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Altimmune, Inc.

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 metabolic dysfunction-associated steatohepatitis (“MASH”), previously termed non-alcoholic steatohepatitis (“NASH”).

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

Our lead product candidate, pemvidutide (formerly known as ALT-801), is a novel, investigational, peptide-based GLP-1/glucagon dual receptor agonist.

Pemvidutide is currently in clinical development for obesity and metabolic associated steatohepatitis (“MASH”).

We also expect to pursue additional indications for pemvidutide that leverage the differentiated clinical profile of pemvidutide.

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 pemvidutide, a novel peptide-based GLP-1/glucagon dual receptor agonist product candidate designed to treat obesity and the metabolic dysfunction that causes MASH.

Pemvidutide is a novel, investigational, peptide-based GLP-1/glucagon dual receptor agonist currently in clinical development for the treatment of obesity and MASH.

Activation of the GLP-1 and glucagon receptors is believed to mimic the complementary effects of diet and exercise on weight loss, with GLP-1 suppressing appetite and glucagon increasing energy expenditure.

Glucagon is also recognized as having direct effects on hepatic fat metabolism, which is believed to lead to rapid reductions in levels of liver fat and serum lipids.

Pemvidutide mechanism of action:

Optimized for obesity and MASH

Over 500 subjects have received pemvidutide to date in 6 completed clinical trials.

In those trials pemvidutide appear safe and demonstrated what we believe to be a favorable safety profile, compelling weight loss, class-leading lean mass preservation, and robust reductions in triglycerides, low density lipoprotein (“LDL”), liver fat content, measures of liver inflammation, and blood pressure.

Our clinical development has always focused on the comorbidities of obesity and MASH as these often drive the outcomes of these diseases.

Based on the clinical data we have accumulated, we believe pemvidutide may be able to address the most common comorbidities associated with both obesity and MASH as shown below.

prevalence of comorbidities in obesity and MASH

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 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.

Some of the leading risk factors or comorbidities of obesity include elevated LDL cholesterol (“LDL-C”) and other serum lipids, high liver fat content, 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.

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.

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

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 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 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 serum lipids, including LDL-C.

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 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

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 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 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.

Weight loss occurred rapidly and consistently over 12 weeks.

Summary of 12-week MAD weight loss findings

Characteristic

Pooled Placebo

Baseline demographics

Body weight (kg)

BMI (kg/m 2 )

Weight loss (kg)

Weight loss (%)

-10.3 (3.4) %**

-9.0 (3.3) %*

*p < .01, **p < .005, compared to placebo

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.

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).

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.

Summary of 12-week MAD safety findings

Characteristic

Pooled Placebo

Discontinuations due to adverse events (n)

Early withdrawal (n)

Gastrointestinal adverse events

Other adverse events (n)

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 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 (“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.

Phase 1 Clinical Trial Results – Liver Fat Content

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 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.

We believe these findings support the potential combined beneficial effects of weight loss and glucagon agonism on liver fat content.

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

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

Weight Loss (%) at Week 6

Absolute ∆ at Week 6 (%)

Relative ∆ at Week 6 (%)

LOD (limit of detection) = 1.5%;

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

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.

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.

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.

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 table 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 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.

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 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 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 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 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%.

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 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.

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 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 0 to 4 beats per minute and independent of dose.

Below is a summary 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)

*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)

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

MOMENTUM Phase 2 Obesity Trial – 48-Week Analyses

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

2 unchanged sentences

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.

At baseline, subjects had a mean age of approximately 50 years, mean body mass index (“BMI”) of approximately 37 kg/m 2 and mean body weight of approximately 104 kg.

Approximately 75% of the subjects were female.

At Week 48, subjects receiving pemvidutide achieved mean weight loss 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.

1 unchanged sentence

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.

Glucose homeostasis was maintained.

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.

Weight loss of 15.6% achieved at Week 48 on 2.4 mg pemvidutide

On September 10, 2024, we presented additional results of an MRI-based body composition sub-study from the 48-week MOMENTUM Phase 2 obesity trial of pemvidutide in subjects with overweight and obesity.

The body composition analyses included 67 subjects, 50 of whom were treated with pemvidutide, and calculated of the lean loss ratio, defined as the change in lean mass compared to the change in total mass, and the percent change in amount of body fat in the subcutaneous and visceral fat compartments.

The results demonstrated that treatment with pemvidutide resulted in only 21.9% of the total weight loss was associated with lean mass.

These results compare favorably to results obtained with other weight loss agents in the class where up to 40% of weight loss came from lean mass.

Lean mass preservation was greater in subjects aged 60 years and older, in whom the lean loss ratio was only 19.9%.

In addition to lean mass preservation, there was a preferential reduction of visceral adipose tissue (“VAT”), the fat compartment most clearly associated with cardiovascular risk.

At the 2.4mg dose of pemvidutide, VAT was reduced by 28.3% at week 48 compared to a 19.5% loss in subcutaneous adipose tissue.

Pemvidutide class leading lean mass preservation

One of the most prevalent comorbidities associated with obesity is dyslipidemia, including elevated serum triglycerides, total cholesterol and LDL-C.

In the MOMENTUM obesity trial, patients with mildly elevated serum lipids at baseline pemvidutide treatment realized significant reductions in each of these lipid classes at 48-weeks.

We believe the reduction in LDL-C is insightful for two reasons;

first, high levels of LDL-C are known to increase the risk of cardiovascular disease, and second, the decreases in LDL-C were also observed in subjects already on statins, causing a further decrease in serum LDL-C over that achieved by statin therapy.

Greater lipid reductions in subjects with elevated baseline levels

Regarding safety and tolerability, 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.

and vomiting comprised the majority of the adverse events (“AEs”), which were predominantly mild to moderate in severity with 25.5%, 59.6% and 51.5% of patients reporting nausea at the 1.2 mg, 1.8 mg and 2.4 mg doses, respectively, compared to 11.3% receiving placebo, and 6.2%, 27.3% and 27.8% of subjects reporting vomiting at the 1.2 mg, 1.8 mg and 2.4 mg doses, respectively, compared to 3.1% on placebo, and 8.2%, 10.1% and 18.6% reporting diarrhea at the 1.2 mg, 1.8 mg and 2.4 mg doses, respectively, compared to 5.2% on placebo.

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.

It is important to note that unlike other obesity studies with GLP-1 based agents, dose-reduction was not allowed in MOMENTUM.

Only one subject experienced a drug-related serious adverse event (“SAE”), a case of vomiting at the 2.4 mg dose.

No AEs of special interest or major adverse cardiac events (“MACE”) were observed, and there were low rates of cardiac AEs, including arrhythmias, with no imbalance across pemvidutide or placebo groups.

MASH is caused by multiple metabolic pathways that lead to an abnormal accumulation of liver fat, toxic lipid metabolites, and inflammation, that leads to liver fibrosis and increased risk of death due to cardiovascular disease and liver failure.

Metabolic associated steatotic liver disease (“MASLD”), the precursor to MASH, is characterized by excess liver fat and is present in up to 75% of patients with obesity.

Up to 20% of MASLD patients progress to MASH.

Accumulating clinical evidence suggests that reduction in liver fat is associated with resolution of liver inflammation and improvement in liver fibrosis, and that the magnitude of liver fat reduction is proportional to the improvement in these indices.

As 80-90% of individuals with MASH also have overweight or obesity we believe that combining a reduction in liver fat content with weight loss could be a compelling solution for treating MASH.

Food and Drug Administration (“FDA”) has granted Fast Track designation to pemvidutide for the treatment of MASH.

Clinical Trial Results –Data from a Phase 1b trial of pemvidutide in MASLD

We studied the effects of pemvidutide in subjects with MASLD in two clinical trials, an initial 12-week trial followed by a 12-week extension trial in the majority of the same subjects.

In the parent trial, 94 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.

In the extension trial, 64 subjects who completed the parent trial and consented to the extension trial were enrolled and remained in their original treatment group and the trial remained double-blinded.

Both trials were conducted without adjunctive diet and exercise interventions.

Identical endpoints were evaluated in the 12-week parent trial and the 12-week extension trial, with the primary efficacy endpoint as percent (%) reduction in relative liver fat content, and key secondary endpoints including liver inflammation, as measured by serum alanine aminotransferase (“ALT”) levels and corrected T1 (“cT1”), and percent weight loss.

In December 2022, we announced the topline results from the extension trial where subjects received a total of 24 weeks of treatment with either pemvidutide or placebo.

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 in the extension trial, 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.

Both the parent and extension trials met the primary endpoint in all pemvidutide treatment groups.

For the extension trial, in subjects receiving 1.8 mg and 2.4 mg pemvidutide, mean relative reduction of liver fat content was 75.2% and 76.4%, respectively, compared to 14% in subjects receiving placebo;

92.3% and 100% of subjects at the 1.8 mg and 2.4 mg doses, respectively, achieved a 30% reduction in liver fat, compared to 5.6% on placebo;

and 53.8% and 45.5% of subjects, respectively, achieved normalization of liver fat content to below 5%, compared to none of subjects receiving placebo.

Reductions in Liver Fat Content

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.

Subjects receiving placebo saw a 2.2% decline in ALT that was not significant.

In subjects with ALT levels above 30 IU/L at baseline, a statistically significant 17 IU/L or greater reduction in ALT was observed at all pemvidutide dose levels, compared to a 3.1 IU/L reduction in the placebo group that was not significant.

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, compared to none of the subjects receiving placebo.

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

Elevated cT1 relaxation times have been associated with increased risk of MACE and major adverse liver outcomes, and an 80 ms reduction in cT1 relaxation time has been associated with a 2-point reduction of NAFLD Activity Score.

Pemvidutide was generally well tolerated in this MASLD population.

As typical of GLP-1 based agents, AEs occurred primarily in months of dosing and occurred more frequently in the 12-week parent MASLD trial compared to the 12-week extension trial.

In the parent trial of 94 randomized subjects, nausea and vomiting comprised the majority of AEs, which were predominantly mild to moderate in severity with 17.4%, 52.2% and 37.5% of patients reporting nausea at the 1.2 mg, 1.8 mg and 2.4 mg doses, respectively, compared 12.5% receiving placebo, and 13.0%, 8.7% and 8.3% of subjects reporting vomiting at the 1.2 mg, 1.8 mg and 2.4 mg doses, respectively, compared to no subjects on placebo, and 13.0%, 21.7% and 4.2% reporting diarrhea at the 1.2 mg, 1.8 mg and 2.4 mg doses, respectively, compared to 16.7% on placebo.

Dose reduction for intolerability was not allowed in the parent or extension trials.

There were no drug-related SAEs, and rates of drug-related AEs leading to treatment discontinuation were 0.0% in subjects receiving placebo and 0.0%, 4.3%, and 4.2% in subjects receiving 1.2 mg, 1.8 mg and 2.4 mg of pemvidutide, respectively.

The incidence of AEs was markedly reduced in the 12-week extension trial of 64 subjects with 0.0%, 20.0% and 7.1% of patients reporting nausea at the 1.2 mg, 1.8 mg and 2.4 mg doses, respectively, compared to 0.0% receiving placebo;

no reported cases of vomiting in any treatment group;

and 6.3%, 6.7% and 0.0% reporting diarrhea at the 1.2 mg, 1.8 mg and 2.4 mg doses, respectively, compared to 5.3% on placebo.

Study discontinuations related to AEs occurred in 0.0% of placebo subjects and 12.5%, 6.7% and 0.0% in subjects receiving 1.2 mg, 1.8 mg and 2.4 mg of pemvidutide, respectively.

Three serious or severe AEs occurred in the extension trial;

and were the same events, one (5.3%) occurred in the placebo group for chest pain following elective coronary stent placement, one (6.3%) at 1.2 mg pemvidutide for Salmonella infection, and one (6.7%) at 1.8 mg pemvidutide for hypotension occurring greater than 3 weeks post-pemvidutide dosing, all unrelated to study drug.

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

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.

Significant Reductions in cT1 Response Rates and ALT

Two independent indicators of reduced liver inflammation

Additional Pemvidutide Indications

In addition to obesity and MASH, we intend to develop pemvidutide for additional indications which may leverage the clinical profile of pemvidutide in indications where there are few to no effective therapies.

Pemvidutide Differentiation and Target Profile

We believe the unique molecular structure of pemvidutide is responsible for the diverse and differentiated clinical profile of the compound.

With respect to obesity and MASH, pemvidutide has been demonstrated in clinical trials to date to achieve key clinical endpoints that, in the aggregate, may differentiate it from other incretin-based approaches to these diseases.

We have shown the important clinical endpoints listed below in our clinical trials to date.

Pemvidutide Target Profile

Pemvidutide Clinical Development Plan

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 biopsy-driven trial enrolled 212 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”).

Approximately 300 million people worldwide live with chronic HBV infection, including approximately 2.4 million in the United States.

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

Approximately 820,000 people die per year worldwide due to cirrhosis and liver cancer.

Current antivirals prevent disease progression but rarely clear chronic infection.

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.

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

We believe our approach allows HepTcell to break immune tolerance by activating T-cells against critical viral sequences with decreased probability of immune escape due to viral mutation.

HepTcell is based on our synthetic peptide technology platform and is given by intramuscular injection.

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.

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.

Patients received three injections 28 days apart and were followed for six months after the final dose.

All dose combinations were generally well-tolerated and met the primary endpoint of safety.

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

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 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.

Enrollment in this trial was completed in April 2023.

Patient enrollment in the IMPACT Phase 2b trial was completed in September 2024.

Top-line efficacy data is expected in the second quarter of 2025.

In November 2024, we successfully completed our End-of-Phase 2 Meeting with the FDA and agreed on the design of a Phase 3 registrational program for pemvidutide in the treatment of obesity.

The interaction with the FDA included an extensive review of the preclinical and clinical data generated to date, including data from six completed clinical trials of pemvidutide.

The planned registrational program will include four Phase 3, randomized, double-blind, placebo-controlled, parallel-group trials, each evaluating treatment with pemvidutide over a 60-week period.

The Phase 3 program is expected to enroll approximately 5,000 subjects across the four trials.

The safety and efficacy of pemvidutide doses of 1.2 mg, 1.8 mg, and 2.4 mg will be evaluated with the intention of seeking approval for all three doses.

The Phase 3 program is designed to leverage the key attributes of pemvidutide, including the effects of balanced GLP-1/glucagon dual agonism in subjects with overweight and obesity.

● VELOCITY-1:

This trial will assess the effects of pemvidutide on body weight in patients with obesity or overweight without diabetes.

Other endpoints will include reductions in waist circumference, serum lipids, and blood pressure.

● VELOCITY-2:

This trial will assess the effects of pemvidutide on body weight and serum lipids in subjects with obesity or overweight and elevated LDL cholesterol levels.

The study population will include a subset of subjects with elevated LDL cholesterol levels despite ongoing statin therapy.

A large proportion of patients taking statins fail to achieve target LDL levels, and in a previous Phase 2 clinical trial in subjects with overweight or obesity, pemvidutide appeared to enhance LDL-lowering effects in subjects receiving concomitant statin therapy.

● VELOCITY-3:

This trial will assess the effects of pemvidutide on body weight in subjects with obesity or overweight and elevated liver fat.

Excess liver fat is highly prevalent in patients with obesity and is associated with an increased risk of cardiovascular disease.

● VELOCITY-4:

This trial will assess the effects of pemvidutide on body weight and body composition, including in an elderly population, with emphasis on individuals entering the study with sarcopenia at baseline.

Functional measures and activities of daily living will also be assessed in this patient population.

The FDA agreed that a committed study of subjects with Type 2 diabetes was not required and agreed that the number of these subjects in the VELOCITY-2, VELOCITY-3 and VELOCITY-4 trials was sufficient to assess the safety of pemvidutide in this population.

No cardiovascular safety signals were identified, and the FDA did not indicate a requirement for committed cardiovascular safety trial designed to demonstrate the absence of cardiac harm relative to placebo.

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.

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Key elements of our strategy include the following:

● 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, MASH and other metabolic diseases.

Our Technology Platforms

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

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, 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 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, 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

Densigen is our synthetic fluorocarbon peptide technology platform.

HepTcell, an immunotherapeutic developed using our Densigen platform, is designed to activate T-cells to generate a cytotoxic immune response against intracellular pathogens.

This synthetic peptide technology is based on peptides of 30 – 40 amino acids that comprise a high density of CD4 and CD8 T-cell epitopes selected to focus the T-cell response on highly conserved targets and allow diverse populations to respond to the product candidate.

Densigen technology is protected by patents owned by us.

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

● elicit responses across multiple targets for the disease;

● direct an immune response precisely to specific antigen sites, thereby avoiding more reactive but less effective sites present in the full-length protein;

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

● Develop pemvidutide for MASH as well as other indications that benefit from the dual activity of GLP-1 and glucagon;

● Pursue partnering of pemvidutide to advance the obesity program and indication;

● Continue to build our experience and capabilities to support the development and commercialization of pemvidutide;

● Research and develop alternative formulations, doses, and presentations of pemvidutide for the benefit of patients;

● Leverage our knowledge in liver and cardiometabolic disease by developing, acquiring, or in-licensing additional investigational candidates.

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

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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.

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, 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 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 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;

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 and Eli Lilly, whose GLP-1/glucose-dependent insulinotropic polypeptide receptor (“GIP”) dual agonist, brand named Zepbound, or compound name tirzepatide, was approved for obesity in November 2023.

Other companies with potentially competitive product candidates include Roche and Viking Therapeutics with GLP-1/GIP dual agonists;

Boehringer Ingelheim, AstraZeneca, D&D Pharmatech, and Innovent Biologics/Eli Lilly, 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.

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;

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;

Merck/Hanmi Pharmaceutical and Boehringer Ingelheim, which are developing GLP-1/glucagon dual agonists, 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;

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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 have and may in the future use license agreements to access external products and technologies, and may in the future use license agreements 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 EuPort Platform Technology

Patent Rights Related to EuPort Technology

EuPort Technology — In-Licensed from Mederis Diabetes, LLC

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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 are 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.

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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 2035.

Patent Rights Related to our Densigen Platform Technology

Fluorocarbon Antigen Delivery Vectors

We are developing a fluorocarbon antigen construct platform technology.

Our patents covering this technology are issued in the United States, China, Japan and certain European countries, including the United Kingdom, Germany and France.

Additional patents are issued in other commercially relevant jurisdictions and an application is pending in the United States.

The claims are directed to the fluorocarbon linked antigen construct, compositions comprising the construct and methods of using the construct to stimulate an immune response.

The patents and, if issued, the patent(s) resulting from the pending patent applications, are expected to have an expiration date no earlier than April 2025, not giving effect to any potential extensions and assuming payment of all associated fees.

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 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.

The patents and, if issued, the patent(s) resulting from the pending patent applications, are expected to have an expiration date no earlier than December 2031, not giving effect to any potential extensions and assuming payment of all associated fees.

Patent Rights Related to our Product Candidates

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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.

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 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.

The patents, and if issued, the patent(s) resulting from the pending patent applications, are expected to have an expiration date no earlier than December 2033, not giving effect to any potential extensions and assuming payment of all associated fees.

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

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

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.

United States Government Regulation

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Clinical trials involve the administration of the product candidate to healthy volunteers or patients under the supervision of qualified investigators.

Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria, and the parameters to be used to monitor subject safety, including stopping rules that assure a clinical trial will be stopped if certain adverse events (“AEs”) should occur.

Each protocol and any amendments to the protocol must be submitted to the FDA as part of the IND during applicable phases of development.

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In addition, holders of an approved NDA or BLA are required to keep extensive records, submit annual reports, report certain adverse reactions and production problems to the FDA, provide updated safety and efficacy information, and comply with requirements concerning advertising and promotional labeling for their products.

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.

In addition, 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.

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.

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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.

further marketing.

Newly discovered or developed safety or efficacy data may require changes to a product’s approved labeling, including the addition of new warnings and contraindications.

From time to time, legislation is drafted, introduced, passed in Congress and signed into law that could significantly change the statutory provisions governing the approval, manufacturing, and marketing of products regulated by the FDA.

In addition to new legislation, FDA regulations, guidance, and policies can be revised or reinterpreted by the agency in ways that may significantly affect the manner in which pharmaceutical products are regulated and marketed.

Regulatory Incentives and Other Programs

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In particular, a biosimilar could be significantly less costly to bring to market and priced significantly lower than our product, if approved by the FDA.

Additionally, products approved under an NDA or BLA may qualify for the restoration of a portion of the patent term lost during product development and FDA review of the application, if approval of the application is the first permitted commercial marketing of a drug containing the active ingredient.

commercial marketing of a drug containing the active ingredient.

The patent term restoration period is generally one-half the time between the effective date of the IND or the date of patent grant (whichever is later) and the date of submission of the NDA or BLA, plus the time between the date of submission of the NDA or BLA and the date of FDA approval of the product.

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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.

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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Most states have adopted similar state false claims laws, some of which are broader than the FCA, and these state laws have their own penalties which may be in addition to FCA penalties.

The Health Care Reform Law significantly strengthened the FCA and federal Anti-Kickback Law provisions, which could lead to the possibility of increased whistleblower or relator suits, and among other things, made clear that a federal Anti-Kickback Law violation can be a basis for federal FCA liability.

The Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, significantly strengthened the FCA and federal Anti-Kickback Law provisions, which could lead to the possibility of increased whistleblower or relator suits, and among other things, made clear that a federal Anti-Kickback Law violation can be a basis for federal FCA liability.

The bringing of any FCA or other enforcement investigation or action, even if unsuccessful, could require us to devote resources to investigate and defend the action, as well as result in reputational harm.

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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.

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 (including 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

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

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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.

Other states, including Virginia, Colorado, Utah, Connecticut, Texas, Oregon, Tennessee, Delaware, Iowa, have recently passed or enacted similarly comprehensive privacy and data protection legislation which differ from each other in significant ways.

It is not yet fully clear how such laws will be enforced and interpreted.

In addition to these comprehensive consumer privacy laws and proposals, a number of other states have passed or proposed more limited privacy laws that focus on specific privacy issues such as biometric data and the privacy of health and medical information, such as Washington state’s My Health My Data Act, which has a private right of action that further increases the relevant compliance risk.

Connecticut and Nevada have also passed similar laws regulating consumer health data, and New York’s new health privacy law is awaiting that state’s governor’s signature.

The existence of new comprehensive and health privacy laws in different states adds additional complexity, variation in requirements, restrictions and potential legal risk.

Such new laws also require additional investment of resources in compliance programs, impact strategies regarding and the availability of personal data, and may 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.

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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.

Regulators and legislators in the U.S.

and other countries are also increasingly scrutinizing and restricting certain personal data transfers and transactions involving foreign countries.

For example, Executive Order 14117 of February 28, 2024, on Preventing Access to Americans’ Bulk Sensitive Personal Data and United States Government-Related Data by Countries of Concern as implemented by Department of Justice regulations issued in December 2024, prohibits data brokerage transactions involving certain sensitive personal data categories, including health data, genetic data, and biospecimens, to countries of concern, including China.

The regulations also restrict certain investment agreements, employment agreements and vendor agreements involving such data and countries of concern, absent specified cybersecurity controls.

Actual or alleged violations of these regulations may be punishable by criminal and/or civil sanctions, and may result in exclusion from participation in federal and state programs.

Health Care Reform Law

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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.

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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Certain provisions of the Health Care Reform Law have been subject to judicial challenges, as well as efforts to repeal, replace or otherwise modify them or to alter their interpretation or implementation.

For example, the Tax Cuts and Jobs Act enacted on December 22, 2017, eliminated the tax-based payment for individuals who fail to maintain minimum essential coverage under section 5000A of the Internal Revenue Code of 1986, as amended, commonly referred to as the “individual mandate,” effective January 1, 2019.

Further, the Bipartisan Budget Act of 2018 among other things, amended the Medicare statute, effective January 1, 2019, to reduce the coverage gap in most Medicare prescription drug plans, commonly known as the “donut hole,” by raising the manufacturer discount under the Medicare Part D coverage gap discount program to 70%.

Additional legislative changes, regulatory changes and judicial challenges related to the Health Care Reform Law remain possible, but the nature and extent of such potential changes or challenges are uncertain at this time.

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 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.

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), to certain non-physician providers such as physician assistants, nurse practitioners, clinical nurse specialists, certified nurse anesthetists and certified nurse-midwives, and to 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.

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 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.

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

Starting in 2023, manufacturers must pay refunds to Medicare for single source drugs or biologicals, or biosimilar biological products, reimbursed under Medicare Part B and packaged in single-dose containers or single-use packages, for units of discarded drug reimbursed by Medicare Part B in excess of 10% of total allowed charges under Medicare Part B for that drug.

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.

For example, the Budget Control Act of 2011 and subsequent legislation 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 through 2031.

As another example, the Inflation Reduction Act of 2022 (“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 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.

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There have been several Congressional inquiries and proposed and enacted federal and state legislation and regulatory initiatives designed to, among other things, bring more transparency to product pricing, evaluate the relationship between pricing and manufacturer patient programs, and reform government healthcare program reimbursement methodologies for drug products.

For example, in May 2019, CMS issued a final rule to allow Medicare Advantage Plans the option of using step therapy, a type of prior authorization, for Part B drugs beginning January 1, 2020.

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.

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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.

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.

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.

insurers and other third-party payers.

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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Government Regulations

European Drug Development

European Union Drug Development

Our products will also be subject to extensive regulatory requirements in the European Union (“EU”).

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See “European Marketing Authorization” below.

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

In the EU, the Clinical Trials Regulation 536/2014 has been applicable since January 31, 2022.

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;

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

The main characteristics of the 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.

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 (Member States concerned) of a draft report prepared by a Reference Member State.

II is assessed separately by each Member State concerned.

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.

Similar to the FDA, the European Medicines Agency’s Committee for Medicinal Products for Human Use (“CHMP”) has adopted ICH S6 (R1) 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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Good Clinical Practices and Other Considerations for Clinical Trials

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.

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 (R3) guideline, which the CHMP has adopted.

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

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

The IMPD should include, among other things, (i) an adequate description of the process and process controls, including a flow chart of all successive steps and details of in-process testing and (ii) a description and justification of “any reprocessing during manufacture of the drug substance.” The guideline also recognizes that sponsors will improve and optimize their manufacturing processes during clinical development and describes the steps sponsors should take following these changes.

The guideline also recognizes that sponsors will improve and optimize their manufacturing processes during clinical development and describes the steps sponsors should take following these changes.

Specifically, the sponsor must compare the quality attributes of the pre- and post-change biological active substances and relevant intermediates and conduct a comparability exercise where necessary.

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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.

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

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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.

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

Advice also might address a sponsor’s proposal to deviate from a CHMP guideline.

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The process of obtaining advice from the national competent authorities is often less formal than requesting advice from the EMA, and such advice can prove helpful.

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

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).

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

Generally, the parallel scientific advice procedure (a program shared by the EMA and FDA) is available for “important medicinal products”, 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) or products being developed for indications lacking development guidelines.

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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● 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.

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 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.

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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.

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.

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 a further 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.

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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.

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 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:

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, to an authorized orphan 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.

or (iii) the second applicant can establish the its product 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.

All of the aforementioned EU rules are generally applicable in the EEA.

Reform of the Regulatory Framework in the European Union

The European Commission introduced legislative proposals in April 2023 that, if implemented, will replace the current regulatory framework in the EU for all medicines (including those for rare diseases and for children).

The European Commission has provided the legislative proposals to the European Parliament and the European Council for their review and approval, and, in April 2024, the European Parliament proposed amendments to the legislative proposals.

Once the European Commission’s legislative proposals are approved (with or without amendment), they will be adopted into EU law.

Brexit and the Regulatory Framework in the United Kingdom

The UK formally left the EU on January 31, 2020.

As a result of the Northern Ireland protocol, following Brexit, the EMA remained responsible for approving novel medicines for supply in Northern Ireland under the EU centralized procedure, and a separate authorization was required to supply the same medicine in Great Britain (England, Wales and Scotland).

On February 27, 2023, the UK government and the European Commission announced a political agreement in principle to replace the Northern Ireland Protocol with a new set of arrangements, known as the “Windsor Framework”.

The Windsor Framework was approved by the EU-UK Joint Committee on March 24, 2023, and the medicines aspects of the Windsor Framework have applied since January 1, 2025.

This new framework fundamentally changes the previous

system under the Northern Ireland Protocol, including with respect to the regulation of medicinal products in the UK.

In particular, the MHRA is now responsible for approving all medicinal products destined for the UK market (i.e., Great Britain and Northern Ireland), and the EMA no longer has any role in approving medicinal products destined for Northern Ireland under the EU centralized procedure.

A single UK-wide marketing authorization will be granted by the MHRA for all novel medicinal products to be sold in the UK, enabling products to be sold in a single pack and under a single authorization throughout the UK.

In addition, the new arrangements require all medicines placed on the UK market to be labelled “UK only”, indicating they are not for sale in the EU.

However, although a separate authorization is now required to market medicinal products in the UK, under an international recognition procedure which was put in place by the MHRA on January 1, 2024, the MHRA may take into account decisions on the approval of a marketing authorization from the EMA (and certain other regulators) when considering an application for a UK marketing authorization.

Other government regulation in the European Union and United Kingdom

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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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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.

In April 2012, the EMA published a reflection paper on ethical and GCP aspects of clinical trials of medicinal products conducted outside the EU/EEA and submitted in MAAs to EU regulatory authorities.

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.

Manufacturing and Source of Supply

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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.

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

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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.

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.

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

What changed 10-K

Item 1. Business