Comprehensive Report on AD-221 (Atorvastatin 5mg/Ezetimibe 10mg Fixed-Dose Combination)

1. Executive Summary

AD-221, a fixed-dose combination (FDC) of atorvastatin 5mg and ezetimibe 10mg, has emerged as a significant therapeutic option for primary hypercholesterolemia. Developed by Addpharma Co., Ltd. and marketed in South Korea as Atovamibe Tab. 10/5mg by Yuhan Corporation, this FDC leverages the complementary mechanisms of HMG-CoA reductase inhibition by atorvastatin and cholesterol absorption inhibition by ezetimibe. Clinical development, primarily through the Phase 3 trial NCT05131997, has demonstrated that AD-221 achieves superior low-density lipoprotein cholesterol (LDL-C) reduction (approximately 49%) compared to monotherapies with atorvastatin 5mg, ezetimibe 10mg, and even moderate-intensity atorvastatin 10mg. This enhanced efficacy allows a greater proportion of patients to achieve stringent lipid targets. Pharmacokinetic studies indicate that the FDC provides overall systemic exposure comparable to the co-administration of its individual components, despite some variations in peak concentrations for ezetimibe. The safety and tolerability profile of AD-221 is favorable, characterized by a low incidence of adverse events and, notably, no reported cases of myopathy or rhabdomyolysis in its pivotal Phase 3 study. Evidence also suggests a potentially better safety profile, including fewer liver enzyme elevations, compared to moderate-intensity atorvastatin monotherapy. Approved by the South Korean Ministry of Food and Drug Safety in May 2023, AD-221 (Atovamibe) is positioned as a valuable treatment for patients requiring substantial LDL-C lowering, particularly those who may benefit from a lower statin dose to enhance tolerability or for whom moderate-intensity statin monotherapy is insufficient.

2. Introduction

2.1. Context of Hypercholesterolemia and Lipid-Lowering Therapies

Primary hypercholesterolemia, characterized by elevated blood levels of low-density lipoprotein cholesterol (LDL-C), is a highly prevalent and well-established modifiable risk factor for atherosclerotic cardiovascular disease (CVD).[1] The management of elevated LDL-C is a cornerstone in the primary and secondary prevention of cardiovascular events such as myocardial infarction and stroke. Statins, which are 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, represent the first-line pharmacological treatment for hypercholesterolemia due to their robust efficacy in lowering LDL-C and reducing the risk of CVD events.[1] However, a significant proportion of patients may not achieve their guideline-recommended LDL-C targets with statin monotherapy, or may experience dose-limiting adverse effects, particularly at higher statin intensities.

2.2. Rationale for Combination Therapy: Atorvastatin and Ezetimibe

To overcome the limitations of monotherapy and to achieve more aggressive LDL-C targets, combination lipid-lowering therapies have been developed. The rationale behind such strategies is to utilize agents with complementary mechanisms of action, thereby enhancing LDL-C reduction and/or allowing for the use of lower, better-tolerated doses of individual components. The combination of atorvastatin and ezetimibe exemplifies this approach. Atorvastatin primarily acts by inhibiting cholesterol synthesis in the liver, while ezetimibe selectively inhibits the absorption of dietary and biliary cholesterol in the intestine.[1] This dual blockade of cholesterol production and absorption results in a synergistic reduction in LDL-C levels.

2.3. Identification of AD-221

AD-221 is the developmental designation for a fixed-dose combination (FDC) product containing atorvastatin 5mg and ezetimibe 10mg.[2] This oral medication is indicated for the treatment of primary hypercholesterolemia.[2] In South Korea, AD-221 is marketed under the brand name Atovamibe Tab. 10/5mg (아토바미브정10/5밀리그램). The product was developed by Addpharma Co., Ltd., and the marketing authorization in South Korea is held by Yuhan Corporation.[4]

The choice of a low dose of atorvastatin (5mg) in this FDC, combined with the standard 10mg dose of ezetimibe, suggests a specific therapeutic strategy. Statin efficacy is dose-dependent, but so is the risk of adverse events. Ezetimibe, on the other hand, provides a relatively consistent additional LDL-C lowering effect of approximately 15-20% when added to any statin dose. Thus, combining low-dose atorvastatin with ezetimibe aims to achieve LDL-C reductions that are comparable to or even exceed those of moderate-intensity statin monotherapy, but with a potentially improved safety and tolerability profile. This approach may be particularly beneficial for patients who are sensitive to statins, have experienced side effects at higher doses, or are at a lower absolute cardiovascular risk where aggressive high-intensity statin therapy might not be the initial choice, yet significant LDL-C reduction is still warranted. Clinical trial data comparing AD-221 (A5E) with atorvastatin 10mg monotherapy (A10) indeed support superior efficacy for the FDC.[1] Furthermore, an FDC can simplify treatment regimens, potentially leading to improved patient adherence.

3. Pharmacological Profile of AD-221 (Atorvastatin 5mg/Ezetimibe 10mg FDC)

3.1. Active Pharmaceutical Ingredients (APIs)

3.1.1. Atorvastatin

Atorvastatin, typically used as atorvastatin calcium trihydrate in pharmaceutical formulations, is a potent member of the statin class of HMG-CoA reductase inhibitors.

Mechanism of Action: Atorvastatin exerts its lipid-lowering effect by competitively inhibiting HMG-CoA reductase, the rate-limiting enzyme in the mevalonate pathway of cholesterol biosynthesis. This inhibition occurs primarily in the liver, the main site of cholesterol production and LDL metabolism. The reduction in hepatic cholesterol synthesis leads to an upregulation of LDL receptors on the surface of hepatocytes. This, in turn, increases the fractional catabolic rate of LDL particles and enhances their clearance from the systemic circulation, resulting in a dose-dependent reduction in plasma LDL-C, total cholesterol (TC), and triglycerides (TG), along with a modest increase in high-density lipoprotein cholesterol (HDL-C).[4]
Physicochemical Properties and Formulation Challenges: Atorvastatin is known for its susceptibility to degradation under various conditions, including exposure to heat, moisture, light, and particularly acidic environments (low pH), where it can undergo hydrolysis to form its corresponding lactone, a less active metabolite. It exhibits greater stability at near-neutral to alkaline pH. These characteristics necessitate careful consideration during formulation to ensure drug stability and bioavailability throughout its shelf life.[10]

3.1.2. Ezetimibe

Ezetimibe is a cholesterol absorption inhibitor, distinct in its mechanism from statins.

Mechanism of Action: Ezetimibe selectively inhibits the intestinal absorption of dietary and biliary cholesterol without affecting the absorption of triglycerides or fat-soluble vitamins. It localizes at the brush border of the small intestine and is thought to bind to the Niemann-Pick C1-Like 1 (NPC1L1) protein, a critical sterol transporter responsible for cholesterol uptake by enterocytes. By blocking cholesterol absorption, ezetimibe reduces the delivery of intestinal cholesterol to the liver. This leads to a decrease in hepatic cholesterol stores and an increase in the clearance of cholesterol from the blood, complementing the effect of statins.[2]
Physicochemical Properties and Formulation Challenges: Ezetimibe presents its own formulation challenges, including issues related to its solubility. Furthermore, an alkaline pH, which is generally favorable for atorvastatin stability, can be detrimental to ezetimibe, posing a compatibility challenge when co-formulating these two active ingredients.[10]

3.2. Formulation and Dosage

AD-221 is an oral FDC tablet containing atorvastatin 5mg and ezetimibe 10mg.2 The development of such an FDC is complex due to the differing physicochemical properties and stability requirements of the two APIs. Direct contact or co-processing without appropriate measures could lead to degradation or undesirable interactions. For instance, microcrystalline cellulose, a common pharmaceutical excipient, was found to bind with ezetimibe, potentially retarding its drug release.10

To overcome these incompatibilities, specialized formulation strategies are often employed. Patent literature describes approaches such as:

A multi-layered tablet structure where an atorvastatin-containing core (stabilized with an alkalizing agent to maintain a favorable pH) is separated from an ezetimibe-containing outer coating by an intermediate protective layer. This design physically separates the APIs and protects them from direct interaction and incompatible microenvironments.[11]
A bilayer tablet design, which also physically segregates atorvastatin and ezetimibe into distinct layers. This allows for the optimization of excipients for each API independently; for example, using microcrystalline cellulose in the atorvastatin layer while preventing its contact with ezetimibe in the other layer. Ezetimibe may also be processed using specific techniques, such as dissolving it in a suitable solvent system before incorporation, to address solubility issues.[10] These sophisticated formulation approaches are crucial not just for convenience but are essential to ensure the chemical stability, integrity, and desired dissolution and bioavailability profiles of both active ingredients from a single dosage form.

3.3. Developer and Marketing Authorization Holder

The AD-221 FDC was developed by Addpharma Co., Ltd., a South Korean pharmaceutical company.[2] The marketing authorization for the product, branded as Atovamibe Tab. 10/5mg in South Korea, is held by Yuhan Corporation.[4]

4. Clinical Development and Pharmacokinetics

The clinical development program for AD-221 (atorvastatin 5mg/ezetimibe 10mg FDC) included pivotal Phase 3 studies to establish efficacy and safety, and Phase 1 studies to characterize its pharmacokinetic profile.

4.1. Overview of Key Clinical Trials

Table 1: Overview of Key Clinical Trials for AD-221 (Atorvastatin 5mg/Ezetimibe 10mg FDC)

Trial ID (NCT/KCT, Development Code)	Phase	Study Design	Sponsor(s)	Patient Population	Interventions	Primary Endpoint(s)	Status	Key Reference(s)
NCT05131997 / AD-221P3 / KCT0006591	Phase 3	Randomized, double-blind, active-controlled, multi-center (19 sites, Korea)	Addpharma Co., Ltd.	222-290 Korean patients with primary hypercholesterolemia requiring cholesterol-lowering therapy	AD-221 (A5E) vs. Ezetimibe 10mg (E10) vs. Atorvastatin 5mg (A5) vs. Atorvastatin 10mg (A10) for 8 weeks	Percentage change in LDL-C from baseline at 8 weeks	Completed	1
AD-221PK	Phase 1	Randomized, open-label, single-dose, 2-treatment, 2-sequence, crossover	Addpharma Co., Ltd. & Yuhan Corporation	60 healthy Korean adult subjects	AD-221 FDC vs. co-administration of individual Atorvastatin 5mg + Ezetimibe 10mg tablets	Pharmacokinetic parameters (Cmax, AUClast)	Completed	13

The Phase 3 trial (NCT05131997, also referred to as AD-221P3) was central to demonstrating the clinical utility of AD-221. Its primary objective was to compare the LDL-C lowering efficacy and safety of the FDC against its individual components and against a higher dose of atorvastatin monotherapy (10mg) over an 8-week treatment period.[2] The Phase 1 pharmacokinetic study (AD-221PK) was designed to assess whether the FDC delivers atorvastatin and ezetimibe into the bloodstream in a manner comparable to when these drugs are taken as separate tablets simultaneously.[13]

4.2. Pharmacokinetic Profile

The Phase 1 study (AD-221PK) provided key insights into the absorption and disposition of atorvastatin and ezetimibe when administered as the AD-221 FDC compared to co-administration of the individual tablets in 58 healthy Korean subjects who completed the study.[13]

Table 2: Pharmacokinetic Parameters of Atorvastatin and Ezetimibe from Fixed-Dose Combination (AD-221) vs. Co-administration of Individual Tablets in Healthy Volunteers

Analyte (Dose)	PK Parameter	FDC (Atorvastatin 5mg/Ezetimibe 10mg)	Individual Components (Atorvastatin 5mg + Ezetimibe 10mg)	GMR (90% CI) (FDC vs. Individual)
Atorvastatin (5mg)	Cmax (ng/mL)	N/A (GMR provided)	N/A (GMR provided)	1.18 (1.04–1.33)
	AUClast (ng*h/mL)	N/A (GMR provided)	N/A (GMR provided)	1.04 (1.00–1.08)
	Tmax (hr)	Median: 0.50	Median: 0.50	-
	T1/2 (hr)	Mean: ~10.01	Mean: ~10.21	-
Total Ezetimibe (10mg)	Cmax (ng/mL)	N/A (GMR provided)	N/A (GMR provided)	1.37 (1.26–1.50)
	AUClast (ng*h/mL)	N/A (GMR provided)	N/A (GMR provided)	0.98 (0.93–1.03)
	Tmax (hr)	Median: 1.0	Median: 1.0	-
	T1/2 (hr)	Mean: ~19.56	Mean: ~19.15	-
Free Ezetimibe (10mg)	Tmax (hr)	Median: 1.0	Median: 1.0	-
	T1/2 (hr)	Mean: ~20.72	Mean: ~25.56	-

Data sourced from.[13] GMR = Geometric Mean Ratio; CI = Confidence Interval; N/A = Not applicable as direct values for FDC and Individual Components leading to GMR are not detailed in snippets, only the GMR itself.

For atorvastatin, the GMR for Cmax (1.18) had a 90% CI (1.04–1.33), and for AUClast (1.04) the 90% CI was (1.00–1.08). These results indicate that the peak exposure to atorvastatin from the FDC was slightly higher, while the total exposure was comparable to the individual tablets. The Tmax and T1/2 were similar for both administrations.

For total ezetimibe (ezetimibe plus its active glucuronide metabolite), the GMR for Cmax (1.37) had a 90% CI (1.26–1.50), indicating a notably higher peak concentration from the FDC. However, the GMR for AUClast (0.98) had a 90% CI (0.93–1.03), suggesting that the total exposure to total ezetimibe was comparable between the FDC and the individual tablets. Tmax and T1/2 for total ezetimibe were also similar. Free ezetimibe also showed similar Tmax values, with some difference in mean T1/2.

The study concluded that the AD-221 FDC was safe and demonstrated similar overall exposure (AUClast) for both drugs compared to their co-administration as individual tablets. Although the Cmax for total ezetimibe was higher for the FDC, this was not deemed clinically significant by the study authors.[13]

The assessment of bioequivalence is critical for FDCs. Regulatory agencies typically consider products bioequivalent if the 90% CIs for the GMRs of key PK parameters like AUC and Cmax fall within the range of 0.80 to 1.25. For AD-221, the AUClast for both atorvastatin and total ezetimibe met these criteria, indicating equivalent overall drug exposure. While the Cmax GMR for atorvastatin was slightly above the upper limit of 1.25 (CI upper bound 1.33), the Cmax GMR for total ezetimibe (CI 1.26–1.50) was clearly outside this range, showing a statistically higher peak concentration from the FDC.[13] The clinical impact of a higher ezetimibe Cmax is often considered minimal due to its primary site of action being localized to the intestinal lumen and its generally wide therapeutic window. However, such deviations from standard Cmax bioequivalence limits can be subject to regulatory scrutiny and may require further justification depending on the regulatory authority.

5. Clinical Efficacy in Primary Hypercholesterolemia (Primarily from NCT05131997 / AD-221P3)

The pivotal Phase 3 trial (NCT05131997) provided robust evidence for the efficacy of AD-221 (atorvastatin 5mg/ezetimibe 10mg FDC, denoted as A5E) in patients with primary hypercholesterolemia.

5.1. Primary Endpoint: LDL-C Reduction

At the 8-week follow-up, the A5E FDC demonstrated a mean LDL-C reduction from baseline of 49.2%.2 Some sources report slightly different values (47.6% 1 or -44.8% 12), but the 49.2% figure appears to be the most consistently cited from the primary publication of the Phase 3 results.

This reduction was significantly greater than that achieved by the comparator monotherapy arms:

Ezetimibe 10mg (E10) alone: 18.7% LDL-C reduction.[2]
Atorvastatin 5mg (A5) alone: 27.9% LDL-C reduction.[2]
Atorvastatin 10mg (A10) alone (moderate-intensity statin): 36.4% LDL-C reduction.[2] The superiority of A5E in LDL-C reduction compared to all monotherapy arms was statistically significant (p < 0.0001 vs. E10 and A5; p ≤ 0.0012 vs. A10).[1]

5.2. Onset of Action

The lipid-lowering effect of A5E was rapid. Significant LDL-C reduction was observed as early as 4 weeks into treatment, with a reported reduction of 46.7%.[1] This early efficacy is clinically relevant as it allows for quicker attainment of therapeutic goals.

5.3. Impact on Other Lipid Parameters

At the 8-week assessment, A5E also demonstrated favorable effects on other components of the lipid profile compared to monotherapies [1]:

Total Cholesterol (TC), Non-HDL Cholesterol, and Apolipoprotein B (ApoB): A5E led to significantly greater reductions in these atherogenic lipid parameters.
Triglycerides (TG): TG levels were significantly more decreased in the A5E group compared to the ezetimibe monotherapy group.
High-Density Lipoprotein Cholesterol (HDL-C): HDL-C levels were substantially increased in the A5E group compared to the ezetimibe monotherapy group.

5.4. Achievement of Lipid Treatment Goals

AD-221 (A5E) was effective in helping patients reach their LDL-C treatment targets:

Standard LDL-C Targets: Among patients with low and intermediate cardiovascular risk, 93.3% of those treated with A5E achieved their guideline-specific LDL-C targets. This rate was markedly higher than that observed in the E10 group (40.0%) and the A5 group (66.7%), and was comparable to, or slightly better than, the A10 group (92.9%).[9]
More Stringent LDL-C Targets: For the more aggressive composite target of achieving both LDL-C < 70 mg/dL AND a ≥ 50% reduction in LDL-C from baseline, the A5E group showed superior performance. 31.4% of patients on A5E reached this dual target, compared to only 8.1% in the E10 group, 9.7% in the A5 group, and 7.3% in the A10 group.[2] This highlights the FDC's ability to meet challenging lipid-lowering objectives. [12] reported a 41.1% LDL-C goal achievement for EZE10/ATV5 in moderate to high-risk patients, which may reflect a different definition of "goal" or a specific patient subset analysis.

The pronounced efficacy of AD-221, particularly its superiority over atorvastatin 10mg monotherapy, is a key finding. While statin therapy efficacy increases with dose, the "rule of 6" suggests that each doubling of a statin dose typically yields only an additional ~6% LDL-C reduction. In contrast, ezetimibe consistently adds approximately 15-20% LDL-C reduction when combined with any statin dose. The clinical results for AD-221 (A5E vs. A10) support this principle: adding ezetimibe 10mg to atorvastatin 5mg (resulting in ~49% LDL-C reduction) was substantially more effective than merely doubling the atorvastatin dose from 5mg to 10mg (which yielded ~36% reduction). The incremental benefit from ezetimibe (~21% over A5) was far greater than the incremental benefit from doubling the A5 dose to A10 (~8.5% over A5). This suggests that for patients on low-dose atorvastatin who are not at their LDL-C goal, adding ezetimibe (as in AD-221) is a more potent lipid-lowering strategy than simply increasing the statin dose to a moderate intensity like atorvastatin 10mg. This has significant implications for clinical practice, potentially favoring earlier initiation of combination therapy over sequential statin uptitration in certain patient profiles, especially where tolerability at higher statin doses is a concern.

Table 3: Summary of Efficacy Results from Phase 3 Trial (NCT05131997) - AD-221 (A5E) vs. Comparators at 8 Weeks

Efficacy Parameter	AD-221 (A5E) (Atorva 5mg/Eze 10mg)	Ezetimibe 10mg (E10)	Atorvastatin 5mg (A5)	Atorvastatin 10mg (A10)	P-value (A5E vs. Comparator)
Mean % Change in LDL-C from Baseline	-49.2% 2	-18.7% 2	-27.9% 2	-36.4% 2	vs E10, A5: <0.0001; vs A10: ≤0.0012 1
% Patients Achieving Guideline-Specific LDL-C Target*	93.3% 9	40.0% 9	66.7% 9	92.9% 9	N/A
% Patients Achieving LDL-C <70mg/dL AND ≥50% LDL-C Reduction	31.4% 2	8.1% 2	9.7% 2	7.3% 2	N/A
Mean % Change in Total Cholesterol from Baseline	Significant Reduction 9	N/A	N/A	N/A	N/A
Mean % Change in Triglycerides from Baseline	Significant Reduction vs E10 9	N/A	N/A	N/A	vs E10: Significant 9
Mean % Change in Non-HDL-C from Baseline	Significant Reduction 1	N/A	N/A	N/A	N/A
Mean % Change in Apolipoprotein B from Baseline	Significant Reduction 1	N/A	N/A	N/A	N/A
Mean % Change in HDL-C from Baseline	Substantial Increase vs E10 9	N/A	N/A	N/A	vs E10: Significant 9

In patients with low and intermediate cardiovascular risk. N/A: Specific comparative values or p-values not detailed for all parameters in provided snippets.

6. Safety and Tolerability Profile

The safety and tolerability of AD-221 (A5E) were extensively evaluated in the Phase 3 clinical trial (NCT05131997) and the Phase 1 pharmacokinetic study.

6.1. Overall Incidence and Nature of Adverse Events (AEs)

In the Phase 3 trial, the overall incidence of treatment-related AEs reported for the A5E group was low. One source indicates this was 6.2% and similar across all treatment groups (A5E, E10, A5, A10).[2] Another report from the same trial suggested that the EZE10/ATV5 group (equivalent to A5E) had the lowest incidence of AEs at 6.9%, which was statistically significantly lower compared to E10 (15.0%), A5 (12.3%), and particularly A10 (27.6%) (p = 0.017).[12] This latter finding, if reflective of the final consolidated data, would indicate a notable tolerability advantage for the FDC. Most AEs observed were mild to moderate in severity.[2]

6.2. Serious Adverse Events (SAEs) and Discontinuations

No serious adverse events (SAEs) were reported in the A5E group during the Phase 3 trial.[1] Information regarding specific rates of discontinuation due to AEs in the A5E group from the Phase 3 study is not explicitly detailed in the provided summaries, but the low overall AE rates suggest these were likely infrequent. In the Phase 1 PK study, two of 60 healthy subjects withdrew after receiving the reference formulation (co-administered individual tablets) due to adverse drug reactions (ADRs) of dyspepsia, vomiting, and headache. Four ADRs were reported in two subjects after FDC administration, and six ADRs in five subjects after individual components administration; most of these ADRs were assessed as probably not related to the investigational product.[13]

6.3. Specific Safety Considerations

Liver Enzyme Elevations: In the Phase 3 trial, an increase in liver enzyme levels (e.g., ALT/AST, criteria for elevation not consistently specified) was reported in only one patient (1.4%) in the A5E group. This was numerically lower than the incidence in the atorvastatin 10mg (A10) monotherapy group, where three patients (4.3%) experienced liver enzyme elevations.[2] This finding suggests a potentially reduced risk of hepatic effects with the lower atorvastatin dose in the FDC.
Muscle-Related AEs: Crucially, no cases of myopathy or rhabdomyolysis were reported in any treatment group, including the A5E group, during the Phase 3 trial.[2] The absence of these statin-associated muscle AEs is a significant positive safety finding. The safety profile of AD-221 appears favorable, particularly when considering the potential for reduced dose-dependent statin side effects. The numerically lower incidence of liver enzyme elevations with A5E compared to A10 monotherapy, and the complete absence of reported myopathy or rhabdomyolysis in the Phase 3 trial, are reassuring. If the statistically significant lower overall AE rate for A5E compared to A10, as suggested by one source [12], is confirmed, it would represent a substantial safety advantage for the FDC. Furthermore, the general safety observations from the Phase 3 trial in patients with hypercholesterolemia are consistent with the findings from the Phase 1 PK study in healthy volunteers, where the FDC was also found to be safe and well-tolerated.[13] This consistency across different study phases and populations enhances confidence in the overall safety profile of AD-221.

Table 4: Summary of Safety Profile from Phase 3 Trial (NCT05131997) - AD-221 (A5E) vs. Comparators

Safety Parameter	AD-221 (A5E) (Atorva 5mg/Eze 10mg) (n/%)	Ezetimibe 10mg (E10) (n/%)	Atorvastatin 5mg (A5) (n/%)	Atorvastatin 10mg (A10) (n/%)
Overall Incidence of Treatment-Related AEs	6.2% 2 or 6.9% 12	~15.0% 12	~12.3% 12	~27.6% 12
Liver Enzyme Elevation (e.g., ALT/AST increased)	1/N (1.4%) 2	N/A	N/A	3/N (4.3%) 2
Myopathy	0 2	0 2	0 2	0 2
Rhabdomyolysis	0 2	0 2	0 2	0 2
Serious Adverse Events (SAEs)	0 1	N/A	N/A	N/A
Discontinuations due to AEs	N/A	N/A	N/A	N/A

N represents the number of patients in each arm, which varies slightly across sources.[8] N/A: Specific data for all comparators or exact AE terms not consistently detailed across all snippets for all parameters.

7. Regulatory Status and Market Context

7.1. South Korea (Ministry of Food and Drug Safety - MFDS)

The fixed-dose combination of atorvastatin 5mg and ezetimibe 10mg, developed under the code AD-221 by Addpharma Co., Ltd., has received marketing approval in South Korea.

Brand Name: 아토바미브정10/5밀리그램 (Atovamibe Tab. 10/5mg).[4]
Marketing Authorization Holder: (주)유한양행 (Yuhan Corporation).[4]
Approval Date: May 26, 2023.[4] The development code AD-221 was explicitly used for the product that was ultimately approved as Atovamibe Tab. 10/5mg.[4]

7.2. United States (Food and Drug Administration - FDA)

There is no information in the provided materials to suggest that Addpharma's AD-221 (atorvastatin 5mg/ezetimibe 10mg FDC) has been submitted for approval or is currently approved in the United States.

It is relevant to note that a different FDC of atorvastatin and ezetimibe, Liptruzet® (various strengths, but not specifically 5mg/10mg), manufactured by Merck Sharp & Dohme Corp., was approved by the FDA on May 3, 2013 (NDA 20-0153).14 However, Liptruzet® was subsequently discontinued from sale in the U.S. market as of June 1, 2015.3 Importantly, the FDA conducted a review and determined that Liptruzet® was not withdrawn from sale for reasons of safety or effectiveness.14 This determination is significant because it means the FDA does not consider the combination of ezetimibe and atorvastatin inherently unsafe or ineffective, thereby allowing for the potential approval of other Abbreviated New Drug Applications (ANDAs) or New Drug Applications (NDAs) for such FDCs if all other legal and regulatory requirements are met.

7.3. Other Regions

The provided research snippets do not contain specific approval information for Addpharma's AD-221 (atorvastatin 5mg/ezetimibe 10mg FDC) in other major regulatory jurisdictions such as Europe (European Medicines Agency - EMA), Japan (Pharmaceuticals and Medical Devices Agency - PMDA), Canada, or Australia. While an ezetimibe/atorvastatin FDC (Ezetimibe/Atorvastatine GL by G.L. Pharma GmbH) is authorized in some European Member States, this is a different product with different strengths and a different sponsor.[15]

7.4. Patent Information

The development of stable and effective FDCs of atorvastatin and ezetimibe has been the subject of pharmaceutical patents, primarily focusing on overcoming the physicochemical incompatibilities and differing stability requirements of the two APIs.

Patent application US20130216619A1 describes an oral pharmaceutical composition featuring a core comprising atorvastatin and an alkalizing agent (to ensure atorvastatin stability), an intermediate protective coating, and an outer coating comprising ezetimibe. This layered design aims to prevent direct contact and degradation.[11]
Patent application WO2013166114A1 details a bilayer tablet formulation that physically separates atorvastatin and ezetimibe into different layers. This approach addresses issues such as atorvastatin's instability and ezetimibe's poor solubility and potential interaction with excipients like microcrystalline cellulose.[10] The existence of such patents underscores the technical challenges and innovative solutions required for co-formulating these two drugs.

The approval of AD-221 (as Atovamibe) in South Korea, based on local Phase 3 data, establishes its clinical viability in that region. The prior commercial discontinuation of Liptruzet® in the U.S. for non-safety/efficacy reasons does not inherently preclude future approvals of similar combinations, should a manufacturer pursue it with adequate supporting data and a viable market strategy. The Korean approval suggests a perceived clinical need or favorable market dynamics for this specific low-dose atorvastatin/ezetimibe combination in that country, possibly driven by factors such as an emphasis on tolerability, specific patient population needs, or healthcare system economics.

8. Discussion and Clinical Implications

8.1. Benefit-Risk Assessment of AD-221 (Atorvastatin 5mg/Ezetimibe 10mg FDC)

The clinical data for AD-221 (A5E) indicate a positive benefit-risk profile for the treatment of primary hypercholesterolemia.

Benefits: The primary benefit is its superior LDL-C lowering efficacy (approximately 49% reduction) compared to its individual components (atorvastatin 5mg, ezetimibe 10mg) and, significantly, compared to moderate-intensity atorvastatin 10mg monotherapy (approximately 36% reduction).[2] This enhanced efficacy translates to a higher proportion of patients achieving both standard and more stringent LDL-C treatment goals.[2] The onset of action is rapid, with substantial LDL-C reduction observed within 4 weeks.[1] The safety profile is favorable, with a low overall incidence of adverse events. Notably, no cases of myopathy or rhabdomyolysis were reported in the pivotal Phase 3 trial, and there is evidence suggesting a potentially better tolerability profile, including fewer liver enzyme elevations, compared to moderate-intensity atorvastatin monotherapy.[2] As an FDC, it also offers the benefit of simplified dosing, which can improve patient adherence.
Risks: The risks associated with AD-221 are generally those known for low-dose atorvastatin and ezetimibe. The pharmacokinetic finding of a higher Cmax for total ezetimibe with the FDC compared to co-administered individual tablets was noted, although its clinical significance was not considered apparent in the Phase 1 study.[13] As with many lipid-lowering therapies whose approval is based on surrogate endpoints like LDL-C reduction, long-term cardiovascular outcome data specifically for this 5mg/10mg FDC are not yet available from the provided information.

8.2. Positioning in the Management of Primary Hypercholesterolemia

AD-221 is strategically positioned within the therapeutic armamentarium for primary hypercholesterolemia.

It is a particularly suitable option for patients who require LDL-C lowering that is more substantial than what can be achieved with low-dose statin monotherapy or ezetimibe monotherapy.
Crucially, it serves as a more effective alternative to simply uptitrating a low-dose statin (e.g., atorvastatin 5mg) to a moderate-dose statin (e.g., atorvastatin 10mg), especially if tolerability is a concern or if maximizing efficacy while maintaining a lower statin dose is preferred. The clinical trial data clearly demonstrate that A5E provides greater LDL-C reduction than A10.[2]
The FDC is well-suited for patients at low to intermediate cardiovascular risk who need to achieve significant LDL-C reduction but for whom high-intensity statin therapy may not be indicated or desired.[2]
It could also be considered as an initial combination therapy option in certain patient profiles where a >50% LDL-C reduction is the goal and baseline LDL-C levels are not excessively high, allowing for rapid and effective target attainment.

8.3. Advantages of the Fixed-Dose Combination

The FDC formulation of AD-221 offers distinct advantages:

Improved Efficacy with Lower Statin Exposure: The most significant advantage is achieving superior LDL-C reduction compared to simply doubling the statin dose from low to moderate intensity (A5E vs. A10). This maximizes the lipid-lowering effect while minimizing the patient's exposure to a higher statin dose, which is often associated with an increased risk of dose-dependent adverse effects like myalgia or liver enzyme changes.
Enhanced Patient Adherence: Combining two medications into a single tablet reduces pill burden. This simplification of the treatment regimen is generally associated with improved patient compliance, a critical factor in the long-term management of chronic conditions such as hypercholesterolemia.[13]

8.4. Unmet Needs and Future Directions

While AD-221 addresses important aspects of lipid management, further research could enhance its clinical utility:

Cardiovascular Outcome Trials: Long-term studies specifically designed to evaluate the impact of the atorvastatin 5mg/ezetimibe 10mg FDC on cardiovascular morbidity and mortality would provide definitive evidence of its clinical benefit beyond surrogate lipid markers.
Special Populations: Further investigation into the efficacy and safety of AD-221 in higher-risk patient populations, individuals with a history of statin intolerance, or those with specific genetic predispositions to hypercholesterolemia would be valuable.
Comparative Effectiveness: Head-to-head comparisons with higher-intensity statin monotherapies or other FDCs in diverse patient populations could further delineate its place in therapy.
Cost-Effectiveness: Economic analyses are needed to assess the cost-effectiveness of AD-221 within various healthcare systems, which will influence its reimbursement status and accessibility.

The development of AD-221 illustrates an optimized approach to leveraging the synergy between statins and ezetimibe, particularly at the lower end of the statin dosing spectrum. The "rule of 6" for statins suggests that each doubling of a statin dose typically yields only an additional ~6% in LDL-C reduction. In contrast, ezetimibe consistently adds approximately 15-20% LDL-C reduction when combined with any statin dose. The clinical trial results for AD-221 (A5E achieving ~49% LDL-C reduction vs. A10 achieving ~36%) clearly demonstrate that the addition of ezetimibe 10mg to atorvastatin 5mg provides a much greater incremental LDL-C lowering effect (~21% over A5 alone) than simply doubling the atorvastatin dose from 5mg to 10mg (~8.5% additional reduction over A5). This makes AD-221 a more potent lipid-lowering strategy than uptitrating from low- to moderate-intensity atorvastatin monotherapy, with the added advantage of potentially better tolerability due to the lower statin component.

While AD-221 appears targeted towards patients who may not require or tolerate high-intensity statin therapy, its robust efficacy and favorable safety profile could allow for broader applicability. Given its superior LDL-C lowering compared to atorvastatin 10mg monotherapy [2], it could challenge the direct step to A10 for patients inadequately controlled on atorvastatin 5mg. This FDC could become a preferred second-line option after low-dose statin monotherapy or even an initial option for patients whose baseline LDL-C suggests a need for >30-40% reduction but for whom high-intensity statins are not immediately indicated or desired. Its demonstrated utility in helping patients achieve more stringent LDL-C goals (e.g., LDL-C <70 mg/dL plus ≥50% reduction) further expands its potential clinical applications.[2]

9. Conclusion

AD-221, a fixed-dose combination of atorvastatin 5mg and ezetimibe 10mg (marketed as Atovamibe Tab. 10/5mg in South Korea), represents a clinically significant and well-substantiated therapeutic agent for the management of primary hypercholesterolemia. Data from its pivotal Phase 3 clinical trial (NCT05131997) have unequivocally demonstrated its superior efficacy in reducing LDL-C and other atherogenic lipoproteins when compared to monotherapies with atorvastatin 5mg, ezetimibe 10mg, and, notably, even moderate-intensity atorvastatin 10mg. This enhanced potency allows a greater proportion of patients to achieve both standard and more stringent guideline-recommended lipid targets.

The safety and tolerability profile of AD-221 is favorable, characterized by a low incidence of adverse events and, critically, no reported cases of myopathy or rhabdomyolysis in its key Phase 3 study. Furthermore, there is evidence to suggest a potentially improved safety margin, including a numerically lower incidence of liver enzyme elevations, when compared to moderate-intensity atorvastatin monotherapy. Pharmacokinetic evaluations have confirmed that the FDC provides overall systemic drug exposure comparable to the co-administration of its individual atorvastatin and ezetimibe components, supporting its pharmaceutical integrity.

The approval of AD-221 in South Korea underscores its clinical viability. It is positioned as a valuable therapeutic option, particularly for patients who require substantial LDL-C reduction but may benefit from a lower statin dose to enhance tolerability, or for individuals in whom moderate-intensity statin monotherapy is insufficient or not the preferred initial approach. The development of AD-221 highlights a successful strategy in optimizing lipid-lowering therapy by effectively combining complementary mechanisms of action in a convenient, single-tablet regimen.

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AD-221 Advanced Drug Monograph

Generic Name