What changed in this filing

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Item 1. Business

2025-02-28 compared with 2024-02-29 · 120 added, 161 removed, 175 unchanged (62% of the section changed)

20 unchanged sentences

We expect the VenoValve to

be eligible for FDA approval first, followed two to three years later by enVVe.

be eligible for FDA approval first, followed approximately three years later by enVVe.

If approved, we expect the VenoValve and enVVe to co-exist,

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valves, and there are currently no effective treatments for deep venous CVI caused by incompetent valves.

team of officers and directors has been affiliated with numerous medical devices that have received FDA approval or CE marking and

that have been commercially successful.

We develop and manufacture our products in connection with our clinical trials in a 14,507

leased manufacturing facility in Irvine, California, which has been ISO 13485-2016 certified for the design, development and

manufacturing of tissue based implantable medical devices.

team of officers and directors has been affiliated with numerous medical devices that have received FDA approval or CE marking and that

have been commercially successful.

We develop and manufacture our products in connection with our clinical trials in a 14,507 sq.

leased manufacturing facility in Irvine, California, which has been ISO 13485-2016 certified for the design, development and manufacturing

of tissue based implantable medical devices.

venous disease (“CVD”) is the world’s most prevalent chronic disease.

CVD is clinically classified using a

standardized system known as CEAP (clinical, etiological, anatomical, and pathophysiological).

The CEAP system consists of seven

clinical classifications (C0 to C6) with C4, C5 and C6 being the most severe categories of CVD.

CVD is clinically classified using a standardized

system known as CEAP (clinical, etiological, anatomical, and pathophysiological).

The CEAP system consists of seven clinical classifications

(C0 to C6) with C4, C5 and C6 being the most severe categories of CVD.

Venous Insufficiency (“CVI”) is a large subset of CVD and is generally used to describe patients with C4 to C6 CVD.

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has been estimated to exceed $3 billion a year.

VenoValve® is a porcine based replacement venous valve developed at enVVeno Medical to be surgically implanted in the deep

venous system of the leg to treat severe CVI caused by valvular incompetence.

By reducing reflux and lowering pressure (venous

hypertension) within the deep venous system of the leg, the VenoValve has the potential to reduce or eliminate the symptoms of

severe deep venous CVI, including the potential to heal recurring venous leg ulcers.

The VenoValve is implanted into the femoral

vein of the patient in an open surgical procedure via a 5-to-6-inch incision in the upper thigh.

As our planned initial entrant to

the replacement venous valve market, we estimate that approximately 2.5 million people each year with severe deep venous CVI in the

VenoValve is a replacement venous valve developed at enVVeno Medical to be surgically implanted in the deep venous system of the leg

to treat severe CVI caused by valvular incompetence.

By lowering pressure (venous hypertension) within the deep venous system of the

leg, the VenoValve has the potential to reduce or eliminate the symptoms of severe deep venous CVI, including the potential to heal recurring

venous leg ulcers.

The VenoValve is implanted into the femoral vein of the patient in an open surgical procedure via a 5-to-6-inch incision

in the upper thigh.

As our planned initial entrant to the replacement venous valve market, we estimate that approximately 2.5 million

people each year with severe deep venous CVI in the U.S.

would be candidates for the VenoValve.

The VenoValve has been granted Breakthrough

Device designation by the FDA.

Clinical Status

consultation with the FDA, and as a precursor to the U.S.

pivotal trial, in 2020 we conducted a small first-in-human study for the

VenoValve in Colombia which included eleven (11) patients.

The purpose of the first-in-human study was to provide proof of concept,

and to provide feedback to make any necessary product modifications or adjustments to our surgical implantation procedure for the

VenoValve prior to conducting the VenoValve pivotal trial.

Endpoints for the VenoValve first-in-human study included safety (device

related adverse events), popliteal reflux time, measured by Duplex Ultrasound, rVCSS scoring, which is a measurement created by

international vascular societies and is used by the clinician to measure disease progression and regression, a VAS score used by the

patient to measure pain, and quality of life measurements.

from the one year first-in-human study were presented at the Charing Cross International Symposium in April of 2021.

eleven (11) patients in the study, rVCSS scores improved an average of 6 points, popliteal reflux time improved an average of 54%,

and visual analog scale (VAS) scores, which are used by patients to measure pain, improved an average of 76%, all at one (1) year

when compared to pre-surgery levels.

Revised Venous Clinical Severity Scoring (rVCSS) is a validated measurement commonly used to

objectively assess outcomes in the treatment of venous disease, and include ten characteristics consisting of physician assessments

and patient reported outcomes including pain, inflammation, skin changes such as pigmentation and induration, the number of active

ulcers, and ulcer duration.

The improvement in VCSS scores was significant and indicates the VenoValve patients who had severe CVI

pre-surgery, had mild CVI or the complete absence of disease at one-year post surgery.

safety incidences during the one year first-in-human study for the VenoValve included one (1) fluid pocket (which was aspirated), intolerance

from Coumadin anticoagulation therapy, three (3) minor wound infections (treated with antibiotics), and one occlusion due to patient

non-compliance with anti-coagulation therapy.

the end of the VenoValve first-in-human study, eight (8) study participants agreed to additional monitoring.

In November of 2022, three-year, positive

follow-up data was presented for this cohort of patients at the 49th Annual VEITH Symposium in New York city.

August 3, 2020, we announced that the FDA granted Breakthrough Device Designation status to the VenoValve.

The FDA’s Breakthrough

Devices Program was established to enable priority review for devices that provide more effective treatment or diagnosis of life threatening

or irreversibly debilitating diseases or conditions.

The goal of the FDA’s Breakthrough Devices Program is to provide patients

and health care providers with timely access to medical devices by speeding up their development, assessment, and review, while preserving

the FDA’s mission to protect and promote public health.

March 2021, we submitted an IDE application with the FDA and in April 2021, we received notification from the FDA that our IDE application

was approved.

An investigational device exemption or IDE from the FDA is required before a medical device company can proceed with a

pivotal trial for a Class III medical device.

This approval allowed us to proceed with our U.S.

pivotal study for the VenoValve which

is called the SAVVE (Surgical Anti-reflux Venous Valve Endoprosthesis) clinical study.

The SAVVE study is a prospective, non-blinded,

single arm, multi-center study of seventy-five (75) CVI patients enrolled at 21 U.S.

endpoints for the SAVVE pivotal study include rVCSS scores, which will be used to provide evidence of clinically meaningful benefit,

as well as reflux time measurements, VAS pain scores, quality of life measurements, ulcer healing (for CEAP class C6 patients), and intra-operative

March of 2021 we received IDE approval from the FDA to begin the VenoValve pivotal study.

An investigational device exemption or IDE

from the FDA is required before a medical device company can proceed with a pivotal trial for a Class III medical device.

approval allowed us to proceed with our U.S.

pivotal study for the VenoValve which is called the SAVVE® (Surgical Anti-reflux

Venous Valve Endoprosthesis) a prospective, non-blinded, single arm, multi-center clinical study.

The seventy-five patient SAVVE study reached full enrollment on September 1, 2023.

endpoints for the SAVVE pivotal study include rVCSS scores, which are used to provide evidence of clinically meaningful benefit, as well

as reflux time measurements, VAS pain scores, quality of life measurements, ulcer healing (for CEAP class C6 patients), and intra-operative

and one-year vein patency and valve functionality.

Safety endpoints include device related events and procedure related events –including mortality, pulmonary embolism, ipsilateral deep vein thrombosis, infection and bleeding.

first patient in the SAVVE pivotal study was enrolled in October of 2021.

Following enrollment of the first patient the SAVVE study was

delayed due to COVID-19 restrictions.

In November of 2022, we announced we had passed a preliminary safety review by the FDA for the

first twenty (20) patients enrolled in the SAVVE trial.

The FDA had requested that we submit preliminary safety data at thirty (30) days

post VenoValve® implantation for the first twenty (20) patients enrolled in the study.

The preliminary safety data included one (1)

device related (mild) and two (2) procedure related (moderate) adverse events.

After review by the FDA, the study was cleared to continue

without modification or interruption.

October 6, 2023, we announced we had achieved full enrollment (75 subjects) in the SAVVE trial, having enrolled eighteen (18) patients

over the final two (2) months of the study.

Full enrollment occurred approximately four (4) months earlier than expected due to increased

demand for the VenoValve.

November 16, 2023, we presented positive preliminary device related Material Adverse Event (MAE) data at the 50th Annual VEITH

The preliminary device related MAE rate for the fully enrolled 75 subject study was eight percent (8%).

SAVVE study are defined as all-cause mortality, pulmonary embolisms (PEs), ipsilateral deep vein thromboses (DVTs), bleeding, and

deep wound infections, occurring within thirty (30) days of enrollment in the study.

The report on MAEs presented at the conference

indicated no deaths, no pulmonary embolisms, and six (6) deep vein thromboses (DVTs), from the fully enrolled cohort of 75

All DVTs were adjudicated as being mild in severity.

Left untreated, post-thrombotic patients with severe CVI are

known to DVT recurrence rates as high as eighteen percent (18%) at one year.

expect to release initial, topline rVCSS efficacy data from the SAVVE study at the VENOUS2024 American Venous Forum Annual Meeting on March 6, 2024.

With the FDA indicating that one-year

data for all 75 patients will be necessary prior to the filing of the application seeking pre-market (PMA) approval for the VenoValve,

the Company will be eligible to file the PMA application seeking approval in Q4 of 2024.

Safety endpoints include device related events and procedure related events including

mortality, pulmonary embolism, ipsilateral deep vein thrombosis, infection and bleeding.

In November 2024, one year preliminary

efficacy and safety data from the SAVVE was presented at the 51th Annual VEITH Symposium, the largest vascular conference in the world.

The data indicated that eighty-five percent (85%) of the patients enrolled in SAVVE experienced a clinical meaningful benefit from the

VenoValve, defined as a three (3) or more point improvement in revised Venous Clinical Severity Score (rVCSS), at one year, compared to

The average rVCSS improvement in the clinically meaningful responder cohort was 7.91 points.

Patients in the SAVVE study also

experienced a seventy-five percent (75%) median reduction in pain and improvements in quality-of-life indicators.

For patients with venous

ulcers (CEAP C6 patients), ulcer area was reduced a median average of eighty-seven percent (87%).

Over the course of the one (1) year

period, there was one (1) death (unrelated to the VenoValve), zero (0) pulmonary embolisms, twelve (12) target vein thromboses, ten (10)

surgical pocket hematomas, four (4) other bleeds, and seven (7) deep wound infections.

Ninety four percent (94%) of the patients that

experienced a material safety event also went on to experience a clinically meaningful benefit from the VenoValve.

Also, the reported

target vein patency rates at thirty (30) days and one (1) year were ninety one percent (91%) and ninety seven percent (97%), respectively.

November 19, 2024, the Company submitted the final module of its PMA application for review by the FDA.

The VenoValve is designated

as a breakthrough product and, as a result, its PMA application is subject to priority review.

This may serve to shorten the PMA

review process.

Regardless, it is difficult to predict precisely how long the PMA process will

take, and the Company’s best estimate is to expect an FDA decision during the second half of 2025.

September 21, 2022, we announced the development of a non-surgical transcatheter based replacement venous valve called enVVe®, for

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Initial preliminary bench testing and pre-clinical testing for enVVe have been successfully

October 6, 2023, contemporaneously with the announcement of a twenty-eight-million-dollar capital raise, we announced plans to

expedite the development of enVVe.

The Company expects to begin a six (6) month Good Laboratory Practice animal study for enVVe in the

first quarter of 2024 and to be ready to file for IDE approval for the enVVe pivotal trial, the Transcatheter Anti-Reflux, Venous

Valve Endoprosthesis or TAVVE, by the end of 2024.

is delivered into the femoral vein of the patient via a minimally invasive procedure requiring no general anesthesia and no overnight

hospital stay.

Due to the minimally invasive nature of the procedure, we expect to be able to reach patients with less severe CVI or

who may otherwise not be good candidates for a surgical device, and estimate the U.S.

market for enVVe to be approximately 3.5 million

December 16, 2024, we announced the successful completion of the final wave of implants for the six-month pre-clinical GLP study for enVVe.

The first wave of implants, for

the long-term subjects, was successfully completed in October, and the final wave for the shorter-term subjects was completed in December.

The GLP study is a prerequisite to seeking IDE approval from the FDA to begin the enVVe U.S.

pivotal study.

The Company expects to file

for IDE approval for the enVVe pivotal study in mid-2025.

product candidates and our operations are subject to extensive regulation by the FDA, and other federal and state authorities in the

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III devices such as the VenoValve and enVVe generally require pre-market approval (PMA) before they can be marketed in the U.S.

review and approval process is more demanding than the 510(k) premarket notification process.

In a PMA, the manufacturer must demonstrate

that the device is safe and effective, and the PMA must be supported by extensive data, including data from preclinical studies and human

clinical trials.

The PMA also must contain a full description of the device and its components, a full description of the methods, facilities

and controls used for manufacturing, and proposed labeling.

Following receipt of a PMA, the FDA determines whether the application is

sufficiently complete to permit a substantive review.

If the FDA accepts the application for review, it has 180 days under the FDCA to

complete its review of a PMA, although in practice, the FDA’s review often takes significantly longer, and can take several years.

An advisory panel of experts from outside the FDA may be convened to review and evaluate the application and provide recommendations

to the FDA as to the approvability of the device.

PMA review and approval process is more demanding than the 510(k) premarket notification process.

In a PMA, the manufacturer must

demonstrate that the device is safe and effective, and the PMA must be supported by extensive data, including data from preclinical

studies and human clinical trials.

The PMA also must contain a full description of the device and its components, a full description

of the methods, facilities and controls used for manufacturing, and proposed labeling.

Following receipt of a PMA, the FDA

determines whether the application is sufficiently complete to permit a substantive review.

If the FDA accepts the application for

review, it has 180 days under the FDCA to complete its review of a PMA, although in practice, the FDA’s review often takes

significantly longer, and can take several years.

With the recent reduction in workforce that has taken place within the federal

government, including at the FDA, we may experience longer review periods from the FDA for any applicable regulatory approvals.

advisory panel of experts from outside the FDA may be convened to review and evaluate the application and provide recommendations to

the FDA as to the approvability of the device.

The FDA may or may not accept the panel’s recommendation.

In addition, the FDA

generally will conduct a pre-approval inspection of the applicant or its third-party manufacturers’ manufacturing facility or facilities

to ensure compliance with the QSR.

The FDA will approve the new device for commercial distribution if it determines that the data and

information in the PMA constitute valid scientific evidence and that there is reasonable assurance that the device is safe and effective

for its intended use(s).

FDA may approve a PMA with post-approval conditions intended to ensure the safety and effectiveness of the device, including, among

other things, restrictions on labeling, promotion, sale and distribution, and collection of long-term follow-up data from patients

in the clinical study that supported PMA approval, or requirements to conduct additional clinical studies post-approval.

condition PMA approval on some form of post-market surveillance when deemed necessary to protect the public health or to provide

additional safety and efficacy data for the device in a larger population or for a longer period of use.

In such cases, the

manufacturer might be required to follow certain patient groups for a number of years and to make periodic reports to the FDA on the

clinical status of those patients.

Failure to comply with the conditions of approval can result in material adverse enforcement

action, including withdrawal of the PMA approval.

Certain changes to an approved device, such as changes in manufacturing

facilities, methods or quality control procedures, or changes in the design performance specifications, which affect the safety or

effectiveness of the device, require submission of a PMA supplement.

PMA supplements often require submission of the same type of

information as a PMA, except that the supplement is limited to information needed to support any changes from the device covered by

the original PMA and may not require as much clinical data or the convening of an advisory panel.

Certain other changes to an

approved device require the submission of a new PMA, such as when the design change causes a different intended use, mode of

operation and technical basis of operation, or when the design change is so significant that a new generation of the device will be

developed, and the data that were submitted with the original PMA are not applicable for the change in demonstrating a reasonable

assurance of safety and effectiveness.

generally will conduct a pre-approval inspection of the applicant or its third-party manufacturers’ manufacturing facility or

facilities to ensure compliance with the QSR.

The FDA will generally approve the new device for commercial distribution if it

determines that the data and information in the PMA constitute valid scientific evidence and that there is reasonable assurance that

the device is safe and effective for its intended use(s).

FDA may approve a PMA with post-approval conditions intended to ensure the safety and effectiveness of the device, including, among other

things, restrictions on labeling, promotion, sale and distribution, and collection of long-term follow-up data from patients in the clinical

study that supported PMA approval, or requirements to conduct additional clinical studies post-approval.

The FDA may condition PMA approval

on some form of post-market surveillance when deemed necessary to protect the public health or to provide additional safety and efficacy

data for the device in a larger population or for a longer period of use.

In such cases, the manufacturer might be required to follow

certain patient groups for a number of years and to make periodic reports to the FDA on the clinical status of those patients.

to comply with the conditions of approval can result in material adverse enforcement action, including withdrawal of the PMA approval.

Certain changes to an approved device, such as changes in manufacturing facilities, methods or quality control procedures, or changes

in the design performance specifications, which affect the safety or effectiveness of the device, require submission of a PMA supplement.

PMA supplements often require submission of the same type of information as a PMA, except that the supplement is limited to information

needed to support any changes from the device covered by the original PMA and may not require as much clinical data or the convening

of an advisory panel.

Certain other changes to an approved device require the submission of a new PMA, such as when the design change

causes a different intended use, mode of operation and technical basis of operation, or when the design change is so significant that

a new generation of the device will be developed, and the data that were submitted with the original PMA are not applicable for the change

in demonstrating a reasonable assurance of safety and effectiveness.

Both the VenoValve and enVVe will require the approval of a PMA.

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All clinical investigations of devices to determine safety and effectiveness

must be conducted in accordance with the FDA’s investigational device exemption (IDE) regulations, which govern investigational

must be conducted in accordance with the IDE regulations, which govern investigational

device labeling, prohibit promotion of the investigational device and specify an array of recordkeeping, reporting and monitoring responsibilities

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has its own rules and regulations with respect to the manufacture, marketing and sale of medical

For example, in December of 2018, we received regulatory approval from Instituto Nacional de Vigilancia de Medicamentos y Alimentos,

the Colombian equivalent of the U.S.

Food and Drug Administration, for our first-in-human study for the VenoValve in Colombia.

time, other than the first-in-human trial in Colombia, we have not determined which countries outside of the U.S., if any, we will seek

approval for our product candidates.

devices, including, but not limited to the European Medicines Agency in the European Union.

For example, in December of 2018, we received

regulatory approval from Instituto Nacional de Vigilancia de Medicamentos y Alimentos, the Colombian equivalent of the U.S.

Drug Administration, for our first-in-human study for the VenoValve in Colombia.

At this time, other than the first-in-human trial in

Colombia, we have not determined which countries outside of the U.S., if any, we will seek approval for our product candidates.

Competitive Strengths

1 unchanged sentence

approved, for the following reasons:

We have extensive experience

of proprietary processing and manufacturing methodology specifically applicable to the design, processing, manufacturing and sterilization

of our biologic tissue devices.

We operate a 14,507 square

foot manufacturing facility in Irvine, California.

Our facility is designed expressly for the manufacture of Class III tissue based

implantable medical devices and is equipped for research and development, prototype fabrication, current good manufacturing practices (cGMP), and manufacturing and shipping for Class III medical devices, including biologic cardiovascular devices.

We have attracted senior

executives who are experienced in research and development and who have worked on numerous medical devices that have received FDA

approval or CE marking.

We also have the advantage of an experienced board of directors and scientific advisory board who will provide

guidance as we move towards market launch.

have extensive experience of proprietary processing and manufacturing methodology specifically applicable to the design, processing,

manufacturing and sterilization of our biologic tissue devices.

operate a 14,507 square foot manufacturing facility in Irvine, California.

Our facility is designed expressly for the manufacture

of Class III tissue based implantable medical devices and is equipped for research and development, prototype fabrication, current

good manufacturing practices (cGMP), and manufacturing and shipping for Class III medical devices, including biologic cardiovascular

have attracted senior executives who are experienced in research and development and who have worked on numerous medical devices

that have received FDA approval or CE marking.

We also have the advantage of an experienced board of directors and scientific advisory

board who will provide guidance as we move towards market launch.

possess an extensive proprietary processing and manufacturing methodology specifically applicable to the design, processing, manufacturing

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Patent and Trademark Office (USPTO) and throughout the world.

We currently have twenty-six (26) patents

granted from agencies around the world including seven (7) from the USPTO.

of February 27, 2024, we had thirty-one (31) full-time employees.

We currently have thirty-nine (39) patents

granted from agencies around the world including eight (8) from the USPTO.

of February 25, 2025, we had thirty-seven (37) full-time employees.

None of our employees are represented by a collective bargaining

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business