UNITED
STATES
SECURITIES
AND EXCHANGE COMMISSION
Washington,
D.C. 20549
FORM
10-K
(Mark
One)
For
the fiscal year ended December 31, 2024
or
For
the transition period from ___________ to __________
Commission
file number: 001-36199
PULMATRIX,
INC.
(Exact
name of registrant as specified in its charter)
(Address of principal executive offices) (Zip Code)
(888)355-4440
Registrant’s
telephone number, including area code
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, 2024, the last business day of registrant’s most recently completed
second fiscal quarter, was $7,048,862.
As
of March 17, 2025, the registrant had 3,652,285shares
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. 54
Item 1C. Cybersecurity. 54
Item 2. Properties. 55
Item 3. Legal Proceedings. 55
Item 4. Mine Safety Disclosures. 55
PART II
Item 6. Reserved. 56
Item 7A. Quantitative and Qualitative Disclosures About Market Risk. 65
Item 8. Financial Statements and Supplementary Data. 65
Item 9A. Controls and Procedures. 66
Item 9B. Other Information. 66
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections. 67
PART III
Item 10. Directors, Executive Officers and Corporate Governance. 67
Item 11. Executive Compensation. 73
Item 14. Principal Accountant Fees and Services. 82
PART IV
Item 15. Exhibits, Financial Statement Schedules. 83
Signatures 88
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:
● adverse market and economic conditions;
● loss of one or more key executives or scientists; and
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, and its subsidiaries, Pulmatrix Operating Company, Inc. and PCL Merger Sub, Inc., both
Delaware corporations, and PCL Merger Sub II, LLC, a Delaware limited liability company.
“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 biopharmaceutical company that has focused on the development of novel inhaled therapeutic products intended to prevent and treat
migraine and respiratory diseases with important unmet medical needs using our patented iSPERSETM technology. Our proprietary
product pipeline includes treatments for central nervous system (“CNS”) disorders such as acute migraine and serious lung
diseases such as Chronic Obstructive Pulmonary Disease (“COPD”) and allergic bronchopulmonary aspergillosis (“ABPA”).
Our product candidates are based on our proprietary engineered dry powder delivery platform, iSPERSETM, which seeks to
improve therapeutic delivery to the lungs by optimizing pharmacokinetics 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, 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
were incorporated in 2013 as a Delaware corporation.
After
a comprehensive review of strategic alternatives, including identifying and reviewing potential candidates for a strategic transaction,
on November 13, 2024, Pulmatrix entered into an Agreement and Plan of Merger and Reorganization (the “Merger Agreement”),
by and among Pulmatrix, PCL Merger Sub, Inc., a Delaware corporation and a wholly owned subsidiary of Pulmatrix (“Merger Sub I”),
PCL Merger Sub II, LLC, a Delaware limited liability company and a wholly owned subsidiary of Pulmatrix (“Merger Sub II”
and together with Merger Sub I, “Merger Subs”) and Cullgen Inc., a Delaware corporation (“Cullgen”), pursuant
to which, and subject to the satisfaction or waiver of the conditions set forth in the Merger Agreement, among other things, Merger Sub
I will merge with and into Cullgen, with Cullgen surviving the merger as the surviving corporation (the “First Merger” and
the effective time of the First Merger, the “First Effective Time”) and as part of the same overall transaction, Cullgen
will merge with and into Merger Sub II, with Merger Sub II continuing as a wholly owned subsidiary of Pulmatrix and the surviving corporation
of the merger (the “Second Merger” and together with the First Merger, the “Merger”). The Merger Agreement was
unanimously approved by the Pulmatrix board of directors, which resolved to recommend approval of the Merger Agreement to Pulmatrix stockholders.
The
closing of the Merger (the “Closing”) is subject to approval by Pulmatrix stockholders and Cullgen stockholders, as well
as other customary closing conditions, including the effectiveness of a registration statement filed with the SEC in connection with
the transaction, Nasdaq’s approval of the listing of the shares of Pulmatrix common stock to be issued in connection with the Merger,
and approval from the China Security Regulatory Commission. If the Merger is completed, the business of Cullgen will continue as the
business of the combined company (the “Combined Company”). We are currently seeking opportunities to monetize our existing
clinical assets.
The
Company’s future operations are highly dependent on the success of the Merger and there can be no assurances that the Merger will
be successfully consummated. There can be no assurance that the strategic review process or any transaction relating to a specific asset,
including the Merger and any asset sale, will result in the Company pursuing such a transaction, or that any transactions, if pursued,
will be completed on terms favorable to the Company and its stockholders in the existing Pulmatrix entity or any possible entity that
results from a combination of entities. If the strategic review process is unsuccessful, and if the Merger is not consummated, the Pulmatrix
board of directors may decide to pursue a dissolution and liquidation of the Company.
Business
Strategy
Our
goal has been 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 of clinical assets is aligned to this goal and includes 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 PUR3100 for the treatment of acute migraine, PUR1800 for the treatment of acute exacerbations of chronic obstructive pulmonary
disease (“AECOPD”), and PUR1900 for the treatment of ABPA in patients with asthma and in patients with cystic fibrosis (“CF”).
Each program is enabled by its unique iSPERSETM formulation designed to achieve specific therapeutic objectives.
We
are exploring opportunities to monetize these clinical assets in connection with the Merger. Continued development of these candidates,
if that were to occur, would be contingent on securing additional funding and would require significant expenditures to advance. Thereafter,
if development of such product candidates were to be continued and successfully advanced (of which there can be no assurance), it would
be necessary to seek and obtain marketing approval to commercialize such product candidates, which could be expected to require the expenditure
of significant additional resources and expenses related to regulatory, product sales, medical affairs, marketing, manufacturing and
distribution.
Contingent
on securing additional funding and continuing development of these candidates, we would expect to continue to incur substantial expenses
and operating losses for at least the next several years, as we would:
● Position the Company to be able to consider strategic alternatives.
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 concentrations from 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
PUR3100
In
2020, we developed PUR3100, the iSPERSETM formulation of DHE, for the treatment of acute migraine. Currently DHE is only
available as subcutaneous, intravenous infusion or intranasal delivery. If approved for commercialization, PUR3100 has the opportunity
to be the first orally inhaled DHE treatment for acute migraine and be an alternative to other acute therapies. Given the oral inhaled
route of delivery, PUR3100 is anticipated to provide relief from the rapid onset of migraine symptoms and provide a favorable tolerability
profile.
Competition
and Market Opportunities
The
American Migraine Foundation estimates that at least 39 million people in the United States and 1 billion people worldwide live with
migraine, but because many people are not diagnosed or do not receive the treatment they need, the actual number may be higher. Current
treatments for migraine include oral, intranasal, IV or subcutaneous formulations of triptans, DHE, and calcitonin gene-related peptide
(“CGRP”) antagonists (gepants). 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, healthcare systems, and employers. All current treatments are limited by incomplete efficacy and/or intolerability.
Therefore, development of additional treatments for acute migraine is warranted.
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,
subcutaneous or intranasal dosing. IV dosing generally requires administration in a healthcare setting and may result in nausea and vomiting.
Hence, its use has generally been limited to patients with intractable or medication-overuse migraine. Intranasal dosing with DHE, including
Migranal (Bausch Health US LLC), approved in December 1997, and Trudhesa (Impel NeuroPharma, Inc.), approved by the FDA in September
2021, have been poorly adopted due to incomplete efficacy and intolerability of nasal inhalation in patients during a migraine.
There
is precedent for an orally 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 orally 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.
We
believe that an iSPERSE formulation of DHE can provide the positive rapid onset and long-lasting efficacy seen in the MAP0004 data by
enabling a similar pharmacokinetic profile while eliminating the manufacturing and device issues which led to the MAP0004 FDA complete
response letters.
Vectura
Inc. is developing an orally inhaled powder formulation of DHE for the acute treatment of migraines in adults. Vectura completed a Phase
1 clinical trial in 2024, with results pending. To the best of our knowledge, there are no other orally inhaled DHE formulations currently
in development or on the market. Migranal and Trudhesa are the two currently FDA approved intranasal formulations of DHE. Satsuma Pharmaceuticals,
a subsidiary of Shin Nippon Biomedical Laboratories (“Satsuma”), has developed a dry powder formulation of DHE for intranasal
dosing and has 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. In January 2024, the FDA declined to approve the treatment, citing manufacturing concerns. Satsuma resubmitted its
NDA in November 2024.
Non-Clinical
Development
A
total of three 14-day GLP toxicology studies have been completed with PUR3100 to support single-dose clinical studies. We are planning
to conduct a chronic toxicology study to support long-term dosing. Based on discussions with the FDA, this would complete the non-clinical
requirements to support an NDA.
Clinical
Development
Our
interactions with the FDA have indicated 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 an NDA is
submitted.
On
September 26, 2022, we announced the completion of patient dosing in a Phase 1 clinical study, performed in Australia. 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. This study may also provide
preliminary comparative bioavailability data to support the use of the 505(b)(2) pathway for marketing authorization. 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. We presented the Phase 1 study data at the American Headache Society 65th Annual Meeting
in June 2023. The study showed that PUR3100 achieved peak exposures in the targeted therapeutic range and time to maximum concentration
occurred at five minutes after dosing at all dosing levels. The PUR3100 dose groups also showed a lower incidence of nausea and no vomiting
compared to observations of nausea and vomiting in the IV administered DHE dose group.
Based
on the rapid systemic exposure in the therapeutic range and the improved side effect profile relative to IV dosing, we believe the PUR3100
formulation of DHE may differentiate from approved DHE products or those known to be in development. If effectiveness is demonstrated,
PUR3100 may offer the convenience of being self-administered with a pharmacokinetic profile that may potentially provide rapid onset
of action.
In
September 2023, we announced that the FDA accepted the PUR3100 IND and the receipt of a “study may proceed” letter for the
clinical study: “A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Single Event Study to Evaluate the Safety,
Tolerability, and Efficacy of PUR3100 (Dihydroergotamine Mesylate Inhalation Powder) in the Acute Treatment of Migraine”. We anticipate
that this Phase 2 clinical study will initiate once financing or partnership arrangements have been made.
On
May 15, 2024, we announced publication of, “Safety, tolerability, and pharmacokinetics of a single orally inhaled dose of PUR3100,
a dry powder formulation of dihydroergotamine versus intravenous dihydroergotamine: A Phase 1 randomized, double-blind study in healthy
adults” in the peer-reviewed publication Headache: The Journal of Head and Face Pain.
We
believe that in this trial, PUR3100 demonstrated the potential for rapid pain relief and improved DHE tolerability versus IV DHE. With
a Tmax of 5 minutes and a Cmax in the therapeutic window for all doses tested, we believe that PUR3100 has the
potential to address an unmet need for acute migraine sufferers and we are pursuing different options to advance PUR3100 into a Phase
2 clinical trial to further investigate its promising profile in treating acute migraine.
The
completed Phase 1 study demonstrated optimal pharmacokinetics and improved tolerability of PUR3100 compared to IV DHE. The Phase 1 trial
was a randomized, double-dummy, double-blinded design to assesses the safety, tolerability, and pharmacokinetics (PK) of three dose groups
treated with inhaled PUR3100 with intravenous (IV) placebo, compared to a single dose of IV DHE (DHE mesylate injection) with inhaled
placebo in healthy volunteers. All doses of PUR3100 were generally well tolerated with a lower incidence of nausea (21% vs. 86%), vomiting
(0% vs. 29%), and headache (16% vs. 57%) compared to IV DHE. The PK profile of PUR3100 versus IV DHE was characterized by a similar mean
time to Cmax (5 vs. 5.5 min), with reduced AUC0–2h (1120–4320 vs. 6340), and a lower Cmax (3620–14,400
vs. 45,000). All doses of PUR3100 were associated with mean Cmax above the minimum level required to achieve efficacy (1000
pg/mL).
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.
Competition
and Market Opportunities
There
are 18 million moderate-to-severe episodes of AECOPD in the US 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 substantial
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. A generic version of roflumilast, a phosphodiesterase inhibitor approved by the FDA for use in managing COPD exacerbations,
became available in 2022.
Non-Clinical
Development
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.
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, within the safety margin identified, enabling us to explore PUR1800 therapy for chronic respiratory
diseases 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.
Clinical
Development
We
completed a 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.
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 included 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 pharmacokinetics
(“PK”) were evaluated.
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 diseases. These data will inform the
design of a potential Phase 2 study in the treatment of AECOPD.
PUR1900
PUR1900
is our iSPERSETM inhaled formulation of itraconazole, an antifungal drug commercially available as an oral drug. We developed
PUR1900 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 dose-limiting 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.
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 Teva 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). 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 orally 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, which is focused on prevention
of exacerbations in individuals with at least one or more severe respiratory exacerbations, completed in February 2024 and is pending
results.
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 substantial value based on treating and preventing pulmonary fungal infections in multiple
patient populations.
Clinical
Development
We
completed a Phase 1/1b clinical study in 2018, wherein 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.
Successful
completion of the Phase 1/1b clinical study 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 enabled the conduct of a new Phase 2b clinical study.
The
new Phase 2b study included a 16-week dosing regimen and exploration of potential regulatory approval endpoints. We dosed the first patient
during the first quarter of 2023. In January 2024, pursuant to the Third Amendment (as defined herein), we announced plans to stop patient
enrollment at 8 subjects in this study, effective immediately, and to terminate the study as soon as reasonably possible between the
date of the Third Amendment and July 30, 2024. We completed all Phase 2b wind down activities in the third quarter of 2024. As such,
we no longer bear further financial responsibility for the commercialization and development with respect to the Product in the Cipla
Territory, with such commercialization and development expenses of the Product in the Cipla Territory to be borne at Cipla’s sole
cost and expense after January 6, 2024.
Our
partner Cipla has continued clinical development outside the United States and has advised us that they have completed their Phase 2
study in India. Should Cipla successfully market PUR1900 outside the United States, Pulmatrix will receive 2% royalties on any potential
future net sales by Cipla outside the United States. Within the United States, we and Cipla will seek to monetize PUR1900 for indications
where an orally inhaled antifungal may provide a therapeutic benefit or fulfill an unmet medical need.
Business
Development
PUR3100
We
are currently exploring opportunities to monetize PUR3100.
In
September 2023, we announced the FDA’s acceptance of an IND application for PUR3100 and receipt of a “study may proceed”
letter for a Phase 2 study. The IND includes a Phase 2 clinical protocol where safety and preliminary efficacy of PUR3100 will be investigated
in patients with acute migraine.
PUR1800
We
are currently exploring opportunities to monetize PUR1800.
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 & Immunology (AAAAI)
conference in the first quarter of 2023. The results indicated PUR1800 was safe and well tolerated with no observed safety signals. 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 diseases.
PUR1900
We
are currently exploring opportunities to monetize PUR1900 within the United States.
On
April 15, 2019, we entered into a Development and Commercialization Agreement (the “Cipla Agreement”) with 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 “Second Amendment”) and a subsequent
amendment on January 6, 2024 (the “Third Amendment”). All references to the Cipla Agreement herein refer to the Cipla Agreement,
as amended. The Cipla Agreement will remain in effect in perpetuity, unless otherwise earlier terminated in accordance with its terms.
Pursuant
to the Third Amendment, all development and commercialization activities with respect to the Product in all markets other than the United
States (the “Cipla Territory”) will be conducted exclusively by Cipla at Cipla’s sole cost and expense, and Cipla shall
be entitled to all profits from the sale of the Product in the Cipla Territory, except that we will receive 2% royalties on any potential
future net sales by Cipla outside the United States.
Also
pursuant to the Third Amendment, we and Cipla stopped patient enrollment for the ongoing Phase 2b clinical study. We agreed that during
the period commencing on January 6, 2024 and ending July 30, 2024 (the “Wind Down Period”), we would complete all Phase 2b
activities, assign or license all patents to Cipla and their registration with the appropriate authorities in the Cipla Territory, complete
a physical and demonstrable technology transfer and secure all data from the Phase 2b study for inclusion in the safety database for
the Cipla Territory.
For
the duration of the Wind Down Period, we and Cipla were each responsible for 60% and 40%, respectively, of our Direct Costs. We shared
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. Reimbursements from Cipla to us for these costs were subject to a maximum reimbursement
amount as approved by the joint steering committee.
We
completed all Phase 2b wind down activities in the third quarter of 2024. As such, we no longer bear further financial responsibility
for the commercialization and development with respect to the Product in the Cipla Territory, with such commercialization and development
expenses of the Product in the Cipla Territory to be borne at Cipla’s sole cost and expense after January 6, 2024. We will receive
2% royalties on any potential future net sales by Cipla outside the United States. Within the United States, we and Cipla will seek to
monetize PUR1900, our inhaled iSPERSETM formulation of the antifungal drug itraconazole for indications where an orally
inhaled antifungal may provide a therapeutic benefit or fulfill an unmet medical need.
Intellectual
Property
Patents
and Patent Applications
We
protect our intellectual property by filing and advancing patent applications and maintaining granted patents on our iSPERSETM
platform technology and in-licensed kinase inhibitors, which includes claims to compositions of matter and methods of use for
our PUR3100, PUR1800, PUR1900 and other programs, as well as manufacturing processes, devices and packaging relevant to our iSPERSETM
platform and product candidates.
The
status of our patent portfolio changes frequently in the ordinary course of patent prosecution. As of December 31, 2024, our patent portfolio
related to iSPERSETM included approximately 149 granted patents, 19 of which are granted US patents, with expiration dates from
2024 to 2037, and approximately 50 additional pending patent applications in the US and other jurisdictions. Our in-licensed portfolio
related to kinase inhibitors included approximately 281 granted patents, 33 of which are granted US patents, with expiration dates from
2029 to 2035, and approximately 17 additional pending patent applications in the US and other jurisdictions. We have national phase applications
pending in Australia, Brazil, Canada, China, Europe, Israel, India, Japan, Korea, Mexico, New Zealand, Russia, and the United States
that cover certain formulations and methods of use relevant to our PUR3100 program.
There
can be no assurance that the patent applications will be granted. The term of individual patents depends upon the legal term of the patents
in the countries in which they are obtained. In most countries in which we file, the patent term is 20 years from the earliest date of
filing a non-provisional patent application. In the United States, the patent term of a patent that covers a FDA-approved drug may also
be eligible for patent term extension, which permits patent term restoration as compensation for the patent term lost during the FDA
regulatory review process. The length of the patent term extension is related to the length of time the drug is under regulatory review.
Patent term extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval and only
one patent applicable to an approved drug may be extended. In the future, if and when our products receive FDA approval, we expect to
apply for patent term extensions on patents covering those products. Similar provisions are available in Europe and other foreign jurisdictions
to extend the term of a patent that covers an approved drug. We plan to seek patent term extensions to extend the patent coverage of
any of our products that received regulatory approval in any jurisdiction where these extensions are available. However, there is no
guarantee that the applicable authorities, including the FDA in the United States, will agree with our assessment on whether such extensions
should be granted, and if granted, the length of such extensions.
The
patent positions of biotechnology companies like ours are generally uncertain and involve complex legal, scientific and factual questions.
In addition, the coverage claimed in a patent application can be significantly reduced before the patent is issued, and its scope can
be reinterpreted after issuance. Consequently, we may not obtain or maintain adequate patent protection for any of our product candidates.
We cannot predict whether the patent applications we are currently pursuing will issue as patents in any particular jurisdiction or whether
the claims of any issued patents will provide sufficient proprietary protection from competitors. Any patents that we hold may be challenged,
circumvented or invalidated by third parties.
Trade
Secrets
We
also rely on trade secret protection of our confidential and proprietary information, including the iSPERSETM
technology. Although we take steps to protect our proprietary information and trade secrets, including through contractual means with
our employees, consultants and others, third parties may independently develop substantially equivalent proprietary information and techniques
or otherwise gain access to our trade secrets or disclose our technology. Thus, we may not be able to meaningfully protect our trade
secrets. It is our policy to require our employees, consultants, outside scientific collaborators, sponsored researchers and other advisors
to execute confidentiality agreements upon the commencement of employment or consulting relationships with us. These confidentiality
agreements provide that all confidential information concerning our business or financial affairs developed or made known to the individual
during the course of the individual’s relationship with us must be kept confidential and not disclosed to third parties except
in specific circumstances. Our confidentiality agreements with our employees also provide that all inventions conceived by the employee
in the course of employment with us or from the employee’s use of our confidential information are our exclusive property.