VX-828: A Novel Investigational CFTR Corrector for Cystic Fibrosis

1. Introduction to VX-828: A Next-Generation CFTR Modulator

VX-828 is an investigational small molecule therapeutic agent currently under development by Vertex Pharmaceuticals. It is classified as a next-generation cystic fibrosis transmembrane conductance regulator (CFTR) modulator, specifically functioning as a CFTR corrector. This compound is a central component of Vertex's "next gen 3.0 CFTRm regimen," a novel triple combination therapy designed to treat cystic fibrosis (CF).[1] The development of CFTR modulators represents a paradigm shift in CF management, moving from symptomatic treatment to addressing the underlying protein defect. Each subsequent generation of modulators aims to enhance efficacy, broaden the range of responsive mutations, improve patient tolerability, or simplify dosing regimens. VX-828 embodies this ongoing effort to refine and optimize CFTR-targeted therapies.

The primary therapeutic goal for VX-828, as part of the NG 3.0 regimen, is to achieve a superior level of CFTR protein function compared to currently available modulators. This enhanced function is anticipated to translate into more profound clinical benefits for individuals with CF. Vertex Pharmaceuticals has articulated a mission of elevating CFTR function in patients towards "normal levels," with the NG 3.0 regimen (incorporating VX-828) being a critical step in this endeavor. Preclinical data indicate that this regimen yields "even greater improvement in CFTR-dependent chloride transport than in ALYFTREK".[2] While existing highly effective CFTR modulators (HEMTs) like elexacaftor/tezacaftor/ivacaftor (Trikafta/Kaftrio) and vanzacaftor/tezacaftor/deutivacaftor (Alyftrek) have transformed CF care for many, there remains a therapeutic ceiling. Achieving near-normal CFTR function could potentially mitigate a wider array of CF manifestations, further improve long-term outcomes, and benefit patient populations who have a suboptimal response to current HEMTs.[1]

Vertex Pharmaceuticals, a company with a significant track record and global leadership in the discovery and development of CFTR modulators, is solely responsible for the development of VX-828.[1] Vertex's deep institutional knowledge of CFTR biology, modulator chemistry, and clinical development in CF provides a robust platform for advancing next-generation compounds like VX-828. Their commitment is further underscored by a pipeline strategy that includes multiple approaches to treat CF.

The explicit labeling by Vertex of its CFTR modulator regimens as "NG 1.0" (Trikafta/Kaftrio), "NG 2.0" (Alyftrek), and "NG 3.0" (VX-828 based regimen) reveals a highly structured, iterative innovation strategy.[2] This numerical "generation" labeling suggests a pre-defined roadmap of incremental advancements, where each new regimen is benchmarked against the previous, aiming for superior efficacy or other benefits. This implies a long-term vision for CF care, moving progressively towards the goal of normalizing CFTR function, which requires sustained R&D investment and a deep understanding of the target protein and disease.

Furthermore, the repeated assertion that Human Bronchial Epithelial (HBE) cell assays are "highly predictive of clinical outcomes" for CFTR modulators is significant.[2] Pharmaceutical development is characterized by high attrition rates, making a reliable preclinical model that accurately predicts human clinical response invaluable. If Vertex's internal data consistently supports this predictive capacity, then the reported superior in vitro efficacy of the VX-828 regimen in HBE cells serves as a strong internal validation.[1] This likely de-risks, from the company's perspective, the decision to advance VX-828 into more complex and costly clinical trials, justifying the resources allocated to its development. The ambition to achieve "normal levels of CFTR function" with the VX-828 regimen signifies a potential shift in the therapeutic paradigm for CF.[2] It suggests moving beyond substantial clinical improvement towards a state where the underlying protein defect is so effectively corrected that the disease's impact is minimized to an unprecedented degree, approaching a functional cure for many. This has profound implications for patients, healthcare systems, and the definition of treatment success in CF.

2. Drug Profile: VX-828

VX-828 is identified as an orally administered small molecule therapeutic agent.[3] Its development is being spearheaded by Vertex Pharmaceuticals.

Table 1: VX-828 Key Drug Information

Feature	Details	Supporting Snippets
Official Name/Identifier	VX-828	1
Alternative Names	VX 828, VX828	3
Developer	Vertex Pharmaceuticals	1
Chemical Nature	Small Molecule	3
Mechanism Class	CFTR Corrector	1
Route of Administration	Oral (Suspension, Tablet)	3
Current Development Phase	Phase 1	3
Primary Therapeutic Indication	Cystic Fibrosis	1
Key Combination Partners (NG 3.0 Regimen)	Tezacaftor, Deutivacaftor (VX-118)	1

The specific chemical structure or scaffold of VX-828 remains proprietary and is not disclosed in the available information.[4] Small molecule drugs typically offer the advantage of oral bioavailability and the ability to target intracellular proteins, essential for CFTR correctors acting on the protein during its biogenesis and trafficking. Oral administration is crucial for the long-term management of chronic diseases like CF, promoting patient adherence and ease of use. The current Phase 1 development stage indicates that VX-828 is in the early phases of human testing, focused on safety, tolerability, and pharmacokinetics.

The consistent use of the "VX-" prefix followed by a number (e.g., VX-828, VX-118, VX-522) is a standard pharmaceutical industry practice that also underscores Vertex's systematic approach to building a portfolio of CFTR modulators with distinct properties.[1] This organized nomenclature reflects an organized R&D process, where the numbers likely differentiate compounds based on discovery series, mechanism, or development timeline.

A key strategic decision in the NG 3.0 regimen is the selection of Deutivacaftor (VX-118), the deuterated form of ivacaftor, as the potentiator component.[2] Deuteration is a well-established medicinal chemistry technique to modify a drug's metabolic fate, often to prolong its half-life or reduce the formation of undesirable metabolites by slowing down cytochrome P450-mediated metabolism at the deuterated positions. Given the proven efficacy of ivacaftor, developing its deuterated version, Deutivacaftor, for the next-generation regimen suggests an attempt to optimize this established component. This optimization could lead to improved pharmacokinetic properties, such as a more stable plasma concentration profile or a longer duration of action, potentially enabling more convenient dosing (e.g., once-daily) and enhancing the overall consistency of the therapeutic effect within the triple combination. This approach balances innovation in the corrector components, like VX-828, with the leveraging of proven pharmacology, thereby potentially reducing the development risk for at least one part of the combination.

The concurrent or closely timed evaluation of both suspension and tablet formulations for VX-828 in Phase 1 studies (NCT06154447 utilizing both, and NCT06861413 specifically comparing tablet to suspension bioavailability) highlights the importance Vertex places on early formulation development.[10] For a chronic therapy intended for lifelong use, a patient-friendly and commercially viable oral dosage form is critical. While suspensions may be suitable for initial human studies or pediatric populations, a stable and bioavailable tablet is generally preferred for adult patients due to ease of administration and dosing accuracy. Addressing potential formulation challenges at an early stage can prevent significant delays in later-stage clinical development and ensure that the drug can be optimally delivered if it proves efficacious.

3. Mechanism of Action

VX-828 is primarily characterized as a cystic fibrosis transmembrane conductance regulator (CFTR) corrector.[1] CFTR correctors are a class of therapeutic agents designed to address the fundamental molecular defects caused by certain CFTR mutations, most notably the F508del mutation. Their principal mechanism involves facilitating the proper folding, conformational maturation, and subsequent trafficking of the mutant CFTR protein from its site of synthesis in the endoplasmic reticulum to the apical surface of epithelial cells, where it can function as an ion channel.[14]

The F508del mutation, the most prevalent CF-causing variant, leads to a misfolded CFTR protein that is recognized by cellular quality control mechanisms and prematurely targeted for proteasomal degradation. Consequently, insufficient amounts of F508del-CFTR reach the cell membrane.[17] Correctors like VX-828 aim to rescue this F508del-CFTR protein, enabling a greater quantity of the protein to escape degradation and be inserted into the plasma membrane. While the precise binding site of VX-828 on the CFTR protein is not detailed in the available information, its function as a corrector implies a direct or indirect interaction that stabilizes the protein's structure or facilitates its interaction with cellular chaperones. Different classes of correctors have been identified that may bind to distinct sites on the CFTR protein, such as the nucleotide-binding domains (NBDs), transmembrane domains (TMDs), or interfaces between these domains, to exert their corrective effects.[18]

VX-828 is a cornerstone of Vertex's "Next-Generation 3.0 CFTRm Regimen," a triple combination therapy. This regimen also includes Tezacaftor, another CFTR corrector, and Deutivacaftor (VX-118), a CFTR potentiator.[1] The rationale behind such triple combinations is to maximize both the quantity of CFTR protein at the cell surface (via the action of two correctors) and the functional activity of these channels (via the potentiator). This multi-pronged approach has been highly successful, as exemplified by therapies like Trikafta. The NG 3.0 regimen represents an evolution of this strategy, aiming for enhanced synergistic effects by employing potentially more effective or complementary next-generation components.

The CFTR protein itself is an anion channel, primarily responsible for the transport of chloride and bicarbonate ions across epithelial cell membranes. This ion transport is critical for maintaining hydration of epithelial surfaces in various organs, including the lungs, pancreas, and intestines.[20] The CFTR protein consists of two transmembrane-spanning domains (MSDs), which form the ion pore; two cytosolic nucleotide-binding domains (NBDs), which bind and hydrolyze ATP to control channel gating; and a cytosolic regulatory (R) domain, whose phosphorylation by protein kinase A is required for channel activation.[18] Mutations in the CFTR gene, such as F508del (a Class II mutation), lead to defects in protein folding, processing, stability, and/or function, resulting in the multisystem manifestations of CF.[19]

The inclusion of two distinct correctors, VX-828 and Tezacaftor, in the NG 3.0 regimen suggests a therapeutic strategy based on the hypothesis that these molecules may target different structural defects or binding sites on the F508del-CFTR protein.[2] If VX-828 and Tezacaftor possessed identical mechanisms of action, their combination might offer limited additive benefits rather than the anticipated synergistic or enhanced effect characteristic of a "next-generation" therapy. The decision to combine two correctors implies an expectation of a more comprehensive rescue of the mutant protein's conformation or trafficking pathway. This aligns with research that has identified different classes of CFTR correctors (e.g., Type I, II, III) which are understood to bind to distinct domains or interfaces of the CFTR protein, such as NBD1, TMDs, or inter-domain regions.[18] By addressing multiple points of conformational instability or misfolding, a dual-corrector approach could lead to a higher yield of F508del-CFTR reaching the cell surface.

Vertex's explicit goal of achieving "normal levels of CFTR function" with the NG 3.0 regimen, coupled with its demonstrated superior efficacy over ALYFTREK in preclinical HBE cell assays, indicates that the combined mechanism of VX-828, Tezacaftor, and Deutivacaftor is anticipated to be exceptionally potent.[1] This implies a mechanism that not only significantly increases the quantity of CFTR channels at the cell surface but also ensures that these rescued channels are highly responsive to potentiation, leading to a greater overall restoration of ion transport. The development of VX-828 as a "next-generation" corrector may be aimed at overcoming the efficacy ceilings observed with previous correctors. This could involve improved binding affinity for CFTR, enhanced stabilization of specific conformations critical for proper folding and trafficking, or a greater ability to bypass cellular quality control checkpoints that would otherwise target misfolded F508del-CFTR for degradation. If earlier correctors only achieved partial rescue, VX-828, in its combination, might more effectively guide the protein through its complex biogenesis pathway, resulting in a substantially higher density of functional channels at the plasma membrane.

4. Therapeutic Indication: Cystic Fibrosis

The primary therapeutic indication for VX-828 is Cystic Fibrosis (CF), a life-limiting autosomal recessive genetic disorder.[1] The initial clinical evaluation of VX-828 in CF patients, as detailed in Part E of the NCT06154447 trial, focuses on adults aged 18 years and older.[13] A key characteristic of this target patient cohort is their genetic makeup: heterozygous for the F508del CFTR mutation and possessing a second CFTR allele classified as a minimal function (MF) mutation that is not responsive to the highly effective modulator therapy elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA).[13] Furthermore, eligible patients for this specific arm of the study are required to have a baseline lung function, measured as Forced Expiratory Volume in 1 second (FEV1), of ≥40% predicted, and a bodyweight of ≥35 kg.[27] An interesting aspect of the trial design for this cohort is the requirement for participants to be stable on Trikafta (elexacaftor/tezacaftor/ivacaftor) prior to enrollment, suggesting an evaluation of whether the new VX-828 containing regimen can offer additional benefits or address tolerability issues in this population.[27] This initial focus on F508del/MF patients who are sub-optimal responders to current HEMTs underscores a commitment to addressing a significant unmet medical need.

The development of next-generation modulators like VX-828 aims to address several unmet needs in CF care. The overarching ambition is to elevate CFTR function to "normal levels" for all eligible individuals, suggesting that even the most effective current therapies do not achieve this benchmark for every patient or to a complete extent.[2] The NG 3.0 regimen, which includes VX-828, is projected to offer "even greater improvement in CFTR-dependent chloride transport than in ALYFTREK".[2] ALYFTREK (vanzacaftor/tezacaftor/deutivacaftor), itself a newer generation modulator, demonstrated further reductions in sweat chloride concentrations compared to Trikafta in clinical trials, indicating a continuous pursuit of enhanced CFTR activity.[15] Approximately 10% of the CF population remains nonresponsive or intolerant to existing CFTR modulators, representing a critical group for whom new therapeutic options are urgently needed.[25] Additionally, improvements in treatment convenience, such as the once-daily dosing achieved with Alyftrek [30], are desirable attributes that future regimens, potentially including VX-828, might also target to enhance long-term patient adherence.

The strategic decision to initially target F508del/MF patients who are non-responsive to ELX/TEZ/IVA in the NCT06154447 Part E study is noteworthy.[13] Demonstrating clear efficacy in this particularly challenging patient population would provide compelling evidence of the VX-828 regimen's potential superiority and distinct value. If a new therapeutic only offers marginal improvements in patients already well-managed by existing treatments, its clinical utility and market positioning can be difficult. However, achieving significant gains in a group with limited or no current modulator options would immediately establish a critical clinical niche and address a pressing unmet medical need, potentially streamlining regulatory pathways and encouraging physician adoption.

Moreover, the advent of successively more potent CFTR modulator regimens, such as the one involving VX-828, may lead to a re-evaluation of how "responsiveness" to CFTR modulator therapy is defined. CFTR mutations previously categorized as "minimal function" or "non-responsive" based on their interaction with older modulators might become amenable to effective treatment with these more powerful combinations. The classification of a mutation's responsiveness is inherently relative to the efficacy of available therapeutic agents. As the potency of modulators increases—a trend evident from the progression from Kalydeco to Orkambi, Symdeko, Trikafta, Alyftrek, and potentially to the VX-828 regimen—the threshold for what is considered a "treatable" mutation may shift. This has significant implications for genetic screening protocols, diagnostic algorithms, and patient access to transformative therapies. The ongoing generation of new evidence for modulator response in additional rare mutations supports this evolving landscape.[34]

If the VX-828 regimen successfully elevates CFTR function to near-normal levels for a broader spectrum of patients, particularly if initiated early in life, the long-term impact could be a profound reduction in the accumulation of irreversible organ damage, such as bronchiectasis and pancreatic insufficiency, which are hallmarks of CF. This would represent a significant step beyond symptomatic relief, towards true disease modification from an early age, fundamentally altering the natural history of cystic fibrosis for affected individuals. The emphasis on improving sweat chloride levels, a direct physiological measure of CFTR function, as seen with Alyftrek [15], and the aspiration for even greater CFTR activity with the VX-828 regimen [2], are consistent with this long-term vision of profound disease modification.

5. Preclinical Development Highlights

The preclinical development of VX-828, particularly as part of the NG 3.0 regimen, has centered on demonstrating superior efficacy in established in vitro models that are considered predictive of clinical response in cystic fibrosis.

In Vitro Efficacy in Human Bronchial Epithelial (HBE) Cells:

A significant preclinical finding is that the VX-828 combination regimen (NG 3.0) has been described by Vertex Pharmaceuticals as the "most efficacious CFTR corrector Vertex has ever studied in vitro in Human Bronchial Epithelial (HBE) assays".1 Specifically, this regimen, comprising VX-828, VX-118 (Deutivacaftor), and Tezacaftor, demonstrated "even greater improvement in CFTR-dependent chloride transport than in ALYFTREK" in these HBE cell assays.2 Vertex has emphasized that their HBE cell assays have proven to be "highly predictive of clinical outcomes".2 HBE cells cultured from individuals with CF, especially those homozygous or heterozygous for the F508del-CFTR mutation, are a gold-standard preclinical model. These cells are used to assess the ability of investigational CFTR modulators to rescue the trafficking of the mutant CFTR protein to the cell surface and to restore its function as a chloride channel. An increase in chloride transport in these assays is a key in vitro endpoint that correlates with potential clinical efficacy.21

Comparative Preclinical Performance:

The preclinical data position the VX-828 based NG 3.0 regimen as superior to ALYFTREK (vanzacaftor/tezacaftor/deutivacaftor, designated NG 2.0) in these in vitro HBE assays.2 ALYFTREK, in its own development, was designed to offer improvements over TRIKAFTA (elexacaftor/tezacaftor/ivacaftor, NG 1.0), with a particular focus on achieving further reductions in sweat chloride levels, a direct measure of CFTR function.15 This hierarchical demonstration of improved efficacy in preclinical models forms the scientific basis for advancing these next-generation combinations into human clinical trials.

Pharmacokinetics (PK), ADME, and Toxicology (Preclinical):

Specific details regarding the preclinical pharmacokinetics, absorption, distribution, metabolism, excretion (ADME), or toxicology profile of VX-828 are not extensively provided in the currently available snippets. While general principles of PK/PD in drug development 39 and data for other compounds 41 are mentioned, these do not directly delineate VX-828's specific preclinical characteristics. It is standard pharmaceutical practice that comprehensive preclinical PK, ADME, and toxicology evaluations in relevant animal models are completed before an investigational drug progresses to first-in-human studies. Although not detailed here, such studies would have been integral to the regulatory submissions for initiating Phase 1 trials of VX-828.

While the assertion of "greater improvement in CFTR-dependent chloride transport" for the VX-828 regimen compared to ALYFTREK in HBE cells is a strong claim [2], the precise magnitude of this improvement is not quantified in the provided information. This quantitative difference—whether it represents a modest or a substantial increase in chloride transport—would be critical for assessing the potential for clinically meaningful differentiation from existing highly effective therapies. The degree of enhanced efficacy observed in these preclinical assays would significantly shape expectations for clinical trial outcomes and the ultimate therapeutic advantage for patients. This missing quantitative detail remains a key aspect for future data disclosures.

The progression from TRIKAFTA (NG 1.0) to ALYFTREK (NG 2.0) and now to the VX-828 regimen (NG 3.0) suggests that Vertex is continually elevating its internal benchmarks for what defines a successful CFTR modulator. Initial therapeutic goals focused on achieving significant clinical improvements; the current aspiration is to reach "normal levels of CFTR function".[2] This indicates that even with the availability of highly effective therapies like Trikafta and Alyftrek, Vertex identifies further opportunities for enhancing CFTR function. The emphasis on the VX-828 regimen's superiority in HBE cell assays over already successful drugs points to a research and development strategy focused on maximizing biochemical correction, under the premise that this will translate into even better and more comprehensive long-term clinical outcomes for individuals with CF. The company's stated confidence in the predictive power of its HBE cell assays [2] suggests that the promising in vitro data for VX-828 provides a strong rationale for its continued clinical development and a heightened probability of success in human trials.

6. Clinical Development Program

VX-828 is currently undergoing Phase 1 clinical development, marking its initial evaluation in human subjects.[3] Phase 1 trials are primarily designed to assess the safety, tolerability, and pharmacokinetic (PK) profile of an investigational drug. In some instances, particularly for diseases like cystic fibrosis where biomarkers of drug activity are available, early signals of efficacy may also be explored in small cohorts of patients. Two key clinical trials have been identified for VX-828: NCT06154447 (VX23-828-001) and NCT06861413 (VX25-828-002).

Table 2: Overview of Key Clinical Trials for VX-828

Feature	NCT06154447 (VX23-828-001)	NCT06861413 (VX25-828-002)
Vertex Study ID	VX23-828-001	VX25-828-002
Phase	Phase 1	Phase 1
Brief Title/Purpose	A Phase 1 Study of VX-828 in Healthy Subjects and in Subjects With Cystic Fibrosis. To evaluate safety, tolerability, and PK of VX-828 alone and in TC.	A Phase 1 Study to Evaluate the Relative Bioavailability of a VX-828 Tablet Formulation compared to suspension.
Status	Recruiting (as of Jan 15, 2025)	Active, not recruiting 3
Key Interventions	VX-828 (suspension/tablet), Tezacaftor (tablet), Deutivacaftor/VX-118 (tablet), Placebo, Itraconazole, Midazolam	VX-828 (tablet formulation), VX-828 (suspension)

6.1. Clinical Trial NCT06154447 (Vertex Study ID: VX23-828-001)

This multi-part Phase 1 study, titled "A Phase 1, Study of VX-828 in Healthy Subjects and in Subjects With Cystic Fibrosis," is sponsored by Vertex Pharmaceuticals Incorporated and is actively recruiting participants.[3] The primary objective is to evaluate the safety, tolerability, and pharmacokinetics of VX-828 administered as a single agent and as part of a triple combination (TC) regimen with Tezacaftor (TEZ) and VX-118 (Deutivacaftor) in both healthy adult volunteers and adult participants with CF.[13]

The study is divided into several parts:

• Part A (SAD): Single Ascending Doses of VX-828 (oral suspension) versus placebo in healthy participants.[13]
• Part B (MAD): Multiple Ascending Doses of VX-828 (oral suspension) versus placebo in healthy participants.[13]
• Part C (DDI): An open-label, optional cohort in healthy participants to assess drug-drug interactions. This involves VX-828 with Itraconazole (oral solution), and the triple combination of VX-828/TEZ/VX-118 (or Deutivacaftor) with Midazolam (oral syrup).[13]
• Part D (TC in Healthy): VX-828 (oral suspension) in triple combination with TEZ (tablets) and VX-118/Deutivacaftor (tablets) versus placebo in healthy participants.[13]
• Part E (TC in CF Patients): An open-label evaluation of VX-828 (tablets) in triple combination with TEZ (tablets) and Deutivacaftor (tablets) in adult CF patients.[13]

The study aims to enroll an estimated 225 participants in total.[13] It commenced on December 12, 2023, with an estimated primary completion date of April 30, 2025, and an estimated study completion date around December 31, 2025, to February 4, 2026.[3]

Primary outcome measures across all parts include safety and tolerability, assessed by the number of participants experiencing adverse events (AEs) and serious adverse events (SAEs). Pharmacokinetic parameters such as maximum observed concentration (Cmax​) and area under the concentration-time curve (AUC) for VX-828 (Parts A, B) and for VX-828, TEZ, Deutivacaftor, and their metabolites (Parts D, E) are also primary endpoints.[13] For Part E, a key secondary outcome is the absolute change in sweat chloride concentration, a direct measure of CFTR function, along with pre-dose plasma concentrations (Ctrough​) of the study drugs and their metabolites.[13]

Eligibility criteria for healthy volunteers (Parts A-D, ages 18-55) include a BMI between 18.0 and 32.0 kg/m², a total body weight >50 kg, and non-smoker status. For CF patients (Part E, ages ≥18), criteria include a confirmed CF diagnosis, body weight ≥35 kg, heterozygous for the F508del mutation with a second CFTR allele carrying a minimal function mutation not responsive to ELX/TEZ/IVA therapy, and an FEV1 ≥40% predicted. Part E participants are also required to be stable on Trikafta prior to enrollment.[13] General exclusion criteria include acute illness or conditions affecting drug absorption. Specific exclusions for Part E involve certain CF-related complications like particular lung infections or clinically significant cirrhosis.[13] The trial is being conducted at sites in the United States, including Altasciences Clinical Kansas in Overland Park.[28]

6.2. Clinical Trial NCT06861413 (Vertex Study ID: VX25-828-002)

This Phase 1 study, titled "A Phase 1 Study to Evaluate the Relative Bioavailability of a VX-828 Tablet Formulation," is also sponsored by Vertex Pharmaceuticals Incorporated.[10] Its primary purpose is to compare the relative bioavailability of a new VX-828 tablet formulation against a VX-828 suspension formulation. The study will also assess the safety and tolerability of the tablet formulation.[10]

The trial is designed to enroll approximately 68 healthy adult volunteers aged 18-55.[10] The study status has been reported as "Active - Not Recruiting" as of May 5, 2025 [3], though earlier updates in March 2025 indicated "Active - Recruiting".[16] The study was scheduled to start on April 1, 2025, with an estimated primary completion date of May 12, 2025, and study completion around the same time.[3] The design is likely a randomized, crossover study, a common approach for bioavailability assessments.[12]

Key interventions are the VX-828 tablet formulation and the VX-828 suspension.[10] While specific outcome measures for this trial are not detailed in the snippets for VX-828, they would typically include standard pharmacokinetic parameters (Cmax​, AUC, Tmax​) to determine relative bioavailability, alongside comprehensive safety and tolerability monitoring. Eligibility criteria for these healthy volunteers include a BMI of 18.0-32.0 kg/m², body weight >50 kg, non-smoker status, and non-childbearing potential. Exclusions involve recent febrile or acute illness and any condition that might affect drug absorption.[10]

The rapid pace of development, evidenced by the initiation of a dedicated formulation bioavailability study (NCT06861413) concurrently with or shortly after the broader SAD/MAD/DDI and early patient cohort study (NCT06154447), suggests a high degree of confidence from Vertex in the fundamental properties of VX-828.[10] Such parallel or closely sequenced activities often indicate a strategy to compress overall development timelines, which is common when a company believes it possesses a potentially best-in-class therapeutic asset.

The consistent pairing of VX-828 and Tezacaftor with Deutivacaftor (VX-118) in the triple combination arms of NCT06154447 reinforces the strategic importance of Deutivacaftor as Vertex's chosen next-generation potentiator.[13] This selection, likely driven by an improved pharmacokinetic or pharmacodynamic profile compared to ivacaftor (e.g., suitability for once-daily dosing), indicates its integral role in the envisioned final therapeutic product. The design of Part E in NCT06154447, which includes CF patients with minimal function mutations and assesses sweat chloride as an outcome measure, points to a strategy aimed at obtaining early proof-of-concept of clinical benefit in a patient population with high unmet need.[13] Positive results from this cohort could significantly expedite future development decisions and discussions with regulatory authorities.

7. Combination Therapy Strategy: The NG 3.0 Regimen

The development of VX-828 is intrinsically linked to its role within a triple combination therapy, designated by Vertex Pharmaceuticals as the "Next-Generation 3.0 CFTRm Regimen" (NG 3.0 regimen). This regimen comprises VX-828, identified as a next-generation CFTR corrector; Tezacaftor, an established CFTR corrector; and Deutivacaftor (also known as VX-118), a next-generation CFTR potentiator.[1]

The rationale for this triple combination approach is rooted in the mechanistic understanding of CFTR protein dysfunction and the synergistic potential of different classes of modulators. CFTR correctors, such as VX-828 and Tezacaftor, are designed to address the primary folding and trafficking defects of mutant CFTR proteins (particularly F508del-CFTR), thereby increasing the quantity of CFTR protein that reaches the epithelial cell surface.[15] CFTR potentiators, like Deutivacaftor, work to enhance the channel gating function of the CFTR protein already present at the cell surface, increasing the probability that the channel is open and allowing for greater transepithelial chloride and bicarbonate transport.[15] By combining these distinct mechanisms, the NG 3.0 regimen aims to maximize both the amount and the activity of functional CFTR protein, leading to a more robust physiological effect. This strategy builds upon the proven success of earlier triple-combination CFTR modulators, most notably elexacaftor/tezacaftor/ivacaftor (Trikafta/Kaftrio), which has set a high standard for efficacy in CF treatment.[14] The NG 3.0 regimen seeks to further elevate this standard by incorporating potentially more effective or complementary next-generation components.

Vertex's concept of an "NG 3.0 regimen" explicitly positions this therapeutic approach as the third iteration in their evolving CFTR modulator portfolio, following Trikafta/Kaftrio (NG 1.0) and Alyftrek (vanzacaftor/tezacaftor/deutivacaftor, NG 2.0).[2] The stated objective for this advanced regimen is to achieve "even greater improvement in CFTR-dependent chloride transport" than that observed with ALYFTREK, with the ultimate aspiration of enabling patients to reach "normal levels of CFTR function".[2] This nomenclature and the clearly defined goals underscore Vertex's commitment to continuous innovation within the CF therapeutic space.

A critical component of the NG 3.0 regimen is Deutivacaftor (VX-118). This molecule is the deuterated analog of ivacaftor, a highly effective CFTR potentiator.[2] Deuteration, the strategic replacement of hydrogen atoms with deuterium, is a medicinal chemistry technique that can modify a drug's metabolic profile, often leading to improved pharmacokinetic characteristics such as a longer half-life or reduced rate of metabolic clearance.[46] The selection of Deutivacaftor for the NG 3.0 regimen, rather than ivacaftor itself, suggests a targeted effort to optimize the potentiator component, potentially for enhanced dosing convenience (e.g., facilitating a once-daily regimen for the entire triple combination) or more consistent drug exposure levels.

The anticipated benefits of the NG 3.0 regimen, driven by the inclusion of VX-828, are significant. These include the potential for achieving higher levels of CFTR function restoration than currently possible, which could translate to further improvements in clinical outcomes such as lung function, sweat chloride levels, nutritional status, and overall quality of life for individuals with CF.[1] Furthermore, a more potent regimen may expand effective treatment options to a broader range of CF patients, including those with specific genotypes that exhibit a suboptimal response to existing modulator therapies.

The NG 3.0 strategy likely relies on achieving a greater quantity of partially corrected F508del-CFTR at the cell surface through the combined, and potentially synergistic, actions of the two correctors, VX-828 and Tezacaftor. This increased pool of cell-surface CFTR can then be more effectively gated by the potent next-generation potentiator, Deutivacaftor/VX-118, resulting in superior overall chloride transport. The "greater efficacy" noted in preclinical HBE cell assays [2] likely stems from optimized activity in both the correction and potentiation phases of CFTR rescue.

While not explicitly detailed for the VX-828 regimen in the provided documents, the development of Alyftrek (NG 2.0) with a once-daily dosing schedule [30] signals a broader strategic objective at Vertex to improve treatment convenience. Reducing pill burden and simplifying dosing regimens are crucial for enhancing long-term adherence and quality of life in chronic conditions like CF. It is therefore plausible that the NG 3.0 regimen, with its next-generation components, is also being developed with the goal of a simplified, ideally once-daily, dosing schedule. This would depend on the collective pharmacokinetic profiles of VX-828, Tezacaftor, and Deutivacaftor. The success of such a regimen could further solidify the multi-component corrector-potentiator strategy as the cornerstone of CF pharmacotherapy, with continuous refinement of individual drug components aimed at maximizing therapeutic benefit and patient convenience, thereby pushing the boundaries towards a functional cure for a larger proportion of the CF population.

8. Formulation

VX-828 is being developed as an orally administered medication, a route that is critical for chronic therapies like those for cystic fibrosis.[3] The clinical development program for VX-828 includes the evaluation of different oral formulations.

In the multi-part Phase 1 clinical trial NCT06154447 (VX23-828-001), VX-828 is being administered as an oral suspension in the initial single ascending dose (SAD, Part A) and multiple ascending dose (MAD, Part B) cohorts in healthy volunteers, as well as in the triple combination cohort in healthy volunteers (Part D).[13] However, for Part E of the same study, which involves CF patients receiving the triple combination, VX-828 is being administered as tablets.[13]

Further emphasizing the focus on an optimized solid oral dosage form, Vertex Pharmaceuticals has initiated a dedicated Phase 1 clinical trial, NCT06861413 (VX25-828-002). The specific purpose of this study is to evaluate the relative bioavailability of a VX-828 tablet formulation compared to the VX-828 suspension formulation in healthy adult volunteers.[10]

The use of simpler formulations like suspensions is common in early-phase clinical trials, particularly for dose-finding and initial safety assessments. However, the progression to and specific evaluation of a tablet formulation is a key step in pharmaceutical development. Tablets generally offer advantages in terms of stability, dosing accuracy, patient convenience, and manufacturing scalability compared to liquid suspensions, especially for long-term administration.

The initiation of a dedicated bioavailability study (NCT06861413) focused on comparing tablet and suspension formulations of VX-828 early in its Phase 1 development program underscores the importance Vertex Pharmaceuticals places on establishing a patient-friendly and commercially viable oral dosage form.[10] For a chronic condition requiring likely lifelong therapy, such as cystic fibrosis, the ease of use, portability, and taste-masking potential of a tablet formulation are significant factors that can influence patient adherence and overall treatment success. By addressing formulation optimization at this early stage, Vertex aims to ensure consistent drug delivery and potentially mitigate delays that could arise later in the development pathway if formulation issues were deferred. A successful, stable, and consistently bioavailable oral tablet formulation for VX-828, and subsequently for its combination partners in the NG 3.0 regimen, will be critical for maximizing the real-world effectiveness and patient acceptance of this next-generation therapy, should it ultimately gain regulatory approval.

9. Future Outlook

The clinical development of VX-828, as a key component of Vertex's NG 3.0 regimen, is progressing with significant anticipation within the cystic fibrosis community. The company has outlined plans to initiate a clinical trial of the VX-828 combination regimen in CF patients by the end of 2025.[1] This timeline suggests that the initial safety and pharmacokinetic data from the ongoing Phase 1 studies in healthy volunteers (NCT06154447 Parts A-D, NCT06861413) are likely meeting internal progression criteria. While one source hinted at a potential advancement to Phase 2 in the latter half of 2025 [1], the specific compound was not definitively VX-828, but the general timeline aligns with an accelerated development pathway. Successful completion of the current Phase 1 investigations, demonstrating an acceptable safety profile and predictable pharmacokinetics, will be pivotal for advancing VX-828 into larger Phase 2 trials designed to assess efficacy in a broader CF patient population.

The potential impact of the VX-828-based NG 3.0 regimen on the CF treatment landscape is substantial. Vertex's aspiration to achieve "normal levels of CFTR function" with this regimen sets a new benchmark for therapeutic ambition.[2] If the robust preclinical efficacy observed in HBE cell assays translates into superior clinical outcomes, patients could experience further improvements in lung function, more significant reductions in sweat chloride concentrations (a direct indicator of CFTR activity), better nutritional status, and an enhanced quality of life, potentially exceeding the benefits conferred by current leading therapies like Trikafta and Alyftrek. Moreover, a more potent and potentially broadly acting regimen could expand effective treatment options for individuals with CF who have specific genotypes that yield a limited or suboptimal response to currently approved CFTR modulators.

The development of VX-828 is a clear testament to Vertex's sustained commitment to the CF community. The company's stated mission to "bring all patients with CF to normal levels of CFTR function" and to continuously "raise the bar ever higher" for therapeutic efficacy is evident in their iterative drug discovery and development approach.[2] Beyond small molecule CFTR modulators like VX-828, Vertex's comprehensive CF portfolio includes investigational mRNA therapies (e.g., VX-522) aimed at treating the approximately 5-10% of CF patients whose mutations do not produce any CFTR protein and are therefore not amenable to corrector/potentiator therapies.[1] This multi-pronged strategy underscores a long-term vision to provide transformative treatments for virtually all individuals living with CF.

Vertex's ambitious goal of achieving "normal levels of CFTR function" with regimens like the VX-828 combination is pushing the therapeutic frontier closer to what might be considered a "functional cure" for many individuals with CF.[2] While not a genetic cure that corrects the underlying DNA defect, restoring CFTR protein activity to near-normal physiological levels could profoundly minimize the diverse and progressive manifestations of the disease. If successful, this could transform CF into a condition where the daily symptomatic burden is substantially reduced, potentially allowing for a life expectancy and quality of life that closely mirrors that of individuals without CF. This represents a significant evolution from merely improving key clinical markers to fundamentally altering the disease's long-term trajectory.

The rapid succession of "next-generation" CFTR modulator regimens—from Trikafta/Kaftrio (NG 1.0) to Alyftrek (NG 2.0), and now to the investigational VX-828 regimen (NG 3.0)—indicates that Vertex is engaged in a highly competitive internal innovation cycle.[2] This strategy of actively seeking to improve upon their own market-leading products ensures that the company remains at the forefront of CF therapeutic development. It is a proactive approach to pre-empt potential external competition by consistently advancing the standard of care through internal R&D. The timeline for initiating studies in CF patients by the end of 2025 for the VX-828 regimen is an indirect positive indicator.[1] It suggests that the early data from healthy volunteer cohorts in NCT06154447 and the formulation studies in NCT06861413 are likely yielding results that support continued investment and progression into patient populations.

10. Conclusion

VX-828 is an investigational, orally administered, next-generation small molecule CFTR corrector currently in Phase 1 clinical development by Vertex Pharmaceuticals. It forms a critical part of the "NG 3.0 regimen," a novel triple combination therapy that also includes the CFTR corrector Tezacaftor and the CFTR potentiator Deutivacaftor (VX-118). Preclinical studies, particularly in Human Bronchial Epithelial (HBE) cell assays, have indicated that this regimen possesses superior efficacy in restoring CFTR-dependent chloride transport compared to previous modulator combinations, including ALYFTREK. Current Phase 1 clinical trials (NCT06154447 and NCT06861413) are designed to meticulously evaluate the safety, tolerability, and pharmacokinetic profile of VX-828, both as a single agent and in its intended triple combination, in healthy volunteers and in adults with cystic fibrosis. These studies are also focused on optimizing its oral formulation.

Should the promising preclinical signals be replicated in human clinical trials, the VX-828-based NG 3.0 regimen holds the potential to significantly advance the treatment of cystic fibrosis. By aiming to restore CFTR function to even higher, potentially near-normal levels, this therapy could offer enhanced clinical benefits to a broad spectrum of CF patients. This includes individuals with specific genotypes who currently have limited therapeutic options or derive suboptimal benefit from existing CFTR modulators. The ongoing commitment from Vertex Pharmaceuticals to iterative innovation in CF is evident in the progression to this "third-generation" modulator regimen.

The readouts from the ongoing Phase 1 trials will be critical in determining the future trajectory of VX-828. Positive data will pave the way for larger Phase 2 and Phase 3 studies to definitively establish its efficacy and safety in diverse CF populations. Future research will likely focus on precisely defining the patient subgroups who stand to benefit most from this new regimen and understanding the long-term clinical and physiological impacts of achieving near-normal CFTR function.

As therapeutic interventions aim for "normal CFTR function," the metrics for evaluating success in CF clinical trials may need to evolve. While FEV1 remains a crucial endpoint, biomarkers that reflect a more holistic physiological correction—such as the normalization of sweat chloride concentrations, modulation of inflammatory markers, and arrest or reversal of structural lung damage—could gain increasing prominence.[13] If lung function is already well-preserved or significantly improved by prior highly effective modulators, demonstrating substantial further gains in FEV1 might be challenging. However, improvements in CFTR function at the cellular and organ levels, even if FEV1 changes are modest in some populations, could translate into significant long-term benefits, including reduced systemic disease burden and prevention of comorbidities. The development of VX-828 and the NG 3.0 regimen represents a continued, sophisticated commitment to molecularly targeted therapy in cystic fibrosis, driven by a deep understanding of CFTR protein biology and a systematic medicinal chemistry effort. This approach sets a high standard for innovation in the development of treatments for rare genetic diseases.

Works cited

1. First Quarter 2025 Financial Results - Investor Relations | Vertex ..., accessed June 4, 2025, https://investors.vrtx.com/static-files/f1e5e23f-953d-442a-b8b9-db44de4bdea9
2. Vertex Pharmaceuticals (VRTX) Q4 2024 Earnings Call Transcript ..., accessed June 4, 2025, https://www.fool.com/earnings/call-transcripts/2025/02/10/vertex-pharmaceuticals-vrtx-q4-2024-earnings-call/
3. VX-828 Drug Profile - Ozmosi, accessed June 4, 2025, https://pryzm.ozmosi.com/product/31857
4. Health Risk Assessment for The Nerve Agent VX - NCBI, accessed June 4, 2025, https://www.ncbi.nlm.nih.gov/books/NBK208324/
5. TEZACAFTOR - Inxight Drugs - ncats, accessed June 4, 2025, https://drugs.ncats.io/drug/tezacaftor
6. EP3473618A1 - 6-substituted 3-fluoro-2-pyridinaldoxime, 3-fluoro-2-pyridine hydroxamic acid, and 3-fluoro-2-pyridinamidoxime scaffolds - Google Patents, accessed June 4, 2025, https://patents.google.com/patent/EP3473618A1/en
7. Provide a document that describes your proposed sabbatical activities. The document should include at a minimum the following components: - • Project Abstract/Executive Summary - Lake Superior State University, accessed June 4, 2025, https://www.lssu.edu/wp-content/uploads/2020/11/Mosey-Proposal-web.pdf
8. US20240285596A1 - Solid dosage forms and dosing regimens comprising (2r,3s,4s,5r)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl) tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide - Google Patents, accessed June 4, 2025, https://patents.google.com/patent/US20240285596A1/ko
9. Vertex Reports First Quarter 2025 Financial Results, accessed June 4, 2025, https://news.vrtx.com/news-releases/news-release-details/vertex-reports-first-quarter-2025-financial-results
10. Our Science | R&D Pipeline - Vertex Pharmaceuticals, accessed June 4, 2025, https://www.vrtx.com/our-science/pipeline/
11. VX-118 - Drug Targets, Indications, Patents - Patsnap Synapse, accessed June 4, 2025, https://synapse.patsnap.com/drug/5f59514ab5e84aefbc8eb8193f9b0be8
12. VX-118 by Vertex Pharmaceuticals for Cystic Fibrosis: Likelihood of Approval, accessed June 4, 2025, https://www.pharmaceutical-technology.com/data-insights/vx-118-vertex-pharmaceuticals-cystic-fibrosis-likelihood-of-approval/
13. Evaluation of VX-828 in Healthy Participants and in Parti... - Esperity Clinical Trials, accessed June 4, 2025, https://clinicaltrial.be/en/details/420124?per_page=20&only_recruiting=0&only_eligible=0&only_active=0
14. Redox Imbalance in Cystic Fibrosis: The Multifaceted Role of Oxidative Stress - MDPI, accessed June 4, 2025, https://www.mdpi.com/1424-8247/18/6/784
15. Alyftrek® Common Name: vanzacaftor, tezacaftor, and deutivacaftor PDL Category: Cystic Fibrosis Agents - PDL DRUG REVIEW, accessed June 4, 2025, https://www.iowamedicaidpdl.com/content/dam/ffs-medicare/ia/drug-monographs/ndr-alyftrek-02122025.pdf
16. A Phase 1 Study to Evaluate the Relative Bioavailability of a VX-828 Tablet Formulation | Clinical Research Trial Listing - CenterWatch, accessed June 4, 2025, https://www.centerwatch.com/clinical-trials/listings/NCT06861413/a-phase-1-study-to-evaluate-the-relative-bioavailability-of-a-vx-828-tablet-formulation?id=53&slug=cystic-fibrosis
17. CFTR Modulator Types - Cystic Fibrosis Foundation, accessed June 4, 2025, https://www.cff.org/managing-cf/cftr-modulator-types
18. Small molecule correctors of F508del-CFTR discovered by structure-based virtual screening, accessed June 4, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4010227/
19. Effects of Elexacaftor/Tezacaftor/Ivacaftor on Cardiorespiratory Polygraphy Parameters and Respiratory Muscle Strength in Cystic Fibrosis Patients with Severe Lung Disease - MDPI, accessed June 4, 2025, https://www.mdpi.com/2073-4425/14/2/449
20. The revolution of personalized pharmacotherapies for cystic fibrosis: what does the future hold? - PMC, accessed June 4, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10528905/
21. Tezacaftor / Ivacftor / VX-445 (TRKAFTA or KAFTRIO) - Cystic Fibrosis Medicine, accessed June 4, 2025, https://cysticfibrosis.online/tezacaftor-ivacftor-vx-445/
22. Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-Targeted Therapeutics for Cystic Fibrosis | Request PDF - ResearchGate, accessed June 4, 2025, https://www.researchgate.net/publication/380089121_Cystic_Fibrosis_Transmembrane_Conductance_Regulator_CFTR-Targeted_Therapeutics_for_Cystic_Fibrosis
23. Discovery of GLPG2737, a Potent Type 2 Corrector of CFTR for the Treatment of Cystic Fibrosis in Combination with a Potentiator and a Type 1 Co-corrector | Journal of Medicinal Chemistry - ACS Publications, accessed June 4, 2025, https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c01790
24. One Size Does Not Fit All: The Past, Present and Future of Cystic Fibrosis Causal Therapies, accessed June 4, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9220995/
25. Using a Systems Approach to Identify the Mechanism of Action of Correctors - Repositório da Universidade de Lisboa, accessed June 4, 2025, https://repositorio.ulisboa.pt/bitstream/10451/34859/1/ulsd732235_td_Nikhil_Awatade.pdf
26. Recommended Tool Compounds for Modifying the Cystic Fibrosis Transmembrane Conductance Regulator Channel Variants - ACS Publications, accessed June 4, 2025, https://pubs.acs.org/doi/10.1021/acsptsci.3c00362
27. Study of VX-828 in combination with Tezacaftor and Deutivacaftor in healthy participants and in adults with cystic fibrosis. (VX23-828-001 Cohort E) | CFF Clinical Trials Tool - CFF.org, accessed June 4, 2025, https://apps.cff.org/Trials/Finder/details/757/Study-of-VX-828-in-combination-with-Tezacaftor-and-Deutivacaftor-in-healthy-participants-and-in-adults-with-cystic-fibrosis-
28. A Phase 1, Study of VX-828 in Healthy Subjects and in Subjects With Cystic Fibrosis, accessed June 4, 2025, https://www.medifind.com/conditions/Cystic%20Fibrosis/1467/clinical-trial/504452308
29. Evaluation of VX-828 in Healthy Participants and in Participants With Cystic Fibrosis | Clinical Research Trial Listing - CenterWatch, accessed June 4, 2025, https://www.centerwatch.com/clinical-trials/listings/NCT06154447/evaluation-of-vx-828-in-healthy-participants-and-in-participants-with-cystic-fibrosis
30. Vertex Highlights First Oral Presentation of Phase 3 Clinical Data of the Vanza Triple and New Data on Long-Term Impact of TRIKAFTA® at the North American Cystic Fibrosis Conference, accessed June 4, 2025, https://news.vrtx.com/news-releases/news-release-details/vertex-highlights-first-oral-presentation-phase-3-clinical-data
31. CF-AIR & CF@LANTA Newsletter March 2025 - Pediatric Research Alliance, accessed June 4, 2025, https://pedsresearch.org/uploads/pages/doc/CF-AIR-CF%40LANTA-Newsletter-March-2025.pdf
32. 2025 - Cystic Fibrosis Medicine, accessed June 4, 2025, https://cysticfibrosis.online/2025-2/
33. Advances in the treatment of cystic fibrosis: CFTR modulators | Anales de Pediatría, accessed June 4, 2025, https://www.analesdepediatria.org/en-advances-in-treatment-cystic-fibrosis-articulo-S2341287925001322
34. Patient and Clinician Group Input - Canada's Drug Agency, accessed June 4, 2025, https://www.cda-amc.ca/sites/default/files/DRR/2025/SR0896_Alyftrek_Patient_Clinician_Input.pdf
35. Vanzacaftor-tezacaftor-deutivacaftor for children aged 6-11 years with cystic fibrosis (RIDGELINE Trial VX21-121-105): an analysis from a single-arm, phase 3 trial - PubMed, accessed June 4, 2025, https://pubmed.ncbi.nlm.nih.gov/39756425/
36. Sweat chloride reflects CFTR function and correlates with clinical outcomes following CFTR modulator treatment | Request PDF - ResearchGate, accessed June 4, 2025, https://www.researchgate.net/publication/387736800_Sweat_chloride_reflects_CFTR_function_and_correlates_with_clinical_outcomes_following_CFTR_modulator_treatment
37. cftr mutation frequencies: Topics by Science.gov, accessed June 4, 2025, https://www.science.gov/topicpages/c/cftr+mutation+frequencies
38. common cftr mutation: Topics by Science.gov, accessed June 4, 2025, https://www.science.gov/topicpages/c/common+cftr+mutation.html
39. Preclinical Pharmacokinetic/Pharmacodynamic Studies and Clinical Trials in the Drug Development Process of EMA-Approved Antifungal Agents: A Review - PubMed Central, accessed June 4, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10786742/
40. Use of Preclinical Drug vs. Food Choice Procedures to Evaluate Candidate Medications for Cocaine Addiction - PMC - PubMed Central, accessed June 4, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4441409/
41. (PDF) Preclinical Pharmacokinetics, Toxicity and Therapeutic Evaluation of QD502, accessed June 4, 2025, https://www.researchgate.net/publication/389543251_Preclinical_Pharmacokinetics_Toxicity_and_Therapeutic_Evaluation_of_QD502?_tp=eyJjb250ZXh0Ijp7InBhZ2UiOiJzY2llbnRpZmljQ29udHJpYnV0aW9ucyIsInByZXZpb3VzUGFnZSI6bnVsbCwic3ViUGFnZSI6bnVsbH19
42. Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine - PMC, accessed June 4, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5511603/
43. Of rAAV and Men: From Genetic Neuromuscular Disorder Efficacy and Toxicity Preclinical Studies to Clinical Trials and Back - PubMed Central, accessed June 4, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7768510/
44. Bictegravir Plus Tenofovir Alafenamide Nanoformulation as a Long-Acting Pre-Exposure Prophylaxis Regimen: Application of Modeling to Design Non-Human Primate Pharmacokinetic Experiments - Frontiers, accessed June 4, 2025, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.603242/full
45. Cystic Fibrosis (CF) (DBCOND0040212) | DrugBank Online, accessed June 4, 2025, https://go.drugbank.com/conditions/DBCOND0040212
46. Category - Case Studies - Drug Hunter, accessed June 4, 2025, https://drughunter.com/category/case-studies
47. Clinical Trials Finder - CFF.org, accessed June 4, 2025, https://apps.cff.org/trials/finder/?search=%7B%22Keyword%22%3A%22ivacaftor%22%7D