30, 2022, the last business day of registrant’s most recently completed
second fiscal quarter, was $15,546,729.
As
of March 27, 2023, the registrant had 3,652,285 shares of common stock, par value $0.0001 per share, issued and outstanding.
DOCUMENTS
INCORPORATED BY REFERENCE
None.
PULMATRIX,
INC.
TABLE
OF CONTENTS
Page No.
Forward-Looking Statements 1
PART I
Item 1. Business. 2
Item 1A. Risk Factors. 19
Item 1B. Unresolved Staff Comments. 40
Item 2. Properties. 40
Item 3. Legal Proceedings. 40
Item 4. Mine Safety Disclosures. 40
PART II
Item 6. Reserved. 41
Item 7A. Quantitative and Qualitative Disclosures About Market Risk. 51
Item 8. Financial Statements and Supplementary Data. 51
Item 9A. Controls and Procedures. 52
Item 9B. Other Information. 52
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections. 52
PART III
Item 10. Directors, Executive Officers and Corporate Governance. 53
Item 11. Executive Compensation. 59
Item 14. Principal Accountant Fees and Services. 66
PART IV
Item 15. Exhibits, Financial Statement Schedules. 67
Signatures 72
i
PART
I
Forward-Looking
Statements
This
Annual Report on Form 10-K contains forward-looking statements. All statements other than statements of historical fact contained herein,
including statements regarding our business plans or strategies, projected or anticipated benefits or other consequences of our plans
or strategies, projected or anticipated benefits from acquisitions to be made by us, or projections involving anticipated revenues, earnings,
or other aspects of our operating results, are forward-looking statements. Words such as “anticipates,” “assumes,”
“believes,” “can,” “could,” “estimates,” “expects,” “forecasts,”
“guides,” “intends,” “is confident that,” “may,” “plans,” “seeks,”
“projects,” “targets,” and “would,” and their opposites and similar expressions, as well as statements
in future tense, are intended to identify forward-looking statements. Forward-looking statements should not be read as a guarantee of
future performance or results and may not be accurate indications of when such performance or results will actually be achieved. Forward-looking
statements are based on information we have when those statements are made or our management’s good faith belief as of that time
with respect to future events and are subject to risks and uncertainties that could cause actual performance or results to differ materially
from those expressed in or suggested by the forward-looking statements. Important factors that could cause such differences include,
but are not limited to:
● our inability to carry out research, development and commercialization plans;
● termination of certain license agreements;
● adverse market and economic conditions;
● loss of one or more key executives or scientists; and
● difficulties in securing regulatory approval to market our product candidates.
For
a more detailed discussion of these and other risks that may affect our business and that could cause our actual results to differ from those projected in these forward-looking statements, see the risk factors and uncertainties described under the heading
“Risk Factors” in Part I, Item 1A of this Annual Report on Form 10-K. The forward-looking statements contained in this Annual
Report on Form 10-K are expressly qualified in their entirety by this cautionary statement. We do not undertake any obligation to update
any forward-looking statement to reflect events or circumstances after the date on which any such statement is made or to reflect the
occurrence of unanticipated events, except as required by law.
Unless
otherwise stated, references in this Annual Report on Form 10-K to “us,” “we,” “our,” or “Company”
refer to Pulmatrix, Inc., a Delaware corporation.
“iSPERSETM”
is one of our trademarks used in this Annual Report on Form 10-K. Other trademarks appearing in this report are the property of their
respective holders. Solely for convenience, these and other trademarks, trade names and service marks referred to in this report appear
without the ®, TM and SM symbols, but those references are not intended to indicate, in any way, we or the owners of such
trademarks will not assert, to the fullest extent under applicable law, their rights to these trademarks and trade names.
ITEM 1. BUSINESS.
Overview
We
are a clinical-stage biotechnology company focused on the discovery and development of novel inhaled therapeutic products intended to
prevent and treat respiratory and other diseases with significant unmet medical needs using its patented iSPERSETM technology.
The Company’s proprietary product pipeline includes treatments for serious lung diseases, such as allergic bronchopulmonary aspergillosis
(“ABPA”) and Chronic Obstructive Pulmonary Disease (“COPD”), and central nervous system (“CNS”) disorders
such as acute migraine. Our product candidates are based on its proprietary engineered dry powder delivery platform, iSPERSETM,
which seeks to improve therapeutic delivery to the lungs by maximizing local concentrations and reducing systemic side effects to improve
patient outcomes.
We
design and develop inhaled therapeutic products based on our proprietary dry powder delivery technology, iSPERSETM
(inhaled Small Particles Easily Respirable and Emitted), which enables delivery of small or large molecule drugs to the lungs by inhalation
for local or systemic applications. The iSPERSETM powders are engineered to be small, dense particles with highly
efficient dispersibility and delivery to airways. iSPERSETM powders can be used with an array of dry powder inhaler
technologies and can be formulated with a broad range of drug substances including small molecules and biologics. We believe the iSPERSETM
dry powder technology offers enhanced drug loading and delivery efficiency that outperforms traditional lactose-blend inhaled
dry powder therapies.
We
believe the advantages of using the iSPERSETM technology include reduced total inhaled powder mass, enhanced dosing
efficiency, reduced cost of goods, and improved safety and tolerability profiles.
We
were incorporated in 2013 as a Delaware corporation.
Business
Strategy
Our
goal is to develop breakthrough therapeutic products that are safe, convenient, and more effective than the existing therapeutic products
for respiratory and other diseases where iSPERSETM properties are advantageous.
Our
current pipeline is aligned to this goal as we develop iSPERSETM-based therapeutic candidates which target
the prevention and treatment of a range of diseases, including CNS disorders and pulmonary diseases. These therapeutic candidates
include PUR1900 for the treatment of ABPA in patients with asthma and in patients with cystic fibrosis (“CF”), PUR3100
for the treatment of acute migraine, and PUR1800 for the treatment of acute exacerbations of chronic obstructive pulmonary disease
(“AECOPD”). Each program is enabled by its unique
iSPERSETM formulation designed to achieve specific therapeutic objectives.
We
intend to capitalize on our iSPERSETM technology platform and our expertise in inhaled therapeutics to identify
new product candidates for the prevention and treatment of diseases with significant unmet medical needs and to build our product pipeline
beyond our existing candidates. In order to advance clinical trials for our therapeutic candidates and leverage the iSPERSETM
platform to enable delivery of partnered compounds, we intend to form strategic alliances with third parties, including pharmaceutical
and biotechnology companies or academic or private research institutes.
We
expect to continue to incur significant expenses and operating losses for at least the next several years based on our drug development
plans. We expect our expenses and capital requirements will increase substantially in connection with our ongoing activities, as we:
We
will continue to direct resources to advance the research and development of PUR1900 for ABPA in patients with asthma and CF. In
2018, we completed a Phase 1 study of PUR1900 in normal healthy volunteers and asthma patients. In 2019, we began a Phase 2 study of
PUR1900 with patients with asthma and are suffering from ABPA but stopped the Phase 2 study due to the COVID-19 pandemic and its
impact on enrollment. In January 2021, we conducted a Type C meeting with the U.S Food and Drug Administration (“FDA”)
to discuss our plans for a Phase 2b study. Utilizing the FDA feedback, we advanced PUR1900 into a new Phase 2b
efficacy study that includes a sixteen-week dosing regimen with potential registration efficacy endpoints, rather than the four-week dosing regimen in the terminated Phase 2 safety biomarker study. The current Phase 2b study began dosing patients in the first
quarter of 2023. The PUR1900 Phase 2b study is anticipated to deliver topline data in mid-2024.
We
developed PUR3100, an iSPERSETM formulation of DHE in 2020. We completed GLP toxicology studies in 2021 and 2022.
On September 26, 2022, we announced the completion of patient dosing in a Phase 1 trial evaluating PUR3100, a novel pulmonary inhaled
formulation for the treatment of acute migraine. On January 4, 2023, we announced PUR3100 was safe and all doses had fewer GI side effects
compared to intravenous (“IV”) DHE. PUR3100 demonstrated a five-minute Tmax and Cmax within the targeted
therapeutic range for all three doses tested. The Phase 1 study design was a double-dummy, double-blinded trial to assess the safety,
tolerability, and pharmacokinetics of three dose levels of single doses of inhaled PUR3100 with IV placebo, as compared to IV DHE (DHE
mesylate injection) with inhaled placebo. Twenty-six healthy subjects were enrolled and each of the four groups contained at least six
subjects. Oral inhalation of PUR3100 achieved peak exposures in the targeted therapeutic range at all doses and the Tmax occurred
at five minutes after dosing.
We
believe these data are encouraging and suggest that the orally inhaled formulation of DHE, PUR3100, will result in
rapid systemic exposure in the therapeutic range, while minimizing the risk of side effects related to exposure levels associated with
IV dosing. We believe the PUR3100 formulation of DHE is highly differentiated from other DHE products already approved or in development,
can be immediately self-administered and has a pharmacokinetic profile that may potentially advance the treatment of patients with acute migraine.
We
completed preclinical safety studies for our lead iSPERSETM formulation in 2018 and advanced our formulation
and process development efforts to support clinical testing in stable moderate-severe COPD patients. We completed a Phase 1b safety,
tolerability, and pharmacokinetics clinical study of PUR1800 for subjects with stable moderate-severe COPD and received topline data
from the Phase 1b clinical study in the first quarter of 2022. We analyzed data from the completed Phase 1b clinical study of
PUR1800 for AECOPD and presented study results at the American Academy of Allergy, Asthma and Immunology (AAAAI) conference in
February 2023. We completed all data analysis to inform a study design for a potential Phase 2 efficacy and safety study, treating
subjects with AECOPD.
To
add additional inhaled therapeutics to our discovery pipeline and facilitate additional discovery collaborations, we are leveraging our
iSPERSETM technology and our management’s expertise in inhaled therapeutics and particle engineering to
identify potential product candidates. These potential product candidates are potentially safer and more effective than the current standard
of care for prevention and treatment of diseases with significant unmet medical needs.
The
status of our patent portfolio changes frequently in the ordinary course of patent prosecution. As of December 31, 2022, our patent
portfolio related to iSPERSETM included approximately 137 granted patents, 19 of which are granted US
patents, with expiration dates from 2024 to 2037, and approximately 49 additional pending patent applications in the US and other
jurisdictions. Our in-licensed portfolio related to kinase inhibitors included approximately 276 granted patents, 32 of which are
granted US patents, with expiration dates from 2029 to 2035, and approximately 26 additional pending patent applications in the US
and other jurisdictions. On March 1, 2022, we filed a patent cooperation treaty application that discloses and claims certain formulations and methods of use relevant to our PUR3100
program.
During
2022, we were staffed to support two active clinical programs. In first quarter of 2022, we hired our Chief Medical Officer,
among other personnel, to support these programs.
iSPERSETM
Technology
We
use simple, safe excipients, including proprietary cationic salt formulations, to create a robust and flexible dry powder platform technology
that can accommodate a wide range of drug loads in highly dispersible particles. Our initial delivery platform emerged from development
of iCALMTM (inhaled Cationic Airway Lining Modulators), a non-steroidal anti-inflammatory therapy. The high degree of aerosol efficiency
and the density profile of our dry powder iCALMTM formulations provided the foundation for our development of iSPERSETM
in 2012, which uses other monovalent and divalent salts.
iSPERSETM
particles are engineered with a small, dense and dispersible profile to exceed the performance of traditional dry powder particles
as the iSPERSETM particles have the dispersibility advantages of porous engineered particles. We believe this
results in superior drug delivery compared to traditional oral and injectable forms of treatment for certain diseases. Unlike lactose-blended
carrier formulations or low-density particles which disperse poorly, we believe that the iSPERSETM technology
platform offers several potential benefits, achieved through the following technological innovations:
iSPERSETM
particles can be engineered to include significantly less than one percent (1%) to greater than eighty percent (80%) active
pharmaceutical ingredients (“APIs”), which allows flexibility for dosing both high potency and high-drug load therapeutics.
● Superior flow rate independent lung delivery without carriers.
The
iSPERSETM technology enables pulmonary delivery independent of lactose or other carriers, which results in significantly
greater lung dose at a matched nominal dose of conventional lactose-based formulations. iSPERSETM formulations
are dispersible across a range of flow rates with consistent emitted dose and particle size. Performance across flow rates provides reliable
dose delivery across patient populations and reduces patient-to-patient variability.
● Delivery of macromolecules and biologics.
iSPERSETM
powders can be used with an array of dry powder inhaler technologies and can be formulated with a broad range of therapeutic
compounds ranging from small molecules to proteins for both local and systemic drug delivery applications.
● Homogenous combinations of multiple drugs.
iSPERSETM
creates homogenous particles including excipients and API, which allow for the consistent delivery of multiple APIs in a product.
We have successfully formulated iSPERSETM-based products with dual and triple API combinations.
● Strong safety profile.
Current
iSPERSETM products and planned clinical-stage products to be formulated in iSPERSETM are
supported by robust preclinical safety profiles. iSPERSETM excipients include those with inhalation precedent
and those that are generally regarded as safe by other routes of administration.
Therapeutic
Candidates
PUR1900
We
are developing an iSPERSETM inhaled formulation of the antifungal drug itraconazole for the prevention and treatment
of fungal infections and allergic/hypersensitivity reactions to fungus in patients with severe lung disease, including those with asthma
and CF. On January 28, 2020, PUR1900 received Fast Track designation from the FDA for the treatment of ABPA. Aspergillus colonization
and infections are likely underdiagnosed and occur frequently in patients of all ages. Colonization and infection with Aspergillus.
can lead to clinical disease with differing severities and complications depending on the immune status of the host. Invasive aspergillosis
is a frequently fatal disease that occurs in patients that are typically immune suppressed as a result of treatment for hematologic cancers
or immunosuppression prior to solid organ transplantation. In patients with asthma and CF, Aspergillus can cause chronic infections
that may be associated with worsening disease and larger declines in lung function than patients without infection. A subset of patients
with asthma and CF with Aspergillus colonization and/or infection develop ABPA, which is a complex hypersensitivity reaction to
fungal antigens. ABPA is a disease resulting in mucus production, wheezing, pulmonary infiltrates, worsening bronchiectasis, and fibrosis
of the lung.
In
patients with both asthma and CF, ABPA is commonly treated with oral steroids to treat inflammation and with oral antifungals to reduce
fungal infection. The inhalation administration of a drug affords direct delivery of the drug to the infected parts of the lung, maximizing
the dose to the affected sites and minimizing systemic exposure to the rest of the body where it could cause significant side effects.
Therefore, treatment of lung infections by direct administration of anti-infective products to the lung may improve both the safety and
efficacy of treatment compared to systemic administration by other routes, as well as improving patient convenience as compared to oral
and injectable forms of the treatment. We believe that local lung delivery by inhalation of our iSPERSETM formulation
could provide convenient, effective and safe management of the debilitating and often life-threatening lung infections that are not currently
addressed by inhaled therapies.
PUR1900
is our inhaled formulation of itraconazole, an antifungal drug commercially available as an oral drug that we are developing to
treat and prevent pulmonary fungal infections. Development of PUR1900 is focused on treatment of Aspergillus. colonization
and infection in patients with asthma and CF. In a Phase 1/1b clinical trial, PUR1900 appeared to be safe and well tolerated in
healthy normal volunteers (Parts 1 and 2) and in patients with asthma (Part 3). In Part 3 of the Phase 1/1b clinical study,
following a single dose of PUR1900, the pharmacokinetics (“PK”) analysis of sputum samples demonstrated approximately
70-fold higher maximum lung concentration of itraconazole following inhalation of PUR1900 compared to oral Sporanox®
(Janssen Pharmaceuticals) despite inhaling only one-tenth the dose of itraconazole (20 mg) relative to the dose of oral
Sporanox® (200 mg). Lung exposure, as measured by sputum induction and analysis, was approximately 50-fold higher and
plasma exposure was approximately 85-fold lower following inhalation of 20 mg of PUR1900 compared to 200 mg of oral
Sporanox®. All endpoints from the Phase 1/1b clinical study were successfully met.
On
April 15, 2019, we entered into a Development and Commercialization Agreement (the “Cipla Agreement”) with Cipla Technologies
LLC (“Cipla”) for the co-development and commercialization, on a worldwide, except for the Cipla Territory defined below,
exclusive basis, of PUR1900, our inhaled iSPERSETM drug delivery system (the “Product”) enabled formulation
of the antifungal drug, itraconazole, which is only available as an oral drug, for the treatment of all pulmonary indications, including
ABPA in patients with asthma. We entered into an amendment to the Cipla Agreement on November 8, 2021 (the “Amendment”),
and all references to the Cipla Agreement herein refer to the Agreement as amended.
The
Cipla Agreement will remain in effect in perpetuity, unless otherwise earlier terminated in accordance with its terms. In the event of
circumstances affecting the continuity of development of the Product in line with the Cipla Agreement or certain development milestones
are not achieved within a specified timeframe discussed in greater detail below, the joint steering committee (“JSC”) will
evaluate the cause and effect and make a recommendation as to the most optimal option available to Cipla and us. In such events, the
parties are not obligated to follow the recommendation of the JSC and, either party may elect to terminate (a “Terminating Party”)
its obligation to fund additional costs and expenses for the development and/or commercialization of the Product. If the non-Terminating
Party wishes to continue the development of the Product, it will have the right to purchase the rights of the Terminating Party in the
Product at its fair market value. If both Cipla and we abandon the development program, Cipla and we shall make commercially reasonable
efforts to monetize the Product and development program in connection with the Pulmonary indications. Cipla and we will equally share
the proceeds.
We
and Cipla will each be responsible for 60% and 40%, respectively, of our overhead costs and the time spent by our employees and consultants
on development of the Product (“Direct Costs”), in addition to which, Cipla will reimburse us an amount equal to 10% of aggregate
Direct Costs upon the achievement of the development milestones set forth in the table below, potentially bringing the sharing of
Direct Costs to a 50/50 basis. We will continue to share all other development costs with Cipla that are not Direct Costs, such as the
cost of clinical research organizations, manufacturing costs and other third-party costs, on a 50/50 basis.
Pursuant
to the Cipla Agreement, (i) all development and commercialization activities with respect to the Product in India, South Africa, Sri
Lanka, Nepal, Iran, Yemen, Myanmar and Algeria (such countries, the “Cipla Territory”) will be conducted exclusively by Cipla
at Cipla’s sole cost and expense, and (ii) Cipla shall be entitled to all profits from the sale of the Product in the Cipla Territory,
except that if Cipla successfully transfers manufacturing of the Product for the Cipla Territory to a manufacturing site determined by
Cipla, we will become entitled to a royalty equal to 2% of net sales in the Cipla Territory.
In
partnership with Cipla, we initiated a Phase 2 clinical study in 2019, entitled: “A Randomized, Double-Blind, Multicenter,
Placebo-Controlled, Phase 2 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Itraconazole Administered as a Dry
Powder for Inhalation (PUR1900) in Adult Asthmatic Patients with ABPA.” This clinical study was terminated in July 2020 due to the
ongoing impact of the COVID-19 pandemic on patient enrollment and clinical study conduct.
Following
termination of the Phase 2 clinical study, we conducted a Type C meeting with the FDA on January 27, 2021, in order to discuss
the program overall development plan and the currently ongoing Phase 2b clinical study design. The current Phase 2b clinical study design includes
a 16-week dosing regimen with an 8-week follow up and is intended to explore potential efficacy endpoints, whereas the terminated Phase
2 clinical study had comprised only a 4-week dosing regimen with safety and tolerability as its primary endpoint. The longer dosing regimen
of the new Phase 2b clinical study is supported by the 6-month inhalation toxicology study in dogs completed in April 2020. The new development
plan, including the new Phase 2b clinical study, was approved by the partnership JSC on November 8, 2021. On February 6, 2023, we announced the first patient dosed in the Phase 2b study and the study is currently on track
with topline data anticipated in mid-2024.
In
addition to the terms of the Cipla Agreement described above, if any of the below development milestones are not met by the date that
is nine months after the applicable deadline for achieving such development milestone, either party may elect to terminate its obligation
to fund additional development costs, in which case either (i) the non-Terminating Party can acquire the rights of the Terminating Party
for fair market value or (ii) the parties will monetize the Product. The table below sets forth the development milestones.
Phase 2b Development Plan – Development Milestones
Development Milestone Milestone Date
25% of patients enrolled in Phase 2b clinical study are dosed June 30, 2023
Phase 3 Development Plan – Development Milestones
Development Milestone Milestone Date
25% of patients enrolled in Phase 3 clinical study dosed To be proposed by JSC
Company delivers Topline Results to the JSC To be proposed by JSC
The Prescription Drug User Fee Act (the “PDUFA”) To be proposed by JSC
Competition
and Market Opportunities
Current
treatments of pulmonary fungal infections highlight the limitations of oral or intravenous anti-infective treatments for lung infections.
Itraconazole is one of the most commonly prescribed therapies for treating Aspergillus. infections in patients with asthma and
CF. Itraconazole is available commercially as Sporanox® in both a capsule and oral solution form. Itraconazole is metabolized
in the liver by CYP3A4 and coadministration with a large number of drugs is contraindicated due to the potential for severe drug-drug
interactions.
We
have demonstrated that PUR1900 achieves higher local lung itraconazole concentrations with lower systemic exposure relative
to oral dosing, thus allowing for the potential to improve upon both the efficacy and safety profiles observed with oral itraconazole.
Furthermore, administration by inhalation reduces the exposure of the drug in the rest of the body, which may be beneficial
in reducing systemic side effects and the risk of potentially toxic drug-drug interactions.
There
is precedent for both dry powder and nebulized inhaled anti-infective therapy to address specific pulmonary infections in patients
which demonstrates potential utility of inhaled drug delivery and market opportunity. Mylan currently markets TOBI Podhaler for
treatment of Pseudomonas aeruginosa infection in the United States and Forest Laboratories U.K. Limited (a subsidiary of
Actavis PLC) markets inhaled colistin, Colobreathe, for the same infection in Europe. Insmed currently markets Amikacin Liposome
Inhalation Suspension (Arikayce) in the United States for the treatment of lung disease caused by a group of bacteria, Mycobacterium
avium complex in a limited population of patients with the disease who do not respond to conventional treatment (refractory
disease). Arikayce was the first drug to be approved under the Limited Population Pathway for Antibacterial and Antifungal Drugs, or
LPAD pathway, established by Congress under the 21st Century Cures Act to advance development and approval of
antibacterial and antifungal drugs to treat serious or life-threatening infections in a limited population of patients with unmet
need. As required for drugs approved under the LPAD pathway, labeling for Arikayce includes certain statements to convey that the
drug has been shown to be safe and effective only for use in a limited population. Arikayce was also approved under the accelerated
approval pathway. Under this approach, the FDA may approve drugs for serious or life-threatening diseases or conditions where the
drug is shown to have an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. The
approval of Arikayce was based on achieving three consecutive negative monthly sputum cultures by month six of treatment. Insmed was
required by the FDA to conduct an additional, post-market study to describe the clinical benefits of Arikayce. There are currently
no products specifically approved for treatment of ABPA, however, there are several inhaled antifungal agents currently under
development for the treatment of invasive aspergillosis or ABPA. Treatments under development for invasive aspergillosis include PC945, a novel azole antifungal being developed
by Pulmocide as a liquid for nebulization, and a dry powder formulation of voriconazole being developed by TFF Pharmaceuticals. In principle,
development of an inhaled antifungal for the treatment of invasive aspergillosis could also be effective for ABPA but would require additional clinical studies in the target patient population. Zambon has
also developed a dry powder formulation of voriconazole for the treatment of ABPA and completed a Phase 1 study in the third quarter of
2020. However, no additional development has since been reported. Regeneron Pharmaceuticals is currently running a clinical trial with
Dupilumab (NCT04442269) for the treatment of ABPA in asthma. This trial is anticipated to run through December 2023 and is focused on
prevention of exacerbations in individuals with at one or more severe respiratory exacerbations.
New
methods to detect Aspergillus. infection in sputum have improved the sensitivity of diagnosis and clinical appreciation for these
infections. Pulmonary Aspergillus. infections affect approximately 14 million patients worldwide according to the Global Action
Fund for Fungal Infections (Improving Outcomes for Patients with Fungal Infections across the World: A Road Map for the Next Decade).
The majority of these cases occur in patients with asthma who have allergic disease and also include invasive Aspergillus. infections
that are associated with a high rate of mortality in immunocompromised patients. We believe that PUR1900 compares favorably to the products
discussed above and has the potential to generate significant value based on treating and preventing pulmonary fungal infections in multiple
patient populations.
Clinical
Development
We
successfully completed a Phase 1/1b clinical study in 2018 which enabled us to initiate a Phase 2 clinical study in 2019, entitled: “A
Randomized, Double-Blind, Multicenter, Placebo-Controlled, Phase 2 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of
Itraconazole Administered as a Dry Powder for Inhalation (PUR1900) in Adult Asthmatic Patients with ABPA.” This clinical study was terminated
in July 2020 due to the impact of the COVID-19 pandemic on patient enrollment and clinical study conduct. The completion of a 6-month
inhalation toxicology study in dogs in 2020 enables the conduct of the current Phase 2b clinical study.
The current Phase 2b study includes a 16-week
dosing regimen and exploration of potential regulatory approval endpoints. We dosed the first patient in this current Phase 2b
clinical study during the first quarter of 2023 with topline data expected in mid-2024.
This clinical study may be affected by
remaining conditions related to the COVID-19 pandemic and its ongoing effects with respect to clinical study conduct and patient
enrollment. For more discussion of risks related to the COVID-19 pandemic and its ongoing effects, please see “Item 1A. RISK
FACTORS.—Risks Related to Our Business—Business interruptions could limit our ability to operate our
business.”
PUR3100
In
2020, we began developing PUR3100, the iSPERSETM formulation of DHE, for the treatment of acute migraine.
Over 38 million people suffer from migraine in the United States. Currently DHE is only available as intravenous infusion or
intranasal delivery. If approved for commercialization, PUR3100 should be the first orally inhaled DHE treatment for acute migraine
and be an alternative to other acute therapies, such as oral and intravenous triptans that currently represent the majority of the
annual migraine prescriptions in the United States. Given the oral inhaled route of delivery, we believe PUR3100 could
provide a rapid onset of migraine symptom relief with a favorable tolerability profile.
Competition
and Market Opportunities
Current
treatments for migraine include oral, intranasal, IV or intramuscular (“IM”) formulations of
triptans, DHE, and calcitonin gene-related peptide (“CGRP”) antagonists. Studies show that people with migraines
are underdiagnosed, undertreated, and experience substantial decreases in functioning and productivity, which translates into diminished
quality of life for individuals, and financial burdens to patients, health-care systems, and employers. All current treatments suffer
from limited efficacy and/or tolerability and there exists a significant unmet need for safe and effective alternatives to current treatments.
DHE
has been shown to be effective in the treatment of migraine and, in particular, hard to treat migraines, such as menstrual migraine,
migraine upon awakening, and severe migraine. Utilization of DHE has been limited due to its poor oral bioavailability, requiring IV
or intranasal dosing. IV dosing generally requires administration in a healthcare setting and the high exposure levels results in
significant nausea and vomiting and as such has generally been limited to use only in patients with intractable migraine.
Intranasal dosing with Migranal (Bausch Health US LLC), approved in December 1997, has been poorly adopted due to poor exposure
resulting in inconsistent efficacy. Trudhesa (Impel NeuroPharma, Inc.), another nasal spray utilizing DHE, was approved by the FDA
in September 2021.
There
is precedent for an inhaled DHE therapy. MAP Pharmaceuticals, Inc. developed MAP0004, also known as Levadex or Semprana, a liquid suspension
formulation of DHE, designed to be dosed via a pMDI inhalation device. Their published data indicate a safe and well tolerated formulation
with rapid onset and long-lasting efficacy that compared favorably to existing treatments. Development of MAP0004 led to a new drug
application (“NDA”) but was halted after multiple complete response letters from the FDA citing Chemistry, Manufacturing
and Controls (“CMC”) issues related to dose uniformity and stability issues. Regardless of the failure of MAP0004, the efficacy
and tolerability of the formulation reported by MAP Pharmaceuticals provides proof of concept for an inhaled DHE formulation. PUR3100,
the iSPERSETM formulation planned by Pulmatrix, is anticipated to deliver DHE to the lung with efficacy and tolerability
that compares favorably with MAP0004, while avoiding the device-related issues of MAP0004 by delivering PUR3100 as an iSPERSETM
dry powder.
To the best of our knowledge, there are no other
orally inhaled DHE formulations currently in development. Migranal and Trudhesa are the two currently FDA approved intranasal formulations.
of DHE. Satsuma Pharmaceuticals has developed a dry powder formulation of DHE for intranasal dosing and have completed two Phase 3 clinical
studies (ClinicalTrials.gov NCT03901482 and NCT04940390). Despite failure of both clinical studies to achieve primary endpoints, Satsuma
filed an NDA in the first quarter of 2023 based on post-hoc analysis showing benefit in secondary endpoints. Satsuma’s
NDA filing is pending, and they are actively seeking a commercialization partner.
Non-Clinical
Development
A total of three 14-day good laboratory practices
(“GLP”) toxicology studies have been completed with PUR3100 to support single dose clinical studies. Preparations are underway
for chronic toxicology to support long-term dosing and an eventual NDA.
Clinical Development
We have completed several interactions with the
FDA and they have confirmed that, in addition to the Planned Phase 2 and Phase 3 studies, long-term safety should be assessed in a minimum
of one hundred patients for six months of dosing and fifty patients for twelve months of dosing. The FDA also confirmed that it will be
necessary to perform a safety study administering PUR3100 to otherwise healthy patients with asthma before a NDA is submitted.
On September 26, 2022, we announced the
completion of patient dosing in a Phase 1 clinical study, performed in Australia, designed to assess not only safety, tolerability,
and pharmacokinetics of PUR3100 in humans, but also provide preliminary comparative bioavailability data to support the use of the
505(b)(2) pathway for marketing authorization.
The study design was a double-dummy,
double-blinded trial to assess the safety, tolerability, and pharmacokinetics of three dose levels of single doses of inhaled
PUR3100 with IV placebo, as compared to IV DHE (DHE mesylate injection) with inhaled placebo. Twenty-six healthy subjects were
enrolled and each of the four groups contained at least six subjects. On January 4, 2023, we announced topline results. PUR3100 was
well-tolerated and there was a lower incidence of nausea in PUR3100 dose groups compared to IV DHE. No vomiting was observed in any
of the PUR3100 dose groups. Oral inhalation of PUR3100 achieved peak exposures in the targeted therapeutic range at all doses and
the Tmax occurred at five minutes after dosing.
We
believe these data are encouraging and suggest that the orally inhaled formulation of DHE, PUR3100, will result in
rapid systemic exposure in the therapeutic range, while minimizing the risk of side effects related to exposure levels associated with
IV dosing. We believe the PUR3100 formulation of DHE is highly differentiated from other DHE products already approved or in development,
can be immediately self-administered and has a pharmacokinetic profile that may potentially advance the treatment of patients with acute migraine.
We plan to open an IND in the second quarter of 2023 in order to conduct a randomized placebo-controlled Phase 2 clinical study in patients with
migraine to assess the safety and effectiveness of two doses of PUR3100, in which the selection of the two doses has been informed by
the initial Phase 1 clinical study. We anticipate that this Phase 2 clinical study will initiate once financing or partnership arrangements have been made.
Clinical
study starts may be affected by conditions related to the COVID-19 pandemic and its ongoing effects with respect to clinical study
conduct and patient enrollment. For more discussion of risks related to the COVID-19 pandemic, please see “Item 1A. RISK
FACTORS—Risks Related to Our Business—Business interruptions could limit our ability to operate our
business.”
PUR1800
Reduced
responsiveness to corticosteroids represents an important barrier to effective treatment of COPD and AECOPD and provides a clear rationale
to seek novel medicines to treat these respiratory diseases. In addition, current treatments generally fail to treat the underlying source
of the AECOPD, in particular when a viral or bacterial infection is the cause, which occurs in approximately 80% of exacerbations. RV1162,
the active ingredient of PUR1800, is a novel, potent anti-inflammatory that inhibits the phosphorylation of a narrow spectrum of kinases.
In pre-clinical studies, RV1162 demonstrated direct anti-inflammatory activity in a model of viral induced respiratory inflammation.
RV1162 also demonstrated a reduction in corticosteroid-resistant inflammatory responses in a model of cigarette smoke induced inflammation.
These findings suggested that RV1162 has the potential to deliver effective anti-inflammatory outcomes in corticosteroid-resistant patients
while also reducing the underlying source of inflammation in an exacerbation, such as a viral and/or bacterial respiratory infection.
Clinical
studies conducted by RespiVert/Janssen with RV1162 formulated as a lactose blend for inhalation demonstrated that the molecule was well
tolerated for up to 14 days of dosing in patients with COPD. Analysis of sputum collected from patients with COPD treated with RV1162
showed reduced levels of p38 phosphorylation in sputum cells and decreases in the number of neutrophils recovered in sputum after 12
days of dosing. These findings suggest that inhalation of RV1162 may confer anti-inflammatory benefits after a short dosing regimen.
Long-term toxicology studies with RV1162 as a lactose blend suggested that this formulation was not suitable for chronic dosing.
Based upon the clinical results generated by
RespiVert/Janssen for RV1162 and the anticipated benefits of an iSPERSETM formulation of RV1162, we entered into
a License, Development and Commercialization Agreement with RespiVert Ltd. (“RespiVert”), a wholly owned subsidiary of Janssen
Biotech, Inc. on June 9, 2017. RespiVert granted us an exclusive, royalty-bearing license in a portfolio of narrow spectrum kinase inhibitor
compounds (“NSKI”). We subsequently formulated RV1162 into PUR1800 for development as a potential therapy for AECOPD.
We conducted two 28-day GLP toxicology studies in rats and dogs. Results
from the two GLP toxicology studies supported the potential for PUR1800 to improve lung exposure, with reduced lung accumulation, as compared
to RV1162 as a lactose blend formulation, suggesting potential for chronic dosing.
On December 26, 2019, we entered into a License,
Development and Commercialization Agreement (the “JJEI License Agreement”) with Johnson & Johnson Enterprise Innovation,
Inc. (“JJEI”). Under the JJEI License Agreement, we granted JJEI an option to acquire (1) the Company’s rights to an
intellectual property portfolio of materials and technology related to NSKI and (2) an exclusive, worldwide, royalty bearing license to
PUR1800. As part of the agreement, Pulmatrix was to complete chronic toxicology studies in rats and dogs, with durations of six and nine
months, respectively. Pulmatrix was also to complete a Phase 1b clinical trial in stable COPD patients. JJEI had the right to execute
its option for licensure (option period) any time up to three months following the later of (i) receipt of the final report for the clinical
study, or (ii) receipt of the audited draft reports for the toxicology study. JJEI terminated the JJEI License Agreement effective July
6, 2021, prior to delivery of any data from the ongoing toxicology studies and ongoing Phase1b clinical study.
All rights to the kinase inhibitor portfolio,
including PUR1800 and PUR5700, reverted back to us along with all data generated from the ongoing studies predominantly funded through
proceeds from the terminated JJEI License Agreement.
Toxicology studies in rats and dogs, with durations
of six and nine months, respectively, were then completed. The data from both studies demonstrated that PUR1800 is safe and well tolerated
with chronic dosing, with no progression of findings from 28-day studies. We believe this indicates potential for chronic dosing of PUR1800,
enabling us to explore PUR1800 therapy for chronic respiratory disease such as steroid resistant asthma, COPD, or idiopathic pulmonary
fibrosis. While the program is currently in development for treatment of AECOPD, these positive toxicology study results could expand
potential indications and value of the program.
Competition
and Market Opportunities
There
are 18 million moderate-to-severe episodes of AECOPD in the U.S. each year. AECOPD are sudden onset increases in symptoms, including
increased dyspnea, sputum purulence and volume, and wheezing, coughing, and shortness of breath that require medical intervention and
can lead to hospitalization. The occurrence of an exacerbation greatly increases the likelihood of a further exacerbation within the
following 6 months and creates a significant financial burden to healthcare systems.
Steroids
are standard of care for moderate-to-severe acute exacerbations, which occur across all patient severity types. We believe a
significant unmet need exists in AECOPD for those patients with underlying infection and/or steroid resistance. Acumapimod (BCT-197)
is an oral p38 MAP kinase inhibitor being developed by Mereo BioPharma. BCT-197 completed Phase 2 development as first-line therapy
for severe AECOPD. In April 2019, Mereo BioPharma announced completion of an end of Phase 2 meeting with the FDA and stated the
company is continuing discussions with potential partners for BCT-197. We are not aware of any further progress in either
clinical development or partnership efforts on this product.
Clinical Development
The clinical study, performed at the Medicines
Evaluation Unit in Manchester, UK, was a randomized, three-way crossover double-blind study with 14 days of daily dosing which includes
placebo and one of two doses of PUR1800, and included a 28 day follow up period after each treatment period. A total of 18 adults with
stable COPD were enrolled. Safety and tolerability, as well as systemic PK were evaluated.
We completed the Phase 1b safety, tolerability,
and pharmacokinetics of PUR1800 for patients with stable moderate-severe COPD. Topline data was delivered in the first quarter of 2022
and presented at the American Academy of Allergy, Asthma and Immunology conference in the first quarter of 2023. PUR1800 was well tolerated
and there were no observed safety signals. The PK data indicate that PUR1800 results in low and consistent systemic exposure when administered
via oral inhalation. The topline data, along with the results from chronic toxicology studies, support the continued development of PUR1800
for the treatment of AECOPD and other inflammatory respiratory disease. These data will inform the design of a potential Phase 2 study
in the treatment of AECOPD.
Business
Development
PUR1900
On
April 15, 2019, we entered into the Cipla Agreement with Cipla for the co-development and commercialization, on a worldwide exclusive basis, except for the Cipla Territory
defined below, of PUR1900, our inhaled iSPERSETM drug delivery system enabled formulation of the antifungal drug,
itraconazole, which is only available as an oral drug, for the treatment of all pulmonary indications, including ABPA in patients with
asthma. We entered into the Amendment on November 8, 2021.
The
Cipla Agreement will remain in effect in perpetuity, unless otherwise earlier terminated in accordance with its terms. In the event
of circumstances affecting the continuity of development of the Product in line with the Cipla Agreement or certain development
milestones are not achieved within a specified timeframe discussed in greater detail below, the JSC will evaluate the cause and
effect and make a recommendation as to the most optimal option available to Cipla and us. In such events, the parties are not
obligated to follow the recommendation of the JSC and, either Terminating Party may elect to terminate its obligation to fund
additional costs and expenses for the development and/or commercialization of the Product. If the non-Terminating Party wishes to
continue the development of the Product, it will have the right to purchase the rights of the Terminating Party in the Product at
its fair market value. If both Cipla and we abandon the development program, Cipla and we shall make commercially reasonable efforts
to monetize the Product and development program in connection with the Pulmonary indications. Cipla and we will equally share the
proceeds.
We
and Cipla will each be responsible for 60% and 40%, respectively, of the Direct Costs, in addition to which, Cipla will
reimburse us an amount equal to 10% of aggregate Direct Costs upon the achievement of the development milestones set forth in
the table below, potentially bringing the sharing of Direct Costs to a 50/50 basis. We will continue to share all other development
costs with Cipla that are not Direct Costs, such as the cost of clinical research organizations, manufacturing costs and other
third-party costs, on a 50/50 basis. Additionally, upon commercialization, Cipla and the Company will share equally, both positive
and negative total free cash-flows earned by Cipla in respect of the Product.
Pursuant
to the Cipla Agreement, (i) all development and commercialization activities with respect to the Product in the Cipla Territory will be conducted exclusively by Cipla
at Cipla’s sole cost and expense, and (ii) Cipla shall be entitled to all profits from the sale of the Product in the Cipla Territory,
except that if Cipla successfully transfers manufacturing of the Product for the Cipla Territory to a manufacturing site determined by
Cipla, we will become entitled to a royalty equal to 2% of net sales in the Cipla Territory.
In
partnership with Cipla, we initiated a Phase 2 clinical study in 2019, entitled: “A Randomized, Double-Blind, Multicenter, Placebo-Controlled,
Phase 2 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Itraconazole Administered as a Dry Powder for Inhalation
(PUR1900) in Adult Asthmatic Patients with ABPA.” This clinical study was terminated in July 2020 due to the ongoing impact of the COVID-19
pandemic on patient enrollment and clinical study conduct.
Following termination of the Phase 2 clinical
study, we conducted a Type C meeting with the FDA on January 27, 2021, in order to discuss the program overall development plan and the
current Phase 2b clinical study design. The currently ongoing Phase 2b clinical study design includes a 16-week dosing regimen with an