Fipravirimat (GSK3640254): A Comprehensive Monograph on a Next-Generation HIV-1 Maturation Inhibitor and its Strategic Discontinuation

Section 1: Executive Summary and Compound Profile

1.1. Overview

[Fipravirimat, also known by its developmental codes GSK3640254 and BMS 986197, represents a significant chapter in the pursuit of novel antiretroviral therapies for Human Immunodeficiency Virus Type 1 (HIV-1). As an orally administered small molecule, Fipravirimat belongs to the investigational class of HIV-1 maturation inhibitors (MIs), agents designed to disrupt the final stages of the viral lifecycle. The drug was originated by Bristol Myers Squibb (BMS) and subsequently advanced through a comprehensive clinical development program by ViiV Healthcare, a specialist HIV company majority-owned by GSK.]

[The compound demonstrated potent, dose-dependent antiviral activity in early clinical studies, successfully engaging its target and validating its novel mechanism of action. This mechanism, termed sub-stoichiometric modulation, allowed a small number of drug molecules to disrupt the entire cooperative assembly of the viral Gag polyprotein shell, leading to high intrinsic potency. Fipravirimat was specifically engineered to overcome the limitations of previous-generation MIs, showing broad activity against HIV-1 strains with baseline Gag polymorphisms that had rendered earlier compounds ineffective.]

[Despite these promising attributes, the clinical program also revealed a critical vulnerability: a low genetic barrier to resistance, typified by the rapid emergence of the Gag A364V mutation in short-term monotherapy trials. After progressing through Phase IIb dose-ranging studies in combination with other antiretrovirals, ViiV Healthcare and GSK terminated the development of Fipravirimat in early 2023. The decision was not based on a catastrophic failure of efficacy or safety but on a strategic assessment of its place in the modern HIV treatment landscape. The primary rationales for its discontinuation were a lack of sufficient clinical differentiation compared to the highly effective and convenient standard-of-care regimens already on the market, and the presence of a clinically significant food effect, which would have compromised patient convenience. This monograph provides an exhaustive analysis of Fipravirimat's chemical properties, its sophisticated mechanism of action, its complete clinical development history, and the multi-faceted strategic and scientific factors that ultimately led to the cessation of its development.]

1.2. Compound Identification

Precise identification of an investigational compound is critical for scientific and regulatory clarity. Fipravirimat has been designated by multiple names and codes throughout its development. The International Nonproprietary Name (INN) stem '-virimat' explicitly categorizes it as an antiviral agent that acts as a disruptor of viral maturation.[1][ The compound's fundamental physicochemical and structural properties are consolidated in Table 1.]

Table 1: Fipravirimat Key Identifiers and Properties

Category	Identifier/Property	Source(s)
Names and Codes
International Nonproprietary Name (INN)	Fipravirimat	[1, 4]
Developmental Codes	GSK3640254, GSK'254, BMS 986197	[4, 5, 6]
Chemical Properties
Chemical Formula	$C_{43}H_{67}FN_{2}O_{4}S$	[4, 7]
Molar Mass	727.08 g·mol⁻¹	[4, 7]
Monoisotopic Mass	726.48055796 Da	[1, 7]
Structural Identifiers
IUPAC Name	(1R)-4--5a,5b,8,8,11a-pentamethyl-1-prop-1-en-2-yl-1,2,3,4,5,6,7,7a,11,11b,12,13,13a,13b-tetradecahydrocyclopenta[a]chrysen-9-yl]-1-(fluoromethyl)cyclohex-3-ene-1-carboxylic acid	[4, 7]
SMILES	CC(=C)[C@@H]1CC[C@]2([C@H]1[C@H]3CC[C@H]4[C@]([C@@]3(CC2)C)(CC[C@@H]5[C@@]4(CC=C(C5(C)C)C6=CC[C@@](CC6)(CF)C(=O)O)C)C)NCCN7CCS(=O)(=O)CC7	[4, 7]
InChIKey	YFSNREBZTKMFEB-DHGHKPCRSA-N	[4, 7]
Registration Numbers
CAS Number	1818867-24-1	[4, 7]
PubChem CID	118435805	[4, 7]
UNII	M5FP5REG5Q	[4, 7]
KEGG ID	D12523	[4, 7]
Drug Characteristics
Drug Type	Small Molecule	[1, 8]
Route of Administration	Oral	[8]

Section 2: The HIV-1 Maturation Inhibitor Class: A Novel Antiretroviral Paradigm

2.1. Introduction to HIV-1 Maturation as a Therapeutic Target

[The HIV-1 lifecycle is a multi-step process that offers numerous targets for antiretroviral intervention. While most established drug classes, such as reverse transcriptase inhibitors and integrase inhibitors, act during the early stages of infection, the final steps of viral assembly and maturation present a distinct and compelling therapeutic opportunity. After an infected host cell produces new viral components, these components assemble at the cell membrane into an immature, non-infectious virion. This immature particle then buds from the cell.]

For this new virion to become infectious, it must undergo a process of maturation. This critical step is driven by the viral protease enzyme, which systematically cleaves the large Gag and Gag-Pol polyproteins into their smaller, functional constituent proteins. The most crucial and final cleavage event occurs between the capsid protein (CA or p24) and spacer peptide 1 (SP1). This cleavage triggers a dramatic conformational rearrangement of the capsid proteins, which assemble into the characteristic conical core that houses the viral genetic material. This mature, conical core is essential for the virus to successfully infect a new cell. By specifically targeting and inhibiting this final cleavage event, maturation inhibitors prevent the formation of the mature core, effectively trapping the virus in an immature, non-infectious state.[9]

2.2. History and Evolution of Maturation Inhibitors (MIs)

[The development of Fipravirimat is best understood within the context of the historical evolution of the MI class, a journey marked by both significant promise and recurring challenges.]

2.2.1. First-Generation MIs (e.g., Bevirimat)

The first-in-class MI to enter clinical development was bevirimat (PA-457). This compound validated the Gag maturation process as a druggable target, demonstrating viral load reduction in clinical trials. However, its development was ultimately halted around 2010 due to a critical flaw: a significant portion of the patient population, estimated at up to 50%, exhibited baseline resistance. This inherent resistance was not due to prior drug exposure but was traced to naturally occurring genetic variations, or polymorphisms, in the Gag protein, particularly in the region spanning amino acids 369 to 371. These polymorphisms prevented bevirimat from binding effectively, rendering it inactive in a large subset of HIV-1 strains and making it commercially unviable.[9]

2.2.2. Second-Generation MIs (e.g., BMS-955176/GSK'795)

The failure of bevirimat spurred the development of second-generation MIs designed specifically to overcome the issue of baseline Gag polymorphisms. A leading candidate was BMS-955176 (later known as GSK3532795 or GSK'795), which demonstrated improved potency and activity against viruses containing the polymorphisms that conferred resistance to bevirimat.[12] However, this compound also encountered insurmountable hurdles in Phase IIb studies. After acquiring the asset from BMS, GSK discontinued its development due to a combination of dose-limiting gastrointestinal intolerability and the emergence of new treatment-related resistance mutations.[14]

2.2.3. Fipravirimat (GSK'254) as a Next-Generation Candidate

Fipravirimat (GSK'254) was engineered as the direct successor to BMS-955176. It emerged from a dedicated medicinal chemistry program that aimed to preserve the broad activity against Gag polymorphisms while optimizing the safety and tolerability profile that had plagued its predecessor.[12] The key structural difference between Fipravirimat and BMS-955176 was the replacement of a benzoic acid moiety with a substituted cyclohexene carboxylic acid, a modification that improved polymorphic coverage while maintaining favorable pharmacokinetic properties.[17][ Fipravirimat thus represented the most advanced effort to create a clinically and commercially viable MI.]

[The developmental trajectory of the MI class reveals a consistent pattern: each successive generation of compounds successfully addressed the primary virologic or tolerability limitation of its forerunner, only to uncover a new, more subtle liability. Bevirimat's failure was due to baseline polymorphisms. BMS-955176 solved that but failed due to tolerability and emergent resistance. Fipravirimat, in turn, improved on tolerability but still possessed a low barrier to emergent resistance and ultimately failed to meet the high commercial bar of the modern HIV market. This iterative process suggests that the Gag maturation target itself is fundamentally challenging, with the virus possessing multiple avenues for escape, making the development of a truly robust and durable inhibitor exceedingly difficult.]

2.3. Fipravirimat's Molecular Mechanism of Action

[Fipravirimat exerts its antiviral effect through a novel and highly specific mechanism that distinguishes it from all other approved antiretroviral classes.]

2.3.1. Target Engagement and Phenotypic Effect

Unlike protease inhibitors, which directly bind to and inhibit the active site of the HIV-1 protease enzyme, Fipravirimat binds to the Gag polyprotein itself, at or near the cleavage site between the CA (p24) and SP1 domains.[9] By binding to this site, it physically obstructs the protease from performing the final, rate-determining cleavage step required for maturation. This blockage has a profound morphological consequence. The virions produced in the presence of Fipravirimat are unable to form the mature, conical capsid core. Instead, they are released from the host cell with a defective, spherical, and immature core structure, rendering them non-infectious and incapable of propagating the infection.[9]

2.3.2. Sub-stoichiometric Modulation and Target Vulnerability

A particularly sophisticated aspect of Fipravirimat's mechanism is its ability to act via sub-stoichiometric modulation. The immature HIV-1 virion is essentially a large, ordered shell composed of approximately 1,300 to 1,600 individual Gag polyprotein monomers that interact in a cooperative fashion.[9] Fipravirimat exploits this cooperative structure. The binding of a relatively small number of Fipravirimat molecules to a fraction of the Gag monomers is sufficient to disrupt the entire assembly and prevent the maturation of the whole particle. This phenomenon, where the drug-to-target ratio required for inhibition is far less than 1:1, is a hallmark of "target vulnerability" and is responsible for the high in-vitro potency observed with Fipravirimat and other MIs.[10]

[While this sub-stoichiometric mechanism conferred impressive potency at the molecular level, this advantage did not translate into durable clinical efficacy when the drug was used as monotherapy. The potent initial viral load reduction was quickly negated by the virus's ability to develop resistance through simple mutations. This demonstrates a critical lesson from the Fipravirimat program: high intrinsic potency, even when achieved through an elegant mechanism like sub-stoichiometric modulation, cannot compensate for a fragile resistance profile in a highly mutable virus like HIV. The clinical durability of an antiretroviral is ultimately determined by its resistance barrier, not just its raw power.]

Section 3: Clinical Development Program: From First-in-Human to Phase IIb

3.1. Overview of Clinical Strategy

[The clinical development program for Fipravirimat was designed as a systematic, multi-stage process to evaluate its potential as a new antiretroviral agent. The strategy followed a logical progression: Phase I studies established the foundational safety, tolerability, and pharmacokinetic (PK) profile in healthy volunteers and assessed key drug-drug interactions. A Phase IIa proof-of-concept study then provided the first evidence of its antiviral activity in individuals living with HIV. Finally, two parallel Phase IIb studies were conducted to determine the optimal dose and evaluate its efficacy and safety as part of a complete combination antiretroviral regimen, which is the standard for HIV treatment.]

3.2. Phase I Studies: Safety, Tolerability, and Pharmacokinetics

The initial phase of clinical testing focused on establishing the fundamental human pharmacology of Fipravirimat. First-in-human (FIH) studies in healthy volunteers demonstrated that the compound was generally well-tolerated and possessed a PK profile that supported convenient once-daily oral dosing.[20]

A critical step for any new HIV drug is to assess its potential for interactions with existing therapies, as it will almost certainly be used in combination. Dedicated drug-drug interaction (DDI) studies were conducted and found no clinically meaningful interactions between Fipravirimat and two key components of modern HIV regimens: the nucleotide reverse transcriptase inhibitor backbone of tenofovir alafenamide/emtricitabine (TAF/FTC) and the cornerstone integrase inhibitor dolutegravir (DTG).[21] These favorable DDI results were essential for advancing Fipravirimat into combination therapy trials. Furthermore, a thorough QT/QTc study, a regulatory requirement to assess a drug's potential to cause cardiac arrhythmias, was conducted and showed that Fipravirimat did not have a clinically relevant effect on the QT interval, clearing a significant safety hurdle.[8]

3.3. Phase IIa Proof-of-Concept Study (NCT03784079)

The first test of Fipravirimat's efficacy in people living with HIV came in the NCT03784079 study, a pivotal trial whose results were presented at the Conference on Retroviruses and Opportunistic Infections (CROI) in 2021.[24]

3.3.1. Study Design

This was a randomized, placebo-controlled, adaptive-design study in 34 treatment-naïve adults. The adaptive design allowed for modifications based on emerging data. In the first part of the study, participants received once-daily monotherapy with either Fipravirimat 10 mg, 200 mg, or a placebo for 10 days. However, an interim analysis of this part revealed a crucial finding that reshaped the trial. As a result of this finding, the protocol was amended for the second part of the study, in which participants received Fipravirimat 40 mg, 80 mg, 140 mg, or placebo for a shortened duration of only 7 days.[24]

3.3.2. Efficacy and Safety Results

The study successfully met its primary endpoint, demonstrating potent and dose-dependent antiviral activity. The most significant reductions in plasma HIV-1 RNA were observed at the highest doses. After 7 to 10 days of monotherapy, the 140 mg dose group achieved a mean viral load reduction of 1.5 $log_{10}$ copies/mL, while the 200 mg group achieved a mean reduction of 2.0 $log_{10}$ copies/mL.[24]

From a safety perspective, the drug was generally well-tolerated. There were no discontinuations due to adverse events (AEs) and no deaths. The most commonly reported drug-related AEs were mild-to-moderate in intensity and primarily gastrointestinal in nature, such as diarrhea and abdominal pain.[27]

3.3.3. Emergence of Resistance

The critical finding that prompted the protocol amendment was the rapid emergence of drug resistance. In the first part of the study, 4 of the 6 participants who received the 200 mg dose for 10 days developed the Gag A364V resistance-associated mutation (RAM) by day 11. One of these participants also exhibited phenotypic resistance.[12] This observation was a major red flag, indicating that the drug had a very low genetic barrier to resistance when used as monotherapy. The decision to shorten the dosing duration to 7 days in the second part of the study was a direct measure to mitigate this risk and prevent the selection of resistant virus before participants could be started on a standard combination therapy.[28]

3.4. Phase IIb Dose-Ranging Studies: Combination Therapy Evaluation

Following the successful proof-of-concept, Fipravirimat advanced into two parallel Phase IIb studies designed to evaluate its efficacy and safety as part of a complete, durable antiretroviral regimen and to identify the optimal dose for potential Phase III development. The 24-week results from both of these pivotal studies were presented at the European AIDS Conference (EACS) in 2023.[31]

3.4.1. DOMINO Study (NCT04493216)

The DOMINO study evaluated Fipravirimat in a more traditional regimen structure. Treatment-naïve adults were randomized to receive one of three doses of Fipravirimat (100 mg, 150 mg, or 200 mg) in combination with two nucleoside reverse transcriptase inhibitors (NRTIs), the standard "backbone" of many HIV regimens. This was compared to a standard of care (SoC) three-drug regimen.[1]

3.4.2. DYNAMIC Study (NCT04900038)

The DYNAMIC study explored a more innovative, two-drug regimen approach. Treatment-naïve adults were randomized to receive one of the three Fipravirimat doses (100 mg, 150 mg, or 200 mg) combined only with the integrase inhibitor dolutegravir (DTG). The comparator arm was the established and highly effective two-drug SoC regimen of DTG plus lamivudine (3TC).[8]

The 24-week results from the DYNAMIC study showed that the two-drug regimens containing Fipravirimat demonstrated generally high rates of virologic suppression (HIV-1 RNA <50 copies/mL), which were comparable to the efficacy of the DTG + 3TC control arm. All treatment groups also showed robust increases in CD4+ T-cell counts from baseline. The safety profile was also generally comparable, although a numerically higher incidence of diarrhea was observed in the 150 mg and 200 mg Fipravirimat arms compared to the control group.[31]

[The comprehensive clinical trial program for Fipravirimat is summarized in Table 2, and the key efficacy outcomes from the Phase IIb studies are presented in Table 3.]

Table 2: Summary of Fipravirimat Clinical Trials

NCT Number	Trial Name/Title	Phase	Patient Population	Status	Key Outcomes/Presentations
NCT03784079	Phase IIa Proof-of-Concept Study	IIa	Treatment-Naïve Adults	Completed	Demonstrated potent, dose-dependent antiviral activity (-2.0 log₁₀ VL reduction at 200mg). Revealed rapid emergence of A364V resistance in 10-day monotherapy. Presented at CROI 2021.
NCT04493216	DOMINO: Dose-Range Finding Study	IIb	Treatment-Naïve Adults	Terminated	Evaluated Fipravirimat + 2 NRTIs vs. SoC. 24-week efficacy and safety data presented at EACS 2023.
NCT04900038	DYNAMIC: Fipravirimat + Dolutegravir Study	IIb	Treatment-Naïve Adults	Terminated	Evaluated Fipravirimat + DTG vs. DTG + 3TC. 24-week data showed comparable virologic suppression to SoC. Presented at EACS 2023.
NCT03836729	DDI Study with TAF/FTC	I	Healthy Volunteers	Completed	No clinically significant pharmacokinetic interactions between Fipravirimat and TAF/FTC.
NCT04263142	DDI Study with Dolutegravir	I	Healthy Volunteers	Completed	No clinically significant pharmacokinetic interactions between Fipravirimat and dolutegravir.
NCT04425902	DDI Study with Probe Substrates	I	Healthy Volunteers	Completed	Assessed potential for Fipravirimat to interact with various metabolic pathways.
NCT04507321	Thorough QT/QTc Study	I	Healthy Volunteers	Completed	No clinically significant effect on cardiac repolarization (QT interval).

Table 3: Efficacy Outcomes from Phase IIb DYNAMIC Study at Week 24

Treatment Arm	Virologic Suppression (HIV-1 RNA <50 copies/mL)	Mean Change in CD4+ Count (cells/mm³)
Fipravirimat 100 mg + DTG	High rate, comparable to control	+200.6
Fipravirimat 150 mg + DTG	High rate, comparable to control	+317.7
Fipravirimat 200 mg + DTG	High rate, comparable to control	+231.1
Dolutegravir (DTG) + Lamivudine (3TC) (SoC)	High rate (control)	+139.5
Note: Data derived from EACS 2023 presentation summaries. Specific percentages for virologic suppression were not detailed in the provided materials but were described as "generally high" and "comparable" across groups.31

Section 4: Efficacy and Resistance Profile: Promise and Pitfalls

4.1. Antiviral Spectrum and Potency

A central strength of Fipravirimat, and the primary goal of its design, was its robust in-vitro antiviral profile. The compound demonstrated potent activity against a wide range of HIV-1 strains, including both subtype B and subtype C, which are globally prevalent. Crucially, it retained its potency against viruses engineered to contain the specific Gag polymorphisms (such as V362I and variations in the 369-371 region) that had conferred high-level baseline resistance to the first-generation MI, bevirimat.[12] This broad coverage was a key differentiating feature and represented a significant scientific advancement for the MI class. In terms of raw power, Fipravirimat was highly potent, with median 50% effective concentration ($EC_{50}$) values in the low single-digit nanomolar range against panels of clinical isolates, confirming its strong intrinsic ability to inhibit viral replication.[12]

4.2. The Achilles' Heel: Low Genetic Barrier to Resistance

[Despite its impressive potency and breadth of activity, Fipravirimat harbored a critical flaw that is often fatal for an antiretroviral candidate: a low genetic barrier to resistance.]

4.2.1. The A364V Mutation

Virologic analysis consistently identified a single amino acid substitution in the Gag protein, A364V, as the primary and signature pathway for resistance to Fipravirimat.[12] In vitro studies confirmed that this single mutation was sufficient to confer a massive reduction in susceptibility, increasing the concentration of drug required for inhibition by more than 600-fold.[38]

4.2.2. Rapid Emergence in Monotherapy

The clinical relevance of this mutation was starkly demonstrated in the Phase IIa proof-of-concept study. As previously noted, when Fipravirimat was administered as a single agent at a high dose for just 10 days, this specific resistance mutation emerged in the majority of participants.[24][ The speed with which the virus could escape the drug's pressure highlighted an inherent fragility. This finding implied that any therapeutic regimen containing Fipravirimat would be highly dependent on perfect patient adherence and the potency of its partner drugs to suppress viral replication completely and prevent the emergence of this simple escape mutation.]

The mechanism by which the A364V mutation confers resistance is believed to be an acceleration of the p25 cleavage rate. This increased processing speed effectively outcompetes the inhibitory action of the drug, allowing maturation to proceed despite the presence of Fipravirimat.[12]

This profile created a fundamental tension for the drug. On one hand, Fipravirimat was designed to solve the problem of pre-existing resistance (baseline polymorphisms) that plagued first-generation MIs. On the other hand, it proved to be highly susceptible to treatment-emergent[ resistance. In essence, the development program traded one resistance problem for another, failing to create a compound with the robust, durable resistance profile required to compete in the modern therapeutic landscape. The rapid selection of resistance in the short, 10-day monotherapy study was a profound warning sign. In an era where the standard of care is defined by drugs like dolutegravir, which has a very high genetic barrier to resistance, the introduction of a new agent with such a low barrier would represent a step backward in terms of regimen forgiveness and durability. This single finding from the Phase IIa trial likely cast a long shadow over the program's internal risk assessment and its perceived viability long before the final Phase IIb data became available.]

Section 5: Strategic Assessment and Discontinuation Analysis

5.1. The Decision to Discontinue

In early 2023, following the completion of the Phase IIb DOMINO and DYNAMIC trials, ViiV Healthcare and GSK made the decision to halt the clinical development of Fipravirimat and not advance the compound into Phase III studies.[4][ This decision was not triggered by an unexpected safety crisis or a complete failure of efficacy, but rather by a pragmatic and strategic evaluation of the drug's overall profile in the context of the highly evolved HIV treatment market.]

5.2. Rationale 1: Lack of Differentiation in a Mature Market

By 2023, the landscape for treating HIV-1 in treatment-naïve individuals was dominated by exceptionally effective, safe, and convenient therapies. The standard of care had coalesced around single-tablet regimens (STRs), typically containing a potent integrase strand transfer inhibitor (INSTI) like dolutegravir or bictegravir, combined with two NRTIs.[41][ These regimens offer near-universal virologic suppression, excellent tolerability, a high barrier to resistance, and the simplicity of a single pill taken once a day.]

[The bar for any new daily oral drug to enter this market is therefore incredibly high. A new agent must offer a clear and compelling advantage over the existing standard of care, such as superior efficacy, a significantly better safety profile (particularly concerning long-term toxicities like weight gain or renal effects), a higher resistance barrier, or a solution for a specific, underserved patient population.]

The 24-week data from the Phase IIb DYNAMIC study showed that Fipravirimat, when combined with dolutegravir, was effective and generally safe. However, its virologic suppression rates were merely comparable to, not superior to, the existing two-drug standard of care, DTG + 3TC.[31] Without a demonstrable clinical benefit, the argument for its development weakened considerably. A novel mechanism of action is scientifically valuable, but it does not guarantee clinical or commercial success if it fails to solve an existing clinical problem better than current therapies. Fipravirimat was simply not sufficiently differentiated to justify the enormous cost and risk of a Phase III program and subsequent market launch.[44]

5.3. Rationale 2: The "Food Effect" Liability

A second, highly practical limitation was the drug's "food effect".[44][ A food effect occurs when the absorption, and therefore the concentration and effectiveness, of an oral drug is significantly altered by the presence or absence of food. This necessitates specific instructions for patients, such as requiring the drug to be taken with a meal (or on an empty stomach), which adds a layer of complexity and inconvenience to a daily regimen. In a market where competitors offer the simplicity of dosing with or without food, a drug with a food effect is at a distinct disadvantage. This practical liability further eroded Fipravirimat's potential to compete with the highly convenient regimens that define the current standard of care.]

5.4. The Broader Strategic Pivot at ViiV/GSK

The discontinuation of Fipravirimat must also be viewed within the context of ViiV/GSK's overarching R&D strategy. The company has been transparent about its strategic shift away from developing new daily oral medications and toward pioneering the next generation of HIV therapies: long-acting (LA) and ultra-long-acting (ULA) injectable regimens. Their clinical pipeline is now focused on assets like long-acting cabotegravir, broadly neutralizing antibodies (bNAbs), and capsid inhibitors, with the goal of extending the dosing interval from months to potentially twice a year or longer.[40][ Investing further in a daily oral pill like Fipravirimat, which offered no clear advantage over existing oral options, was incongruent with this forward-looking strategy.]

This strategic exit from the MI class was solidified by the subsequent halt in the development of the follow-on compound, VH3739937. The suspension of this next-generation MI was reportedly triggered by preliminary findings from a preclinical study of a "similar maturation inhibitor"—almost certainly Fipravirimat.[5][ This suggests that even after the strategic decision to discontinue Fipravirimat was made, ongoing, long-term preclinical toxicology studies may have uncovered a new, previously unknown safety signal. The fact that this finding was considered relevant enough to halt the development of a different molecule in the same class implies a potential class-wide liability was identified. This provides a second, reinforcing layer of justification—first strategic, then scientific—for ViiV/GSK's complete and definitive departure from the maturation inhibitor field.]

[Ultimately, the story of Fipravirimat is a clear case study in modern pharmaceutical development. The drug was not a scientific failure in the traditional sense; it engaged its target and demonstrated antiviral activity. Rather, it was a commercial and strategic failure. It was a 2023 drug candidate attempting to solve a problem that the market had already addressed more effectively and conveniently by 2015. The therapeutic landscape had evolved faster than the drug's development timeline, leaving it without a viable clinical or commercial niche.]

Section 6: Future Perspectives: The Legacy of Fipravirimat and the Maturation Inhibitor Class

6.1. Lessons Learned from the Fipravirimat Program

[The development and discontinuation of Fipravirimat offers several critical lessons for the field of antiretroviral therapy. It serves as a stark reminder that in a mature therapeutic area like HIV, the bar for innovation is extraordinarily high. A novel mechanism of action, while scientifically intriguing, is no longer sufficient for success. Any new agent, particularly a daily oral drug, must be paired with a high genetic barrier to resistance, an impeccable safety and tolerability profile, and supreme convenience (e.g., no food effect, minimal drug interactions) to have a chance of competing with the current standard of care. Fipravirimat's journey underscores the importance of a holistic product profile, where clinical efficacy must be complemented by practical advantages that matter to both clinicians and patients.]

6.2. The Future of Maturation Inhibitors

[The discontinuation of Fipravirimat, following the failures of bevirimat and BMS-955176, and capped by the pre-emptive halt of VH3739937, casts a long shadow over the future of the maturation inhibitor class. The repeated challenges with baseline polymorphisms, emergent resistance, tolerability, and potential preclinical safety signals suggest a fundamental difficulty in successfully drugging the HIV-1 Gag target in a way that is both durable and safe. For this class to be resurrected, a future candidate would need to demonstrate a radically improved profile, including a significantly higher barrier to resistance and an unimpeachable safety record, to attract the substantial investment required for clinical development. At present, the prospects for the MI class appear bleak.]

6.3. ViiV/GSK's Evolving HIV R&D Strategy

The Fipravirimat program, while ultimately unsuccessful, was a pivotal data point that helped to validate and solidify ViiV/GSK's strategic pivot. By demonstrating the immense difficulty of differentiating a new daily oral agent, the experience reinforced the company's decision to focus its resources on paradigm-shifting therapies. Their current pipeline, with its emphasis on ultra-long-acting injectables and novel mechanisms like capsid inhibition and broadly neutralizing antibodies, reflects a clear strategy to leapfrog the current standard of care rather than compete with it incrementally.[45][ The legacy of Fipravirimat, therefore, is not just one of a discontinued drug, but of a crucial learning experience that has helped shape the future direction of HIV research and development, steering the industry toward less frequent, more convenient options in the ongoing global effort to end the HIV epidemic.]

Works cited

1. Fipravirimat - DrugBank, accessed October 31, 2025, https://go.drugbank.com/unearth/q?button=&c=_score&d=down&page=98&query=hearing+syrup+dha&search_type=drugs&searcher=drugs
2. Advanced Filter - DrugBank, accessed October 31, 2025, https://go.drugbank.com/unearth/q?button=&c=_score&d=down&page=302&query=lactam+302+al&searcher=drugs
3. Advanced Filter - DrugBank, accessed October 31, 2025, https://go.drugbank.com/unearth/q?button=&c=_score&d=down&page=277&query=smart+of&searcher=drugs
4. Fipravirimat - Wikipedia, accessed October 31, 2025, https://en.wikipedia.org/wiki/Fipravirimat
5. Fipravirimat - Drug Targets, Indications, Patents - Patsnap Synapse, accessed October 31, 2025, https://synapse.patsnap.com/drug/857082ac7d33433cbc76f53dc04fcc78
6. Fipravirimat Drug Profile - Ozmosi, accessed October 31, 2025, https://pryzm.ozmosi.com/product/18199
7. Sub-stoichiometric Modulation of Viral Targets—Potent Antiviral Agents That Exploit Target Vulnerability - PMC - PubMed Central, accessed October 31, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10424314/
8. Sub-stoichiometric Modulation of Viral Targets Potent Antiviral Agents That Exploit Target Vulnerability | ACS Medicinal Chemistry Letters - ACS Publications, accessed October 31, 2025, https://pubs.acs.org/doi/10.1021/acsmedchemlett.3c00279
9. Maturation inhibitors | Research Starters - EBSCO, accessed October 31, 2025, https://www.ebsco.com/research-starters/health-and-medicine/maturation-inhibitors
10. GSK3640254 Is a Novel HIV-1 Maturation Inhibitor with an Optimized Virology Profile | Antimicrobial Agents and Chemotherapy - ASM Journals, accessed October 31, 2025, https://journals.asm.org/doi/10.1128/AAC.01876-21
11. BMS-955176 - Wikipedia, accessed October 31, 2025, https://en.wikipedia.org/wiki/BMS-955176
12. GSK3640254 Is a Novel HIV-1 Maturation Inhibitor with an Optimized Virology Profile - NIH, accessed October 31, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8765437/
13. GSK discontinues development of maturation inhibitor BMS-955176 - HIV i-Base, accessed October 31, 2025, https://i-base.info/htb/30865
14. GSK Discontinues BMS' Maturation Inhibitor - NATAP - HIV, accessed October 31, 2025, https://www.natap.org/2017/HIV/041717_01.htm
15. The Discovery of GSK3640254, a Next-Generation Inhibitor of HIV-1 Maturation - PubMed, accessed October 31, 2025, https://pubmed.ncbi.nlm.nih.gov/36044257/
16. Sub-stoichiometric Modulation of Viral Targets-Potent Antiviral Agents That Exploit Target Vulnerability - PubMed, accessed October 31, 2025, https://pubmed.ncbi.nlm.nih.gov/37583823/
17. Sub-stoichiometric Modulation of Viral Targets Potent Antiviral Agents That Exploit Target Vulnerability | ACS Medicinal Chemistry Letters - ACS Publications, accessed October 31, 2025, https://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.3c00279
18. A phase I, first‐in‐human study investigating the safety, tolerability, and pharmacokinetics of the maturation inhibitor GSK3739937 - NIH, accessed October 31, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10238757/
19. Efficacy and safety of the HIV-1 maturation inhibitor GSK3640254 plus two NRTIs in adults naive to antiretroviral therapy (DOMINO): 24-week results from a randomised phase 2b study - ResearchGate, accessed October 31, 2025, https://www.researchgate.net/publication/396684309_Efficacy_and_safety_of_the_HIV-1_maturation_inhibitor_GSK3640254_plus_two_NRTIs_in_adults_naive_to_antiretroviral_therapy_DOMINO_24-week_results_from_a_randomised_phase_2b_study
20. A Phase I Evaluation of the Pharmacokinetics and Tolerability of the HIV-1 Maturation Inhibitor GSK3640254 and Tenofovir Alafenamide/Emtricitabine in Healthy Participants - ResearchGate, accessed October 31, 2025, https://www.researchgate.net/publication/350287761_A_Phase_I_Evaluation_of_the_Pharmacokinetics_and_Tolerability_of_the_HIV-1_Maturation_Inhibitor_GSK3640254_and_Tenofovir_AlafenamideEmtricitabine_in_Healthy_Participants
21. Effects of the HIV‐1 maturation inhibitor GSK3640254 on QT interval in healthy participants, accessed October 31, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10644204/
22. ViiV Healthcare presents positive proof-of-concept findings for ... - GSK, accessed October 31, 2025, https://www.gsk.com/en-gb/media/press-releases/viiv-healthcare-presents-positive-proof-of-concept-findings-for-gsk3640254-a-novel-investigational-maturation-inhibitor-for-the-treatment-of-hiv/
23. ViiV Healthcare to present new data on long-acting regimens for HIV prevention and treatment, alongside pipeline advances at CROI 2021, accessed October 31, 2025, https://viivhealthcare.com/en-us/media-center/news/press-releases/2021/march/viiv-healthcare-to-present-new-data-on-long-acting-regimens-for-hiv/
24. CROI 2021: Once-daily GSK254 maturation inhibitor as treatment for HIV multidrug resistance, accessed October 31, 2025, https://i-base.info/htb/40180
25. Maturation Inhibitor Shows Promise for HIV - Northwell Health, accessed October 31, 2025, https://www.northwell.edu/sites/northwell.edu/files/2021-03/Maturation%20Inhibitor%20Shows%20Promise%20for%20HIV%20_%20MedPage%20Today.pdf
26. Phase IIa Proof-of-Concept Evaluation of the Antiviral Efficacy, Safety, Tolerability, and Pharmacokinetics of the Next-Generation Maturation Inhibitor GSK3640254 - PMC - NIH, accessed October 31, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9536290/
27. ViiV Healthcare presents positive proof-of-concept findings for GSK3640254, a novel, investigational maturation inhibitor for the treatment of HIV, accessed October 31, 2025, https://viivhealthcare.com/en-us/media-center/news/press-releases/2021/march/viiv-healthcare-presents-positive-proof-of-concept-findings/
28. Maturation inhibitor advances into clinical trials - CATIE.ca, accessed October 31, 2025, https://www.catie.ca/treatmentupdate-247/maturation-inhibitor-advances-into-clinical-trials
29. Efficacy and Safety of the HIV-1 Maturation Inhibitor ... - ViiV Exchange, accessed October 31, 2025, https://viivexchange.com/content/dam/cf-viiv/viivexchange/medical/pdf/eacs-2023-joshi-dynamic-slides-disclaimer.pdf
30. ViiV Healthcare to present 23 abstracts from innovative HIV treatment and prevention portfolio at EACS 2023, accessed October 31, 2025, https://viivhealthcare.com/hiv-news-and-media/news/press-releases/2023/october/viiv-healthcare-to-present-23-abstracts/
31. Efficacy and Safety of the HIV-1 Maturation Inhibitor GSK3640254 + Dolutegravir as a 2-Drug Regimen in Treatment-Naive Adults:24-Week Results From the Phase IIb DYNAMIC Study - NATAP, accessed October 31, 2025, https://www.natap.org/2023/EACS/EACS_60.htm
32. Efficacy and Safety of the HIV-1 Maturation Inhibitor GSK3640254 + 2 NRTIs in Treatment-Naive Adults: 24-Week Results From the Phase IIb, Dose-Range Finding DOMINO Study - NATAP, accessed October 31, 2025, https://natap.org/2023/EACS/EACS_94.htm
33. Advanced Filter - Search Results | DrugBank Online, accessed October 31, 2025, https://go.drugbank.com/unearth/q?button=&c=_score&d=down&page=303&query=car+1&searcher=drugs
34. HIV Infection Terminated Phase 2 Trials for Fipravirimat (DB21578, accessed October 31, 2025, https://go.drugbank.com/indications/DBCOND0048882/clinical_trials/DB21578?phase=2&status=terminated
35. Dolutegravir Terminated Phase 2 Trials for Human Immunodeficiency Virus (HIV) Infections Treatment | DrugBank Online, accessed October 31, 2025, https://go.drugbank.com/drugs/DB08930/clinical_trials?conditions=DBCOND0035016&phase=2&purpose=treatment&status=terminated
36. gsk3640254 is a novel maturation inhibitor with an optimized virology profile - 2013 ViiV Slide Template, accessed October 31, 2025, https://www.hivandmore.de/kongresse/croi2021/slides/viiv/003466-GSK3640254-is-a-novel-maturation-inhibitor-with-an-optimized-virology-profile--SLIDES-ONLY-.pdf
37. en.wikipedia.org, accessed October 31, 2025, https://en.wikipedia.org/wiki/Fipravirimat#:~:text=Fipravirimat%20is%20an%20experimental%20drug,drugs%20known%20as%20maturation%20inhibitors.&text=Fipravirimat%20was%20being%20developed%20by,development%20was%20stopped%20in%202023.
38. GSK's ViiV Halts Phase 2 HIV Drug Development - Patsnap Synapse, accessed October 31, 2025, https://synapse.patsnap.com/article/gskE28099s-viiv-halts-phase-2-hiv-drug-development
39. What's New: Adult and Adolescent ARV HIV Clinical Guidelines | NIH, accessed October 31, 2025, https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-arv/whats-new
40. BHIVA guidelines on antiretroviral treatment for adults living with HIV-1 2022 (2025 interim update), accessed October 31, 2025, https://bhiva.org/clinical-guideline/hiv-1-treatment-guidelines/
41. Selecting an Initial ART Regimen - Clinical Guidelines Program - HIVguidelines.org, accessed October 31, 2025, https://www.hivguidelines.org/guideline/hiv-initial-art/
42. GSK drops one of 2 maturation inhibitors in HIV pipeline, accessed October 31, 2025, https://www.fiercebiotech.com/biotech/gsk-drops-one-two-maturation-inhibitors-hiv-pipeline
43. Pipeline - GSK, accessed October 31, 2025, https://www.gsk.com/en-gb/innovation/pipeline/
44. HIV medicines in development - ViiV Healthcare, accessed October 31, 2025, https://viivhealthcare.com/hiv-research-and-innovation/medicines-development/
45. Our Pipeline - ViiV Medical Information, accessed October 31, 2025, https://viivhcmedinfo.com/our-pipeline/