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Item 1. Business

2023-02-28 compared with 2022-03-15 · 372 added, 290 removed, 567 unchanged (54% of the section changed)

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is a clinical stage biopharmaceutical company focused on developing treatments for obesity and liver diseases.

Our lead product candidate, pemvidutide (proposed INN, formerly known as ALT-801), is a GLP-1/glucagon dual receptor agonist that is being developed for the treatment of obesity and non-alcoholic steatohepatitis (“NASH”).

Our lead product candidate, pemvidutide (formerly known as ALT-801), is a GLP-1/glucagon dual receptor agonist that is being developed for the treatment of obesity and non-alcoholic steatohepatitis (“NASH”).

In addition, we are developing HepTcell, an immunotherapeutic agent designed to achieve a functional cure for chronic hepatitis B.

Our business is the result of a merger between PharmAthene, Inc.

(“PharmAthene”) and the business previously known as Altimmune, Inc.

(“Private Altimmune”).

On May 4, 2017, Private Altimmune merged with PharmAthene in a series of mergers and reorganizations (collectively, the “Mergers”) pursuant to an Agreement and Plan of Merger and Reorganization (the “PharmAthene Merger Agreement”) dated January 18, 2017, among Private Altimmune, PharmAthene, its wholly owned acquisition subsidiaries Mustang Merger Sub Corp I Inc.

and Mustang Merger Sub II LLC.

Upon closing of the Mergers, all equity instruments of Private Altimmune were exchanged for corresponding equity instruments of PharmAthene.

Prior to the Mergers, PharmAthene was a publicly traded biodefense company engaged in Phase 2 clinical trials.

Except where the context indicates otherwise, references to “we,” “us,” “our,” “Altimmune” or the “Company” refer, for periods prior to the completion of the Mergers, to Private Altimmune and its subsidiaries, and for periods following the completion of the Mergers to the combined company and its subsidiaries.

Except where the context indicates otherwise, references to “we,” “us,” “our,” “Altimmune” or the “Company” refer to the company and its subsidiaries.

We completed an acquisition in July 2019 of all of the equity interests of Spitfire Pharma, Inc.

(“Spitfire”).

Spitfire was a privately held, preclinical pharmaceutical company with the primary asset being a novel peptide-based dual GLP-1/glucagon receptor agonist for the treatment of NASH.

We refer to this product candidate as pemvidutide, and it is designed to treat obesity and the metabolic dysfunction that causes NASH.

Spitfire was a privately held, preclinical pharmaceutical company with the primary asset being pemvidutide, a novel peptide-based GLP-1/glucagon dual receptor agonist product candidate designed to treat obesity and the metabolic dysfunction that causes NASH.

Obesity is a significant burden to the global healthcare systems and is implicated in two-thirds of the leading causes of death from non-communicable diseases worldwide.

Some of the leading co-morbidities of obesity include high blood pressure, high cholesterol, type 2 diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis, sleep apnea and breathing problems, certain cancers and NASH.

According to the Center for Disease Control and Prevention, total obesity related medical care in the U.S.

is estimated to be $147.0 billion per annum.

Some of the leading co-morbidities of obesity include high blood pressure, high cholesterol, type 2 diabetes, heart disease, stroke, gallbladder disease, osteoarthritis, sleep apnea and breathing problems, certain cancers and NASH.

According to the Center for Disease Control and Prevention, the estimated annual medical cost of obesity in the U.S.

was nearly $173.0 billion in 2019 dollars.

Globally, the market size for weight loss alone was $2.4 billion in 2022 and is estimated that it will reach $54.0 billion by 2030.

Previous approaches to the treatment of obesity have been associated with safety concerns, limiting the success of those approaches.

NASH involves multiple metabolic pathways leading to the abnormal accumulation of liver fat, toxic lipid metabolites, and inflammation, leading to fibrosis or eventually liver cancer.

Non-alcoholic fatty liver disease (“NAFLD”), the fatty liver precursor to NASH, is present in up to 90% of obese patients, and approximately 20% of NAFLD patients progress to NASH.

In addition, up to 40% of NASH patients develop NAFLD recurrence one year after liver transplant, which we believe indicates that the underlying metabolic disease is still present after transplant.

We believe the treatment of obesity is the cornerstone of treating NASH and the principal morbidities of NASH.

Pemvidutide’s dual agonist mechanism of action is designed to combine the activity of GLP-1 for the reduction of appetite and inflammation, with the direct activity of glucagon on the liver, including increased energy expenditure, adipose browning, lipolysis and mobilization of the liver fat.

NASH involves multiple metabolic pathways leading to the abnormal accumulation of liver fat, toxic lipid metabolites, and inflammation, leading to fibrosis and increased risk of death due to liver failure and cardiovascular disease.

Non-alcoholic fatty liver disease (“NAFLD”), the fatty liver precursor to NASH, is present in up to 50% of obese patients, and up to 20% of NAFLD patients progress to NASH.

We believe the treatment of obesity is a cornerstone of treating NASH and the principal morbidities of NASH.

In addition, clinical evidence from recent trials of potential NASH products indicates that reduction in liver fat may play an important role in the resolution of inflammation and fibrosis.

We believe that combining a reduction in liver fat content with weight loss could be the optimal approach for NASH resolution.

Pemvidutide’s dual agonist mechanism of action is designed to combine the activity of GLP-1 for the reduction of appetite and inflammation, with the activity of glucagon, including increased energy expenditure, adipose browning and mobilization of the liver fat through lipolysis and reduction of lipid synthesis.

Pemvidutide incorporates a proprietary side chain, referred to as the EuPort domain, which is designed to enhance pharmacokinetics for tolerability in the gastrointestinal tract and permit weekly dosing.

As observed in a well-established preclinical model of the disease, pemvidutide is capable of inducing significant weight loss with concomitant decreases in liver fat, inflammation and fibrosis.

As observed in a well-established preclinical model of the disease, pemvidutide is capable of inducing significant weight loss with concomitant decreases in liver fat content, inflammation and fibrosis.

In a first-in-human, randomized, placebo-controlled, single-ascending and multiple-ascending dose study of pemvidutide in overweight and obese volunteers, at 12 weeks, we observed significant reductions in body weight, and in the absence of caloric restriction or lifestyle modification, as well as reduction in low density lipoprotein cholesterol (“LDL-C”).

In addition, pemvidutide demonstrated improved metabolic function and exhibited pleiotropic effects in our preclinical testing across multiple metabolic pathways involved in NASH.

We also observed in these studies that pemvidutide resulted in profound suppression of genes associated with steatosis, inflammation and stellate cell fibrosis by RNA sequencing.

Clinical Trial Results – Obesity

We also observed in these studies that pemvidutide resulted in suppression of genes associated with steatosis, inflammation and stellate cell fibrosis by RNA sequencing.

Additionally, we have now observed profound decreases and normalization in liver fat content and significant reductions in body weight at 12 weeks in a Phase 1 trial of pemvidutide in healthy volunteers and at both 12 weeks and 24 weeks in a Phase 1b trial of pemvidutide in subjects with NAFLD as well as reductions and normalization in serum alanine aminotransferase (“ALT”) at both 12 weeks and 24 weeks in the Phase 1b trial.

We believe that pemvidutide is the only

NASH candidate in development with observed rapid effects in liver fat reduction and liver inflammation together with significant weight loss.

Regulatory Basis for Clinical Trials of Pemvidutide

On November 9, 2020, we announced that we received clearance from the Human Research and Ethics Committee and filed a Clinical Trial Notification with the Australian regulatory authority prior to commencing our first-in-human trial of pemvidutide.

On September 28, 2021, we announced that we received clearance of our Investigational New Drug (“IND”) Application in NASH from the U.S.

Food and Drug Administration (“FDA”) prior to commencing our Phase 1b trial of pemvidutide in NAFLD.

On January 23, 2022, we further announced that we received clearance of our IND Application from the FDA prior to commencing our 48-week Phase 2 trial of pemvidutide in obesity.

Phase 1 Clinical Trial Results – Obesity

In September 2021, we announced the completion of a 12-week Phase 1 clinical trial of pemvidutide in Australia under a clinical trial application.

The trial was a first-in-human, randomized, placebo-controlled, single-ascending and multiple-ascending dose (“MAD”) study in overweight and obese volunteers.

The trial was a first-in-human, randomized, placebo-controlled, single-ascending and multiple-ascending dose (“MAD”) study in non-diabetic overweight and obese volunteers.

The endpoints of the Phase 1 trial were to assess the safety, tolerability and pharmacokinetics of pemvidutide, with primary readouts on safety, pharmacokinetics and weight loss.

Additional readouts included metabolic and lipid profile, cardiovascular measures and glucose homeostasis.

Additional readouts included metabolic and lipid profiles, cardiovascular measures and glucose homeostasis.

At 12 weeks, subjects receiving pemvidutide showed mean weight losses of 4.9%, 10.3% and 9.0% at the 1.2 mg, 1.8 mg and 2.4 mg doses, respectively, while the placebo group experienced a mean weight loss of 1.6%, and in the absence of caloric restriction or lifestyle modification.

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The 1.8 mg dose cohort experienced the highest weight loss, with 100% of the subjects losing at least 5% of body weight and 55% of subjects losing at least 10% of body weight.

The amounts of weight loss at the 1.8 mg and 2.4 mg doses were similar given the sample size and overlapping confidence intervals.

The amounts of weight loss at the 1.8 mg and 2.4 mg

doses were similar given the sample size and overlapping confidence intervals.

No correlation was found between the magnitude of weight loss and either age or baseline body mass index (“BMI”).

Favorable or statistically significant trends were observed in secondary measures, including reductions in systolic and diastolic blood pressure, serum lipids and HOMA-IR (a measure of insulin resistance).

In addition, a rise in ketone bodies was observed, consistent with the effects of glucagon on fat metabolism.

Side effects in this study were mild to moderate, with no serious or severe treatment-emergent adverse events reported.

As seen in the table below, the effect on serum lipids was particularly striking and in the 1.8mg dose, included a greater than 25% decrease in LDL-C, which is known to increase the risk of cardiovascular disease, as well as significant decreases in total cholesterol and triglycerides.

In addition, a rise in serum ketone bodies and a fall in serum tripalmitin was observed, consistent with the stimulatory effects of glucagon on hepatic beta-oxidation of lipids and suppressive effects of pemvidutide on triglyceride synthesis, respectively.

Side effects in this trial were mild to moderate, with no serious or severe treatment-emergent adverse events reported.

No discontinuations due to adverse events were reported.

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Other adverse events (n)

Unlike the majority of other clinical trials with agents within the GLP-1 class, including dual agonists and tri-agonists, a gradual increasing of dose within a subject over a period of weeks to months to improve tolerability was not used in the pemvidutide trial.

Even without that so called dose titration, the symptoms experienced by subjects who received pemvidutide 1.2 mg and 1.8 mg were predominantly mild, did not require treatment and were consistent with known effects of GLP-1-based therapies.

Unlike the majority of other clinical trials with agents within the GLP-1 class, including dual agonists and tri-agonists, dose titration, a gradual increasing of dose within a subject over a period of weeks to months to improve tolerability, was not used in the pemvidutide trial.

Even without that dose titration, the symptoms experienced by subjects who received pemvidutide 1.2 mg and 1.8 mg were predominantly mild, did not require treatment and were consistent with known effects of GLP-1-based therapies.

Tolerability was observed to decrease at the highest dose level.

One subject receiving placebo and one subject receiving pemvidutide 1.8 mg had a 3 to 5-fold elevation in alanine aminotransferase (“ALT”) levels over baseline that resolved rapidly after a pause in dosing.

One subject receiving placebo and one subject receiving pemvidutide 1.8 mg had a 3 to 5-fold elevation in ALT levels over baseline that resolved rapidly after a pause in dosing.

In this trial, no perturbations of glucose control, as assessed by fasting glucose and hemoglobin A1c, were observed in subjects with obesity/overweight with pre-diabetes;

in fact, a reduction of insulin resistance was observed, as expected when significant weight loss is experienced.

We are currently conducting a Phase 1 trial to establish the effects of pemvidutide on glucose control and confirm the reduction in insulin resistance in patients with Type 2 diabetes.

Clinical Trial Results – Liver Fat Content

While the trial inclusion criteria did not pre-specify a minimum liver fat content (“LFC”), the trial did enroll a number of subjects with measurable LFC as determined by magnetic resonance imaging – proton density fat fraction (“MRI-PDFF”).

A post-hoc analysis of the trial data through 6 weeks showed that 8 subjects had hepatic steatosis, defined as liver fat content greater than or equal to 5% (LFC range from 5.5% to 19.5%), at baseline.

We are currently conducting a Phase 1 trial to establish the effects of pemvidutide on glucose control and confirm the reduction in insulin resistance in subjects with Type 2 diabetes.

Phase 1 Clinical Trial Results – Liver Fat Content

While the trial inclusion criteria for the MAD study did not pre-specify a minimum liver fat content (“LFC”), the trial did enroll a number of subjects with measurable LFC as determined by magnetic resonance imaging – proton density fat fraction (“MRI-PDFF”).

A post-hoc analysis of the trial data through 6 weeks showed that 8 subjects had hepatic steatosis, defined as liver fat content greater than or equal to 5% at baseline (LFC range from 5.5% to 19.5% in these 8 subjects).

LFC fell below the limit of detection (“LOD”), or less than 1.5%, within 6 weeks of treatment in all subjects with steatosis receiving the 1.8 mg or 2.4 mg dose of pemvidutide, representing a greater than 90% reduction in the liver fat content (see chart below).

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Images of Representative MRI-PDFF Images at Baseline and Week 6

The chart below displays the changes in liver fat content at Week 6 compared to baseline in the 8 subjects with steatosis at baseline:

The table below displays the changes in liver fat content at Week 6 compared to baseline in the 8 subjects with steatosis at baseline:

Treatment Group

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for absolute and relative ∆, values < LOD are set at 0.75%

Clinical Trial Results – 12-week Phase 1b (NAFLD)

In September 2022, we announced the topline results from our 12-week Phase 1b clinical trial of pemvidutide in subjects with NAFLD.

The trial was a double-blind, placebo-controlled study.

Subjects were randomized 1:1:1:1 to 1.2 mg, 1.8 mg, 2.4 mg pemvidutide or placebo administered weekly for 12 weeks.

No dose titration was used with the 1.2 mg or 1.8 mg dose, while a short 4-week dose titration was employed at the 2.4 mg dose.

The primary efficacy endpoint was the percent (%) reduction in LFC from baseline, and the key secondary efficacy endpoint was the % weight loss from baseline, both at 12 weeks of treatment.

The trial was conducted without adjunctive diet and exercise interventions that are the standard for obesity trials.

Ninety-four (94) subjects were randomized and treated at 13 sites across the U.S.

Mean BMI at baseline was approximately 36 kg/m 2 and mean LFC, as measured by MRI-PDFF, was approximately 22%.

Twenty-seven (29%) subjects had type 2 diabetes at baseline, and approximately 75% of study subjects were of Hispanic ethnicity.

The chart below details the baseline study demographics.

Characteristic

Female, n (%)

Hispanic, n (%)

Non-Hispanic, n (%)

Body weight, kg

Diabetes status

The trial met its primary endpoint in all pemvidutide treatment groups.

As seen in the table below showing reduction in LFC as measured by MRI-PDFF in all subjects, at the 1.8 mg dose (with and without diabetes), pemvidutide achieved a mean reduction of liver fat content of 68.5%, with 94.4% of subjects achieving a 30% reduction in liver fat, 72.2% achieving a 50% reduction in liver fat, and 55.6% of subjects achieving normalization of liver fat, defined as liver fat fraction of 5% or less.

Absolute reduction, %

Relative reduction, %

30% reduction

50% reduction

Normalization (≤ 5% LFC)

*p < .05, **p<.001 compared to placebo

In addition, as shown in the below table, mean serum ALT levels declined in all subjects, and in subjects with baseline serum ALT above 30 IU/L, levels declined more than 17 IU/L at all dose levels and 27.0 IU/L in the 2.4 mg dose cohort.

ALT, change from baseline, IU/L, LSM (SE)

ALT, change from baseline, IU/L, LSM (SE), baseline ≥ 30 IU/L

The trial also met its key secondary endpoint in all pemvidutide treatment groups.

As portrayed in the following table, employing an efficacy estimand, mean weight losses of 4.9% (placebo-adjusted 4.7%) in subjects without diabetes and 4.4% in subjects with diabetes (placebo-adjusted 3.9%) were achieved at the 1.8 and 2.4 mg doses, respectively.

No diabetes, (% change)

Diabetes, (% change)

All subjects (% change)

LSM least square mean;

*p < .05, **p<.001 compared to placebo

Pemvidutide was reported to be generally well tolerated.

Gastrointestinal events comprised the majority of the adverse events (“AEs”).

Even without dose titration, the symptoms experienced by subjects were predominantly mild and transient in nature, consistent with known GLP-1 class effects.

No serious or severe AEs were reported.

Two subjects treated with pemvidutide discontinued treatment due to AEs [1 (4.3%) at 1.8 mg and 1 (4.2%) at 2.4 mg], both secondary to gastrointestinal intolerability.

No clinically significant ALT elevations (defined as an increase to 3-fold or greater the upper limit of normal) were observed.

Glycemic control was unaffected, with no clinically meaningful changes in HbA1c or fasting glucose.

Clinically meaningful reductions in systolic blood pressure were observed, along with the two to three beats per minute increase in heart rate typical for GLP-1 class of drugs.

The table below summarizes the safety findings.

Characteristic

AEs leading to treatment discontinuation

Clinical Trial Results – 24-week Phase 1b (NAFLD)

In December 2022, we announced the topline results from our 24-week (12-week extension) Phase 1b clinical trial of pemvidutide in subjects with NAFLD.

Sixty-six (66) of the 83 subjects who completed the initial 12-week Phase 1b NAFLD trial consented to participate in this 12-week extension trial to receive a total of 24 weeks of treatment, and 64 subjects were enrolled.

The trial was conducted without adjunctive diet and exercise interventions and the double-blinding of the trial was maintained during the extension study.

The same endpoints as the 12-week parent NAFLD trial were employed, with a primary efficacy endpoint of percent (%) reduction in liver fat content;

key secondary endpoints were reduction in liver inflammation, as measured by serum ALT levels and corrected T1 (“cT1”), and percent weight loss.

The population of the 12-week extension trial had similar baseline characteristics as the population of the parent, 12-week Phase 1b NAFLD trial.

At baseline, across all treatment groups, mean BMI was 36.7 kg/m 2 and mean LFC, as measured by MRI-PDFF, was 22.2%.

Type 2 diabetes was present in 26.6% of subjects and 73.4% of study subjects were of Hispanic ethnicity.

The trial met its primary endpoint in all pemvidutide treatment groups.

At the 1.8 mg and 2.4 mg doses, subjects receiving pemvidutide achieved mean relative reductions of liver fat content of 75.2% and 76.4%, respectively;

92.3% and 100% of subjects, respectively, achieved a 30% reduction in liver fat, 84.6% and 72.7% of subjects, respectively, achieved a 50% reduction in liver fat, and 53.8% and 45.5% of subjects, respectively, achieved normalization of liver fat.

As in the 12-week Phase 1b NAFLD trial, statistically significant declines in mean serum ALT levels were observed in all pemvidutide-treated subjects, and in subjects with baseline serum ALT ≥30 IU/L, ALT levels declined at least 17 IU/L at

all pemvidutide dose levels.

In a subset of subjects evaluated for cT1 response, 75.0% and 100% of subjects receiving 1.8 mg or 2.4 mg pemvidutide, respectively, achieved an 80 millisecond (ms) decrease in cT1.

cT1 value is an MRI-based quantitative metric for assessing a composite of liver inflammation and fibrosis.

Elevated cT1 levels have been associated with increased risk of major adverse cardiac events (MACE) and major adverse liver outcomes (MALO), and an 80 ms reduction has been associated with a 2-point reduction of NAFLD Activity Score (NAS).

The trial also met its key secondary weight loss endpoint in all pemvidutide treatment groups.

Employing an efficacy estimand, mean weight losses of 7.2% (placebo-adjusted 6.0%) in subjects without diabetes and 6.2% (placebo-adjusted 4.8%) in all subjects were achieved at the 1.8 mg dose.

A summary of the key primary and secondary efficacy findings is below:

Primary Endpoint—Liver Fat Content

Liver fat reduction, absolute, % change, LSM (SE)

11.2 (2.3) ***

17.0 (2.4) ***

15.6 (2.1) ***

Liver fat reduction, relative, % change, LSM (SE)

56.3 (11.6) ***

75.2 (8.1) ***

76.4 (5.9) ***

Proportion of subjects with 30% reduction, (%)

Proportion of subjects with 50% reduction, (%)

Proportion of subjects with normalization, (%)

Secondary Endpoint—Markers of Inflammation

ALT, change from baseline, IU/L, LSM (SE)

-13.3 (3.7) **

-13.7 (5.1) **

-15.2 (5.8) **

ALT, change from baseline, IU/L, LSM (SE), baseline ≥ 30 IU/

-17.0 (7.6) *

-17.7 (7.2) *

-20.6 (9.8) *

Proportion of subjects with cT1 response, (%)

Secondary Endpoint—Weight Loss

Weight loss, no diabetes, (% change), LSM (SE)

7.2 (1.1) ***

Weight loss, diabetes, (% change), LSM (SE) †

Weight loss, all subjects, (% change), LSM (SE

6.2 (1.3) ***

Normalization of liver fat defined as ≤ 5%;

cT1 response define as an 80 ms change from baseline;

LSM, least square mean

† High variability due to the small numbers of diabetic subjects (n = 5, 3, 6, 3 in respective treatment groups)

** p < 0.01, *** p < 0.001, ****p < 0.0001 compared with placebo

Pemvidutide was generally well tolerated.

A total of three serious or severe AEs were reported, each unrelated to study drug administration (chest pain post-elective cardiac stent placement;

Salmonella infection;

and hypertension greater than three weeks after the completion of treatment).

Three AEs led to treatment discontinuation, one being the Salmonella infection, and two gastrointestinal AEs, one (6.3%) at the 1.2 mg dose and one (6.7%) at the 1.8 mg dose.

As expected, gastrointestinal events comprised the majority of AEs and were predominantly mild in nature.

No clinically significant ALT elevations were observed.

Meaningful reductions in systolic blood pressure were observed, and increases in heart rate, typical of the incretin class of agents, were minimal at zero to four beats per minute and independent of dose.

Below is a summarization of the safety findings:

Characteristic

Serious or severe AEs

AEs leading to treatment discontinuation

Moderate, n (%)

Systolic Blood Pressure, mm Hg, LSM (SE)

-10.1 (4.2) *

-12.0 (3.5) *

Diastolic Blood Pressure, mm Hg, LSM (SE)

Heart Rate, mmHg, LSM (SE)

A total of 3 serious or severe adverse events (AEs) were reported, each unrelated to study drug administration (chest pain post-elective cardiac stent placement;

Salmonella infection;

and hypertension greater than 3 weeks after the completion of treatment), with only the Salmonella infection leading to treatment discontinuation.

The other AEs leading to treatment discontinuation were mild (Grade 1) abdominal pain in 2 subjects.

No significant ALT elevations were reported.

*p < .05 compared with placebo.

As detailed in the table below, glycemic control was maintained in subjects with diabetes, all pemvidutide groups demonstrating trends toward improvements in fasting glucose and either maintaining or demonstrating trends toward improvement in HbA1c over the 24 weeks of treatment:

Characteristic

Fasting glucose

Baseline, mg/dL, mean (SD)

Week 24, mg/dL, mean (SD)

Baseline, %, mean (SD)

Week 24, %, mean (SD)

Fasting glucose

Baseline, mg/dL, mean (SD)

Week 24, mg/dL, mean (SD)

Baseline, %, mean (SD)

Week 24, %, mean (SD)

Clinical Development Plan

We submitted an Investigational New Drug application (“IND”) for evaluation of pemvidutide in obesity to the U.S.

Food and Drug Administration (“FDA”) in December 2021 and we announced on January 31, 2022 that we had received FDA clearance for a Phase 2 trial in this indication.

We expect to initiate this 48-week Phase 2 obesity trial in the first half of 2022.

The readouts of that study will include safety, weight loss and other metabolic measures.

The study will include a 24-week interim analysis of safety and weight loss that we expect will read out in the fourth quarter of 2022.

We are currently conducting a 12-week Phase 1b trial of pemvidutide in patients with NAFLD at multiple sites in the United States.

This double-blind, randomized, placebo-controlled study will enroll approximately 72 diabetic and non-diabetic overweight and obese adult patients with a liver fat content greater than 10% as measured by MRI-PDFF.

The primary efficacy endpoint is the change in liver fat content from baseline, with a secondary endpoint of weight loss.

The study is expected to read out topline results in the third quarter of 2022.

We expect to initiate a 12-week double-blind, placebo-controlled extension study which, combined with the 12-week Phase 1b NAFLD trial, will allow patients to receive up to a total of 24 weeks of continuous pemvidutide or placebo treatment and provide a read out on weight loss after 24 weeks of treatment, which is expected in the fourth quarter of 2022.

Based on the findings of the NAFLD study and evaluation of other priorities, we intend to initiate a 52-week biopsy-driven Phase 2 NASH study in 2022.

We initiated a 48-week Phase 2 MOMENTUM obesity trial in the first half of 2022.

The readouts of this trial will include safety, weight loss and other metabolic measures.

The trial will include a 24-week interim analysis of approximately 160 subjects for safety, weight loss and other measures that we expect will read out in the first quarter of 2023.

The trial is being conducted at approximately 30 sites in the U.S.

The randomized, placebo-controlled trial enrolled approximately 320 non-diabetic subjects randomized 1:1:1:1 to receive either 1.2 mg, 1.8 mg, 2.4 mg pemvidutide or placebo weekly for 48 weeks.

No dose titration is being used with the 1.2 mg or 1.8 mg dose, while a short 4-week dose titration is being employed at the 2.4 mg dose.

The primary endpoint of the trial is the relative (percent) change in body weight at 48 weeks compared to baseline, with additional readouts including metabolic and lipid profiles, cardiovascular measures and glucose homeostasis.

The trial is being conducted with adjunctive diet and exercise interventions that is typical in weight loss studies.

On August 11, 2022, we announced that 167 subjects had been randomized and we further announced on September 28, 2022 the first dosing of all subjects in the MOMENTUM trial.

We intend to initiate a biopsy-driven Phase 2 NASH trial in 2023.

We expect this trial to enroll approximately 200 subjects across 4 treatment arms (placebo, pemvidutide 1.2, 1.8 and 2.4 mg) administered for a period of 48 weeks.

The primary efficacy readout will be based on a biopsy readout at the end of either 24 or 48 weeks.

These details may change by the time of protocol finalization.

HepTcell is an immunotherapeutic product candidate for patients chronically infected with the hepatitis B virus (“HBV”).

Approximately 300 million people worldwide live with chronic HBV infection, including approximately 2.2

million in the United States.

Approximately 300 million people worldwide live with chronic HBV infection, including approximately 2.2 million in the United States.

Chronic HBV infection can lead to serious complications, including cirrhosis and liver cancer.

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HepTcell is designed to drive CD4+ and CD8+ T-cell responses against all HBV genotypes in patients of all ethnic backgrounds.

Stimulating T-cell responses in chronically infected HBV patients has been challenging because chronic infection with HBV strongly suppresses T-cell immunity directed against the virus.

Stimulating T-cell responses in chronically infected HBV patients

has been challenging because chronic infection with HBV strongly suppresses T-cell immunity directed against the virus.

HepTcell focuses the T cell response on discrete, highly conserved regions of the HBV proteome.

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In the two adjuvanted HepTcell arms, T-cell responses against HBV markedly increased over baseline compared to placebo.

The table below presents the immunogenicity against hepatitis B epitopes that was demonstrated in our Phase 1 clinical trial:

We initiated a Phase 2 study during Q4 2020 in the United States, Canada and Europe that is a double-blind, randomized, placebo-controlled study of 80 adult patients with HBeAg-negative inactive CHB and HBsAg ≤ 100 IU/mL.

Patients with HBsAg ≤ 100/mL are more likely to mount effective T cell responses against HBV than those with higher levels.

The vision is that HepTcell could be used in combination with newer direct acting agents that may be more effective than nucleosides in reducing HBsAg to this level.

The chart below presents the immunogenicity against hepatitis B epitopes that was demonstrated in our Phase 1 clinical trial:

We initiated a Phase 2 trial during the fourth quarter of 2020 in the United States, Canada, Europe and Asia that is a double-blind, randomized, placebo-controlled study of 80 adult patients with HBeAg-negative inactive CHB and HBsAg ≤ 200 IU/mL Patients with approximately low HBsAg are more likely to mount effective T cell responses against HBV than those with higher levels.

The rationale for the study design is based in our understanding that HepTcell could be used in combination with newer direct acting agents that may be more effective than the current nucleosides analogs in reducing HBsAg to this level.

Accordingly, selection of patients with HBsAg levels ≤ 200 IU/mL may mimic the eventual combination of HepTcell with the newer antiviral drugs in development.

HepTcell is being administered in 6 doses at the low dose level of HepTcell plus IC31 ® at 4-week intervals for 24 weeks, and patients will be followed for one year to evaluate safety and durability of response.

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Secondary efficacy endpoints include reactivation of anti-HBV T cell responses and other assessments of virologic response.

We expect data from this study in the first half of 2023.

We expect data from this trial in the first half of 2024.

A follow-up phase will assess the safety and durability of response one year after completion of treatment.

Discontinued Programs

AdCOVID was an intranasal COVID-19 vaccine candidate designed to guard the respiratory tract from viral invasion and to provide protection against viral spread through stimulation of both mucosal and systemic antibodies (IgA

and IgG) as well as cell-mediated immunity.

By stimulating mucosal immunity in the nasal cavity, a key point of entry and replication for the SARS-CoV-2 virus, we believed that AdCOVID had the potential to defend against both the infection and spread of the virus to others.

We submitted an IND to the FDA in the fourth quarter of 2020 and received clearance from the FDA in February 2021 to initiate a Phase 1 clinical trial of AdCOVID.

The Phase 1 clinical trial evaluated the safety and immunogenicity of AdCOVID in 92 healthy adult volunteers between the ages of 18 and 55.

In June 2021, we announced the discontinuation of the development program for AdCOVID following our review of findings from the Phase 1 clinical trial and in consideration of the highly competitive COVID-19 landscape.

In the study, the tolerability of AdCOVID was similar to placebo, but the immunogenicity data demonstrated lower than expected immune responses for each of the immune parameters tested.

T-COVID was an intranasal immune modulating therapeutic candidate based on the same replication-deficient adenovirus 5 (“RD-Ad5”) vector technology behind our other intranasal vaccine candidates, but it acted through a different mechanism that may have involved the innate immune system.

With the support of the U.S.

Army Medical Research & Development Command in collaboration with the Medical Technology Enterprise Consortium, during 2020, we initiated a placebo-controlled Phase 1/2 double-blind clinical trial to evaluate the potential of T-COVID to prevent clinical worsening in patients with early COVID-19.

The trial was expected to enroll 96 community-based patients who were 18 years and older that present with fever, cough, or shortness of breath, with onset of symptoms within 48 hours, and a diagnosis of COVID-19 within 72 hours.

The primary endpoint of the trial was the proportion of patients with clinical worsening, defined as a 4% decrease in pulse oxygen saturation, or the need for hospitalization.

Secondary endpoints measured the average decrease in resting pulse oxygen saturation, average increase in resting pulse rate and proportion of patients requiring oxygen supplementation and mechanical ventilation.

However, the effective rollout in the U.S.

of authorized COVID-19 vaccines and decreasing incidence of disease significantly reduced the number of patients meeting our enrollment criteria, and we had been unable to enroll subjects in the final cohort, the cohort most likely to benefit from T-COVID.

As a result of enrollment challenges, we decided to terminate further enrollment and have terminated the development of T-COVID.

NasoShield was an anthrax vaccine product candidate designed to provide rapid and stable protection after a single intranasal administration.

It was being developed with the support of the U.S.

Biomedical Advanced Research and Development Authority (“BARDA”) for post-exposure prophylaxis against anthrax following exposure to aerosolized B.

anthracis spores.

We commenced a Phase 1b trial of NasoShield in adults in 2020 which builds on the Phase 1a trial completed in 2018 and evaluated the effect of modified methods of intranasal dosing on NasoShield safety and immunogenicity.

The trial enrolled 42 healthy subjects who received intranasally administered NasoShield or saline placebo and were then monitored for 6 months post-dosing.

The primary endpoint was the safety and tolerability of NasoShield.

The primary immunogenicity readouts included the serum binding antibody to protective antigen and anthrax toxin blocking antibody responses at 28- and 56-days post-dose administration.

Stimulation of the mucosal IgA immune response in the nasal cavity was also assessed.

In April 2021, we received clinical data from the Phase 1b trial that showed positive immunogenicity results and a NasoShield tolerability profile similar to placebo.

On December 31, 2021, the development support from BARDA ended and we have discontinued further development of the program.

NasoVAX was a recombinant intranasal vaccine product candidate that was being developed for both seasonal and pandemic use.

We believed NasoVAX could simultaneously activate the humoral, mucosal and cellular immune arms which may enable a more comprehensive immune response.

The data from our Phase 2a trial with a monovalent NasoVAX vaccine indicated that NasoVAX achieved 100% seroprotection based on serum antibody responses, which was comparable to published results of a licensed injected influenza vaccine.

Statistically significant increases in mucosal antibody were noted as well as a robust T cell response directed against influenza.

The tolerability profile of NasoVAX was similar to placebo.

Approximately half of the subjects from the highest dose were evaluated between 12 and 14 months after initial dosing for additional immunogenicity assessment.

The durability data show that the immune response elicited by NasoVAX was stable with no overall change in the antibody titer or level of seroprotection over an average of

After evaluating the development path of NasoVAX, we have discontinued further development of the program.

Key elements of our strategy include the following:

● Apply our EuPort platform technologies to design and develop treatments for obesity, NASH and other metabolic diseases;

● Strategically partner or out-license certain product candidates at later stages of development to focus our efforts on early to mid-stage product development;

● In-license or acquire complementary metabolic or immunotherapeutic technologies and product candidates that are either synergistic or complementary to our capabilities to expand our pipeline;

● Apply our EuPort platform technologies to design and develop treatments for obesity, NASH and other metabolic diseases.

Our Technology Platforms

Certain product candidates are based on our proprietary platform technologies as described below:

Incretin-based Peptide Technology – EuPort

EuPort-based Peptide Technology

EuPort is a platform technology that comprises a hydrophobic domain (e.g., substituted or unsubstituted alkyl chain) and a hydrophilic group (e.g., saccharide) conjugated to a non-terminal amino acid of the peptide.

The technology, on which pemvidutide is based, allows the peptide to bind extensively to albumin, an abundant protein in the blood, slowing the elimination of the peptide and increasing its serum half-life, allowing for weekly instead of daily dosing, for example.

EuPort technology may also slow the entry of the peptide into the circulation following subcutaneous injection which may lead to improvements in tolerability or other characteristics of the peptide as have been observed with pemvidutide.

We have license rights to develop incretin-based peptide therapeutics based on EuPort technology for any indication.

Key aspects of our EuPort technology, supported by findings in our preclinical studies, include its potential to:

EuPort technology may also slow the entry of the peptide into the circulation following subcutaneous injection which may lead to improvements in tolerability, cardiovascular risk and other characteristics of the peptide as have been observed with pemvidutide.

We have license rights to develop oxynomodulin (GLP1/glucagon dual receptor agonist)-based peptide therapeutics based on EuPort technology for any indication.

Key aspects of our EuPort technology, supported by findings in our preclinical studies and clinical trial, include its potential to:

● increase the serum half-life of the peptide allowing for extended dosing intervals;

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● prompt a stronger immune response than naked peptides due to depot effect caused by attaching a biologically inert fluorocarbon chain to each peptide.

Intranasal Vaccines – RespirVec

Our RespirVec platform is designed to elicit rapid and long-term immune protection by intranasal delivery of adenovectored pathogen sequences.

We believe that our RespirVec technology may be particularly well-suited for respiratory pathogens as a result of its ability to stimulate mucosal immunity in the nasal cavity, a site of viral attack.

RespirVec is designed to stimulate serum neutralizing antibody and cellular immune response for a broad immune response and is stable at room temperature for several months.

We believe that the favorable stability profile of RespirVec vaccines, when combined with the simple intranasal route of administration, has the potential for efficient and inexpensive distribution of the vaccine.

RespirVec technology is comprised of intranasal delivery of replication-deficient adenoviruses and is protected by patents that we own or license.

Key aspects of our RespirVec technology, supported by findings in our preclinical studies and clinical trials, include its potential to:

● enable intracellular expression of the vaccine antigen for authentic immune presentation;

● mobilize the innate, cellular and mucosal immune systems, not just the antibody-based response triggered by conventional injectable vaccines;

● elicit a more durable antibody response than typical licensed injectable vaccines;

● provide a self-adjuvanting adenovector delivery system with the potential to improve immunogenicity;

● allow a rapid production cycle at anticipated lower costs.

The biopharmaceutical industry is intensely competitive and is characterized by rapid technological progress.

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Accordingly, the speed with which we can develop products, complete the clinical trials and approval processes and supply commercial quantities of the products to the market is an important competitive factor.

Our competitive position also depends upon our ability to show differentiation with a product that is either more efficacious, particularly in the relevant target populations, offers a better safety or tolerability profile, is less expensive or quicker to manufacture, or represents a combination of these advantages.

Our competitive position also depends upon our ability to show differentiation with a product that is either more efficacious,

particularly in the relevant target populations, offers a better safety or tolerability profile, is less expensive or quicker to manufacture, or represents a combination of these advantages.

We also depend upon our ability to attract and retain qualified personnel, obtain patent protection or otherwise develop proprietary products or processes and secure sufficient capital resources for the often substantial period between technological conception and commercial sale.

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We face competition for pemvidutide, our dual GLP-1/glucagon dual agonist for the treatment of obesity and NASH.

For obesity, we face competition from companies such as Novo Nordisk, whose GLP-1 agonist, brand named Wegovy, or compound name semaglutide, was approved in June 2021.

Other companies with potentially competitive candidates in development, include Eli Lilly with GLP-1/glucose-dependent insulinotropic polypeptide receptor (“GIP”)

dual agonists;

Boehringer Ingelheim, Merck/Hamni Pharmaceutical, AstraZeneca, Innovent Biologics/Eli Lilly and D&D Pharma, with GLP-1/glucagon receptor dual agonists;

For obesity, we face competition from companies such as Novo Nordisk, whose GLP-1 agonist, brand named Wegovy, or compound name semaglutide, was approved for weight loss in June 2020.

Other companies with potentially competitive candidates in development, include Eli Lilly with GLP-1/glucose-dependent insulinotropic polypeptide receptor (“GIP”) dual agonists, including Mounjaro, or compound name tirzepatide, which was approved in 2022 for diabetes but has also shown weight loss effect;

Boehringer Ingelheim, Merck/Hanmi Pharmaceutical, AstraZeneca, Innovent Biologics/Eli Lilly, Carmot and D&D Pharma, with GLP-1/glucagon receptor dual agonists;

Hanmi Pharmaceutical and Eli Lilly with GLP-1/glucagon/GIP triple agonists;

Amgen with its GLP-1 agonist/GIP antagonist antibody;

and Novo Nordisk with Amylin and Amylin-GLP-1 combination candidates.

We face competition in NASH from companies such as Intercept Pharmaceuticals, which is developing a farnesoid X receptor (“FXR”) agonist;

Madrigal Pharmaceuticals and Viking Therapeutics, which are developing orally administered, thyroid hormone receptor (“THR”) β-selective agonist;

Akero Therapeutics, 89Bio, Novo Nordisk and Roche, which are developing fibroblast growth factor 21 analogs;

Madrigal Pharmaceuticals, Terns, Aligos and Viking Therapeutics, which are developing orally administered, thyroid hormone receptor (“THR”) β-selective agonist;

Akero Therapeutics, 89Bio, Novo Nordisk, Boston Pharmaceuticals and Roche, which are developing fibroblast growth factor 21 analogs;

Novo Nordisk, which is developing a GLP-1 agonist;

Eli Lilly which is developing a GLP-1/GIP dual receptor agonist;

Merck, which is developing a GLP-1/glucagon dual receptor agonist;

Hanmi Pharmaceutical, which is developing a GLP-1/glucagon receptor/GIP receptor triple agonist;

and, Inventiva, which is developing a pan-peroxisome proliferator-activated receptor (“PPAR”) agonist.

Finally, we face competition for HepTcell, our immunotherapeutic HBV product candidate, from companies such as Janssen, Vaccitech and VBI Vaccines, all of which are developing a therapeutic vaccine against chronic HBV infection.

and, Inventiva, which is developing a pan-peroxisome proliferator-activated receptor (“PPAR”) agonist and orally based GLP-1 agents that either deliver GLP-1 monoagonist activity either as a peptide (Novo Nordisk) or small molecule (Pfizer, Eli Lilly).

In addition, many other small companies are developing other new technologies directed towards obesity or NASH.

Finally, we face competition for HepTcell, our immunotherapeutic HBV product candidate, from companies such as GSK, Janssen, Vaccitech VBI Vaccines, all of which are developing a therapeutic vaccine against chronic HBV infection.

In addition, many other companies are developing direct acting antivirals against HBV.

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In efforts to maintain confidentiality and ownership of trade secrets, proprietary information and developments, all of our employees are required to execute agreements regarding confidentiality and assign to us all rights to any inventions and processes they develop while they are employed by us.

We may in the future use license agreements to access external products and technologies as well as to convey our own intellectual property to others.

We may in the future

use license agreements to access external products and technologies as well as to convey our own intellectual property to others.

We will be able to protect our proprietary rights from unauthorized use by third parties only to the extent that our proprietary rights are covered by valid and enforceable patents or are effectively maintained as trade secrets.

Patent Rights Related to our RespirVec Platform Technology

Immunotherapy for Respiratory Pathogens — Intranasal Application of Adenoviral Vector Vaccines

We have developed a rapid and prolonged immunologic-therapeutic technology, for which we have a patent issued or allowed in the United States, Europe, South Korea and Japan for respiratory pathogens including influenza, coronavirus and anthrax;

and pending applications in the United States, Europe, Japan and other commercially relevant jurisdictions.

The claims are directed to methods for inducing an immune response against respiratory pathogens including influenza, coronavirus and Bacillus anthracis, the causative agent of anthrax, comprising intranasal administration of an effective amount of E1 and/or E3 deleted adenovirus.

The patent and, if issued, the patent(s) resulting from the pending applications have an expiration date no earlier than March 2032, not giving effect to any potential extensions and assuming payment of all associated fees.

We have also developed methods of administering and dosing the intranasal adenoviral vector vaccine compositions, for which we have an international (“PCT”) patent application filed, with expectation that in due course in jurisdictions of commercial consideration (e.g., United States, Europe, Japan) there will be national or regional patent applications based on the PCT.

The claims are directed to transmucosal administration of our respiratory anti-infective product candidates based on our RespirVec platform technology.

The patent(s), if issued, resulting from the pending

application have an expiration date of no earlier than August 2040, not giving effect to any potential extensions and assuming payment of all associated fees.

PER.C6 Cell Line — In-Licensed from Janssen Vaccines & Prevention B.V.

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Upon expiration of the amended license agreement, or if we terminate the amended license agreement for Janssen’s material breach, we retain the right to exploit the rights granted.

The agreement’s current maintenance fee term is set to expire on April 2, 2023, and we have provided notice to Janssen that we do not intend to renew the agreement.

On April 2, 2020, we entered into Amendment No.

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EuPort Technology — In-Licensed from Mederis Diabetes, LLC

Pursuant to a license agreement between the Company and Mederis Diabetes, LLC (“Mederis”) (the “Mederis IP License Agreement”), we are the exclusive licensee of patent rights owned by Mederis to develop and commercialize surfactant functionalized (“EuPort domain”) incretin-based peptide therapeutics, including GLP-1, Glucagon, Oxyntomodulin, and variants thereof, for any indication, and Mederis has certain patent rights granted back to it for the use of the EuPort technology outside of the Company’s exclusive field of incretin-based peptide therapeutics.

Pursuant to a license agreement between the Company and Mederis Diabetes, LLC (“Mederis”) (the “Mederis IP License Agreement”), we are the exclusive licensee of patent rights owned by Mederis to develop and commercialize surfactant functionalized (“EuPort domain”) incretin-based peptide therapeutics, including (GLP-1-glucagon)/oxyntomodulin, and variants thereof, including pemvidutide, for any indication, and Mederis has certain patent rights granted back to it for the use of the EuPort technology outside of the Company’s exclusive field of incretin-based peptide therapeutics.

The EuPort domain comprises a hydrophobic domain (e.g., substituted or unsubstituted alkyl chain) and a hydrophilic group (e.g., saccharide) conjugated to a non-terminal amino acid of the peptide.

Patents under Mederis IP License Agreement have been granted in the United States, Japan and Korea, and applications pending in the United States, Japan as well as other commercially relevant jurisdictions.

Patents under Mederis IP License Agreement have been granted in the United States, Japan and Korea, and applications are pending in the United States, Japan as well as other commercially relevant jurisdictions.

The claims are directed to peptides (at least four amino acids in length), including peptides that bind receptors for glucagon and/or GLP-1, conjugated to an alkyl saccharide surfactant, including an alkyl glycoside surfactant.

The patents and, if issued, the patent(s) resulting from the pending application(s) have an expiration date of no earlier than May 2032, not giving effect to any potential extensions and assuming payment of all associated fees.

Patents subject to the Mederis IP License Agreement have also been granted in the United States, Australia, Israel and Japan, and applications pending in the United States, Europe, Japan, China and other commercially relevant jurisdictions, wherein the claims are directed to specific GLP-1 and/or Glucagon peptides conjugated to the EuPort domain.

Patents subject to the Mederis IP License Agreement have also been granted in the United States, Australia, Israel and Japan, and applications are pending in the United States, Europe, Japan, China and other commercially relevant jurisdictions, wherein the claims are directed to specific GLP-1 and/or glucagon peptides conjugated to the EuPort domain.

The patents and, if issued, the patent(s) resulting from the pending application(s) have an expiration date of no earlier than May 2035.

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Formulation of Antigen Delivery Vectors — Manufacturing Process for the Final Formulation of the Antigen Delivery Vectors

We are developing a manufacturing process for solubilizing certain fluorocarbon peptides and final lyophilized compositions thereof that are soluble in an aqueous solution, for which we have patents issued in the United States, Europe, Korea and Japan and patent applications pending in the United States and Japan, as well as other commercially relevant jurisdictions.

We are developing a manufacturing process for solubilizing certain fluorocarbon peptides and final lyophilized compositions thereof that are soluble in an aqueous solution, for which we have patents issued in the United States, Europe, Korea and Japan as well as other commercially relevant jurisdictions, and a patent application pending in the United States.

The claims are directed to methods of solubilizing certain fluorocarbon antigen peptides using acetic acid formulations and manufactured lyophilized compositions thereof that are soluble in an aqueous solution.

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Patent Rights Related to our Product Candidates

Pemvidutide, Dual GLP-1/Glucagon Dual Agonist for NASH

We are the exclusive licensee of patent rights owned by Mederis Diabetes, LLC (“Mederis”) to develop and commercialize surfactant functionalized GLP-1/Glucagon/Oxyntomodulin-based peptide therapeutics, and variants thereof, for any use including the treatment of obesity, metabolic syndrome, insulin resistance, diabetes and cardiovascular disease.

Patents under this license agreement (“Mederis IP License Agreement”) have been granted in the United States, Europe, Japan, Australia and Mexico with pending applications in the United States, Europe, Japan, and Korea, as well as other commercially relevant jurisdictions.

Pemvidutide, Dual GLP-1/Glucagon Dual Agonist for Obesity and NASH

We are the exclusive licensee of patent rights owned by Mederis to develop and commercialize surfactant functionalized (GLP-1-glucagon)/oxyntomodulin-based peptide therapeutics, and variants thereof, including pemvidutide, for any use including the treatment of obesity, metabolic syndrome, insulin resistance, diabetes and cardiovascular disease.

Patents under the Mederis IP License Agreement have been granted in the United States, Europe, Japan, Australia and Mexico with pending applications in the United States, Europe, Japan and Korea, as well as other commercially relevant jurisdictions.

The claims are directed to GLP-1/glucagon dual agonist peptides conjugated to a surfactant and their use to treat metabolic syndrome, obesity and other related diseases.

The patents and, if issued, the

patent(s) resulting from the pending application(s) have an expiration date of no earlier than May 2032 and extending to May 2035, not giving effect to any potential extensions and assuming payment of all associated fees.

Use of pemvidutide for treating NASH is further covered by, and subject to the Mederis IP License Agreement, pending applications in the U.S., Europe, Japan and other commercially relevant jurisdictions.

If issued, the patent(s) resulting from the pending application(s) have an expiration date of no earlier than January 2039, not giving effect to any potential extensions and assuming payment of all associated fees.

Use of pemvidutide in methods with improved tolerability, dosing and therapeutic regimens is further covered in a U.S.

patent application and PCT patent application owned by us and not subject to the Mederis IP License Agreement, and from which we expect to file National Phase patent applications in commercially relevant jurisdictions.

The claims are directed to the use of pemvidutide in a therapeutic dosing regimen with improved tolerability.

The patents and, if issued, the patent(s) resulting from the

pending application(s) have an expiration date of no earlier than May 2032 and extending to May 2035, not giving effect to any potential extensions and assuming payment of all associated fees.

Use of pemvidutide for treating NASH is further covered by, and subject to the Mederis IP License Agreement, with a granted patent in the United States, and pending applications in the United States, Europe, Japan and other commercially relevant jurisdictions.

The patents and, if issued, the patent(s) resulting from the pending patent applications, are expected to have an expiration date of no earlier than January 2039, not giving effect to any potential extensions and assuming payment of all associated fees.

Use of pemvidutide in methods with improved tolerability, dosing and therapeutic regimens is further covered in pending applications in the United States, Europe, Japan and Korea, as well as other commercially relevant jurisdictions, which are owned by us and not subject to the Mederis IP License Agreement.

The claims are directed to liquid formulations and the use of pemvidutide in a therapeutic dosing regimen with improved tolerability.

If issued, the patent(s) resulting from the pending application(s) have an expiration date of no earlier than February 2041 not giving effect to any potential extensions and assuming payment of all associated fees.

Use of pemvidutide in methods for inducing weight loss is further covered in a U.S.

patent application and corresponding PCT patent application owned by us and not subject to the Mederis IP License Agreement, and from which we expect to file National Phase patent applications in commercially relevant jurisdictions.

Use of pemvidutide in methods for inducing weight loss is further covered in a United States patent application and corresponding international (PCT) patent application owned by us and not subject to the Mederis IP License Agreement, and from which we expect to file National Phase patent applications in commercially relevant jurisdictions.

The claims are directed to the use of pemvidutide in a therapeutic dosing regimen for chronic weight management.

If issued, the patent(s) resulting from the pending application(s) have an expiration date of no earlier than December 2041, not giving effect to any potential extensions and assuming payment of all associated fees.

Use of pemvidutide in methods for reducing body weight in a human with fatty liver disease is further covered in provisional United States patent applications owned by us and not subject to the Mederis IP License Agreement, and from which we expect to file a United States non-provisional patent application and an international (PCT) patent application.

The claims are directed to the use of pemvidutide in methods for reducing body weight in a human with NASH or NAFLD, with or without also having type II diabetes.

If issued, the patent(s) resulting from the pending application(s) have an expiration date of no earlier than September 2043, not giving effect to any potential extensions and assuming payment of all associated fees.

Use of pemvidutide in methods for reducing the risk of cardiovascular (CV) disease is further covered in a provisional United States patent application owned by us and not subject to the Mederis IP License Agreement, and from which we expect to file a United States non-provisional patent application and an international (PCT) patent application.

The claims are directed to the use of pemvidutide in methods for reducing the risk of cardiovascular (CV) disease in a human with or without also having type II diabetes.

If issued, the patent(s) resulting from the pending application(s) have an expiration date of no earlier than November 2043, not giving effect to any potential extensions and assuming payment of all associated fees.

HepTcell, Chronic Hepatitis B Immunotherapy

We are developing an HBV immunotherapy technology directed to compositions comprising fluorocarbon constructs with specific peptide HBV antigen sequences.

We have an issued patent for this technology in the United States, Europe, Japan and Korea and pending applications in the United States, Europe, Japan, China and Korea, as well as other commercially relevant jurisdictions.

We have issued patents for this technology in the United States, Europe, Japan and Korea and pending applications in the United States, Europe, Japan and China, as well as other commercially relevant jurisdictions.

The claims are directed to HBV antigen peptide sequences comprising T-cell epitopes linked to fluorocarbon chains and compositions comprising a combination of HBV antigen peptide sequences.

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HepTcell is also covered by the patents and patent applications relating to our Densigen platform technology.

Use of HepTcell for treating patients with chronic hepatitis B viral (HBV) infection is further covered by a pending U.S.

provisional patent application, from which we expect to file U.S.

and international patent applications.

The claims are directed to treating patients with chronic hepatitis B virus (HBV) infection characterized with low hepatitis B surface antigen (“HBsAg”).

Use of HepTcell for treating patients with chronic HBV infection is further covered by a pending United States provisional patent application, from which we expect to file United States and international (PCT) patent applications.

The claims are directed to treating patients with chronic HBV infection characterized with low hepatitis B surface antigen (“HBsAg”).

If issued, the patent(s) resulting from the pending patent application(s) are expected to have an expiration date no earlier than December 2043, not giving effect to any potential extensions and assuming payment of all associated fees.

Patent Rights Related to our RespirVec Platform Technology

Immunotherapy for Respiratory Pathogens — Intranasal Application of Adenoviral Vector Vaccines

While we are focusing primarily in areas other than intranasal application of adenoviral vector vaccines, we currently own patents and applications in multiple patent families related to intranasal vaccines for respiratory pathogens, including influenza, anthrax and COVID-19, using our RespirVec platform technology, with patents that have issued expiring starting not earlier than July 2024 and extending up to February 2040.

We are evaluating whether we will continue to prosecute and maintain the patents and applications in these families given our current product focus.

Government Contracts

Substantially all of our revenues to date have been derived from grants and United States government contracts.

There can be no assurances that our remaining U.S.

government contract will be continued, renewed beyond the base period, or that we can enter into new contracts or receive new grants to supply the U.S.

We are currently closing out one U.S.

government contract, and have no currently active U.S.

government funded research programs.

There can be no assurances that we can enter into new contracts or receive new grants to supply the U.S.

or other governments with our products.

The process of obtaining government contracts is lengthy and uncertain.

government contracts typically are subject to audit by the government and contain termination provisions for the government allowing it to terminate at its discretion, which subjects us to additional risks.

These risks include the ability of the U.S.

government unilaterally to:

● preclude us, either temporarily or for a set period of time, from receiving new contracts or extending our remaining contracts based on violations or suspected violations of laws or regulations;

● terminate our remaining contracts either for the convenience of the government (at the government’s sole discretion, for example, if funds become unavailable or the government no longer wants the work) or for default (for failing to perform in accordance with the contract schedule and terms);

● revise the scope and value of our contracts and/or the timing for work to be performed;

● audit and object to our contract-related costs and fees, including allocated indirect costs;

● control and potentially prohibit the export of our products;

● claim rights to intellectual property, including our products, developed under the contract;

● add or remove the terms and conditions in our contracts;

● cancel or amend planned procurements, including outstanding request for proposal solicitations.

Termination-for-convenience provisions generally enable us to recover only our costs incurred or committed, settlement expenses, and profit on the work completed prior to termination.

Termination-for-default provisions do not permit these recoveries and would make us liable for excess costs incurred by the U.S.

government in procuring undelivered items from another source.

MTEC COVID-19 Contract

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Under the contract, MTEC paid us a firm fixed fee based on achieving certain milestones for conduct and completion of a Phase 1/2 study.

Through December 31, 2021, we have collected an aggregate of approximately $4.7 million in cash under the contract.

Through December 31, 2021, we collected an aggregate of approximately $4.7 million in cash under the contract and received no further funding from this contract in 2022.

We own the intellectual property rights to inventions made by us in the performance of work under the MTEC contracts provided that we disclose such inventions to the U.S.

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BARDA Anthrax Contract

We were developing our NasoShield anthrax vaccine pursuant to a contract with BARDA that commenced in July 2016.

We were developing our NasoShield anthrax vaccine pursuant to a contract with Biomedical Advanced Research and Development Authority (“BARDA”) that commenced in July 2016.

Under this contract, BARDA paid us a fixed fee and reimburses certain of our costs for the research and development of an Ad5-vectored, protective antigen-based intranasal anthrax vaccine through current good manufacturing practice (“cGMP”) manufacture and conduct of a Phase 1 clinical trial dose ranging assessment of safety and immunogenicity.

The contract consisted of an initial base performance period providing approximately $30.9 million in funding for the period July 2016 through December 2021.

BARDA had seven options to extend the contract to fund certain continued development and manufacturing activities for the anthrax vaccine, including Phase 2 clinical studies for a three-year period.

BARDA had seven options to extend the contract to fund certain continued development and manufacturing activities for the anthrax vaccine, including Phase 2 clinical trials for a three-year period.

Each option, if exercised by BARDA, would have provided additional funding ranging from approximately $1.1 million to $34.4 million, providing a total contract potential of $136.8 million.

Through December 31, 2021, the end of the contract, we have collected an aggregate of approximately $29.2 million in cash under the current BARDA contract.

Through December 31, 2022, we have collected an aggregate of approximately $29.2 million in cash under the BARDA contract.

BARDA did not extend the contract beyond the end of December 2021.

We are currently expecting to collect final payments for indirect rate adjustments for the final two years of the contract.

We have been audited by BARDA through 2019 and have agreed on final indirect rates with BARDA through 2019.

We own the intellectual property rights to inventions made by us in the performance of work under the BARDA contracts, provided that we disclose such inventions to the U.S.

government and notifies the U.S.

government and notify the U.S.

government of our election to retain title.

government will have a non-exclusive, non-transferable, irrevocable, paid-up license to

practice, or have practiced for or on our behalf, such inventions throughout the world, in addition to other rights customarily reserved by the U.S.

government will have a non-exclusive, non-transferable, irrevocable, paid-up license to practice, or have practiced for or on our behalf, such inventions throughout the world, in addition to other rights customarily reserved by the U.S.

government for intellectual property generated using government funds.

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● obtaining approval by an independent Institutional Review Board (“IRB”) at each clinical site before a clinical trial may be initiated at that site;

of human research subjects and their health information, to establish the safety and efficacy of the proposed product for its intended use;

● performance of adequate and well-controlled human clinical trials according to the FDA’s regulations commonly referred to as good clinical practices (“GCP”) and any additional requirements for the protection of human research subjects and their health information, to establish the safety and efficacy of the proposed product for its intended use;

● submission to the FDA of a new drug application (“NDA”) or biologics license application (“BLA”) for marketing approval that includes substantial evidence of safety, purity and potency from results of clinical trials, as well as the results of preclinical testing, detailed information about the chemistry, manufacturing and controls, and proposed labeling and packaging for the product candidate;

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Also, quality control and manufacturing procedures must continue to conform to cGMP regulations and practices, as well as the manufacturing conditions of approval set forth in the NDA or BLA.

The FDA periodically inspects manufacturing facilities to assess compliance with cGMP, which imposes certain procedural, substantive and recordkeeping requirements.

Drug manufacturers and their subcontractors and those supplying products, ingredients, and components are required to register their establishments with the FDA and certain state agencies, and the FDA periodically inspects manufacturing facilities to assess compliance with cGMP, which imposes certain procedural, substantive and recordkeeping requirements.

Manufacturers and other parties involved in the drug supply chain for prescription drug products also must comply with product tracking and tracing requirements and notify the FDA of counterfeit, diverted, stolen and intentionally adulterated products or products that are otherwise unfit for distribution in the United States.

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If, after receiving approval, a company makes a material change in manufacturing equipment, location, or process (all of which are, to some degree, incorporated in the NDA or BLA), additional regulatory review and approval may be required.

Future FDA inspections may identify cGMP compliance issues at manufacturer facilities or at the facilities of third-party suppliers that may disrupt production or distribution or require substantial resources to correct and prevent

recurrence of any deficiencies, and could result in fines or penalties by regulatory authorities.

In addition, discovery of problems with a product or the failure to comply with applicable requirements may result in restrictions on a product, manufacturer or holder of an approved NDA or BLA, including withdrawal or recall of the product from the market or other voluntary, FDA-initiated or judicial action, including warning letters, fines, injunctions, civil penalties, license revocations, seizure, total or partial suspension of production or criminal penalties, any of which could delay or prohibit further marketing.

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A drug is a new chemical entity if the FDA has not previously approved any other new drug containing the same active moiety, which is the molecule or ion responsible for the action of the drug substance.

During the exclusivity period, the FDA may not accept for review an abbreviated new drug application (“ANDA”) or a 505(b)(2) NDA submitted by another applicant for such drug where the applicant does not own or have a legal right of reference to the data required for approval.

During the exclusivity period, the FDA may not accept for review an abbreviated new drug application (“ANDA”) or a 505(b)(2) NDA submitted by another applicant for such drug where the applicant does not own or have a right of reference to the data required for approval.

However, an application may be submitted after four years if it contains a certification of patent invalidity or non-infringement.

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This three-year exclusivity covers only the conditions of use associated with the new clinical investigations and does not prohibit the FDA from approving ANDAs for drugs containing the active ingredient for other conditions of use.

For biological products, the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”), enacted as part of the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010 (collectively, the “Health Care Reform Law”), created an abbreviated regulatory approval pathway in the United States for biological products that are found to be “biosimilar” to (and in some instances “interchangeable” with) a biological “reference product” previously licensed under an NDA or BLA.

For biological products, the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”) created an abbreviated regulatory approval pathway in the United States for biological products that are found to be “biosimilar” to (and in some instances “interchangeable” with) a biological “reference product” previously licensed under an NDA or BLA.

This abbreviated approval pathway is intended to permit a biosimilar to come to market more quickly and less expensively by relying to some extent on the data generated by the reference product’s sponsor and the FDA’s previous review and approval of the reference product.

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and certain states and cities require identification or licensing of sales representatives.

For example, the federal Health Insurance Portability and Accountability Act of 1996, and its implementing regulations (collectively, “HIPAA”), prohibits knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program or obtain, by means of false or fraudulent pretenses, representations, or promises, any of the money or property owned by, or under the custody or control of, any healthcare benefit program, regardless of the payor (e.g., public or private) and knowingly and willfully falsifying, concealing or covering up by any trick or device a material fact or making any materially false statements in connection with the delivery of, or payment for, healthcare benefits, items or services relating to healthcare matters.

For example, the federal Health Insurance Portability and Accountability Act of 1996, and its implementing regulations (collectively, “HIPAA”), prohibits knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program or obtain, by means of false or fraudulent pretenses, representations, or promises, any of the money or property owned by, or under the custody or control of, any healthcare benefit program, regardless of the payer (e.g., public or private) and knowingly and willfully falsifying, concealing or covering up by any trick or device a material fact or making any materially false statements in connection with the delivery of, or payment for, healthcare benefits, items or services relating to healthcare matters.

Similar to the Anti-Kickback Law, a person or entity can be found guilty of violating the HIPAA fraud statute without actual knowledge of the statute or specific intent to violate it.

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The legislative and regulatory landscape for privacy and data protection continues to evolve, and there has been an increasing focus on privacy and data protection issues which may affect our business.

Numerous federal and state laws and regulations, including state data breach notification laws, state health information and/or genetic privacy laws and federal and state consumer protection laws (e.g., Section 5 of the FTC Act and the California Consumer Privacy Act (“CCPA”)), govern the collection, use, disclosure, and protection of health-

related and other personal information.

Many of these laws differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.

Numerous federal and state laws and regulations, including state data breach notification laws, health information and/or genetic privacy laws and federal and state consumer protection laws (e.g., Section 5 of the FTC Act, HIPPA and the California Consumer Privacy Act (“CCPA”)), govern the collection, use, disclosure, and protection of health-related

and other personal information.

Many of these laws differ from each other in significant ways and may be interpreted and applied in a manner that is inconsistent from one jurisdiction to another, thus complicating compliance efforts.

Compliance with these laws is difficult, constantly evolving, and time consuming.

Federal regulators, state attorneys general, and plaintiffs’ attorneys, including class action attorneys, have been and will likely continue to be active in this space.

HIPAA imposes requirements relating to the privacy, security and transmission of individually identifiable health information.

Any failure or perceived failure by us to comply with such laws may result in governmental enforcement actions, litigation, fines and penalties and/or adverse publicity, and could have an adverse effect on our reputation and business.

The CCPA, for example establishes certain requirements for data use and sharing transparency, and provides California residents certain rights concerning their personal data.

In November 2020, California voters approved the California Privacy Rights Act (“CPRA”) which introduced significant amendments to the CCPA and established and funded a dedicated California privacy regulator, the California Privacy Protection Agency.

The amendments introduced by the CPRA became effective on January 1, 2023, and it is not yet fully clear how the CCPA and CPRA will be enforced and interpreted.

The effects of the CCPA and CPRA are potentially significant and may require us to modify our data collection or processing practices and policies and to incur substantial costs and expenses in an effort to comply.

Certain other states have passed legislation similar to the CCPA, which will provide individuals with new privacy rights and increase the privacy and security obligations of entities handling certain personal data of such individuals.

For example, in March 2021, Virginia enacted the Consumer Data Protection Act which became effective on January 1, 2023.

In July 2021, Colorado passed the Colorado Privacy Act, which will become effective on July 1, 2023.

Additionally, in March 2022, Utah enacted the Utah Consumer Privacy Act, which will become effective on December 31, 2023.

Also, in May 2022, Connecticut signed the Connecticut Data Privacy Act into law, which will become effective on July 1, 2023.

A number of additional states have proposed bills for comprehensive privacy legislation, and it is possible that certain of these bills will pass.

The existence of new comprehensive privacy laws in different states in the country, if enacted, could add additional complexity, variation in requirements, restrictions and potential legal risk.

Such new laws could also require additional investment of resources in compliance programs, impact strategies regarding and the availability of personal data, and would result in increased compliance costs and/or changes in business practices and policies.

On the federal level, HIPAA imposes requirements relating to the privacy, security and transmission of individually identifiable health information.

We may obtain health information from third parties, such as research institutions, that are subject to privacy and security requirements under HIPAA.

Although we are not directly subject to HIPAA other than with respect to providing certain employee benefits, we could potentially be subject to criminal penalties if we, our affiliates, or our agents knowingly obtain, use, or disclose individually identifiable health information maintained by a HIPAA-covered entity in a manner that is not authorized or permitted by HIPAA.

In addition, the CCPA establishes certain requirements for data use and sharing transparency, and provides California residents certain rights concerning the use, disclosure and retention of their personal data.

The CCPA and its implementing regulations have already been amended multiple times since their enactment.

In November 2020, California voters approved the California Privacy Rights Act (“CPRA”) ballot initiative which introduced significant amendments to the CCPA and established and funded a dedicated California privacy regulator, the California Privacy Protection Agency (“CPPA”).

The amendments introduced by the CPRA go into effect on January 1, 2023, and new implementing regulations are expected to be introduced by the CPPA.

Failure to comply with the CCPA may result in, among other things, significant civil penalties and injunctive relief, or statutory or actual damages.

In addition, California residents have the right to bring a private right of action in connection with certain types of incidents.

These claims may result in significant liability and damages.

Similarly, there are a number of legislative proposals in the United States, at both the federal and state level, that could impose new obligations or limitations in areas affecting our business.

These laws and regulations are evolving and subject to interpretation, and may impose limitations on our activities or otherwise adversely affect our business.

The CCPA and evolving legislation may require us, among other things, to update our notices and develop new processes internally and with our partners.

Outside of the U.S., the legislative and regulatory landscape for privacy and data security continues to become more comprehensive.

There has been increased attention to privacy and data security issues that could potentially affect our business, including as a result of the General Data Protection Regulation in the EU and the U.K.

and data protection laws in the U.K.

The EU GDPR (and the regulation as incorporated in U.K.

law) imposes fines of up to EUR 20 million (£17.5 million) or 4% of the annual global revenue of a noncompliant company, for non-compliance.

In addition, laws and regulations enacted in the U.S., Europe, Asia and Latin America increases potential enforcement and litigation activity.

If we, our agents, or our third-party partners fail to comply or are alleged to have failed to comply with these or other applicable data protection and privacy laws and regulations, or if we were to experience a data breach involving personal information, we could be subject to government enforcement actions or private lawsuits.

Any associated claims, inquiries, or investigations or other government actions could lead to unfavorable outcomes that have a material impact on our business including through significant penalties or fines, monetary judgments or settlements including criminal and civil liability for us and our officers and directors, increased compliance costs, delays or impediments in the development of new products, negative publicity, increased operating costs, diversion of management time and attention, or other remedies that harm our business, including orders that we modify or cease existing business practices.

Outside the U.S., the legislative and regulatory landscape for privacy and data security continues to evolve.

There has been increased attention to privacy and data security issues that could potentially affect our business, including the EU General Data Protection Regulation imposes fines of up to EUR 20 million or 4% of the annual global revenue of a noncompliant company, whichever is greater.

In addition, laws and regulations enacted in the United States, Europe, Asia and Latin America increases potential enforcement and litigation activity.

Health Care Reform Law

Our financial prospects could be affected by changes in health care spending and policy in the United States and abroad.

We operate in a highly regulated industry and new laws, regulations, or judicial decisions, or new interpretations of existing laws, regulations, or decisions, related to, among other things, health care availability, or the method of delivery of or payment for health care products and services could negatively impact our business, operations and financial condition.

For example, in the United States there is significant interest in promoting health care reform, as evidenced by the enactment in the United States of the Health Care Reform Law.

We operate in a highly regulated industry and new laws, regulations, or judicial decisions, or new interpretations

of existing laws, regulations, or decisions, related to, among other things, health care availability, or the method of delivery of or payment for health care products and services could negatively impact our business, operations and financial condition.

For example, in the United States there is significant interest in promoting health care reform, as evidenced by the enactment in the United States of the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010 (collectively, the “Health Care Reform Law”).

The Health Care Reform Law substantially changed the way health care is financed by both governmental and commercial payers and significantly impacts the pharmaceutical industry.

extending the rebate program to individuals enrolled in Medicaid managed care plans, addressing a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected, and imposing certain annual fees based on pharmaceutical companies’ share of sales to federal health care programs.

The Health Care Reform Law contains provisions that may reduce the profitability of drug products, including, for example, by increasing the minimum rebates owed by manufacturers under the Medicaid Drug Rebate Program, extending the rebate program to individuals enrolled in Medicaid managed care plans, addressing a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected, and imposing certain annual fees based on pharmaceutical companies’ share of sales to federal health care programs.

The Health Care Reform Law established and provided significant funding for a new Patient-Centered Outcomes Research Institute to coordinate and fund comparative effectiveness research.

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It is unclear how the Health Care Reform Law, its implementation, efforts to repeal, replace or otherwise modify, or invalidate, the Health Care Reform Law, or portions thereof, and other health care reform measures that may be adopted in the future will affect our business.

Another provision of the Health Care Reform Law, generally referred to as the Physician Payment Sunshine Act or Open Payments Program, requires manufacturers of drugs, devices, biologics, and medical supplies for which payment is available under Medicare, Medicaid, or the Children’s Health Insurance Program (with certain exceptions) to report annually to CMS information related to direct or indirect payments and other transfers of value made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors) and teaching hospitals, as well as ownership and investment interests held in the company by physicians and their immediate family members.

Effective January 1, 2022, these reporting obligations extend to include transfers of value made (starting in 2021) to certain non-physician providers such as physician assistants, nurse practitioners, clinical nurse specialists, certified nurse anesthetists and certified nurse-midwives.

Another provision of the Health Care Reform Law, generally referred to as the Physician Payments Sunshine Act or Open Payments Program, requires manufacturers of drugs, devices, biologics, and medical supplies for which payment is available under Medicare, Medicaid, or the Children’s Health Insurance Program (with certain exceptions) to report annually to CMS information related to direct or indirect payments and other transfers of value made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors) and teaching hospitals, as well as ownership and investment interests held in the company by physicians and their immediate family members.

Effective January 1, 2022, these reporting obligations have been extended to include transfers of value made to certain non-physician providers such as physician assistants, nurse practitioners, clinical nurse specialists, certified nurse anesthetists and certified nurse-midwives.

CMS publishes information from these reports on a publicly available website.

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In addition, other legislative changes have been proposed and adopted since the Health Care Reform Law was enacted.

For example, the Budget Control Act of 2011, as amended by the American Taxpayer Relief Act of 2012, among other things led to aggregate reductions in Medicare payments for all items and services, including prescription drugs and biologics, to service providers of, on average, 2% per fiscal year beginning April 1, 2013, and, due to subsequent legislation, will continue until 2030 (with the exception of a temporary suspension from May 1, 2020, through March 31, 2022 due to the COVID-19 pandemic).

On December 10, 2021, President Biden signed a law that provides for 1% Medicare sequestration in the second quarter of 2022 and allows the full 2% sequestration thereafter until 2030.

For example, the Budget Control Act of 2011, as amended by the American Taxpayer Relief Act of 2012, among other things led to aggregate reductions in Medicare payments for all items and services, including prescription drugs and biologics, to service providers of, on average, 2% per fiscal year beginning April 1, 2013, and, due to subsequent legislation, will continue until 2030 (with the exception of a temporary suspension that lasted from May 1, 2020, through March 31, 2022 due to the COVID-19 pandemic).

Following the suspension, a 1% payment reduction began April 1, 2022 and remained through June 30, 2022, The 2% payment reduction resumed on July 1, 2022.

To offset the temporary suspension during the COVID-19 pandemic, in 2030, the sequestration will be 2.25% for the first half of the year, and 3% in the second half of the year.

As another example, for calendar quarters beginning January 1, 2022, manufacturers will be required to report the average sales price for certain drugs under the Medicare program regardless of whether we participate in the Medicaid Drug Rebate Program.

As another example, for calendar quarters beginning January 1, 2022, manufacturers will be

required to report the average sales price for certain drugs under the Medicare program regardless of whether we participate in the Medicaid Drug Rebate Program.

Previously, such reporting was only required for manufacturers that participated in that program.

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Manufacturers that fail to pay refunds could be subject to civil monetary penalties of 125% of the refund amount.

The Inflation Reduction Act (“IRA”) was signed into law in August 2022.

The IRA includes several provisions that will impact our business to varying degrees, including provisions that create a $2,000 out-of-pocket cap for Medicare Part D beneficiaries, impose new mandatory discounts from manufacturers under Medicare Part D, allow the U.S.

government to negotiate Medicare Part B and Part D pricing for certain high-cost single-source drugs and biologics without generic or biosimilar competition, and require companies to pay rebates to Medicare for drug prices that increase faster than inflation.

The IRA provides a five-year temporary increase in Medicare Part B payment for certain qualifying biosimilars, and it also delays the rebate rule that would require pass through of pharmacy benefit manager rebates to beneficiaries.

The effect of IRA on our business and the healthcare industry in general is not yet known.

Additional legislative changes, regulatory changes or guidance could be adopted, which may impact the marketing approvals and reimbursement for our product candidates.

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It is possible that the Health Care Reform Law, as currently enacted or may be amended or otherwise modified in the future, as well as other health care reform measures that may be adopted in the future, may result in additional reductions in Medicare payment and other health care financing, more rigorous coverage criteria, and new payment methodologies and in additional downward pressure on coverage and payment and the price that we receive for any approved product.

For example, Congress could enact Medicare Part B and Part D inflation rebates, under which manufacturers would owe additional rebates if the average sales price of a drug were to increase faster than the pace of inflation.

Any reduction in reimbursement from Medicare or other government programs may result in a similar reduction in payments from private payors.

For example, under the IRA, Congress has enacted a program that allows Medicare to negotiate pricing for certain single-source drugs and biologics under Medicare Parts B and D.

The IRA also imposes Medicare Part B and Part D inflation-based rebates, under which manufacturers owe additional rebates if the average sales price of a drug increases faster than the pace of inflation, based on a statutory reference period.

Any reduction in reimbursement from Medicare or other government programs may result in a similar reduction in payments from private payers.

We cannot predict the reform initiatives that may be adopted in the future or whether initiatives that have been adopted will be repealed or modified.

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Coverage and Reimbursement

In the United States and markets in other countries, patients generally rely on third-party payors to reimburse all or part of the costs associated with their treatment.

Adequate coverage and reimbursement from governmental healthcare programs, such as Medicare and Medicaid, and commercial payors is critical to new product acceptance.

In the United States and markets in other countries, patients generally rely on third-party payers to reimburse all or part of the costs associated with their treatment.

Adequate coverage and reimbursement from governmental healthcare programs, such as Medicare and Medicaid, and commercial payers is critical to new product acceptance.

Our ability to successfully commercialize our product candidates will depend in part on the extent to which coverage and adequate reimbursement for these products and related treatments will be available from government health administration authorities, private health insurers and other organizations.

Government authorities and third-party payors, such as private health insurers and health maintenance organizations, decide which medications they will pay for and establish reimbursement levels.

The availability of coverage and extent of reimbursement by governmental and private payors is essential for most patients to be able to afford treatments such as gene therapy products.

Sales of these or other product candidates that we may identify will depend substantially, both domestically and abroad, on the extent to which the costs of our product candidates will be paid by health maintenance, managed care, pharmacy benefit and similar healthcare management organizations, or reimbursed by government health administration authorities, private health coverage insurers and other third-party payors.

Government authorities and third-party payers, such as private health insurers and health maintenance organizations, decide which medications they will pay for and establish reimbursement levels.

The availability of coverage and extent of reimbursement by governmental and private payers is essential for most patients to be able to afford treatments such as gene therapy products.

If coverage and adequate reimbursement is not available, or is available only to limited levels, we may not be able to successfully commercialize our product candidates.

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In the United States, the principal decisions about reimbursement for new medicines may be made by CMS.

CMS decides whether and to what extent certain new medicines will be covered and reimbursed under Medicare and private payors tend to follow CMS to a substantial degree.

CMS decides whether and to what extent certain new medicines will be covered and reimbursed under Medicare and private payers tend to follow CMS to a substantial degree.

Environmental Regulations

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See “European Marketing Authorization” below.

As in the United States, the various phases of preclinical and clinical research in European Union are subject to significant regulatory controls.

The EU Clinical Trials Directive (2001/20/EC) (Clinical Trials Directive) provides the clinical trials regulatory framework in the European Union, but the European Union member states have transposed and applied the provisions of the Directive differently.

This has led to significant variations in the regimes of the different member states.

Under the current regime, before a clinical trial can be initiated it must be approved in each of the European Union countries where the trial is to be conducted by the relevant National Competent Authority (“NCA”), and one or more Ethics Committees (“ECs”), and a Clinical Trial Authorization must be obtained.

As of January 31, 2022, the new EU Clinical Trials Regulation 536/2014 will apply.

The Clinical Trials Regulation will repeal and replace the Clinical Trials Directive, introduces a complete overhaul of the existing regulation of clinical trials for medicinal products in the EU, including a new coordinated procedure for authorization of clinical trials that will be conducted in multiple EU Member States, and increased obligations on sponsors to publish clinical trial results.

Similar to the FDA, Europe’s Committee for Medicinal Products for Human use (“CHMP”) has adopted ICH S6 as a guideline governing preclinical testing of biologics.

In the EU, the new Clinical Trials Regulation 536/2014 has been applicable since January 31.

The Clinical Trials Regulation repealed and replaced the Clinical Trials Directive, and introduced a complete overhaul of the existing regulation of clinical trials for medicinal products in the EU, including a new coordinated procedure for authorization of clinical trials that will be conducted in multiple EU Member States, and increased obligations on sponsors to publish clinical trial results.

The transitory provisions of the new Clinical Trials Regulation provide that ongoing clinical trials previously authorized under the Clinical Trials Directive can remain under the Directive, or they can transition to the Regulation.

By January 31, 2025, when all ongoing clinical trials must have transitioned to the new Regulation.

The new Regulation is directly applicable in all Member States (and so does not require national implementing legislation in each Member State) and aims at simplifying and streamlining the approval of clinical studies in the EU.

The main characteristics of the new Regulation include:

a streamlined application procedure via a single-entry point through the Clinical Trials Information System, or CTIS;

a single set of documents to be prepared and submitted for the application as well as simplified reporting procedures for clinical trial sponsors;

and a harmonized procedure for the assessment of applications for clinical trials, which is divided in two parts (Part I contains scientific and medicinal product documentation and Part II contains the national and patient-level documentation).

Part I is assessed by a coordinated review by the competent authorities of all EU Member States in which an application for authorization of a clinical trial has been submitted (Concerned Member States) of a draft report prepared by a Reference Member State.

Part II is assessed separately by each Concerned Member State.

Strict deadlines have also been established for the assessment of clinical trial applications.

Similar to the FDA, the European Medicines Agency’s Committee for Medicinal Products for Human Use (“CHMP”) has adopted ICH S6 as a guideline governing preclinical testing of biologics.

Sponsors usually must conduct pharmacodynamic (“PD”) studies, such as in vitro binding assays and in vivo studies that assess the product’s pharmacologic activity and define its mechanism of action.

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Safety pharmacology studies, which evaluate the product’s functional effects on major body systems and specific organs, and local tolerance testing can be done separately or subsumed in toxicity testing.

Sponsors also usually conduct single- and multiple-dose pharmacokinetic (“PK”) and/or toxicokinetic studies to assess absorption, disposition, exposure and clearance (in

particular, antibody-mediated clearance), and explore dose-response relationships.

Sponsors also usually conduct single- and multiple-dose pharmacokinetic (“PK”) and/or toxicokinetic studies to assess absorption, disposition, exposure and clearance (in particular, antibody-mediated clearance), and explore dose-response relationships.

This information is used to predict margins of safety for human studies.

Immunogenicity testing might include screening and mechanistic studies.

Clinical Trial Authorization in the European Union

The Clinical Trials Directive and European Commission guidance describe the steps that a sponsor must take before commencing a clinical trial in the European Union.

According to these documents, a clinical trial may commence only if:

(i) the anticipated therapeutic and public health benefits outweigh any foreseeable risks and inconveniences to the subjects;

(ii) the trial subjects understand the objectives and risks of the trial and give informed, written consent to participate;

(iii) the trial safeguards the physical and mental integrity of the subjects;

and (iv) insurance covers the liability of the sponsor and investigator.

To comply with these requirements, the trial sponsor must take certain steps.

In general, the sponsor must take responsibility for trial conduct, appointment of an appropriate investigator, selection of the institution that will conduct the trial, quality control, data collection standards, protocol drafting, and creation of the investigator’s brochure.

The sponsor then must apply for approval from both the ethics committee and the relevant NCA in the member state.

Written authorization may be required for all biologics trials and is required for trials involving medicines containing genetically modified organisms, medicines for gene therapy, and medicines for somatic cell therapy (including xenogeneic cell therapy).

The opinion of the ethics committee should be issued within 60 days.

A review period of 30 days can be added for medicines requiring written authorization noted earlier, and for xenogeneic cell therapy, there are no time limits for authorization.

This timeframe can be extended by an additional 90 days (in addition to the original 90 days) if the ethics committee consults a national group or committee.

The trial may begin only if (i) the ethics committee has issued a favorable opinion and (ii) no competent authority has informed the applicant of grounds for non-acceptance.

Under the Clinical Trials Regulation 536/2014, applicable to new clinical trials as of January 31, 2022, authorization of clinical trials will take place through an EU portal resulting in approval for the various relevant EU Member States.

Different timelines than those described above under the Clinical Trials Directive will apply to the new assessment procedure under the Clinical Trials Regulation.

Under the Clinical Trials Regulation, ethics committee approval will continue to be required in accordance with the laws of the relevant EU Member States.

Good Clinical Practices and Other Considerations for Clinical Trials

Clinical trials of biologics must comply with GCP, as described in Directive 2005/28/EC on Good Clinical Practice and the ICH E6 guideline, which the CHMP has adopted.

Clinical trials of medical products (including biologics) must comply with GCP, as described in Directive 2005/28/EC on Good Clinical Practice and the ICH E6 guideline, which the CHMP has adopted.

The Directive and guideline describe general governing principles for clinical trials.

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Trials must comply with the ethical principles of the World Medical Association’s Declaration of Helsinki.

Specific GCP guidelines apply to trials of advanced therapy medicinal products.

Specific GCP guidelines apply to trials of advanced therapy medicinal products (i.e.

gene therapy, somatic-cell therapy and tissue-engineered medicines).

These guidelines regulate issues such as the donation, procurement and testing of human tissues and cells;

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and specific rules on safety reporting and long-term follow-up.

Under the Clinical Trials Directive and under the Clinical Trials Regulation, special requirements apply to clinical trials conducted on minors and other persons not able to give informed legal consent.

Under the Clinical Trials Regulation, special requirements apply to clinical trials conducted on minors and other persons not able to give informed legal consent.

These requirements are intended to preserve the dignity of the trial subjects, confirm that the benefits of the trial outweigh the risks and ensure that subjects’ representatives give consent with as much involvement of the subject as possible.

Competent authorities must record information regarding trials in the European database of clinical trials which is accessible only to other competent authorities, the European Medicines Agency (“EMA”), and the European Commission.

CHMP has issued a guideline on quality requirements during the clinical trial period for investigational medicinal products containing biological or biotechnology-derived substances.

CHMP has also issued a guideline on quality requirements during the clinical trial period for investigational medicinal products containing biological or biotechnology-derived substances.

The guideline describes quality documentation that should be submitted to the competent authority as part of the sponsor’s investigational medicinal product dossier (“IMPD”).

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For first-in-human clinical trials, sponsors should use product representative of the material used during the non-clinical testing phase.

Finally, with regard to characterization, the guideline requires details on the biological activity to be provided, recognizing that the extent of characterization data will further increase in later phases.

Finally, with

regard to characterization, the guideline requires details on the biological activity to be provided, recognizing that the extent of characterization data will further increase in later phases.

Study Design Considerations

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To ensure that clinical trials in all three phases of development will be adequate to support a marketing authorization application (“MAA”), sponsors should design these trials with the MAA requirements in mind.

Biologics in general need to comply with the requirements set out in Part III of the Annex I to Directive 2003/63/EC (which amends the core EU medicines legislation, Directive 2001/83/EC), and advanced therapy medicinal products need to comply with the requirements described in Part IV.

Certain biologics products need to comply with the requirements set out in Part III of the Annex I to Directive 2003/63/EC (which amends the core EU medicines legislation, Directive 2001/83/EC), and advanced therapy medicinal products need to comply with the requirements described in Part IV.

Consultation with the European Medicines Agency

A sponsor may obtain, from the EMA, scientific advice regarding clinical trial protocols.

Although this advice does not bind the ethics committees or NCAs and is not binding for purposes of a future MAA, it can be useful to guide revisions to the protocol.

A sponsor may obtain, from the EMA, scientific advice regarding the development of a medicinal product.

Although this advice does not bind the EMA and is not binding for purposes of a future MAA, it can be useful to guide developers generally in performing the appropriate preclinical and clinical tests for the product, or on more specific aspects such as guiding revisions to a clinical trial protocol.

EMA’s remarks will only address scientific issues and will generally focus on matters such as the selection of endpoints and comparator, the duration of treatment or follow-up and the design of pivotal studies.

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Consequently, seeking such advice is a common choice among applicants.

Generally, the parallel scientific procedure is available for “important breakthrough drugs,” that is, products that the EMA and FDA have identified as falling within therapeutic areas of overlapping interest (e.g., oncology products, vaccines and blood products).

Generally, the parallel scientific procedure (a program shred by the EMA and FDA) is available for “important breakthrough drugs,” that is, products that the EMA and FDA have identified as falling within therapeutic areas of overlapping interest (e.g., oncology products, vaccines and blood products).

The goal of these meetings is to provide clarity regarding the regulatory requirements of each region and the reasons for any differences between them.

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European Marketing Authorization

In the European Economic Area (“EEA”), which includes the 27-member states of the European Union plus Norway, Iceland and Liechtenstein, medicinal products can only be placed on the market after approval of a Marketing

Authorization Application, or MAA.

In the European Economic Area (“EEA”), which includes the 27 member states of the EU plus Norway, Iceland and Liechtenstein, medicinal products can only be placed on the market after the grant of a marketing authorization.

The MAA is based on the results of pharmaceutical tests, preclinical tests and clinical trials conducted on the medicinal product in question.

There are two types of MAAs:

● The Centralized MAA, which is issued by the European Commission through the Centralized Procedure, based on the opinion of the CHMP and which is valid throughout the entire territory of the EEA.

The Centralized Procedure is mandatory for certain types of drugs, such as biotechnology medicinal products, orphan medicinal products, and medicinal products containing new active substances indicated for certain diseases.

The Centralized Procedure is optional for other drugs provided eligibility criteria are met.

In all cases, to find out whether a product can be evaluated via the Centralized Procedure, applicants must always submit an eligibility request.

● National MAAs, which are issued by the competent authorities of the member states of the EEA and only cover their respective territory, are available for drugs not falling within the mandatory scope of the Centralized Procedure.

Where a drug has already been authorized for marketing in a member state of the EEA, this National MAA can be recognized in other member states through the Mutual Recognition Procedure.

If the drug has not received a National MAA in any member state at the time of application, it can be approved by multiple member states in parallel through the Decentralized Procedure.

Under the above described procedures, before granting the MAA, the EMA or the competent authorities of the Member States of the EEA make an assessment of the risk-benefit balance of the drug on the basis of scientific criteria concerning its quality, safety and efficacy.

There are two types of marketing authorizations:

● The centralized marketing authorization, which is issued by the European Commission through the centralized procedure, based on the opinion of the CHMP and which is valid throughout the entire territory of the EEA.

The centralized procedure is mandatory for certain types of drugs, such as medicinal products derived from biotechnology processes (such as genetic engineering), orphan medicinal products, advanced-therapy medicinal products and medicinal products containing new active substances indicated for the treatment of HIV, AIDS, cancer, neurodegenerative disorders, diabetes, auto-immune and other immune dysfunctions and viral diseases.

The centralized procedure is optional for products containing a new active substance not yet authorized in the EU, or for products that constitute a significant therapeutic, scientific or technical innovation or which are in the interest of public health in the EU.

To find out whether a product can be evaluated via the centralized procedure, applicants should always submit an eligibility request to the EMA, including by a justification of eligibility for evaluation under the centralized procedure.

● National marketing authorizations, which are issued by the competent authorities of the member states of the EEA and only cover their respective territory, are available for drugs not falling within the mandatory scope of the centralized procedure.

Where a drug has already been authorized for marketing in a member state of the EEA, this National marketing authorization can be recognized in other member states through the Mutual Recognition Procedure.

If the drug has not received a National marketing authorization in any member state at the time of application, it can be approved by multiple member states in parallel through the Decentralized Procedure.

Under the above described procedures, before granting the marketing authorization, the EMA or the competent authorities of the member states of the EEA make an assessment of the risk-benefit balance of the drug on the basis of scientific criteria concerning its quality, safety and efficacy.

The Marketing Authorization Application:

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and hybridoma and mAb methods.

For example, cell therapy, gene therapy, vaccines from strains developed through recombinant DNA technology (including gene deletion), and “any medicinal product for which a monoclonal antibody is used at any stage in the manufacturing process” are all subject to the Centralized Procedure.

Gene therapy and cell therapy products are also subject to the centralized procedure as advanced therapy medicinal products.

Nonetheless, some biologics are still approved at the member state level.

For example, many vaccines do not fall within the scope of the Centralized Procedure.

The EMA has published a guideline intended to harmonize the summaries of product characteristics and patient information leaflets for human vaccines.

For example, certain types of vaccines do not fall within the mandatory scope of the centralized procedure (although they may be eligible for the centralized procedure in the interest of public health).

The EMA has published a guideline intended to harmonize the quality aspects to be included in summaries of product characteristics and patient information leaflets for human vaccines.

With respect to the centralized procedure, the approval standards for biotechnology products are the same as for chemically synthesized medicines.

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Because of their special characteristics, however, biotechnology products must comply with several additional dossier requirements.

The MAA for a biotechnology product must meet the standard dossier submission requirements, as described in Article 8 of the Medicines Directive (2001/83/EC).

Consequently, the MAA must generally comply with the Common Technical Document format, including with respect to Module I (administrative information, including labeling and mock-ups), Module 2 (various summaries), Module 3 (chemical, pharmaceutical and biological information), Module 4 (non-clinical reports) and Module 5 (clinical study reports).

MAAs for biologics also must meet special requirements.

The applicant must thoroughly describe the manufacturing process and must:

For example, the applicant must thoroughly describe the manufacturing process and must:

(i) provide information on the origin and history of the starting materials;

(ii) demonstrate that the active substance complies with specific measures for preventing the transmission of animal spongiform encephalopathies;

(ii) demonstrate that the active substance complies with specific measures for preventing the transmission of animal and human spongiform encephalopathies;

(iii) if cell banks are used, demonstrate that cell characteristics remain unchanged at the passage level for production (and beyond);

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Data and Market Exclusivity in the European Union

In the European Union, new medicinal products qualify for eight years of data exclusivity upon marketing authorization and an additional two years of market exclusivity.

This data exclusivity prevents regulatory authorities in the European Union from referencing the innovator’s data to assess a generic or biosimilar application for eight years, after which generic or biosimilar marketing authorization can be submitted, and the innovator’s data may be referenced, but not approved for two years.

In the EU, new chemical entities (including both small molecules and biological medicinal products), sometimes referred to as new active substances, qualify for eight years of data exclusivity upon marketing authorization and an additional two years of market exclusivity.

This data exclusivity if granted, prevents generic or biosimilar applicants from referencing the innovator’s pre-clinical and clinical trial data contained in the dossier of the reference product when applying for a generic or biosimilar marketing authorization, for a period of eight years from the date on which the reference product was first authorized in the EU.

After such eight year period, a generic or biosimilar marketing authorization can be submitted, and the innovator’s data may be referenced, but no generic or biosimilar product can be marketed for two years.

The overall ten-year period may be extended to a maximum of 11 years if, during the period of data exclusivity, the marketing authorization holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies.

Even if an innovative medicinal product gains the prescribed period of data exclusivity, another company may market another version of the product if such company obtained a marketing authorization based on an application with a complete and independent data package of pharmaceutical tests, preclinical tests and clinical trials.

Orphan Designation in the European Union

The European Commission is also able to grant orphan designation in respect of medicinal products.

To qualify the medicinal product must be intended for the diagnosis, prevention or treatment of (i) a life-threatening or chronically debilitating condition affecting not more than 5 in 10,000 persons in the European Union or (ii) a life-threatening, seriously debilitating or serious and chronic condition in the European Union where without incentives it is unlikely that the marketing of the medicinal product in the European Union would generate sufficient return to justify the necessary investment.

Further, no satisfactory method of diagnosis, prevention or treatment of the condition in question must exist in the European Union or, if such method exists, the medicinal product must be of significant benefit to those affected by that condition.

To qualify the medicinal product must be intended for the diagnosis, prevention or treatment of (i) a life-threatening or chronically debilitating condition affecting not more than 5 in 10,000 persons in the EU or (ii) a life-threatening, seriously debilitating or serious and chronic condition in the EU where without incentives it is unlikely that the marketing of the medicinal product in the EU would generate sufficient return to justify the necessary investment in its development.

Further, no satisfactory method of diagnosis, prevention or treatment of the condition in question must exist in the EU or, if such method exists, the medicinal product must be of significant benefit to those affected by that condition.

Orphan medicinal products still remain subject to the same regulatory approval process, albeit that they are always assessed through the centralized procedure.

Effective September 19, 2018, sponsors applying for orphan designation must use EMA’s secure online IRIS platform.

However, sponsors of orphan medicinal products are eligible to benefit from a number of incentives offered, including certain assistance with development of the medicinal product, reduced fees for MAA applications and protection from market competition once the medicinal product is authorized, as below.

Where an MAA in respect of an orphan medicinal product is granted, the European Commission, EMA and the competent authorities of the member states shall not, for a period of ten years, accept another application for an MAA, or grant an MAA or accept an application to extend an existing MAA, for the same therapeutic indication, in respect of a similar medicinal product, unless:

(i) the holder of the MAA for the original orphan medicinal product has given its consent to the second applicant;

(ii) the holder of the MAA for the original orphan medicinal product is unable to supply sufficient quantities of the medicinal product;

or (iii) the second applicant can establish the second medicinal is safer, more effective or otherwise clinically superior.

Other government regulation in the European Union

The European Union and the European Union member states have extensive laws and regulations relating to a variety of other topics that would be of relevance for us if we are active in the European Union, including but not limited to laws and regulations regarding data privacy, drug pricing and reimbursement, advertising and interactions with healthcare professionals.

However, sponsors of orphan medicinal products are eligible to benefit from a number of incentives offered, including certain assistance with development of the medicinal product, reduced fees for MAAs and protection from market competition once the medicinal product is authorized, as described below.

Where a marketing authorization in respect of an orphan medicinal product is granted, the European Commission, EMA and the competent authorities of the EU member states shall not, for a period of ten years, accept another application for a marketing authorization or grant a marketing authorization or accept an application to extend an existing authorization , for the same therapeutic indication, in respect of a similar medicinal product, unless:

(i) the holder of the marketing authorization for the original orphan medicinal product has given its consent to the second applicant;

(ii) the holder of the marketing authorization for the original orphan medicinal product is unable to supply sufficient quantities of the medicinal product;

or (iii) the second applicant can establish the second medicinal is safer, more effective or otherwise clinically superior than the authorized orphan product.

A “similar medicinal product” is defined as a medicinal product containing a similar active substance or substances as contained in an authorized orphan medicinal product, and which is intended for the same therapeutic indication.

Other government regulation in the European Union and United Kingdom

The EU and the EU member states and the U.K.

have extensive laws and regulations relating to a variety of other topics that would be of relevance for us if we are active in the EU and U.K., including but not limited to laws and

regulations regarding data privacy, drug pricing and reimbursement, advertising and interactions with healthcare professionals.

Other Jurisdictions

In addition to regulations in the United States and the European Union, we may be subject to a variety of regulations in other jurisdictions governing, among other things, clinical trials and any commercial sales and distribution of our product.

As the United Kingdom is no longer a member state of the European Union, this may also apply to the United Kingdom.

In addition to regulations in the United States and the EU, we may be subject to a variety of regulations in other jurisdictions governing, among other things, clinical trials and any commercial sales and distribution of our product.

As the United Kingdom is no longer a member state of the EU, this may also apply to the United Kingdom.

Whether or not we obtain FDA approval for a product, we must obtain approval from comparable regulatory authorities in foreign countries before we can commence clinical trials in such countries and the approval of the regulators of foreign countries before we may market products in such countries.

The approval process and requirements governing the conduct of clinical trials, product licensing, pricing and reimbursement vary greatly from place to place, and the time may be longer or shorter than that required for FDA approval.

Acceptance of Foreign Clinical Trials in the United States and Europe

Acceptance of Foreign Clinical Trials in the United States and the European Union

The FDA has issued regulations governing its acceptance of foreign clinical data not conducted under an IND to support IND applications or marketing authorizations, such as BLAs.

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medical practice.

EU Directive 2001/83/EC allows for clinical trials conducted outside the European Union to be taken into consideration during the review of an MAA in the European Union if such trials have been designed, implemented and reported based on principles equivalent to those of the Clinical Trials Directive with regard to good clinical practice and ethical principles.

EU Directive 2001/83/EC allows for clinical trials conducted outside the EU to be taken into consideration during the review of a marketing authorization in the EU if such trials have been designed, implemented and reported based on principles equivalent to those of the Clinical Trials Regulation, including with regard to good clinical practice and ethical principles.

Moreover, they should comply with the ethical principles outlined in the Declaration of Helsinki.

The applicant must submit a statement declaring such compliance as part of the MAA.

The applicant must submit a statement declaring such compliance as part of the marketing authorization.

In December 2008 and April 2012, the EMA published a strategy paper on the acceptance of data from foreign clinical trials conducted in “third countries,” particularly those outside the “‘traditional’ Western European and North American research areas.” According to the 2008 strategy paper, there is a “growing concern both among regulators and in public debate about how well these trials are conducted from an ethical and scientific/organizational standpoint.” The EMA has called for increased cooperation between international regulatory authorities involved in the supervision of clinical trials and has put forth other proposals to address these issues.

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Of our total workforce, 28 are engaged primarily in research and development activities and 19 are engaged primarily in executive, finance and accounting, and administrative functions.

As of December 31, 2021, 45 employees are located in the United States and two employees in the United Kingdom.

As of December 31, 2022, 50 employees are located in the United States and 2 employees in the United Kingdom.

Of our employees, 58% are female and 42% are male.

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Our compensation program is designed to attract and reward talented individuals who possess the skills necessary to support our business objectives, assist in the achievement of our strategic goals and create long-term value for our stockholders.

We provide employees with what we consider to be a very competitive mix of compensation and insurance benefits for all our employees, as well as participation in our equity programs.

We provide all of our employees with what we consider to be a very competitive mix of compensation and insurance benefits, as well as participation in our equity programs.

Hybrid Culture and COVID-19

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What changed 10-K

Item 1. Business