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Item 1. Business

2024-03-27 compared with 2023-02-28 · 219 added, 214 removed, 725 unchanged (37% 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 (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 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 metabolic dysfunction-associated steatohepatitis (“MASH”), previously termed non-alcoholic steatohepatitis (“NASH”).

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

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(“Spitfire”).

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, heart disease, stroke, gallbladder disease, osteoarthritis, sleep apnea and breathing problems, certain cancers and NASH.

Some of the leading risk factors or co-morbidities of obesity include high low density lipoprotein cholesterol (“LDL-C”) and other serum lipids, high liver fat content, high total cholesterol, hypertension, type 2 diabetes, ischemic heart disease, cerebrovascular events, gallbladder disease, osteoarthritis, sleep apnea and breathing problems, certain cancers and MASH.

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

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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 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.

Previous approaches to the treatment of obesity were associated with safety concerns, limiting the success of those approaches;

however, the new class of incretin-based therapeutics has demonstrated both substantial weight loss and beneficial cardiovascular effects in clinical outcome studies.

prevalence of obesity comorbidities

MASH 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 cardiovascular disease and to liver

MASLD, the fatty liver precursor to MASH, is present in up to 75% of patients with obesity, and up to 20% of MASLD patients progress to MASH.

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

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

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

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 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 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.

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

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

In November 2023, we announced topline results from our 48-week MOMENTUM Phase 2 trial of pemvidutide in 391 subjects with obesity or overweight with at least one co-morbidity and without diabetes.

We observed robust reductions in body weight and serum lipids and improvements in blood pressure without imbalances in cardiac events, arrhythmias or clinically meaningful increases in heart rate.

Pemvidutide Target Profile

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

In these studies, by using RNA sequencing, we also observed suppression of genes associated with steatosis, inflammation and stellate cell fibrosis.

Additionally, in Phase 1b trials of pemvidutide in subjects with MASLD, we observed profound rapid decreases and normalization in liver fat content and significant reductions in body weight and serum alanine aminotransferase (“ALT”) at both 12 weeks and 24 weeks of treatment.

We believe that pemvidutide is one of the only MASH candidates currently in development that combines rapid effects on liver fat reduction and liver inflammation 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.

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

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

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

On October 24, 2023, the FDA granted fast track designation to pemvidutide for the treatment of MASH.

Phase 1 Clinical Trial Results – Obesity

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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”).

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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 this trial, no perturbations of glucose control, as assessed by fasting glucose

and hemoglobin A1c (“HbA1c”), 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 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”).

Although 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).

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 on average a greater than 90% reduction in the liver fat content (see chart below).

These findings reinforce the results from preclinical studies of pemvidutide, in which we observed statistically greater reductions in liver fat than an equivalent dose of semaglutide.

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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.

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

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

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

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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.

This MASLD trial was conducted without the adjunctive diet and exercise interventions that would have been the standard for obesity trials.

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

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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.

The table below details the baseline study demographics.

Characteristic

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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.

The trial also met its key secondary endpoint of weight loss 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.

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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.

Clinically meaningful reductions in systolic blood pressure were observed, along with the 2 to 3 beats per minute increase in heart rate typical for GLP-1 class of drugs.

The table below summarizes the safety findings.

Characteristic

Serious AEs (“SAE”s)

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.

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

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

Sixty-six (66) of the 83 subjects who completed the initial 12-week Phase 1b MASLD 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;

The same endpoints as the 12-week parent MASLD 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.

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

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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.

92.3% and 100% of subjects at the 1.8 mg and 2.4 mg doses, 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 content to below 5%.

As in the 12-week Phase 1b MASLD 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 relaxation time.

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

Elevated cT1 relaxation times 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 endpoint of weight loss 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.

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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.

Three AEs led to treatment discontinuation, one being the Salmonella infection, and mild (Grade 1) instances of abdominal pain AEs in two subjects, 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:

Meaningful reductions in systolic blood pressure were observed, and increases in heart rate, typical of the incretin class of agents, were minimal at 0 to 4 beats per minute and independent of dose.

Below is a summary of the safety findings:

Characteristic

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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.

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Week 24, %, mean (SD)

Phase 1b Trial – 12-Week Type 2 Diabetes Safety Trial

In March 2023, we announced topline results from a 12-week Phase 1b safety trial of pemvidutide, which evaluated the safety profile of pemvidutide in subjects with overweight or obesity and type 2 diabetes.

The trial was comprised of 54 subjects randomized 1:1:1:1 to 1.2 mg, 1.8 mg, 2.4 mg pemvidutide or placebo administered weekly for 12 weeks.

No caloric restrictions or lifestyle interventions were employed.

Subjects were required to be 18-65 years of age with BMI ≥ 28 kg/m 2 and type 2 diabetes on a stable regimen of diet and exercise, metformin with absent or mild GI symptoms, or SGLT-2 therapy for at least 3 months.

Subjects receiving pemvidutide achieved mean weight losses of 4.4%, 6.1% and 7.7% at the 1.2 mg, 1.8 mg, and 2.4 mg doses, respectively, over 12 weeks of treatment, with the placebo group experiencing a mean weight gain of 0.8% (efficacy estimand using MMRM analysis).

Below is a summary of the efficacy findings:

∆ Body weight, all subjects

%, LSM (SE) 1

-4.4 (1.1)***

-6.1 (1.6)***

-7.7 (1.4)***

1 MMRM (mixed model for repeated measures), *** p < 0.001 compared with placebo

Glucose homeostasis was maintained throughout the 12 weeks of treatment, with no significant changes in fasting glucose or HbA1c and no hyperglycemic AEs.

No SAEs were observed in patients treated with pemvidutide.

Rates of GI AEs were low, and there were no AEs leading to study discontinuation.

Below is a summary of the safety findings:

Glycemic Control

Fasting glucose

Baseline, mg/dL

Week 24, mg/dL

Adverse events (AEs)

Discontinuations due to AE

Hyperglycemia AEs

Gastrointestinal AEs

Moderate, n (%)

Constipation AEs

Moderate, n (%)

2 Cervical radiculopathy

MOMENTUM Phase 2 Obesity Trial – 48-Week Analysis

On November 30, 2023, we announced topline results from our 48-week MOMENTUM Phase 2 obesity trial of pemvidutide.

The trial enrolled 391 subjects with obesity or overweight with at least one co-morbidity and without diabetes.

Subjects were randomized 1:1:1:1 to 1.2 mg, 1.8 mg, 2.4 mg pemvidutide or placebo administered weekly for 48 weeks in conjunction with diet and exercise.

The 1.2 mg and 1.8 mg doses were administered without dose titration, while a short 4-week titration period was employed for the 2.4 mg dose.

Unlike other obesity studies with GLP-1 based agents, dose-reduction was not allowed.

At baseline, subjects had a mean age of approximately 50 years, mean BMI of approximately 37 kg/m 2 and mean body weight of approximately 104 kg.

Approximately 75% of subjects were female.

At Week 48, subjects receiving pemvidutide achieved mean weight losses of 10.3%, 11.2%, 15.6% at the 1.2 mg, 1.8 mg, and 2.4 mg doses, respectively, compared to weight loss of 2.2% for placebo.

A near-linear trajectory of continued weight loss was observed on the 2.4 mg dose at the end of treatment.

Over 50% of subjects achieved at least 15% weight loss and over 30% of subjects achieved at least 20% weight loss on the 2.4 mg dose.

As in prior clinical trials, pemvidutide resulted in robust reductions in serum lipids and improvements in blood pressure without imbalances in cardiac events, arrhythmias or clinically meaningful increases in heart rate.

Glucose homeostasis was maintained, with no significant changes in fasting glucose or HbA1c.

Below is a summary of the efficacy findings:

Primary Endpoint:

∆ Body weight, all subjects

%, LSM (SE) 1

-10.3 (1.4)***

-11.2 (1.4)***

-15.6 (1.4)***

Responder Analyses

% Subjects w/ ≥5% weight loss

% Subjects w/ ≥10% weight loss

% Subjects w/ ≥15% weight loss

% Subjects w/ ≥20% weight loss

Secondary Endpoints

∆ Total cholesterol

-11.6 (1.7)**

-13.1 (1.9)***

-15.1 (2.0)***

∆ LDL cholesterol

∆ Triglycerides

-21.7 (3.9)***

-22.3 (4.3)***

-34.9 (4.4)***

Blood Pressure and Heart Rate

∆ Systolic BP

∆ Diastolic BP

1 MMRM, 2 CMH (Cochran Mantel Haenszel), 3 ANCOVA (analysis of covariance)

** p < 0.05, *** p < 0.001, ****p < 0.0001 compared with placebo

More subjects receiving pemvidutide stayed on study compared to those receiving placebo, with 74.1% of pemvidutide subjects completing the trial compared to 61.9% of placebo subjects.

Nausea and vomiting comprised the majority of AEs, which were predominantly mild to moderate in severity.

Only one subject experienced a drug-related SAE, a case of vomiting at the 2.4 mg dose.

Rates of AEs leading to treatment discontinuation were 6.2% in subjects receiving placebo and 5.1%, 19.2%, and 19.6% in subjects receiving 1.2 mg, 1.8 mg and 2.4 mg of pemvidutide, respectively.

Study discontinuations related to study drug occurred in 2.1% of placebo subjects and 4.1%, 16.2% and 15.5% in subjects receiving 1.2 mg, 1.8 mg and 2.4 mg of pemvidutide, respectively, with most discontinuations due to AEs in the pemvidutide groups occurring in the first 16 weeks of treatment.

No AEs of special interest or MACE were observed, and there were low rates of cardiac AEs, including arrhythmias, with no imbalance across pemvidutide or placebo groups.

Below is a summary of the safety findings:

Adverse events (AEs)

SAEs related to study drug

All AEs leading to discontinuation

Drug-related AEs leading to discontinuation

Gastrointestinal AEs—mainly mild to moderate

Cardiac AEs including arrhythmias

Summary of Glycemic Control

Fasting glucose

Baseline, mg/dL

Week 48, mg/dL

Clinical Development Plan

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.

In August 2023 we initiated a 48-week Phase 2b trial, IMPACT, to evaluate the safety and efficacy of pemvidutide in subjects with MASH.

The biopsy-driven trial is expected to enroll approximately 190 subjects with and without diabetes randomized 1:2:2 to receive 1.2 mg, 1.8 mg pemvidutide or placebo weekly for 48 weeks.

The key efficacy endpoints are MASH resolution and fibrosis improvement after 24 weeks of treatment, with subjects to be followed for an additional 24 weeks to a total of 48 weeks for assessment of safety and additional biomarker responses.

Top-line 24-week results from this trial are expected in the first quarter of 2025.

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

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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 2018, we completed a Phase 1 trial in the United Kingdom and South Korea in adult patients with chronic HBV.

The HepTcell Phase 1 trial was a double-blinded, placebo-controlled, randomized, dose-escalation study that enrolled 61 subjects with chronic HBV who were HBeAg-negative and well-controlled on licensed antivirals.

The HepTcell Phase 1 trial was a double-blinded, placebo-controlled, randomized, dose-escalation

study that enrolled 61 subjects with chronic HBV who were HBeAg-negative and well-controlled on licensed antivirals.

A total of 41 patients received one of two dose levels of HepTcell, with and without IC31 ® , a depot-forming TLR9 adjuvant developed by Valneva SE, while 20 control patients received either IC31 ® alone or placebo.

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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.

HepTcell was being administered in six 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.

The primary efficacy endpoint is virological response, defined as a 1-log reduction in HBsAg levels from baseline or HBsAg clearance at 24 weeks.

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

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.

Enrollment in this trial was completed in April 2023.

On March 27, 2024, we announced that the overall response in the Phase 2 trial was deemed to be insufficient to warrant further advancement in clinical trials.

As a result, we have stopped any further development related to HepTcell.

Key elements of our strategy include the following:

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● 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.

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

Our Technology Platforms

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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:

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

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

● slow the entry of the peptide into the circulation, increasing the Tmax of the peptide, and potentially improving the tolerability of the peptide.

● slow the entry of the peptide into the circulation, decreasing the Cmax (maximal concentration) increasing the Tmax (time to maximal concentration) of the peptide, and potentially improving the tolerability of the peptide and preventing the increases in heart rate that have been observed with other agents.

Synthetic Peptide Technology - Densigen

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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.

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.

Large and established companies such as Eli Lilly, Roche, Novo Nordisk and Pfizer, among others, compete in the same market as our product candidates.

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.

Large and established companies such as Eli Lilly, Roche through its acquisition of Carmot and D&D Pharma, Novo Nordisk, Pfizer, AstraZeneca, Amgen, Boehringer Ingelheim and Merck, among others, compete in the same market as our product candidates.

These companies compete with us with their greater experience and resources to support their research and development efforts, conduct testing and clinical trials, obtain regulatory approvals to market products, manufacture such products on a broad scale and market approved products.

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We also face competition from smaller companies who, like us, rely on investors to fund research and development and compete for co-development and licensing opportunities from large and established pharmaceutical companies.

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

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

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 2021.

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;

Other companies with potentially competitive products or product candidates, include Eli Lilly with GLP-1/glucose-dependent insulinotropic polypeptide receptor (“GIP”) dual agonists, including Zepbound, or compound name tirzepatide, approved for obesity in November 2023;

Boehringer Ingelheim, AstraZeneca, Innovent Biologics/Eli Lilly, and Roche through its acquisition of Carmot and D&D Pharma, with GLP-1/glucagon receptor dual agonists;

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

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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, 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;

Other companies have been developing oral candidates for the treatment of obesity with GLP-1 monoagonist or GLP-1/GIP dual receptor agonists including Pfizer, Lilly, Structure Therapeutics, AstraZeneca through its acquisition of Eccogene and Roche through its acquisition of Carmot.

In addition, Novo Nordisk has an FDA-approved oral GLP-1 therapy, Rybelsus or compound name semaglutide.

We face competition in MASH from companies such as Madrigal Pharmaceuticals, Terns, Aligos and Viking Therapeutics, which are developing orally administered, thyroid hormone receptor (“THR”) β-selective agonist;

Akero Therapeutics, 89Bio, Novo Nordisk and Boston Pharmaceuticals, which are developing fibroblast growth factor 21 (“FGF-21”) analogs;

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

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.

Merck/Hanmi Pharmaceutical, which is developing a GLP-1/glucagon dual agonist, Eli Lilly, which is developing a GLP-1/GIP dual agonist, Inventiva, which is developing a pan-peroxisome proliferator-activated receptor (“PPAR”) agonist;

Sagimet which is developing a fatty acid synthetase inhibitor, HEC Pharma which is developing a GLP-1/FGF-21dual agonist;

and Pfizer and Eli Lilly, which are developing small molecule GLP-1 agonists.

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

Intellectual Property

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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.

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

(Formerly Crucell Holland, B.V.)

We are the non-exclusive licensee of patent rights held by Janssen Vaccines & Prevention B.V.

(formerly Crucell Holland, B.V.) (“Janssen”), covering a method of producing an adenoviral vector stock using cell lines including the PER.C6 cell line, which may be used for the development and manufacture of vaccine products.

We entered into an amended license agreement with Janssen, effective as of October 4, 2005, which amended and restated our prior license agreements with Janssen.

Under the amended license agreement, we obtained a non-exclusive, worldwide license (with the right to sublicense) under certain patent rights and know-how to use Janssen’s proprietary cell line to develop, manufacture and commercialize vaccines to prevent and/or treat influenza virus and anthrax infection in humans.

In consideration for the license, we paid an up-front license fee, issued equity shares, and agreed to pay certain development-based milestone payments through approval of licensed products by the FDA, up to an aggregate amount of approximately $2.5 million.

We also agreed to pay royalty payments as a percentage of net sales of products in any country where the manufacture of such product is covered by a valid claim of any licensed patent or uses licensed know-how, subject to a royalty stacking reduction and minimum annual royalty payments, until the expiration of the term of the amended agreement.

We further amended our license agreement with Janssen, effective September 25, 2015, primarily to streamline our manufacturing license arrangements.

Prior to the 2015 amendment, we entered into three-party manufacturing license agreements with each manufacturer and Janssen.

The 2015 amendment enables us to directly grant sublicenses of certain of our rights under Janssen’s patent rights and know-how to manufacturers, subject to Janssen’s consent which may not be withheld if the manufacturer meets certain criteria.

We may terminate the amended license agreement without cause, and the agreement contains customary provisions for either party to terminate prior to the expiration of the agreement.

The amended license agreement expires on a product-by-product and country-by-country basis on the later of the date upon which the last of the licensed patents applicable to the relevant product expires or 15 years from the date of first commercial sale of the relevant product.

The Janssen patent rights include patents issued in the United States with an expected expiration date no earlier than April 2020, in each case not giving effect to any potential extensions and assuming payment of all associated fees.

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.

3 to the Second Restated License Agreement and additionally entered into Amendment No.

4, 5 and 6 throughout 2020 (collectively, the “Amendments”), by and between us and Janssen (as amended by Amendment No.

1 to Second Restated License Agreement and Amendment No.

2 to Second Restated License Agreement, together with the Amendments, the “License Agreement”).

Pursuant to the Amendment, the field of licenses granted to us for the use of the PER.C6 cell line under the License Agreement is expanded to cover COVID-19 caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), in addition to the existing licenses related to Bacillus anthracis and influenza virus.

Pursuant to the Amendment, we agreed to pay certain additional development-based milestone payments through approval of licensed products by the FDA for the treatment or prevention of COVID-19, up to an aggregate amount of $1.2 million.

We also agreed to pay royalty payments as a percentage of net sales of products to a royalty stacking reduction and minimum annual royalty payments, until the expiration of the term of the License Agreement, as amended.

We additionally entered into Amendment No.

4, 5 and 6 throughout 2020 to add additional manufacturing partners related to manufacturing AdCOVID.

As of December 31, 2022, we have paid Janssen $3.0 million in cash and equity under the License Agreement.

Patent Rights Related to our EuPort Platform Technology

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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 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.

Patents subject to the Mederis IP License Agreement have also been granted in the United States, Canada, Europe, Korea, 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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Patent Rights Related to our Product Candidates

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

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

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.

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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, 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 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 MASH or MASLD (referred to as NASH or NAFLD in the patent and patent applications) 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.

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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 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.

Use of pemvidutide in methods for inducing weight loss is further covered in pending applications in the United States, Europe, Japan and Korea, as well as other commercially relevant jurisdictions owned by us and not subject to the Mederis IP License Agreement.

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.

Use of pemvidutide in methods for reducing body weight in a human with fatty liver disease is further covered in 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 methods for reducing body weight in a human with MASH or MASLD (referred to as NASH or NAFLD in the patent and patent applications), 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.

Use of pemvidutide in methods for reducing the risk of cardiovascular (CV) disease 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 methods for reducing the risk of cardiovascular (CV) disease in a human with or without also having type 2 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 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.

We have issued patents for HBV immunotherapy technology directed to compositions comprising fluorocarbon constructs with specific peptide HBV antigen sequences 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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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”).

The claims are directed to treating patients with chronic HBV infection characterized with low hepatitis B surface antigen

If issued, the patent(s) resulting from the pending patent application(s) are expected to have an expiration date no earlier than December 2044, 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.

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.

MTEC COVID-19 Contract

We funded our Phase 1/2 clinical trial of T-COVID with a $4.7 million grant from the U.S.

Army Medical Research & Development Command (“USAMRDC”).

The competitive award was granted by USAMRDC in collaboration with the Medical Technology Enterprise Consortium (“MTEC”), a 501(c)(3) biomedical technology consortium working in partnership with the Department of Defense (“DoD”).

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 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.

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 for intellectual property generated using government funds.

BARDA Anthrax Contract

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 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, 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 notify the U.S.

government of our election to retain title.

government for intellectual property generated using government funds.

BARDA is a division of the U.S.

Department of Health and Human Services (“HHS”) in the Office of the Assistant Secretary for Preparedness and Response that supports the advanced research and development, manufacturing, acquisition and stockpiling of medical countermeasures.

Our contracts with BARDA, like those awarded by other U.S.

government agencies, contain provisions not typically found in commercial contracts.

Most notably, BARDA, or the U.S.

government acting through BARDA, may terminate, modify or amend our contract, in whole or in part, for nearly any reason or no reason.

United States Government Regulation

The FDA regulates drugs and biological products under the Federal Food, Drug, and Cosmetic Act (“FD&C Act”), the Public Health Service Act (“PHS Act”), the FDA regulations under Titles 21 and 42 of the Code of Federal Regulations (21 CFR and 42 CFR), as well as other federal, state and local statutes and regulations.

The FDA regulates drugs and biological products under the Federal Food, Drug, and Cosmetic Act (“FD&C Act”), the Public Health Service Act (“PHS Act”), the regulations under Titles 21 and 42 of the Code of Federal Regulations (21 CFR and 42 CFR), as well as other federal, state and local statutes and regulations.

The FD&C Act and the PHS Act and their corresponding regulations govern, among other things, the testing, research, manufacturing, approval, safety, efficacy, labeling, packaging, storage, record keeping, distribution, import, export, reporting, sale, advertising and other promotional practices involving drugs and biological products.

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In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin.

Even after the IND has gone into effect and clinical testing has begun, the FDA may also impose a partial or complete clinical hold on clinical trials due to safety concerns or non-compliance.

A partial clinical hold would limit a trial, for example, to certain doses or for a certain length of time or to a certain number of subjects.

A complete clinical hold order issued by the FDA would delay a proposed clinical study or cause suspension of an ongoing study until all outstanding concerns have been adequately addressed and the FDA has notified the company that investigations may proceed or resume.

Even after the IND has gone into effect and clinical testing has begun, the FDA may impose a partial or complete clinical hold on clinical trials due to safety concerns or non-compliance.

A partial clinical hold can limit a trial, for example, to certain doses or for a certain length of time or to a certain number of subjects.

A complete clinical hold order issued by the FDA would delay a proposed clinical study or suspend an ongoing study until all outstanding concerns have been adequately addressed and the FDA has notified the company that clinical investigations may proceed or resume.

Accordingly, we cannot be sure that submission of an IND will result in the FDA allowing clinical trials to begin, or that, once the trials have begun, issues will not arise that suspend or terminate such studies.

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Certain FDA programs are available to facilitate and expedite the development and review of new drugs intended to address unmet needs in the treatment of serious or life-threatening conditions.

These expedited programs include fast

track designation, breakthrough therapy designation, priority review and accelerated approval.

These expedited programs include fast track designation, breakthrough therapy designation, priority review and accelerated approval.

Each of these programs has its own features and qualifying criteria.

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The testing and approval processes require substantial time and effort and there can be no assurance that the FDA will accept the NDA or BLA for filing and, even if filed, that any approval will be granted on a timely basis, if at all.

Under the Prescription Drug User Fee Act (“PDUFA”), as amended, each NDA or BLA must be accompanied by a significant user fee.

Under the Prescription Drug User Fee Act (“PDUFA”), as amended, each NDA or BLA must be accompanied by a significant application fee.

PDUFA also imposes an annual prescription drug product program fee for biologics.

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During the NDA or BLA review process, the FDA also will determine whether a Risk Evaluation and Mitigation Strategy (“REMS”) is necessary to assure the safe use of the drug or biological product.

If the FDA concludes a REMS is

needed, the sponsor of the NDA or BLA must submit a proposed REMS;

If the FDA concludes a REMS is needed, the sponsor of the NDA or BLA must submit a proposed REMS;

the FDA will not approve the NDA or BLA without a REMS, if required.

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Before approving an NDA or BLA, the FDA will inspect the facilities at which the product is manufactured.

The FDA will not approve the NDA or BLA unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.

specifications.

Additionally, before approving an NDA or BLA, the FDA will typically inspect one or more clinical sites to assure that the clinical trials were conducted in compliance with IND study requirements and GCP requirements.

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In general, no biosimilar application may be accepted by the FDA for review until 4 years after the date the reference product was first licensed by the FDA, and no biosimilar application, once accepted, may receive final approval until 12 years after the reference product was first licensed by the FDA.

While we would expect to be granted this 12-year period of exclusivity for our applicable product candidates, if approved, this period of reference product market exclusivity applies only to the biosimilar pathway and will not, for example, provide protection against any biological product for a similar indication that achieves FDA approval under a traditional NDA or BLA based on the sponsor’s own research data.

Although we would expect to be granted this 12-year period of exclusivity for our applicable product candidates, if approved, this period of reference product market exclusivity applies only to the biosimilar pathway and will not, for example, provide protection against any biological product for a similar indication that achieves FDA approval under a traditional NDA or BLA based on the sponsor’s own research data.

There is also risk that the 12-year period of biological reference product exclusivity could be shortened due to congressional action, or that the FDA will not consider our product candidates, if they are approved, to be reference products for competing products, potentially creating the opportunity for competition sooner than anticipated.

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Moreover, there are no safe harbors for many common practices, such as educational and research grants, charitable donations, product support and patient assistance programs.

Violations of the Anti-Kickback Law may be punished by civil and criminal penalties, damages, fines, or exclusion from participation in

federal health care programs like Medicare and Medicaid.

Violations of the Anti-Kickback Law may be punished by civil and criminal penalties, damages, fines, or exclusion from participation in federal health care programs like Medicare and Medicaid.

Many states have enacted similar laws, some of which apply regardless of payer.

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The FCA is commonly enforced against those who submit allegedly false Medicare or Medicaid claims, as well as those who induce or assist others to submit a false claim.

“False claims” can result not only from non-compliance with the express requirements of applicable governmental reimbursement programs, such as Medicaid or Medicare, but also from non-compliance with other laws, such as the Anti-Kickback Law or laws that require quality care in service delivery.

quality care in service delivery.

Actions under the FCA may be brought by the government or by whistleblowers referred to as “relators,” who may initiate an action in the name of the government and the individual and may share in any monetary recovery.

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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, 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.

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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 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.

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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.

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.

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.

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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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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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.

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.

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 payers.

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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 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;

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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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● 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 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.

29 unchanged sentences

Data and Market Exclusivity in the European Union

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.

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.

16 unchanged sentences

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.

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

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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.

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 the European Union

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To date, we have obtained materials for clinical trials and non-clinical studies from third-party manufacturers who are suppliers to us.

For our product candidates, we intend to identify and qualify additional contract manufacturers to provide commercial scale manufacturing prior to submission of an NDA or BLA to the FDA.

We intend to identify and qualify additional contract manufacturers to provide commercial scale manufacturing prior to submission of an NDA or BLA to the FDA.

Employees and Human Capital Management

4 unchanged sentences

Of our employees, 53% are female and 47% are male.

None are represented by labor unions or covered by collective bargaining agreements.

We consider our relations with our employees to be good.

None of our employees are represented by labor unions or covered by collective bargaining agreements.

Corporate Culture

4 unchanged sentences

Compensation and Benefits Program

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.

stockholders.

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

Like other companies, we have learned to adapt during the ongoing COVID-19 pandemic.

We have prioritized employee safety and transparency during the pandemic and continue to do so, ensuring all employees are set up to work remotely and providing clarity on office closures and evolving guidelines issued by the CDC, the WHO and state and local authorities, where possible.

In the second quarter of 2020, we made the decision to move to a hybrid workplace model, which means that certain of our employees will have the option to be 100% remote, work full-time in our office, or have the flexibility to work between office and remotely until the pandemic is resolved.

This move provides our employees with continued flexibility, through the resolution of the pandemic, to work in person, remotely or in a hybrid model.

This will enable us to grow better as we develop our programs.

Hybrid Culture

In the second quarter of 2020, we made the decision to move to a hybrid workplace model, which means that certain of our employees have the option to be 100% remote, work full-time in our office, or have the flexibility to work between office and remotely.

This move provides our employees with continued flexibility to work in person, remotely or in a hybrid model.

Available Information

8 unchanged sentences

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

What changed 10-K

Item 1. Business